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We would like to thank Karina M. Yelin, Milton Sanchez, Juan Rabionet, Steven Llanes, and Edgar Estrada for their assistance. A very special thanks goes to Yalila Castellon for her secretarial support, to Mathew N. Alfonso and Daniel T. Alfonso for their help with the computer, and to Dr Juan Di Domenico for the spanish translation. We also acknowledge the following individuals for their contributions to the 2001 edition:

Jose Adams, M.D. Nolan N. Altman, M.D. Luis A. Alvarez, M.D. Maria Arias, M.D. Hugo A. Arroyo, M.D. Carol D. Brathwaite, M.D. Kenneth Butler, M.D. Manuel A. Campo, M.D. Omar Costa-Cruz, M.D. Robert F. Cullen, M.D. Gonzalo De Quesada, M.D. Marcel J. Deray, M.D. Gisella Diaz-Monroig, M.D. Catalina Dunoyer, M. D. Mark Epstein, M.D. Felix Estrada, M.D. Enrique Canton, M.D. Carlos A. Gadia, M.D. Olga C. Garcia, M.D. John A. I. Grossman, M.D.

Parul B. Jayakar, M.D. Ian P. Jeffries, M.D. Alex Koetzle, M.D. Pedro Lopez, M.D. Diana Martinez, M.D. Elena Miravet, M.D. Maria E. Oliver, M.D. Jose A. Palomino, M.D. Edgardo Penabad, M.D. Jorge E. Perez, M.D. Bernardo Pimentel, M.D. Genoveva C. Prieto, M.D. Griffith E. Quinby, M.D. Flavio A. Solis, M.D. Mary Schwartz, R.N. Alberto R. Tano, M.D. Leon Tejidor, M.D. Heidi Torosick, M.D. Ernesto Valdez, M.D. Ignacio A. Zabaleta, M.D. Roberto Warman, M.D.

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Israel Alfonso, M.D.

Director of Neonatal Neurology Department of Neurology Miami Children’s Hospital, Miami, Florida, USA

Faculty Member Departament of Neurology University of Miami, Miami, Florida, USA

Oscar Papazian, M.D.

Associate Director, Department of Neurology Director of Clinical Neurophysiology Department of Neurology Miami Children’s Hospital, Miami, Florida, USA

Donald Altman, M.D.

Emeritus Director of Radiology Department of Radiology Miami Children’s Hospital, Miami, Florida, USA

Clinical Professor of Radiology and Pediatrics University of Miami, Miami, Florida, USA

Clinical Professor of Pediatric Nova Southeastern University, Miami, Florida, USA

Andrew Kairalla, M.D.

Director of Neonatology Baptist Children’s Hospital, Miami, Florida, USA Division of Neonatology Department of Pediatric Miami Children’s Hospital, Miami, Florida, USA

Ambassador David McLean Walters

for having the courage to turn a personal tragedy into a grand vision, and the energy to make that vision a reality.

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1

CLINICAL PAROXYSMAL EVENTS

The term clinical paroxysmal events refers to any clinical episode of sudden onset and brief duration that is: (1) phenotypically unlike those usually seen in normal neonates; (2) associated with neurological, respiratory, or cardiovascular abnormalities; or (3) due to a pathological process. Clinical paroxysmal events are characterized by changes in motor

activity, autonomic function, behavior, or respiratory rate.

Clinical paroxysmal events characterized by a change in motor activity are called paroxysmal motor events. Paroxysmal motor events are characterized by increased motor activity or, in rare cases, by a sudden arrest of motor activity. Paroxysmal motor events may be associated with changes in autonomic function, behavior, or respiratory rate unless the changes in respiratory rate fulfill the criteria for apnea. Paroxysmal motor events are the most frequent type of clinical paroxysmal events noted in the neonatal period.

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10

FACIAL WEAKNESS

Facial asymmetry can be produced by structural abnormalities or by unilateral or asymmetrical weakness of the muscles of the face. Structural abnormalities are due to musculoskeletal deformations, soft tissue masses, and tumors. The weak muscles involved in the production of facial asymmetry are the: (1) facial mimetic muscles; (2) levator palpebrae muscles; or (3) muscles of Müller.

The distinction between functional and structural facial asymmetry can be made by observation. Structural facial asymmetry is diagnosed by observing a physical cause for the facial asymmetry. Functional asymmetry is diagnosed by the absence of a physical deformity. The neurogenic system involved in functional asymmetries can be determined by the area of the face involved, the degree of asymmetry at different behavioral stages (crying and quiet awake) and the presence of associated neurological and general findings. (Figure 169.1) Facial asymmetry due to muscle weakness (functional) will disappear when the weak muscle is not being used. This occurs because the facial mimetic muscles, levator palpebrae muscles (common oculomotor system), and the muscles of Müller (oculosympathetic system) are bilateral and usually have

synchronous and symmetrical activity.

Figure 169.1.— Differential diagnosis of neurogenic facial asymmetry. Crossed blue area indicates area of the face involved. CN: cranial nerve; DAOM: depressor angularis oris muscle; M: muscle; SYMP: sympathetic; ABN: abnormality; SYST: system.



2

PAROXYSMAL MOTOR EVENTS

The term paroxysmal motor event refers to any sudden change in motor

activity with or without associated autonomic or behavioral changes. Most paroxysmal motor events are characterized by an increase in motor activity. Decreased motor activity is seldom sudden enough to be considered a paroxysmal motor event.

Paroxysmal motor events are normal or abnormal (Table 5.1). A paroxysmal motor event is normal if: (1) it is not associated with autonomic, respiratory, or behavioral abnormalities, or electroencephalographic seizures; and (2) it has the characteristics of a primitive reflex usually seen in neonates (Moro reflex or Babinski sign). A paroxysmal motor event is abnormal if: (1) it is associated with autonomic, respiratory, or behavioral abnormalities, or electroencephalographic seizures; and (2) it has the characteristics of a primitive reflex not usually seen in normal neonates.

Table 5.1.—Paroxysmal Motor Events

Normal Benign neonatal sleep myoclonus

Behavioral movements

Physiologic reflex activity

Benign jitteriness

Movement arousals

Abnormal Convulsions

Pathological reflexes

Startle disease

Extrapyramidal movements



11

DECREASED LIMB MOVEMENTS

Decreased limb movements are diagnosed by a discrepancy in the frequency and strength of movements between the affected and the not affected limbs. Decreased limb movements may occur because of restricted range of motion, pain, or weakness.

RESTRICTED RANGE OF MOTION

Decreased limb movements due to restricted range of motion during intrauterine life are characterized by limb deformity. The affected limbs have a fixed position and the examiner's efforts to change that position are met by resistance and a quick return to the original position when the limb is released. Limb deformities result from shortened muscles due to fibrosis (Figure 193.1[A]) or from arthrogryposis. Muscle fibrosis is usually associated with cutaneous scars (Figure 193.1[B]). Arthrogryposis results from asymmetrical weakness of the muscles acting upon a joint or due to a restriction in joint movement due to an aberrant sustained intrauterine position.

A B

Figure 193.1.— Muscle fibrosis. [A] Decreased movements of the left hand, inability to fully extend the wrist and fingers, and atrophy of the distal forearm. [B] Scar on the forearm.



3

APNEA

Apnea may present to the physician either as a precise description of a prolonged respiratory pause in a neonate being monitored in the intensive care unit or as an imprecise description of a life-threatening episode. These presentations usually trigger a series of steps aimed at treating the apnea and finding its cause. These steps include: (1) close monitoring, (2) increased level of readiness to provide respiratory support, (3) clinical and laboratory investigations to determine the cause of apnea, and sometimes, (4) empirical or specific treatment to eliminate or correct the cause of apnea based on the results from the initial clinical and laboratory investigations.

A rational approach to determining the cause of apnea rests on clear understanding of the neuroanatomy of the breathing apparatus. Normal breathing occurs because of a well-orchestrated interplay among several neurological (Figure 13.1) and nonneurological structures.

Figure 13.1.— Neurological structures involved in normal breathing. A: midbrain; B: pons; C: medulla; D: cervical spine; 1: chemoreceptor; 2: dorsal respiratory group at the nucleus of the tractus solitarious; 3: ventral respiratory group at the nucleus ambiguus and nucleus retroambigualis; 4: upper airway motor neurons; 5: upper airway motor muscles; 6: phrenic center; 7: diaphragm; 8: intercostal muscle anterior horn cells; 9: intercostal muscles.



12

ARM MONOPARESIS

Arm monoparesis is characterized by decreased frequency and strength of upper extremity movements due to weakness. Arm monoparesis, by definition, excludes arm weakness in the context of hemiparesis, upper extremity diplegia, and decreased arm movements due to restricted range of motion or pain.

NEUROANATOMY OF THE ARM MOTOR SYSTEM

Arm monoparesis is due to arm motor system injury (Figure 201.1). The arm motor system has a central component and a peripheral

component. The central component of the arm motor system consists of the cerebral cortical motor neurons, brainstem neurons whose axons make contact with the motor neurons of the peripheral component of the arm motor system, and cerebellar neurons that influence the arm motor system cortical and brainstem neurons (upper motor neuron). The peripheral component of the arm motor system consists of motor neurons in the cervical enlargement of the spinal cord whose axons innervate the upper extremity muscles (lower motor neuron).

Figure 201.1.— Schematic representation of the motor systems of the face, arms, and legs, and central and peripheral nervous systems structures involved in limb movements. The colored rectangles indicate the location of weakness produced by damage to the different components of the somatic motor system. U: upper motor neurons; V: ventricles; T: thalamus; UQ: upper quadrant; FN: facial nerve; LQ: lower quadrant; L: lower motor neurons; BP: brachial plexus; LSP: lumbosacral plexus.



4

CAUSES AND TREATMENTS OF SEIZURES

Seizures in a neonate, whether clinical or electroencephalographic, are produced by disorders with or without etiological treatment. Seizures produced by disorders with etiological treatment may stop readily once the appropriate etiological treatment is instituted or may continue despite the initiation of the appropriate etiological treatment. Seizures that persists after etiological treatment may require antiepileptic drugs. Seizures produced by disorders without etiological treatment require antiepileptic drugs and occasionally surgery. The causes of neonatal seizures can be classified as those that may not require antiepileptic drugs and those that require antiepileptic drugs.

CAUSES OF SEIZURES THAT MAY NOT REQUIRE ANTIEPILEPTIC DRUGS

Seizures due to easily correctable metabolic derangements usually do not require antiepileptic drugs. Correctable metabolic derangements should be considered first since a delay in their treatment may cause permanent brain damage.



13

LEG MONOPARESIS, HEMIPARESIS, PARAPARESIS,

AND BILATERAL ARM

WEAKNESS

Leg monoparesis is due to lumbosacral somatic motor system injury. The lumbosacral somatic motor system has a central component and a peripheral component. The central component of the lumbosacral somatic motor system includes the cortical and subcortical neurons that influence the peripheral component. The peripheral component of the lumbosacral somatic motor system consists of motor neurons in the lumbosacral enlargement of the spinal cord (lumbosacral motor center), their axons, and the muscles they innervate.

The majority of cortical neurons of the lumbosacral somatic motor system are in the upper third of the postcentral gyrus. The upper third of the postcentral gyrus is located in the the mesial surface of the brain (Figure 227.1). The rest of the cortical neurons of the lumbosacral motor system are scattered in the frontal and parietal areas. The axons from these cortical neurons travel in the centrum semiovale close to the lateral ventricles.

Figure 227.1.— Schematic representation of the somatic motor system. The green line represents the innervation of the leg. A lesion in this system produces leg weakness. V: ventricles; T: thalamus; UQ: upper quadrant; LQ: lower quadrant; BP: brachial plexus; LSP: lumbosacral plexus. The colored rectangles indicate the location of weakness produced by damage to the different components of the somatic motor system.



5

COMA

Coma in neonates is due to dysfunction of the arousing system. The

arousing system has two components: the ascending reticular activating

system (ARAS) and the cortex. The ARAS consists of a network of neurons that form a single midline column in the midbrain and upper half of the pons. This column divides into two smaller columns in the diencephalon (Figure 61.1). The ARAS receives information from multiple areas of the spinal cord, brainstem, and brain. The ARAS projects to the cerebral cortex. The cerebral cortex is located at the rim of the brain.

Figure 61.1.— The arousing system. A: brain; B: brainstem; C: pons; D: medulla; 1: cerebral cortex; 2: ascending reticular activating system efferent projection (curved arrows); 3: diencephalom; 4: ascending reticular activating system; 5: ascending reticular activating system afferent projection (straight arrows).

Coma may be produced by involvement of the ARAS, its projection, or the cerebral cortex. Coma due to ARAS involvement may occur with a small midline lesion in the central core of the midbrain or the upper half of the pons where the ARAS forms a single midline structure. Coma due to involvement of the smaller ARAS columns in the diencephalon, the ARAS projection fibers, or the cerebral cortex occur with extensive and diffuse bilateral diencephalic and brain hemispheric lesions.



14

FOCAL NERVOUS SYSTEM LESIONS

Once a focal lesion is localized to a specific area of the nervous system (anatomical diagnosis), the pathology (pathological diagnosis) and etiology (etiological diagnosis) of the lesion should be determined. The pathological diagnosis can only be made by direct pathological evaluation of a specimen obtained from the focal lesion. When the direct evaluation of specimen is not possible, a tentative pathological diagnosis can be made based on the clinical, neuroradiological, and neurophysiological findings. The etiological diagnosis is determined by a combination of clinical, neuroimaging, and laboratory findings.

The clinical findings that are most helpful to establish a tentative pathological diagnosis are those related to the location of the lesion and the

rate of progression of the neurological deficit.

The location of a lesion helps to establish a tentative pathological diagnosis because certain pathological processes are more likely to occur in specific areas of the nervous system than in others. Neoplasms in the neonatal period occur more often in the supratentorial region than in the infratentorial region. Single artery infarcts occur more often in the middle cerebral circulation than in the posterior cerebral circulation.

The speed of progression of a deficit—the time it takes for a deficit to

reach maximal neurological impairment—may help to differentiate neoplasms, acute cerebrovascular accidents, and infections. Neoplastic processes progress relentlessly during the neonatal period. Acute cerebrovascular accidents reach maximal neurological impairment in minutes or hours. Infectious processes reach maximal neurological impairment in hours or days.

The event surrounding the onset of symptoms does not contribute as much to the fromulation of a pathological diagnosis as the location of the lesion or the speed of progression of the deficit, except with traumatic processes. In traumatic processes the onset of symptoms is usually clearly

related to the traumatic event.



6

GENERALIZED HYPOTONIA

Generalized hypotonia refers to decreased postural tone that involves the four extremities and the trunk. Facial involvement is not a requisite for the diagnosis of generalized hypotonia. Postural tone refers to the resistance that the striated muscles and the tendons offer when stretched by a sustained low-intensity force such as gravity. Postural tone results from the spring-like properties of the striated muscle fibers and the connective tissue. The spring-like properties of the striated muscle fibers are a function of the intrinsic resistance of its contractile elements (actin and myosin) and the effects of the nervous system upon these elements. The spring-like properties of the connective tissue, whether in the muscle (endo-, peri-, and epimysium) or in the tendons, are a function of the intrinsic resistance of the collagen fibers. Postural tone is determined by observing the resting posture and angle of limb flexion, and by testing the resistance to limb extension by slow motion maneuver and testing passive

recoil after such maneuvers.

Hypotonia or low postural tone is assessed by evaluating the patient while awake. The assessment of tone during sleep is unreliable because muscle tone is physiologically decreased during sleep and especially during active sleep. The postural tone of a neonate is assessed by observing the patient’s posture during quiet wakefulness, and his motor

reactions to arm traction, vertical suspension, and horizontal suspension. Facial tone is judged by the facial expression. A certain degree of generalized hypotonia during the first month of life is normal in neonates born before 34 weeks gestation. In neonates born after 34 weeks, any

degree of generalized hypotonia is abnormal.



15

MICROCEPHALY

Microcephaly in the neonatal period is defined as a head circumference that is less than the second standard deviation below the mean for

gestational age (Table 269.1). Race and sex should be considered before making the diagnosis of microcephaly.

Table 269.1— Microcephaly: lower limits of normal head circumference for gestational age

Gestational Age / weeks Head Circumference / cm

28 30 32 34 36 38 40 42 44 46

23 25 27 29 30 31 32 33 34 35


7

UPPER MOTOR NEURON SYSTEM HYPOTONIA

The upper motor neuron system is more a functional concept than an anatomical structure. The term refers to all the neurons in the brain (Figure 103.1[1]), cerebellum (Figure 103.1[2]), and brainstem (Figure 103.1[3]) that directly or indirectly convey information to the motor neurons in the brainstem and in the anterior horns of the spinal cord (lower motor neurons). The term upper motor neuron system includes the axons of these neurons. These axons travel through the brain and brainstem to make contact with the motor neurons in the brainstem and through the brain, brainstem, and spinal cord (Figure 103.1[4]) to make contact with the motor neurons in the anterior horn of the spinal cord.

The neurons of the upper motor neuron system are located in the cerebral cortex (Figure 103.1[1]), basal ganglia (Figure 103.1[2]), cerebellar nuclei (Figure 103.1[3]), red nuclei (Figure 103.1[4), reticular formation (Figure 103.1[5]), and the lateral vestibular nucleus (Figure 103.1[6]). Neurons from the cerebral cortex and the brainstem (red nucleus, reticular formation, and lateral vestibular nucleus) connect directly with the lower motor neurons. Neurons from the basal ganglia and the cerebellum also influence the lower motor neurons but they do so indirectly by connecting with cortical or brainstem neurons that make direct contact with the motor neurons.

Figure 103.1.— Schematic representation of the upper motor neuron system and the muscle motor-sensory unit. 1: motor cortex; 2: basal ganglia; 3: cerebellum; 4: red nucleus; 5: reticular formation; 6: lateral vestibular nucleus; 7: axons from extrapyramidal neurons; 8: intertesial neurons; 9: alpha motor neuron; 10: gamma motor neuron; 11: dorsal ganglion cell; (A) brain; (B) cerebellum; (C) brainstem; and (D) spinal cord.



16

MACROCEPHALY

Macrocephaly in the neonatal period is defined as a head circumference that measures greater than the second standard deviation above the mean

for gestational age (Table 283.1). Race and sex should be considered before making the diagnosis of macrocephaly.

Table 283.1— Macrocephaly: upper limits of normal head circumference for gestational age.

Gestational Age / weeks Head Circumference / cm

28 30 32 34 36 38 40 42 44 46

28 30 32 34 36 37 38 39 40 41


8

MOTOR-SENSORY UNIT HYPOTONIA

The motor-sensory unit system (Figure 129.1) refers to the alpha motor

unit, the gamma motor unit, the sensory nerve fibers that carry information from the intrafusal fiber back to the alpha motor neurons, and the Renshaw cell.

Figure 129.1.— Schematic representation of the motor-sensory unit system. AMN: alpha motor neuron; RC: Renshaw cell; DGC: dorsal ganglion cell; EFMF: extrafusal motor fiber; IFMF: intrafusal motor fiber; GMN: gamma motor neuron. Arrows indicate direction of conduction.



17

NEUROCUTANEOUS DISORDERS

STURGE-WEBER SYNDROME

Sturge-Weber syndrome has three main features: cutaneous capillary

angiomatosis of the face, choroidal angiomata, and leptomeningeal angiomatosis. The possibility of Sturge-Weber syndrome should be considered in neonates with cutaneous capillary angiomatosis in the distribution of the trigeminal nerve, buphthalmos or glaucoma, or seizures. The diagnosis of Sturge-Weber syndrome should be reserved for neonates with leptomeningeal angiomatosis or, in the absence of leptomeningeal angioma, for neonates with facial cutaneous capillary angiomatosis and choroid angioma. Neonates with facial cutaneous capillary angiomatosis regardless of its distribution, or choroidal angiomas alone, do not have Sturge-Weber syndrome.



9

ARTHROGRYPOSIS MULTIPLEX CONGENITA

Arthrogryposis refers to a joint that is in a fixed position. Arthrogryposis multiplex congenita is diagnosed when two or more joints in more than one limb are fixed from birth (Figure 151.1).

Figure 151.1.— Arthrogryposis multiplex congenita.

A joint becomes fixed in a given position because of unevenly impaired motility. Unevenly impaired joint motility results from segmental muscle weakness or hypotonia, or from a sustained asymmetrical posture. Segmental muscle weakness or hypotonia is due to an imbalance between

agonistic and antagonistic muscles acting upon a joint. Sustained asymmetrical posture results from movement constraints that occur as a result of reduced uterine volume or cutaneous bands that restrict

movements.


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A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

A Top

Abducens nerve palsy

Moebius syndrome, 164,181 Abscess, 257 Abuse, 308 Acid maltase deficiency, 131, 133 Acidemia

argininosuccinic, 79

glutaric, type 287

isovaleric, 74

methylmalonic, 76

propionic, 76 Acidosis, lactic, 65, 78, 81 Acute bilirubin encephalopathy, 67 Acyclovir, 69 Adrenoleukodystrophy (neonatal), 113-115 Agenesis of the corpus callosum, 281 Agenesis of the depressor angularis oris, 184 Agyria,

lissencephaly, 47-49 Aicardi syndrome, 281, 52 Alexander disease, 288 Alloisoleucine, 72 Alpha motor neuron, 92

diseases, 99-100 Amino acid metabolism disorder,

branched-chain amino acids, 72

hyperglycinemia, 74, 76

leucine, 71

urea synthesis, 79 Amniotic band, 265 Ammonia metabolism, 79 Arm monoparesis, 201- 226 Amyoplasia congenita, 162 Antley-Bixler syndrome, 154 Antibiotics for meningitis, 44-45 Anticonvulsant fetal syndrome, 272 Antiepileptic drugs, 57-59 Antithrombin III deficiency, 245 Aplasia cutis congenita, 305 Apnea 1, 13-38,

central, 17

definitions, 2

feeding, 30

gastroesophageal reflux, 33

monitors, 36

pulmonary disease, 35

prematurity, 29

seizures, 1, 21-22

systemic illness, 35

types, 18-21

upper airway abnormality, 34 Aqueductal stenosis, 293

X-linked (Bickers-Adams syndrome), 293 Arachnoid cyst 26-27 Argininosuccinic acidemia, 79-80 Arm weakness, 207 Arthrogryposis, 151-168, 193

due to cartilaginous abnormalities,153

due to neurological abnormalities, 157

due to space constraint, 156 Ascending reticular activating system (ARAS), 61 Asphyxia, 55 Astrocytoma, 257 Autosomal dominant microcephaly, 280

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Axonal polyneuropathy, 134

B Top

Bacterial meningitis, 44-45 Bathrocephaly, 293 Beals syndrome, 153 Beckwith-Weidemann syndrome, 40 Behavioral movements, 7 Benign familial neonatal seizures, 56 Benign nonfamilial neonatal seizure, 57 Benign jitteriness, 7 Benign neonatal sleep myoclonus, 6 Bilirubin encephalopathy, 67 Biotinidase deficiency, 43 Bloch-Sulzberger syndrome, 298 Blue sclera, 91 Botulism, 138-139

apnea, 33

hypotonia, 138 Brachial plexus palsy, 203, 214-222, 260-265

due to hemangioma, 265

due to humeral osteomyelitis, 265

due to neck compression, 265

due to tumor, 265 Brachmann-de Lange syndrome, 273 Brainstem lesions

apnea, 25 Brain tumors, 46, 257, 288 Breathing,

apparatus, 13-16 Branched-chain amino acid disorders, 72 Brushfield spots, 111

C Top

Caffeine, 30 Canavan disease, 114, 288 Carbamyl phosphate synthetase deficiency, 80 Carbohydrate metabolism disorders, 81 Carbohydrate-deficient glycoprotein syndrome, 123 Carnitine deficiency, 148 Caput succedaneum, 106, 284 Cauda equina lesion, 265 Central core disease, 146 Cephalohematoma, 106, 285 Cerebral infarction, 55 Cerebrohepatorenal syndrome, 113, 160 Cerebro-oculo-facio-skeletal syndrome, 162 Cerebrospinal fluid examination,

bacterial meningitis, 44

herpetic meningitis, 45 Cervical spinal cord injury, 124 C1-C2 subluxation, 31 Chickenpox, congenital, 264 Choroid plexus papilloma, 257 Chronic inflammatory demyelinating polyneuropathy, 136 Citric acid disorders, 78-79 Cleland-Chiari malformation, 27 Clinical paroxysmal events, 1 Clonus, 97 Coma, 61-85

differentiating coma from, 65

death, 63-64

hypotonia, 64-65

status epilepticus, 64

sleep, 62-63

treatment, 82-84 Common oculomotor system,

anatomy, 188

dysfunction, 189 Cleland-Chiari malformation, 27, 121 Cobb syndrome, 307 Condylomata lata, 91

Congenital fiber type disproportion, 146 Congenital hypomyelinating neuropathy, 135, 164 Congenital hypoventilation syndrome, 25, 30 Congenital muscular dystrophy, 144, 166 Congenital myopathy with typical light microscopic findings, 146-147 Congenital myotonic dystrophy, 104, 142, 165 Congenital pontocerebellar hypoplasia, 123 Congenital sensory neuropathy, 137 Congenital sensory neuropathy with anhidrosis, 135 Congenital varicella syndrome, 306 Continuous video EEG telemetry, 4 Convulsion, 2, 8-9

definition, 2

increased cerebral perfusion, 9 Corpus callosum agenesis,

Aicardi's syndrome, 281 Cortical thumbs, 97 Craniocarpotarsal dysplasia, 166 Cretinism, 110 Cri-du-chat syndrome, 276 Cutis congenital, aplasia, 305 Cytochrome-C oxidase deficiency, 80 Cytomegalic inclusion disease, 277

D Top

Dandy-Walker malformation, 28, 117, 293 Death, brain, 63 Decreased limb movements, 194-199

pain, 194

weakness, 197 Degenerative diseases, 112 DeMorsier's syndrome, 257 Dermal sinus, 307 Depakote, 59 Depressor angularis oris, 185 Diaphragmatic paralysis, 218

Diastrophic dysplasia, 154 DiGeorge syndrome, 41 Dihydrolipoyl dehydrogenase deficiency, 71 Distal arthrogryposis, 165 Down syndrome, 111, 275 Duchenne-Erb palsy, 216 Dysautonomia, familial, 135 Dynamic tone, 96 Dystrophy,

muscular, 144

myotonic, 142

E Top

Edrophonium, 141 Ehlers-Danlos syndrome, 101 Electroencephalographic,

seizure, 2 Encephalocele, 258 Encephalocraniocutaneous lipomatosis, 304 Encephalopathy, acute, 61-85 Errors of metabolism, 70-81 Escobar syndrome, 156 Escherichia coli, 44 Erb palsy, 216 Epidural hematoma, 108, 250 Extrapyramidal movements, 9

F Top

Facial,

asymmetry, 170-191

molding, 171

motor system, 175

nerve branch lesions, 184

nerve lesions, 171, 181, 183, 208, 259 Facioscapular humeral dystrophy, 144 Familial dysautonomia, 135 Farber syndrome, 104, 113 Fascicular syndrome, 221 Fatty acid metabolism disorders, 81 Fetal alcohol syndrome, 271 Flaccid arm monoparesis, 211 Flaccid leg monoparesis, 235 Focal spinal muscular atrophy, 163 Folinic deficiency seizures, 43 Fracture, skull, 105 Freeman-Sheldon syndrome, 166 Fructose-1,6-diphosphatase deficiency, 81 Fructose intolerance, hereditary, 81 Fukuyama-type congenital muscular dystrophy, 145

G Top

Ganciclovir, 278 Ganglioiside metabolism disorders,

GM1 gangliosides, 113

Gelastic seizures, 9 Gentamicin, 45, 68 Germinal matrix hemorrhage, 255-256 Giant axonal neuropathy, 135 Glucagon, 40 Glutathione synthetase deficiency, 67 Glutaric acidemia, 71, 287 Glycine encephalopathy, 75-76, Glycogen metabolism disorders,

acid maltase deficiency, 133

glycogen musce disease, 147 GM1 gangliosides, 104, 113

Group B streptococcus, 44 Guillain-Barre syndrome, 136

H Top

Head circumference measurement, 283 Head trauma, 106 Hematoma, 250

extra-axial, 250

intra-axial, 251 Hemifacial hypertrophy, 172 Hemiparesis, 198, 236 Hemimegalencephaly, 49, 172 Hemorrhage, 22, 250 Hereditary myasthenia gravis syndromes, 141 Herpes simplex, 45, 68, 280 Heterotopia, 50-51

syndromes with, 51 Hiccups, 7, 76

with glycine encephalopathy, 76 Hipomelanosis of Ito, 309 Holocarboxylase, 75 Horner syndrome, 180, 215 Hydrocephalus, 290-293

aqueductal stenosis, 293

Dandy-Walker malformation, 293

intracranial hemorrhage, 291, 253

treatment, 292, 255 Hydroxymethylglutarate CoA lyase, 71 Hyperammonemia, 76, 79, 80 Hyperbilirubinemia, 67 Hyperekplexia, 10, 30 Hyperglycinemia, 75 Hypermagnesemia, 139 Hyperornithinemia-hyperammonemia-homocitrulinuria syndrome, 80 Hyperphenylalaninemia fetal syndrome, 271 Hypnotic-sedative withdrawal, 10

Hypocalcemia, 40 Hypoglossal injury, 31 Hypoglycemia, 40 Hypomelanosis of Ito, 309 Hypomyelinative, neuropathy, congenital, 136 Hyponatremia, 42 Hypoparathyroidism, transient congenital, 41 Hypothryroidism, congenital, 110 Hypotonia,

generalized, 87-102

upper motor neuron system, 103-128

motor-sensory unit, 129-150 Hypoxic-ischemic encephalopathy, 40, 56, 110

I Top

Idiopathic hypoventilation syndrome 25, 30, Inborn error of metabolism, 45, 71-81 Incontinentia pigmenti, 131, 298 Incontinentia pigmenti acromians, 309 Infantile botulism, 138 Infantile neuroaxonal dystrophy, 114 Infantile neuronal degeneration, 163 Infantile porphyria, 137 Infantile spinal muscular atrophy, 131, 163 Infarction, 244

arterial,

brain, 245

cerebellar, brainstem and spinal cord, 248 Infarction, spinal, 126, 244 Infantile sialic acidosis storage disease, 113 Infectious disease,

bacterial meningitis, 44

cytomegalic inclusion disease, 277

herpes simplex encephalitis, 45

toxoplasmosis, 278

Infratentorial subduralhemorrhage, 69 Intracerebellar hemorrhage, 69 Intracerebral hemorrhage, 69 Intracranial hemorrhage/hematoma, 52, 69-70, 251 Intraventricular hemorrhage, 54, 251-255 Isoleucine, 72 I sovaleric acidemia, 71

J Top

Jitteriness, 7 Joubert syndrome 28, 119

K Top

Klippel-Trenaunay syndrome, 297 Klumpke palsy, 188, 220

L Top

Lactate:pyruvate ratio, 81-82 Lactic acidosis, 65, 78, 81 Leg mononeuropathy, 227 Leukodystrophy, 114 Leukomalacia, 247 Leucine metabolism, 71-75 Linear nevus sebaceous, 302 Lipid metabolism disorders, 148 Lissencephaly, 47-49 Listeria monocytogenes, 44 Lowe's syndrome, 111 Lumbar plexus injury, 227

Lumbar puncture, 67-69, 83 Lumbosacral blemish, 307 Lumbosacral plexus, 229

damage, 266

M Top

Macrocephaly, 283-294 Mannitol, 56 Maple syrup urine disease, 71 Marden-Walker syndrome, 162 McArdle's disease, 147 Meckle-Gruber syndrome, 258 Median nerve injuries, 224, 266 Medulloblastoma, 257 Megacisterna magna, 118 Megalencephaly, 283-295 Menkes disease, 114 Meningitis, 67-69 Meningocele, 258 Metabolic disorders

evaluation, 81 Metabolic megalencephaly, 287 Methylmalonic acidemia, 71 Microcephaly, 269-282 Microcephaly vera, 275 Microlissencephaly, 281 Miller-Dieker syndrome, 48, 274 Minimal change myopathy, 146 Mitochondrial respiratory chain disorders, 80 Mobius syndrome, 164, 181 Monoparesis, 197 Monoparesis, arm 201-226 Movement arousal, 8 Multiple carboxylase deficiency, 71, 74-75 Multiple acyl-CoA dehydrogenase deficiency, 80 Multiple pterygia syndrome, 156 Muscular dystrophy, 166

Myasthenia gravis, 33, 140-142, 164 Myasthenic syndrome, 141 Myelomeningocele, 28, 122, 258 Myopathies due to glycogen metabolism abnormalities, 147 Myotubular myopathy, 146, 166 Myositis, infantile, 145 Myotonic dystrophy, 142, 165

apnea, 33 Myotubular myopathy, 146, 166

N Top

N-acetylglutamic acid synthetase deficiency, 80 Narcotic-analgesic withdrawal, 10 Nemaline (rod) myopathy, 146 Neonatal adrenoleukodystrophy, 113 Neonatal facial asymmetry, 169-192 Neostigmine, 141 Nerve injuries, 266 Neuroaxonal dystrophy, 104 Neuroblastoma, 257 Neurocutaneous melanosis, 301 Neurocutaneous syndrome, 287, 295-308 Neurofibromatosis, 301 Neuromuscular disorders,

pathophysiology, 92-100

physiology, 92-100 Neuromuscular transmission disorders, and hypotonia,

botulism, 138

genetic myasthenias, 141

transitory neonatal myasthenia, 140 Neuronal-axonal disease unassociated with Werdnig-Hoffmann disease, 135 Neurocutaneous melanosis, 303 Neurofibromatosis, 301

http://pediatricneuro.com/alfonso/ph164.htm


O Top

Occipital Osteodiastasis, 70 Ocular pterygium, 173 Oculocerebrorenal syndrome, 111 Oculomotor nerve palsy, 188 Oculosympathetic motor system dysfunction, 186 Oligohydramnius sequence, 165 Ornithine transcarbamylase deficiency, 79, 80 Osteogenesis imperfecta, 91 Osteopetrosis, 285 Otahara syndrome, 57

P Top

Pain, decreased limb movements, 194

Papilloma, choroid plexus, 257 Paraparesis, 237 Paroxysmal motor events 1, 5-12

benign, 5-8

differential diagnosis, 10-11

pathological, 8-12 Pena-Shokeir I syndrome, 158 Pena-Shokeir II syndrome, 159 Periventricular-intraventricular hemorrhage, 250-251 Periventricular leukomalacia, 247 Periventricular hemorrhagic infarct, 249 Peroneal nerve injuries, 266 Peroxisomal disorders, 113 Phasic (dynamic) tone, 105 Phenobarbital, 58 Phenytoin, 58 Phosphorylase deficiency, 147

Physiologic reflex, 7 Plagiocephaly, 171 Poliomyelitis, 134 Polymyositis, 145 Pompe's disease, 131 Porencephaly, 254 Porphyria, 137 Posterior fossa tumors, 26 Polycythemia, 66-67 Polysomnography 16-18 Polymicroglia, 49 Polyneuropathy, 136 Posterior fossa arachnoid cyst, 119 Postural tone, 87 Prader-Willi syndrome, 111 Primitive reflex 7 Propionic acidemia, 71, 76-77 Protein C, 54, 245 Protein S, 54, 245 Pseudoparalysis of Parrot, 91 Pseudomonas aeuriginosa, 44 Pyridoxine dependency, 43 Pyrimethamine, in toxoplasmosis, 279 Pyruvate dehydrogenase complex deficiency, 78 Pyruvate metabolism disorders, 78

Q Top

Q-oTC interval, 41

R Top

Radial nerve injuries, 223, 266 Reflexes

Moro reflex, 96

stretch muscle, 97 Renshaw cells, 94 Retinal bleeding, 107, 308 Respiratory centers,

dorsal 15-16

ventral 15-16 Riley-Day syndrome, 135 Robert SC phocomelia syndrome, 274 Romboencephaloclasis, 120 Rubella embryopathy, 279

S Top

Sandhoff disease, 113 Schizoencephaly, 46, 257 Sciatic nerve, 266 Seizures, 2, 8, 39-59

asphyxia, 55

brain tumors, 46

cerebral dysgenesis, 46-52

differential diagnosis, 39-59

gelastic, 9

glucose transport disorder, 43

etiological, 39-56

hypocalcemia, 40-41

hypoglycemia, 40

hyponatremia, 42

hypernatremia, 42

inborn errors of metabolism, 45

infectious disorders, 44-45

intoxication, anesthetics, 42

intracranial hemorrhage, 52-54

patterns, 8-9

pyridoxine, 43

treatment, antiepileptic drugs, 57-58


Sepsis, 69 Spina bifida, 121 Spinal muscular atrophy,

cervical, 163

lumbar, 163 Sialidosis, 113 Sinus, dermal, 307 Single photon emission tomography, 3 Skull and scalp injuries,

caput succedaneum, 106, 284

cephalohematoma, 106, 285 Skull fracture, 106 Skull fracture,

linear, 107

depressed, 107 subgaleal hemorrhage, 106, 284 Smith-Lemli-Opitz syndrome, 159 Soto syndrome, 287 Spastic arm monoparesis, 207 Spastic leg monoparesis, 233 Spinal cord,

injuries, 31

tumors, 257 Staphylococcus aureus, 44 Startle disease, 10, 30 Stenosis, aqueductal, 293 Sternocleidomastoid tumor of infancy, 267 Sturge-Weber syndrome, 295 Subcortical release phenomena, 9, 105 Subarachnoid hemorrhage, 53, 251, 286 Subdural hemorrhage, 53, 250, 286 Subgaleal hemorrhage, 106, 284 Sulfadiazine, in toxoplasmosis, 279 Sulfite oxidase deficiency, 71, 77 Spinal cord injury, 163 Suspension,

horizontal, 90

vertical, 89 Syphilis, 91

T Top

Teratogenic microcephaly, 270 Teratoma, 257 Thalamic hemorrhage, 252 Theophylline, 30 Tone,

evaluation, 87-90

phasic, 98

postural, 87 Toxoplasmosis, 278-279 Traction response, 88 Transient hyperammonemia of the preterm infant, 80 Transitory myasthenic syndrome, 140, 164 Transmission disorders, neuromuscular, 137-142 Transtentorial herniation, 23

central, 23

uncal, 23 Trisomy 13 syndrome, 157, 276 Trisomy 18 syndrome, 158, 276 Tuberous sclerosis, 299 Tumors, brain and spine, congenital, 257

U Top

Ulnar nerve injury, 225, 234 Uncal herniation, 23 Upper extremities diparesis, 239 Upper-middle trunk syndrome, 219 Upper motor facial asymmetry, 177 Urea synthesis disorders, 79

V Top

Valine, 72 Valproic acid, 59 Varicella-zoster virus, 306 Varicella syndrome, congenital, 306 Vein of Galen aneurysm, 289 Ventricular drainage, and progressive hydrocephalus, 254 Ventriculitis, 44 von Hippel-Landau, 256

W Top

Walker-Warburg syndrome, 161 Werdnig-Hoffmann disease, 32, 131,199 Whistling face syndrome, 166 Williams syndrome, 273

Z Top

Zellweger syndrome, 113, 160

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All rights reserved. No part of this book may be reproduced in any form or by any electronic means, including information storage and retrieval systems, without permission in writing from Israel Alfonso M.D.

The authors have used their best efforts in preparing this book; however, they make no warranties regarding the accuracy or completeness. Accurate indications, adverse reactions, and dosage schedules for medications are provided in this book, but it is possible and likely that they will change. The reader should review information data provided by manufacturers.

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An event characterized only by changes in autonomic function, behavior, or respiratory rate other than apnea are referred to as paroxysmal autonomic, behavioral, or respiratory events, respectively.

Paroxysmal behavioral events are characterized by staring episodes and sudden arousal.

Paroxysmal autonomic events are characterized by episodes of flushing and pallor, and sudden changes in heart rate, blood pressure, and

intracranial pressure. They are very rare.

Respiratory paroxysmal events are characterized by bouts of rapid or slow breathing.

Apnea is characterized by a respiratory pause that lasts over 15 seconds in a fullterm infant or 20 seconds in a preterm infant, or a respiratory pause that, regardless of its duration, is associated with pathological consequences such as bradycardia, cyanosis or decrease in arterial oxygen saturation. Apnea may be associated with changes in motor activity, autonomic function, or behavior.

The term seizure refers to any clinical paroxysmal event believed or proven to be associated with a scalp-recorded electroencephalographic seizure. The term seizure should not be used for a clinical paroxysmal event believed or proven not to be associated with a scalp-recorded electroencephalographic seizure or focal hemispheric increased isotope uptake by single photon emission computed tomography. The term electroencephalographic seizure refers to any scalp-recorded electroencephalographic pattern considered to result from pathological, massive, and repetitive neuronal depolarization. An electroencephalographic pattern recorded from scalp electrodes is considered an electroencephalographic seizure if it is rhythmic; has an electrical field; has a precise onset, body, and offset; and is not considered to be physiologic or artifactual in nature (click on clip).


http://pediatricneuro.com/alfonso/clip13.mpg


REFERENCES

Barkovich JA, Peck WW. MR of Zellweger syndrome. Am J Neuroradiol. 1997;18:1163-1170. Boylan KB, Ferriero DM, Greco CM, et al. Congenital hypomyelination neuropathy with arthrogryposis multiplex congenita. Ann Neurol. 1992;31:337-340. Fenichel GM. Neonatal Neurology. New York, NY: Churchill Livingstone; 1990. Giedion A, Boltshauser E, Briner J, et al. Heterogeneity in Schwartz-Jampel chondrodystrophic myotonia. Eur J Pediatr. 1997;156:214-223. Gorlin RJ, Cohen MM, Levin LS. Syndromes of the head and neck. New York, Oxford unniversity press; 1990:889-891. Hageman G, Jenneckens FGI, Vette JK, et al. The heterogeneity of distal arthrogryposis. Brain Dev. 1984;6:273-283. Hageman G, Willemse J. Arthrogryposis multiplex congenita. Neuropediatrics. 1983;14:6-11. Hall JG, Reed SD, Driscoll EP. Amyoplasia: a common sporadic condition with congenital contractures. Am J Med Genet. 1983;15:571-590. Hall JG. In utero movement and use of limbs are necessary for normal growth: a study of individuals with arthrogryposis. Prog Clin Biol Res. 1985;200:155-162. Heymans HS, Wanders RJA, Schutgens RBH. Peroxisomal Disorders. In: Fernandez J, Saudubray JM, Tada K, eds. Inborn Metabolic Diseases. Diagnosis and Treatment. Berlin: Springer-Verlag; 1990:421-433. Holmes LB, Driscoll SG, Bradley WG. Contractures in a newborn infant of a mother with myasthenia gravis. J Pediatr. 1980;96:1067-1069. Jones HR Jr, Bolton CF, Harpen CM Jr. Pediatric Clinical Electromyography. Philadelphia, Penn: Lippincott-Raven; 1996. Jones KL. Smith’s Recognizable Patterns of Human Malformations. Philadelphia, Penn: WB Saunders; 1997. Livingstone IR, Sack GH. Arthrogryposis multiplex congenita occurring with maternal multiple sclerosis. Arch Neurol. 1984;41:1216-1217. Lyon G. Congenital malformation of the brain. In: Levene MI, Lilford RJ, eds. Fetal and Neonatal Neurology and Neurosurgery. Edinburg: Churchill Livingstone; 1994:193-214. Papazian O. Transient neonatal myasthenia gravis. J Child Neurol. 1992;7:135-141. Sarnat HB, Case ME, Graviss R. Sacral agenesis. Neurologic and

neuropathologic features. Neurology. 1976;26:1124-1129. Schneider V, Cabrera-Meza G. eds. Rudolph's Brief Atlas of the Newborn; Hamilton, Ontorio: Decker Publishing Inc; 1998. Volpe JJ. Neurology of the Newborn. Philadelphia, Penn: WB Saunders; 1995.



Facial asymmetry due to structural lesions will vary according to the location of the abnormality. A structural abnormality in the lower quadrant of the face will produce a persistent asymmetry that will not change with action. A structural abnormality in the upper quadrant of the face involving the eyelid will change, but not disappear, with action. An asymmetry due to an anomaly that prevents the affected eyelids from closing, such as a protruding eyeball, may decrease when the normal eye is wide open. An anomaly that keeps that affected eyelid closed may decrease when the

normal eye is closed.

STRUCTURAL FACIAL ASYMMETRY

The most frequent structural anatomical lesions are molding, asymmetrical craniosynostosis, facial tumor, ocular pterygium, and eyelid swelling.



MANAGEMENT OF CLINICAL PAROXYSMAL EVENTS

The initial step in the evaluation of a neonate with clinical paroxysmal events consists of determining whether the events are normal or abnormal. The distinction may be established by history, direct observation of the events, observation of the events during conventional EEG recording, or by reviewing the video-recorded clinical and electroencephalographic events captured by continuous video EEG telemetry.

REFERENCES

Alfonso I, Hahn JF, Papazian O. Bilateral tonic-clonic epileptic seizures in non-familial neonatal convulsion. Pediatr Neurol. 1997;16:249-251. Alfonso I, Papazian O, Litt R, et al. Similar brain SPECT findings in subclinical and clinical seizures in two neonates with hemimegalencephaly. Pediatr Neurol. 1998;19:132-134. Bye AME, Flanagan D. Electroencephalograms, clinical observations and the monitoring of neonatal seizures. J Paediatr Child Health. 1995;31:503-507. Kellaway P, Mizrahi EM. Neonatal seizures. In: Luders H, Lesser RP, eds. Epilepsy: Electroclinical Syndromes. New York, NY: Springer-Verlag; 1987:13-47. Volpe JJ. Neonatal seizures: current concepts and revised classification. Pediatrics. 1993;48:803-875. Volpe JJ. Neurology of the Newborn. Philadelphia, Penn: WB Saunders Co; 1995:172-207.



NORMAL PAROXYSMAL MOTOR EVENTS

Benign Neonatal Sleep Myoclonus

Benign neonatal sleep myoclonus can only be diagnosed in neurologically normal fullterm neonates. The diagnosis requires a clear history or the observation of repetitive myoclonic limb jerks that occur

only during sleep (click on clips) and stop upon awakening. The myoclonic activity may last from several seconds to 90 minutes. The jerks may be felt while the limb is held (click on third clip). Benign neonatal sleep myoclonus may be triggered and exacerbated by noise, rocking, and benzodiazepines. Rocking is especially effective in triggering the events

(click on third clip). The use of benzodiazepines to eliminate benign neonatal sleep myoclonus may lead to sustained myoclonus and to the

misdiagnosis of status epilepticus. Benign neonatal sleep myoclonus is not associated with electroencephalographic seizures during the events. A

10% to 30% increase in heart rate occurs during some events.

Interictally, the EEG is normal. Benign neonatal sleep myoclonus may occur during any sleep stage but it occurs more frequently during quiet sleep. The mechanism of benign neonatal sleep myoclonus is unknown. Immaturity or imbalance of the serotonergic system has been

postulated. In most cases there is no family history of similar events. Benign neonatal sleep myoclonus usually disappears before 6 months of age and requires no treatment. Benign neonatal sleep myoclonus is not associated with subsequent neurological deficit.






Pape KE, Pickering D. Asymmetric crying facies: an index of other congenital anomalies. J Pediatr. 1972;81:21-30. Parmelee AH. Molding due to intrauterine posture: facial paralysis probably due to such molding. Am J Dis Child. 1931;42:1155-1159. Patten J. Neurological Differential Diagnosis. New York, NY: Springer-Verlag; 1977:31-40. Paya K. Facial palsy in a premature infant. Clin Pediatr. 1975;14:877. Prats JM, Monzon MJ, Zuazo E, et al. Congenital nuclear syndrome of oculomotor nerve. Pediatr Nerurol. 1993;9:476-478. Richter RB. Unilateral congenital hypoplasia of the facial nucleus. J Neoropath Exper Neurol. 1960;19:33-41. Shah UK, Ohlms LA, Neault MW, et al. Otologic management in children with CHARGE association. Int J Pediatr Otorhinolaryngol. 1998;44:139-147. Shapiro NL, Cunningham MJ, Parikh SR, et al. Congenital unilateral facial paralysis. Pediatrics. 1996;97:261-264. Smith DW. Recognizable Patterns of Human Malformation. 3rd ed. Philadelphia, Penn: WB Saunders; 1982. Tefft M, Vawter G, Neuhauser EB. Unusual facial tumors in the newborn. Am J Roentgenol Radium Ther Nucl Med. 1965;95:32-40. Volpe JJ. Neurology of the Newborn. 3rd ed. Philadelphia, Penn: WB Saunders; 1995.



PAIN

Decreased limb movements due to pain are referred to as pseudoparalysis (Figure 194.1). The neonate with pseudoparalysis cries and grimaces with even minimal attempts to move the affected extremity. The painful limbs do not adopt the typical postures that characterize segmental brachial plexus palsy or peripheral nerve lesions. Stretch muscle reflexes are normal. Evidence of trauma or infection in the affected limb supports the diagnosis of pseudoparalysis. Pseudoparalysis occurs with bone fracture or with joint, soft tissue, or bone infections.

A B

Figure 194.1.— Right leg drop in a patient with septic arthritis of the right hip [A and B].



Reggin JD, Johnson MI. Exacerbation of benign neonatal sleep myoclonus by benzodiazepines. Ann Neurol. 1989;26:455. Resnick TJ, Moshe SL, Perotta L, et al. Benign neonatal sleep myoclonus. Relationship to sleep states. Arch Neurol. 1986;43:266-268. Rosman NP, Donnelly JH, Braun MA. The jittery newborn and infant: a review. Developmental and Behavioral Pediatrics. 1984;5:263-273. Sher PK, Brown SB. Gelastic epilepsy. Am J Dis Child. 1976;130:1126-1131. Shuper A, Zalzberg J, Weitz R, et al. Jitteriness beyond the neonatal period: a benign pattern of movement in infancy. J Child Neurol. 1991;6:243-245. Stockard-Pope JE, Werner SS, Bickford RG. Atlas of Neonatal Electroencephalography. New York, NY: Raven Press; 1993:93-105. Vigevano F, Di Capua M, Dalla Barnardina B. Startle disease: an avoidable cause of sudden infant death. Lancet. 1989;1:216. Volpe JJ. Neonatal seizures: current concepts and revised classification. Pediatrics. 1989;84:422-428. Volpe JJ. Neurology of the Newborn. Philadelphia, Penn; WB Saunders Co; 2000.



NORMAL RESPIRATION

Effective respiration requires frequent movement of a sufficient amount of air in and out of the alveoli. For a sufficient amount of air to move in and out of the alveoli, several conditions must occur: (1) the diaphragmatic contractions must be strong and timely; (2) the chest wall must not collapse; (3) the lung visceral pleura must remain fixed to the somatic rib cage pleura; (4) the airway must remain patent; and (5) the alveoli must remain open.

A strong and timely diaphragmatic contraction depends on the integrity of the phrenic-diaphragmatic unit (Figure 14.1). The chest wall does not collapse because of the structural integrity of the rib cage and the effective and timely contraction of the intercostal muscles. Lung visceral and somatic pleura stay together because the negative interpleural tension is sufficiently strong to oppose the physical forces that tend to separate them during expiration. The upper airway is kept patent by the structural integrity of the rigid airway and the effective and timely contractions of the upper respiratory muscles. The alveoli are kept open by constant interalveolar tension.

Figure 14.1.— Neurological structures involved in normal breathing. A: midbrain; B: pons; C: medulla; D: cervical spine; 1: chemoreceptor; 2: dorsal respiratory group at the nucleus of the tractus solitarius; 3: ventral respiratory group at the nucleus ambiguus and nucleus retroambigualis; 4: upper airway motor neurons; 5: upper airway motor muscles; 6: phrenic center; 7: diaphragm; 8: intercostal muscle anterior horn cells; 9: intercostal muscles. Not represented are the pontine respiratory center and the fibers that travel from higher cortical centers to the dorsal and ventral respiratory groups.



REFERENCES

Alfonso I, Martin-Jimenez R, Palomino JA, et al. Early congenital syphilis. Int Pediatr. 1988;1:67-69. Brazis PW, Masdeu JC, Biller J. Localization in Clinical Neurology. Boston, Mass: Little, Brown and Co; 1990. Caffey J. Pediatric X-ray Diagnosis. Chicago, Ill: Year Book Pub; 1967. Colville J, Jeffries I. Bilateral acquired neonatal Erb’s Palsy. Ir Med J. 1975;68:399-401.



The bulk of the cortical neurons of the arm motor system are located in

the middle third of the postcentral gyrus (Figure 202.1). The rest of the cortical neurons of the arm motor system are scattered in the frontal and parietal areas. The fibers from these cortical neurons travel in the centrum semiovale lateral to the leg fibers and medial to the facial fibers. They go through the posterior limb of the internal capsule, anterior to the leg fibers and posterior to the face fibers, and continue caudally through the midbrain, pons, and upper medulla. At the lower medulla, these fibers cross to the contralateral side and then continue caudally in the lateral aspect of the spinal cord until they reach the motor neuron in the cervical spinal cord enlargement. The cortical neurons control voluntary movements. Brainstem and cerebellar neurons that influence arm movements are located in the red nucleus (midbrain) and in the pontine, medullary reticular formation, and cerebellar cortex.

Figure 202.1.— Schematic representation of the motor systems of the face, arms, and legs, and central and peripheral nervous systems structures involved in limb movements. The colored rectangles indicate the location of weakness produced by damage to the different components of

the somatic motor system. U: upper motor neurons; V: ventricles; T: thalamus; UQ: upper quadrant; FN: facial nerve; LQ: lower quadrant; L: lower motor neurons; BP: brachial plexus; LSP: lumbosacral plexus.



Miller MJ, Martin RJ. Pathophysiology of apnea of prematurity. In: Polin RA, Fox WW, eds. Fetal and Neonatal Physiology. Philadelphia, Penn: WB Saunders; 1992:872-885. Monod N, Peirano P, Plouin P, et al. Seizure-induced apnea. Ann NY Acad Sci. 1988;553:411-424. National Institutes of health. Consensus statement. National Institutes of Health Consensus Development Conference on Infantile Apnea and Home monitoring, Sept 29 to Oct 1, 1986. Pediatrics. 1987;79:292-299. Orenstein SR, Orenstein DM. Gastroesophageal reflux and respiratory disease in children. J Pediatr. 1988;82:847-858. Pleassure J, Geller SA. Neurofibroma in infancy presenting with congenital stridor. Am J Dis Child. 1967;113:390-393. Rosen CL, Glaze DG, Frost JD. Hypoxemia associated with feeding in the preterm infant and full-term neonate. Am J Dis Child. 1984;138:623-628. Saito Y, Hashimoto T, Iwata H, et al. Apneustic breathing in children with brainstem damage due to hypoxic-ischemic encephalopathy. Dev Med Child Neurol. 1999;41:560-567. Sheldon SH, Spire JP, Levy HB. Sleep-disordered respiration in childhood. Pediatric Sleep Medicine. Philadelphia, Penn: WB Saunders; 1992:136-150. Singh B, AlShawan SA, AlDeeb SM. Partial seizures presenting as life threatening apnea. Epilepsia. 1993;341:901-903. Southall DP, Johnson P, Salmons S, et al. Prolonged expiratory apnea: a disorder resulting in episodes of severe arterial hypoxemia in infants and young children. Lancet. 1985;2:571-576. Swift PGF, Emery JL. Clinical observations on response to nasal occlusion in infancy. Arch Dis Child. 1973;48:947-951. Vigevano F, Di Capua M, Barnardina BD. Startle disease: an avoidable cause of sudden infant death. Lancet. 1989;1:216. (Letter). Volpe JJ. Neuromuscular disorders: muscle involvement and restricted disorder. In: Volpe JJ, ed. Neurology of the Newborn. 3rd ed. Philadelphia, Penn: WB Saunders; 1995:634-671. Young TE, Mangum OB, eds. Neofax ’93: A Manual of Drugs Used in Neonates. 6th ed. Columbus, Ohio: Ross Laboratories; 1993. Watanabe K, Hara K, Miyazaki S, et al. Apneic seizures in the newborn. Am J Dis Child. 1982;136:980-988.


Hypoglycemia

A blood glucose level of less than 40 mg/dL may produce seizures. Hypoglycemia is likely to occur in neonates with low birth weight, hypoxic-ischemic encephalopathy, or diabetic mothers. Neonates with Beckwith-Weidemann syndrome (macrosomia, omphalocele,

macroglossia, and visceromegaly), insulin producing tumors (nesidioblastosis), inborn errors of metabolism (fructose intolerance, fructose-1,6 diphosphatase deficiency, maple syrup urine disease, propionic and methylmalonic acidemia) and those large or small for gestational age may develop hypoglycemia. Maternal use of tocolytic agents, chlorpropamide, or propranolol during pregnancy may predispose

the neonate to hypoglycemia.

Most neonates with hypoglycemic seizures are tachypneic, hypotonic, and lethargic between seizures, but some look healthy between seizures. The treatment of hypoglycemic seizures is glucose 200 mg/kg as 10% solution intravenously over 1 minute (2 mL/kg over 1 minute) followed by a constant infusion of 10% glucose at 8 mg of glucose per kg per minute. Glucose levels should be monitored frequently and the glucose infusion adjusted accordingly. Glucagon 300 micrograms/kg may be given intramuscularly in large infants if an intravenous line can not be placed

immediately.

Hypocalcemia Seizures may occur with a total serum calcium level of less than 7 mg/

dL or an ionized calcium level of less than 1.2 mg/dL. Hypocalcemia in the first week of life usually occurs in low birth weight neonates, infants of mothers with diabetes mellitus or hypoparathyroidism, or neonates with hypoxic-ischemic encephalopathy.



REFERENCES

Brazis PW, Masdeu JC, Biller J. Localization in Clinical Neurology. Boston, Mass: Little Brown; 1990. Carpenter MB, Sutin J. Human Neuroanatomy. Baltimore, Md: Williams & Wilkins; 1983. Haenggeli C, Lacourt G. Brachial plexus injury and hypoglossal paralysis. Pediatr Neurol. 1989;5:197-198. Monrad-Krohn GH. On the dissociation of voluntary and emotional innervation in facial paresis of central origin. Brain. 1924;47:22-35. Painter M. Brachial plexus injuries in neonates. Int Pediatr. 1988;3:120-124. Piatt J Jr. Neurosurgical management of birth injuries of the brachial plexus. Neurosurg Clin N Am. 1991;2:175-185. Volpe J. Neurology of the Newborn. Philadelphia, Penn: WB Saunders Co; 1995.



The axons of the cortical neurons go through the posterior limb of the internal capsule and continue caudally through the midbrain, pons, and upper medulla. At the lower medulla, these fibers cross to the contralateral side and then continue caudally in the lateral and anterior aspect of the spinal cord until they reach the neurons of the lumbosacral somatic motor

center (Figure 228.1). The cortical neurons control voluntary movements. The subcortical neurons of the lumbosacral somatic motor system are located in the midbrain, pons, medulla, and cerebellum. The subcortical neurons influence lower extremity movements by their connections with the cortical component of the lumbosacral somatic motor system and by their connections with the lumbosacral somatic motor center. The subcortical neurons control automatic movements.

Figure 228.1.— Schematic representation of the somatic motor system. The green line represents the innervation of the leg. A lesion in this system produces leg weakness. V: ventricles; T: thalamus; UQ: upper quadrant; LQ: lower quadrant; BP: brachial plexus; LSP: lumbosacral plexus. The

colored rectangles indicate the location of weakness produced by damage to the different components of the somatic motor system.



REFERENCES

Ahmed A, Hickey SM, Ehrett S, et al. Cerebrospinal fluid values in the term neonate. Pediatr Infec Dis J. 1996;15:298-303. Alfonso I, Hahn JS, Papazian O, et al. Bilateral tonic-clonic epileptic seizures in non-benign familial neonatal convulsions. Pediatr Neurol. 1997:16:249-251. Alfonso I, Perea A, Paez JC, et al. Intravenous valproic acid dose in neonates. Epilepsia. 1999;40,(Suppl 7):143. Alfonso I, Alvarez LA, Gilman J, et al. Intravenous valproate dosing in neonates. 2000;15: 827-829. Alvarez LA, Yamamoto T, Wong B, et al. Miller-Dieker syndrome: a disorder affecting specific pathways of neuronal migration. Neurology. 1986;36:489-493. Barkovich AJ. Congenital malformation of the brain and skull. In: Pediatric Neuroimaging. New York, NY: Raven Press; 1995:177-275. Barr PA, Buetiker VE, Antony JH. Efficacy of lamotrigine in refractory neonatal seizures. 1999;20:161-163. Berry PL, Belsha CW. Hyponatremia. Pediatr Clin N Am. 1990;37:351-363. Browne TR, Holmes GL. Handbook of Epilepsy. Philadelphia, Penn: Lippincott-Raven; 1997. Conley SB. Hypernatremia. Pediatr Clin N Am. 1990;37:365-371. Davies PA, Rudd PT. Neonatal Meningitis. London, England: Mac Keith Press; 1994. De Vivo DC, Trifiletti RR, Jacobson RI, et al. Defective glucose transport across the blood-brain barrier as cause of persistent hypoglucorrhagia, seizures and developmental delay. N Engl J Med. 1991;325:703-709. Donnai D, Winter RM. Congenital Malformation Syndromes. London, England: Chapman & Hall Medical; 1995:235-253. ElDahr SS, Chevalier RL. Special needs of the newborn infant in fluid therapy. Pediatr Clin N Am. 1990;37:323-333. Fenichel GM. Neonatal Neurology. New York, NY: Churchill Livingstone; 1990. Fernandez J, Saudubray JM, Tada K, eds. Inborn Metabolic Diseases. Diagnosis and Treatment. Berlin: Springer-Verlag; 1990. Gal P, Oles S, Gilman J, et al. Valproic acid efficacy, toxicity, and pharmacokinetics in neonates with intractable seizures. Neurology. 1988;341:467-471.

Harris F. Paediatric Fluid Therapy. Oxford: Blackwell Scientific Publications; 1972:51-54. Harum K, Hoon AH, Kato GJ, et al. Homozygous factor-V mutation as a genetic cause of perinatal thrombosis and cerebral palsy. Develop Med Child Neurol. 1999;41:777-780. Huang CC, Wang ST, Chang YC, et al. Measurement of urinary lactate:creatinine ratio for early identification of newborn infants at risk for hypoxic-ischemic encephalopathy. N Engl J Med. 1999;341:364-365. Hyland K, Buist NRM, Powell BR, et al. Folinic acid responsive seizures: a new syndrome. J Inher Metab Dis. 1995;18:1-5. Isaacs H. Tumors of the Fetus and the Newborn. Philadelphia, Penn: WB Saunders; 1997. Jones KL. Smith’s Recognizable Patterns of Human Malformation. Philadelphia, Penn: WB Saunders; 1997. Kroll JS. Pyridoxine for neonatal seizures: an unexpected danger. Dev Med Child Neurol. 1985;27:377-379. Levene MI, Lilford RJ, Bennett MJ, et al. Fetal and Neonatal Neurology and Neurosurgery. Edinburgh: Churchill Livingstone; 1995. Lyon G, Adams RD, Kolodny EH. Neurology of hereditary metabolic diseases in children. New York, NY: McGraw-Hill; 1996. Lombroso CT. Neonatal EEG polygraphy in normal and abnormal newborns. In: Niedermeyer E, Lopes Da Silva F, eds. Electroencephalography: Basic Principles, Clinical Application, and Related Fields. Baltimore, Md: Williams and Wilkins; 1993. Painter MJ, Mark MS, Stein AD, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med. 1999;341:485-489. Plouin P. Benign neonatal convulsions (familial and non-familial). In: Roger J, Dravet C, Bureau FE, et al, eds. Epileptic Syndromes in Infancy, Childhood and Adolescence. London: John Libbey Eurotest; 1985:2-11. Torres OA, Miller VA, Buist NMR, et al. Folinic acid-responsive neonatal seizures. J Child Neurol. 1999;8:529-532. Tsang RC. Neonatal magnesium disturbances. Am J Dis Child. 1972;124:282. Volpe JJ. Neurology of the Newborn. Philadelphia, Penn: WB Saunders; 1997. Volpe JJ. Neurology of the Newborn. Philadelphia, Penn; WB Saunders;2000.



DIFFERENTIAL DIAGNOSIS

A comatose neonate lays motionless with eyes totally or partially closed. This appearance resembles and must be differentiated from sleep, death, severe generalized hypotonia with facial involvement, and status epilepticus.

DIFFERENTIATING COMA FROM SLEEP

A comatose neonate may not be aroused regardless of the intensity of the stimuli, may require excessive stimuli to be aroused, or is unable to sustain a normal arousal response. Normal sleeping neonates have a normal arousal response.

A normal arousal response is characterized by eye opening, facial grimacing or crying, and limb movements. The intensity of the stimulus required to provoke an arousal and the duration of the arousal depends on gestational age and has a temporal relation to feeding.



FOCAL CENTRAL NERVOUS SYSTEM LESIONS

Magnetic resonance imaging (MRI) usually confirms the location of the lesion (anatomical diagnosis) and often substantiates the tentative

pathological diagnosis. The most likely pathologies of focal central nervous system (CNS) lesions are vascular accidents, tumors, malformations, and infections. Vascular accidents include infarcts and hemorrhages, porencephalic cysts, and schizoencephaly. Tumors include neoplasms and aneurysms. Malformations include encephalocele and myelomeningocele. Infections may be congenital or acquired in the neonatal period.

CENTRAL NERVOUS SYSTEM INFARCTS

Central nervous system infarcts may occur in the brain, brainstem, cerebellum, or spinal cord. They may involve the arterial or the venous system. Infarcts may be ischemic or hemorrhagic. Arterial infarcts are produced by hypoperfusion, embolic or thrombotic phenomena, or by vasospasm. Venous infarcts are usually thrombotic in nature.

A CNS infarct should be suspected in neonates with predisposing conditions (prematurity, hypercoagulation states, polycythemia, dehydration, hypotension, extracorporeal circulation, or in neonates whose mother had hypertension or used cocaine during pregnancy) and suggestive clinical findings such as clinical paroxysmal events, apnea, coma, facial weakness, or decreased limb movements (monoparesis, hemiparesis, paraparesis, upper extremity diplegia, and quadriparesis).

When a CNS infarct is suspected, B-mode ultrasonogrpahy, MRI, MRA, or CT with and without contrast should be performed as soon as possible after the onset of clinical manifestations.

A B C

Figure 244.1.— [A] MRI of the brain demonstrating a large infarct in the distribution of the left middle cerebral artery; [B] B-mode ultrasonography demonstrating a thrombus at the origin of the internal carotid artery; [C] MRA of the brain demonstrating a narrow internal carotid artery and absence of the middle cerebral artery.

Nevertheless, a normal MRI or CT within the first 24 hours after the onset of clinical manifestations does not eliminate the possibility of an ischemic infarct because ischemic central nervous system parenchymal changes may not be detected by these studies during this period. Diffusion-weighted imaging may reveal ischemic CNS parenchymal changes earlier

than MRI modalities. Hemorrhagic infarcts are usually detected within the first 24 hours after the onset of symptoms. Computed tomography shows blood better than MRI in the first 24 hours after an event. Magnetic resonance arteriogram may demonstrate the flow abnormality earlier than MRI or CT in ischemic infarcts. B-mode ultrasonography should be used to diagnose arterial infarcts if transportation to the MRI area is not possible. B-mode ultrasonography is very useful in premature neonates with periventricular leukomalacia. The studies of choice to diagnose arterial infarcts are MRI and MRA of the appropriate area.

The next step after the diagnosis of a CNS infarct is diagnosed is to find the cause. The cause of the infarct should be sought in all patients except premature neonates with periventricular infarcts. The search for the cause of the infarct should start with a review of the history of the present illness and the family history, followed by a carefully performed physical examination searching for clues that might suggest the cause of the infarct. If a clue is present, the tests should be guided by it. If there are no clues, an extensive evaluation is necessary. The evaluation includes: complete blood cell count with differential and platelets, prothrombin time (PT), partial thromboplastin time (PTT), fibrinolytic proteins, antithrombin III, erythrocyte sedimentation rate, antiphospholipid antibodies, amino and organic acids in serum and urine, proteins S and C, urine analysis, urine for drug screening, and ultrasonographic evaluation of the heart and

carotid arteries. Evaluation of the placenta may be helpful in patients

with arterial infarcts. Lumbar puncture should be performed if the possibility of a CNS infectious process is suspected. Magnetic resonance angiogram of the brain and neck should be performed to visualize the vascular tree in all patients with cerebral infarct.

Arterial and venous CNS ischemic or hemorrhagic infarcts do not have specific treatment. If the primary disorder is found, treatment is indicated. Supportive treatment consists of maintaining systemic blood pressure, oxygenation, and glycemia within normal limits.



Tada K. Nonketotic hyperglycinemia. In: Fernandes J, Saudubray JM, Tada K, eds. Inborn Metabolic Diseases. Diagnosis and Treatment. Berlin: Springer-Verlag; 1990:323-329. Takanashi J, Fujii K, Sugita K, et al. Neuroradiologic findings in glutaric aciduria type II. Pediatr Neurol. 1999;20:142-145. Tharp BR. Unique EEG pattern (comb-like rhythm) in neonatal maple syrup urine disease. Pediatr Neurol. 1992;8:65-68. Volpe JJ. Neurology of the Newborn. Philadelphia, Penn: WB Saunders; 1995. Weisman LE, Merenstein GB, Steenbarger JR. The effect of lumbar puncture position in sick neonates. Am J Dis Child. 1983;137:1077-1079. Wendel U. Disorders of branched-chain amino acid metabolism. In: Fernandes J, Saudubray JM, Tada K, eds. Inborn Metabolic Diseases. Diagnosis and Treatment. Berlin: Springer-Verlag; 1990:263-270.



POSTURAL OBSERVATION

During quiet wakefulness, hypotonic neonates have a characteristic posture. Their arms are either flexed at the elbow with the backs of the hands resting against the bed (Figure 88.1 [A]) or extended with the palms facing up or down. Their legs are fully abducted and flexed at the knees so that the lateral aspect of the thighs rest on the bed. In contrast, normal neonates have their arms raised from the bed and flexed at the elbows during quiet wakefulness, and their hips and knees are flexed so that only the gluteal region and the soles of the feet rest on the bed (Figure 88.1 [B]).

A B

Figure 88.1.— [A] Posture of a hypotonic neonate. [B] Posture of a normal neonate.

ARM TRACTION RESPONSE

The arm traction response is obtained by slowly pulling the neonate by the hands to achieve a sitting position. A hypotonic neonate shows head lag, no arm pull is felt by the examiner, the arms remain extended as the body is pulled up, and the legs remain in contact with the bed (Figure 88.2 [A]). A normal neonate shows minimal head lag, a backward pull is felt by the examiner as the neonate’s arms are pulled, and there is flexion of the elbows, knees, and ankles (Figure 88.2 [B]).

A B

Figure 88.2.— [A] Hypotonic arm traction response. [B] Normal arm traction response.



REFERENCES

Alfonso I, Palomino JA, DeQuesada G, et al. Congenital varicella syndrome. Am J Dis Child. 1984;138:603-604. Alfonso I, Papazian O, Reyes M, et al. Obstetric brachial palsy. Int Pediatr. 1995:10:208-213. Alfonso I, Papazian O, Prieto G, et al. Neoplasm as a cause of brachial plexus palsy in neonates. Pediatr Neurol. 2000;22:309-311. Barkovich AJ. Pediatric Neuroimaging. New York, NY: Raven Press; 1995. Brazis PW, Masdeu JC, Biller J. Localization in Clinical Neurology. Boston, Mass: Little, Brown and Co; 1990. Bruner JP, Richard WO, Tulipan NB, et al. Am J Obstet Gynecol. 1999;180:153-158. Cheng JCY, Tang SP, Chen MK. Sternocleidomastoid pseudotumor and congenital muscular torticollis in infants: a prospective study of 510 cases. J Pediatr. 1999;134:712-716. de Turckheim MC, Clavert JM, Paira M. Exostosis costales compliquees, en periode neonatale, de paralysie du plexus brachial. Entite distincte de la maladie exostosante. Ann Pediatr (Paris). 1991;38:23-25. Dunn DW, Engle WA. Brachial plexus palsy: intrauterine onset. Pediatr Neurol. 1985;1:367-369. du Plessis AJ. Posthemorrhagic hydrocephalus and brain injury in the preterm infant: dilemmas in diagnosis and management. Sem Pediatr Neurol. 1998;5:161-179. Eng GD, Kosch B, Smokvina MD. Brachial plexus palsy in neonates and children. Arch Phys Med Rehabil. 1978;59:458-464. Fanaroff AA. Labor and delivery. In: Klaus MH, Fanaroff AA, eds. Year-Book of Neonatal and Perinatal Medicine. St Louis, Mo: Mosby Year book Publishers; 1994:103. Feldman GV. Radial nerve palsies in the newborn. Arch Dis Child. 1957;32:469-471. Fenichel GM. Clinical Pediatric Neurology. Philadelphia, Penn: WB Saunders Co; 1997. Fischer AQ, Straburger MD. Foot drop in a neonate secondary to use of foot board. J Pediatr. 1982;101:1003-1004. Gilles FH, Matson DD. Sciatic nerve injury following misplaced gluteal injection. J Pediatr. 1991;76:247-254.

Greenwald AG, Schute PC, Shiveley JL. Brachial plexus birth palsy: 10-year report on the incidence and prognosis. J Pediatr Orthop. 1984;4:689-692. Grossman JAI. Brachial plexus surgery. In: Grossman JAI. ed. Hand Clinics. Philadelphia, Penn: WB Saunders; 1995. Haenggeli C, Lacourt G. Brachial plexus injury and hypoglossal paralysis. Pediatr Neurol. 1989;5:197-198. Harum KH, Hoon AH, Kato GJ, et al. Homozygous factor-V mutation as a genetic cause of perinatal thrombosis and cerebral palsy. Dev Med Child Neurol. 1999:41:777-780. Hepner, WR. Some observations on facial paresis in the newborn infant: etiology and incidence. Pediatrics. 1951;8:494-497. Holden KR, Titus O, Tassels VT. Cranial magnetic resonance imaging examination of normal term neonates: a pilot study. J Child Neurol. 1999;14:708-710. Issacs H. eds. Brain tumors. Tumors of the fetus and newborn. In: Issacs H. Major Problems in Pathology. Philadelphia, Penn: WB Saunders Co; 1997:187-228. Kennedy CR, Ayers S, Campbell MJ, et al. Ramdomized trial of acetazolamide and furosamide in posthemorrhagic ventricular dilatation in infancy: follow-up at 1 year of age. Pediatrics. 2001;108:597-607. Krishnamoorthy KS, Soman TB, Takeoka M, et al. Diffusion-weighted imaging in neonatal cerebral infarction. J Child Neurol. 2000;15:592-602. Koenigsberger MR. Brachial plexus palsy at birth: intrauterine or due to delivery trauma? Ann Neurol. 1980;8:228. Kreusser KL, Volpe JJ. Peroneal palsy produced by intravenous fluid infiltration in a new born. Dev Med Child Neurol. 1984;26:522-554. Lucas JW, Holden KR, Purohit DM, et al. Neonatal Hemangiomatosis associated with brachial plexus palsy. J Child Neurol. 1995;10:411-413. McFarland LV, Raskin M, Daling JR, et al. Erb/Duchenne palsy: a consequence of fetal macrosomia and method of delivery. Obstet Gynecol. 1986;68:784-788. McHugh HE. Facial paralysis in birth injury and skull fractures. Arch Otol. 1963;78:57-69. Ogita S, Tokiwa K, Takahashi T, et al. Congenital cervical neuroblastoma associated with Horner syndrome. J Pediatr Surgery. 1988;23:991-992. Raimondi AJ, Maurice C, Di Rocco C. Cerebrovascular Diseases in Children. Berlin: Springer-Verlag; 1992. Renier D, Flandin C, Hirsh E, et al. Brain abcesses in neonates: a study of 30 cases. J Neurosurg. 1998;69:877-882. Ritter S, Loyd YT, Shaddy RE, et al. Are screening echocardiograms warranted for neonates with meningomyelocele? Arch Pediatr Adolesc. 1999;153:1264-1266. Roach ES, Riela AR. Pediatric Cerebrovascular Disorders. New York, NY: Futura Publishing Co; 1995. Ross D, Jones HR, Fisher J, et al. Isolated radial nerve lesion in the

newborn. Neurology. 1983;33:1354-1356. Ruggieri M, Smarason AK, Pike M. Spinal cord insult in the prenatal, perinatal and neonatal period. Develop Med Child Neurol. 1999;41;311-317. Sadleir LG, Connolly MB. Acquired brachial plexus neuropathy in the neonate: a rare presentation of late-onset group-Β streptococcal osteomyelitis. Dev Med Child Neurol. 1998;40:496-499. San Augustin M, Nitowsky HM, Borden JN. Neonatal sciatic palsy after umbilical vessel injection. J Pediatr. 1962;60:408-413. Shapiro NL, Cunningham MJ, Parikh SR, et al. Congenital unilateral facial paralysis. Pediatrics. 1996;97:261-264. Srabstein JC, Morris N, Larke RP, et al. Is there a congenital varicella syndrome? J Pediatrics. 1974;84:239-243. Swaiman KF, Wright FS. Practice of Pediatric Neurology. St Louis, Mo: CV Mosby; 1982. Tsao PN, Lee WT, Peng SF, et al. Power Doppler ultrasound imaging in neonatal cerebral venous sinus thrombosis. Pediatr Neurol. 1999;21:652-655. Tollner U, Bechinger D, Pohlandt F. Radial nerve palsy in a premature infant following long-term measurement of blood pressure. J Pediatr. 1980;96:921-922. Volpe JJ. Neurology of the Newborn. Philadelphia, Penn: WB Saunders Co; 1995. Volpe JJ. Brain injury in the premature infant: overview of clinical aspect, neuropathology, and pathogenesis. Semin Pediatr Neurol. 1998;5:135-151.



Microcephaly occurs in many conditions. Smith’s book on recognizable patterns of human malformation lists microcephaly as a frequent finding in 42 syndromes and as an occasional finding in 33

more. The differential diagnosis of congenital microcephaly can be approached by categorizing each patient in one of the following groups: (1) neonates with dysmorphic facial features and normal karyotype; (2) neonates with dysmorphic facial features and abnormal karyotype; (3) neonates with normal facial features and elevated serum IgM; and (4)

neonates with normal facial features and normal serum IgM.

NEONATES WITH DYSMORPHIC FACIAL FEATURES AND NORMAL KARYOTYPE

Neonates with dysmorphic facial features and normal karyotype include those exposed to teratogenic physical or chemical agents during pregnancy and those with genetic abnormalities that are not detected by chromosomal studies.

Teratogenic Microcephaly Microcephaly due to teratogenic physical or chemical agents results

from exposure of the fetus to a noxious agent at a vulnerable period of brain development. Physical agents include radiation. Microcephaly due to radiation is very rare since the introduction of low-dose ionizing radiation for diagnostic radiological evaluations, the shielding of the pelvis for chest radiographs, and the avoidance of pelvic radiographs if pregnancy is remotely suspected. Hyperthermia is not a significant factor in the production of microcephaly. Hypothermia was once considered a significant factor in the production of microcephaly based on experimental

animal studies and an initial medical report. Chemical agents that may cause microcephaly include phenylalanine, alcohol, and anticonvulsant drugs.



REFERENCES

Brazis PW, Masdeu JC, Biller J. Localization in Clinical Neurology. Boston, Mass: Little, Brown & Co; 1990. Carpenter MB, Sutin J. Human Neuroanatomy. Baltimore, Md: Williams & Wilkins; 1983. Fenichel G. Neonatal Neurology. New York, NY: Churchill Livingstone; 1990. Ingall D, Dobson SR, Musher D. Syphilis. In: Remington JS, Klein JO, eds. Infectious Diseases of the Fetus and Newborn Infant. Philadelphia, Penn: WB Saunders Co; 1990:366-394. Kendall ER, Schwartz JH, Jessell TM. Essentials of Neural Science and Behavior. Norwalk, Conn: Appleton & Lange; 1995. Sarnat HB. Anatomic and physiologic correlates of neurologic development in prematurity. In: Topics in Neonatal Neurology. Orlando, Fla: Grune & Straton, Inc; 1984:1-25. Steinmann B, Superti-Furga A, Royce PM. Heritable disorders of connective tissues. In: Fernandes J, Saudubray JM, Tada K, eds. Inborn Metabolic Diseases. Berlin: Springer-Verlag; 1990.



Upper motor neuron system hypotonia refers to hypotonia that occurs as a consequence of disorders of the neurons that directly or indirectly make contact with the lower motor neurons. Upper motor neuron system hypotonia occurs with diseases of the brain, cerebellum, brainstem, and spinal cord (Figure 104.1 [1,2,3,5]).

Figure 104.1.— Schematic representation of the upper motor neuron system and lower motor unit structures demonstrating possible sites of anatomical involvement that lead to hypotonia. Generalized hypotonia may be due to an upper motor neuron lesion, a lower motor neuron lesion, or a combination of upper and lower motor neuron lesions. Upper motor neuron lesions may occur at the (1) brain, (2) brainstem, (3) rostral cervical spinal cord, or (5) cerebellum. Combined upper and lower motor lesions may occur with damage to lower motor neurons of the arms and the upper motor neurons of the legs in the lower cervical spinal cord (4). Lower motor neuron lesions may occur at the (6) alpha motor neuron, (7) nerve, (8) presynaptic myoneural junction, (9) postsynaptic myoneural junction, or (10) muscle. Brainstem structures that influence muscle tone (red nucleus, reticular formation, and lateral vestibular nucleus) are not shown in this figure. LMN: lower or alpha motor neuron; MNJ: myoneural junction.

Hypotonia due to upper motor neuron system lesions may be associated with decreased dynamic tone or increased dynamic tone. Upper motor neuron system dysfunction is often associated with clinical findings that reflect the involvement of neighboring neurological and nonneurological structures. Upper motor neuron system hypotonia is not associated with any specific electromyographic, nerve conduction velocity, repetitive stimulation test, or muscle biopsy abnormalities unless there is simultaneous involvement of the alpha motor neurons and the muscle fibers (motor-sensory unit). Simultaneous involvement of the upper motor neuron system and motor-sensory unit occur in Farber disease (brain, alpha motor neurons, and nerves), GM1 gangliosidosis (brain and alpha motor neurons), and hypoxic encephalopathy (brain, alpha motor neurons, and muscle), and in neuroaxonal dystrophy (brain and peripheral nerve), congenital muscular dystrophy (brain and muscle), and congenital

myotonic dystrophy (brain and muscle).



REFERENCES

Badson SG, Berda GI. Growth graphs for the clinical assessment of infants of varying gestational age. J Pediatr. 1976;89:814-820. Behrman RE, Kliegman RM, Arvin AM, et al. Nelson’s Textbook of Pediatrics. Philadelphia, Penn: WB Saunders Co; 1996. Brann AW. Neurodevelopmental anomalies and neuromusculature disorders. In: Faranoff AA, Martin RJ, eds. Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant. St Louis, Mo: Mosby; 1992:734-753. Haslam RH. Microcephaly. In: Vinken PJ, Bruyn G, Klawans HL, eds. Handbook of Clinical Neurology. Amsterdam: Elsevier Science Publishers; 1987:50;267-284. Jones KL. Smith’s Recognizable Patterns of Human Malformation. Philadelphia, Penn: WB Saunders Co; 1997. Kotagal S. Microcephaly. In: Hacke G, ed. Essentials of Child Neurology. St Louis, Mo: Ishiyaku EuroAmerica Inc; 1990:79-81. Martin HP. Microcephaly and mental retardation. Am J Dis Child. 1970;119:128-131. Ross JR, Frias JL. Microcephaly. In: Vinken PJ, Bruyn G, Klawans HL, eds. Handbook of Clinical Neurology. Amsterdam: Elsevier Science Publishers; 1977:30;507-524. Rouse B, Matalon R, Kock R, et al. Maternal phenylketonuria syndrome: congenital heart defects, microcephaly, and developmental outcome. J Pediatr. 2000;136:57-61. Volpe JJ. Neurology of the Newborn. 3rd ed. Philadelphia, Penn; WB Saunders Co; 1995.



CAUSES OF MACROCEPHALY

Smith’s book of recognizable patterns of human malformations lists macrocephaly as a frequent finding in 27 syndromes and as an occasional

finding in 16 more. Macrocephaly during the neonatal period results

from enlargement of any component or “space” of the head. The components or spaces of the head most likely to enlarge are the

scalp, skull, subdural space, subarachnoid space, brain parenchyma, intraparenchymal vessels, and ventricles.

SCALP

Three scalp lesions may produce macrocephaly. They are caput

succedaneum, subgaleal hemorrhage, and cephalohematoma. They produce significant head asymmetry.

Caput Succedaneum Caput succedaneum is due to edema between the skin and the epicranial

aponeurosis. It presents as a mass, usually located in the vertex, that crosses the sutures and extends over several bones. The mass is soft, superficial, and pitting. The edema results from compression of the scalp by the uterus or suction on the scalp if a vacuum extractor was used during delivery. More about it... 106

Subgaleal Hemorrhage

Subgaleal hemorrhage is due to blood between the epicranial aponeurosis and the external periosteum. Subgaleal hemorrhage presents as an evenly spread mass throughout a large portion of the scalp (Figure 284.1). The mass is firm, fluctuant, crosses suture lines, and increases in size after birth (sometimes at an alarming speed).

Figure 284.1.— Computed tomography of the brain (axial) at different levels demonstrates subgaleal hemorrhage.

Subgaleal hemorrhage may extend to the neck or the face (Figure 284.2). It is caused by bleeding that results from linear skull fracture, suture diastasis, or fragmentation of the superior margin of the parietal bone. Coagulation problems may contribute to the bleeding. Subgaleal hematoma may lead to anemia and hyperbilirubinemia. Anemia may be

severe enough to require blood transfusion or may even cause death. The volume of blood required may be estimated using the following formula: 38 mL for each cm by which the actual head circumference exceeds that expected or known. If the head circumference at birth was 35 cms and 3 hours later it is 40 cms then multiply 5 (40 minus 35) by 38 to

find the volume of blood required.

Figure 284.2.— Scout film for CT of the brain demonstrates subgaleal hemorrhage extending to the neck.



Petersen MB, Brostrom K, Stilbler H, et al. Early manifestations of the carbohydrate-deficient glycoprotein syndrome. J Pediatr. 1993;122:66-70. Price DA, Ehrlich RM, Walfish PG. Congenital hypothyroidism. Clinical and laboratory characteristics in infants detected by neonatal screening. Arch Dis Child. 1981;56:845-851. Ruggieri M, Smarason AK, Pike, M. Spinal cord insults in prenatal, perinatal and neonatal period. Dev Med Child Neurol. 1999;41:311-317. Smith WL, Alexander RC, Judisch GF, et al. Magnetic resonance imaging evaluation of neonates with retinal hemorrhages. Pediatrics. 1992;89:332-333. Sztriha L, Al-Gazali LI, Aithala GR, et al. Joubert's syndrome: new cases and review of clinicopathological correlation. Pediatr Neurol. 1999;20:274-281. Volpe JJ. Neurology of the Newborn. Philadelphia, Penn: WB Saunders; 1995. Wiedemann HR, Kunze J, Grosse FR, et al. Clinical Syndromes, A Visual Aid to Diagnosis. St Louis, Mo: Mosby Yearbook; 1992.



Diseases of the motor-sensory unit involving the alpha motor

neuron, nerve, myoneural junction, and muscles may produce hypotonia (Figure 130.1). Alpha motor neuron disease refers to disorders that affect the alpha motor neuron located in the anterior horn of the spinal cord, in the motor nucleus of the cranial nerves, or at both locations. Nerve disease refers to disorders that affect the alpha motor neuron axons, the sensory axons that carry information from the muscle spindle, or both. Myoneural junction diseases are disorders that affect the junction between the alpha motor neurons axons and muscle fibers. Muscle disorders are diseases that affect the extrafusal muscle fibers.

Figure 130.1.— Schematic representation of the motor-sensory unit system and the sites of possible lesions producing hypotonia. AMN: alpha motor neuron; RC: Renshaw cell; DGC: dorsal ganglion cell; EFMF: extrafusal motor fiber; IFMF: intrafusal motor fiber; GMN: gamma motor neuron. Arrows indicate direction of conduction. (5) alpha motor neuron; (6) nerve; (7) myoneural junction; (8) muscle.

The possible sites of injury in neonates with hypotonia due to diseases

of the motor-sensory unit system can be represented (Figure 130.2 [6-10])

in a simplified scheme similar to the one used to explain localization in upper motor neuron lesions.

A B C

Figure 130.2.— Schematic representation of the upper motor neuron system [A] and lower motor unit [B] structures demonstrating possible sites of anatomical involvement that lead to generalized hypotonia. Simplified schematic representation of the lower motor system [C] following same numerical order as [B]. Generalized hypotonia may be due to an upper motor neuron lesion at the (1) brain, (2) brainstem, (3) rostral cervical spinal cord, or (5) cerebellum. Generalized hypotonia may result from damage to lower motor neurons of the arms and the upper motor neurons of the legs in the lower cervical spine area (4). Generalized hypotonia may be due to lower motor neuron lesions at the: (6) alpha motor neuron; (7) nerve; (8) presynaptic myoneural junction; (9) postsynaptic myoneural junction; and (10) muscle. LMN: lower or alpha motor neuron; MNJ: myoneural junction.



REFERENCES

Aicardi J. Diseases of the Nervous System in Childhood. London: Mac Keith Press; 1992. Babson SG, Benda GI. Growth graphs for clinical assessment of infants of varying gestational age. J Pediatr. 1976;89:814-820. Barkovich AJ. Pediatric Neuroimaging. New York, NY: Raven Press; 1995. Becker MH. Classification of craniofacial dysmorphism. In: Hoffman HJ, Epstein F, eds. Disorders of the Developing Nervous System: Diagnosis and Treatment. St Louis, Mo: Blackwell; 1986:347-370. DeMyer W. Megalencephaly in children. Neurology. 1972;22:634-643. Govaert P, Vanhaesebrouch P, De Praeter C, et al. Vacuum extraction, bone injury and neonatal subgaleal bleeding. Eur J Pediatr. 1992;151:532-535. Fenichel JM. Clinical Pediatric Neurology. Philadelphia, Penn: WB Saunders Co; 1997:365-382. Jones K. Smith’s Recognizable Patterns of Human Malformation. Philadelphia, Penn: WB Saunders Co; 1997. Kotagal S. Macrocephaly. In: Hacke G, ed. Essentials of Child Neuorlogy. St Louis, Mo: Ishiyaku EuroAmerica Inc; 1990:83-88. Matalon R, Kaul R, Casanova J, et al. Aspartoacylase deficiency: the enzyme defect in Canavan disease. J Inher Metab Dis. 1989;12:329-331. Robinson RJ, Rossiter MA. Massive subaponeurotic hemorrhage in babies of African origin. Arch Dis Child. 1968;43:684-687. Rudd NL. Genetics. In: Hoffman HJ, Epstein F, eds. Disorders of the Developing Nervous System: Diagnosis and Treatment. St Louis, Mo: Blackwell; 1986:37-53. Volpe JJ. Neurology of the Newborn. Philadelphia, Penn; WB Saunders Co; 1995.



Facial capillary angiomatosis presents as a port-wine stain. The port-wine stain in Sturge-Weber syndrome usually involves the whole area of skin innervated by the ophthalmic branch of the trigeminal nerve, but occasionally it involves a smaller area in the distribution of the ophthalmic branch such as the inner corner of the upper eyelid, or a larger area that extends beyond the limits of the ophthalmic branch of the trigeminal nerve. Every neonate with a port-wine stain on the face should have an ophthalmological evaluation (Figure 296.1) unless the port-wine stain is light colored and in the middle of the forehead just above the nose.

Figure 296.1.— Facial hemangioma involving the ophthalmic division on the right trigeminal nerve and maxillary divisions of the trigeminal nerves; buphthalmos on the right.

Glaucoma is the most frequent ocular pathology. Glaucoma is usually detected in the course of a routine ophthalmologic evaluation in a neonate with a facial port-wine stain. Glaucoma may produce buphthamos (Figures 296 and 296.2). Buphthalmos may be the presenting sign of Sturge-Weber syndrome. Buphthalmos is readily diagnosed by observation and by MRI (Figure 296.2[B]).

A B

Figure 296.2.— [A] Facial hemangioma involving the ophthalmic and maxillary divisions of the trigeminal nerve. [B] MRI appearance of buphthalmos (left eye). Compare the distance between the lens and the cornea in the left eye and right eye.

Seizures are an unusual initial manifestation of Sturge-Weber

syndrome in the neonatal period. Hemiparesis and mental retardation do not usually occur in the neonatal period. Arachnoid and piamater angiomatosis usually occurs in the parietal occipital region ipsilateral to the facial angioma. Cerebral cortical atrophy often occurs in the same hemisphere as meningeal angiomatosis. Hydrocephalus due to sagittal sinus and venous obstruction may also occur. Contrast MRI of the brain may show meningeal angiomatosis even in the neonatal period. The skull x-ray finding of “double contour” convolutional calcifications do not occur

in neonates. Sturge-Weber syndrome has a sporadic occurrence.



Sarnat HB. New insights into the pathogenesis of congenital myopathies. J Child Neurol. 1994;9:193-201. Schapira D, Swash W. Neonatal spinal muscular atrophy presenting as respiratory distress: a clinical variant. Muscle Nerve. 1985;8:661-663. Shelbourne P, Davies J, Buxton J, et al. Direct diagnosis of myotonic dystrophy with a disease-specific DNA marker. N Eng J Med. 1993;328:471-475. Sladky JT, Brown MJ, Berman PH. Chronic inflammatory demyelinating polyneuropathy of infancy: a corticosteroid-responsive disorder. Ann Neurol. 1986;20:76-81. Thompson JA, Glasgow LA, Warpinski JR, et al. Infant botulism: clinical spectrum and epidemiology. Pediatrics. 1980;66:936-942. Volpe JJ. Neuromuscular disorders: motor system, evaluation, and arthrogryposis multiplex congenita. In: Neurology of the Newborn. Philadelphia, Penn: WB Saunders; 1995a:585-605. Volpe JJ. Neuromuscular disorders: levels above the lower motor neuron to the neuromuscular junction. In: Neurology of the Newborn. Philadelphia, Penn: WB Saunders; 1995b:606-633. Zellweger H, Afifi A, McCormick WF, et al. Severe congenital muscular dystrophy. Am J Dis Child. 1967;114:591-602.



A pivotal step in the management of arthrogryposis multiplex congenita is to determine its cause. The cause of the arthrogryposis multiplex congenita determines the prognosis and recurrence rate of the disease. There are many causes of arthrogryposis multiplex congenita in neonates. Smith’s book on recognizable patterns of human malformation lists

arthrogryposis multiplex congenita as a feature of over 100 syndromes. The differential diagnosis among these syndromes is made by analyzing the distribution of the arthrogryposis, the presence of facial dysmorphism, and other associated findings.

Arthrogryposis multiplex congenita may involve the distal or the proximal joints. Involvement of the distal joints is more frequent than involvement of the proximal joints. Neonates with distal arthrogryposis

often have a very typical hand position (Figure 152.1). This typical hand position is frequently present in trisomy 13 and 18 syndromes, Pena-Shokeir I and II syndromes, and Smith-Lemli-Opitz syndrome. Proximal arthrogryposis usually involves the shoulders, elbows, hips, and knees.

Proximal arthrogryposis occurs in neonates with amyoplasia congenita.

Figure 152.1.— Trisomy 18 hand position. The middle finger is under the index finger and partially under the fourth finger. The thumb is totally or partially under the index finger.



REFERENCES

Alfonso I, Palomino JA, DeQuesada G, et al. Congenital varicella syndrome. Am J Dis Child. 1984;138:603-604. Alfonso I, Lopez PF, Cullen RF Jr, et al. Spinal cord involvement in encephalocraniocutaneous lipomatosis. Pediatric Neurol. 1986;2:380-384. Alfonso I, Howard C, Lopez PF, et al. Linear nevus sebaceous syndrome: a review. J Clin Neuroophthalmol. 1987;7:170-177. Barkovich AJ, Frieden AJ, Williams ML. MR of neurocutaneous melanosis. AJNR. 1994:15;859-867. Baron Y, Barkovich AJ. MR imaging of Tuberous Sclerosis in neonates and young infants. AJNR. 1999;20:907-916. Gomez MR. Neurocutaneous Diseases: A Practical Approach. Stoneham, Mass: Butterworth Publishers; 1987. Jones KL. Smith’s Recognizable Patterns of Human Malformations. Philadelphia, Penn: WB Saunders Co; 1997. Kadonaga JN, Frieden IJ. Neurocutaneous melanosis: definition and review of the literature. J Am Acad Dermatol. 1991;24:747-755. Martinez-Granero MA, Pascual-Castroviejo I. Neurocutaneous melanosis. Rev Neurol. 1997;25:S265-S268. Punt F. Surgical management of neural tube defects. In: Levene MI, Lilford RJ, Bennett MJ, et al, eds. Fetal and Neonatal Neurology and Neurosurgery. 2nd ed. New York, NY: Churchill Livingstone; 1995. Spitz JL. Genodermatoses. Baltimore, Md: Williams & Wilkins; 1996. Wiedemann HR, Kunze J, Grosse FR. Clinical Syndromes. 3rd ed. London: Mosby Wolfe; 1997.



Moebius Syndrome

Moebius syndrome consists of bilateral facial weakness due to cranial nerve VII motor unit dysfunction (Figure 164.1). The dysfunction may be due to hypoplasia or destruction of the cranial nerve VII motor neurons or the facial nerve. Moebius syndrome has also been described in patients with facial muscle pathology. Moebius syndrome is often associated with inability to abduct the eyes as a result of cranial nerve VI motor unit abnormality and with atrophic changes of the tongue due to cranial nerve XII involvement. Poland sequence may occur in association with Moebius syndrome. Mental deficiency is present in 15% of cases. Moebius syndrome is usually sporadic. A dominant transmission is present in some cases. Arthrogryposis is present in about one-third of patients with

Moebius syndrome. More about...181

A B

Figure 164.1— Moebius syndrome. [A] At rest, no asymmetry is noted. [B] During crying the facial asymmetry becomes obvious.

PERIPHERAL NERVE

Congenital Hypomyelinating Neuropathy Congenital hypomyelinating neuropathy is a rare cause of

arthrogryposis. Neonates are hypotonic and weak. Nerve conduction studies reveal a reduced motor conduction of 5 to 8 meters per second. The diagnosis is established by sural nerve biopsy. Sural nerve biopsy shows a minute amount or absence of myelin sheaths and occasional onion-bulb

formation.

MYONEURAL JUNCTION

Transient Congenital Myasthenia Gravis Neonates with transient myasthenia gravis may have arthrogryposis.

They also have hypotonia, weakness, and fatigability. Fatigability is the hallmark of myasthenia gravis. The diagnosis is established by evaluating the mother. Mothers of neonates with transient congenital myasthenia gravis have a history of myasthenia gravis or have clinical findings of myasthenia gravis. Treatment with neostigmine improves strength.

Physical therapy is effective to relieve contractures.



Pontine Lesions Pontine lesions may involve the facial nucleus or intrapontine facial

nerve fascicles (Figure 181.1). They produce an ipsilateral facial musculature deficit that equally affects the corner of the mouth, the nasolabial fold, the lower eyelid, the upper eyelid, and the forehead. When crying, the mouth deviates toward the normal side and the eyelid remains

open or closes less tightly on the affected side.

Figure 181.1.— Schematic representation of the intrapontine trajectory of the facial nerve. N: nucleus; CN: cranial nerve; C: location of intrapontine lesion.

The facial nucleus is the affected site in Moebious syndrome. Moebious syndrome has been described with degeneration, agenesis, and hypoplasia of the nucleus of the sixth and seventh cranial nerves. Moebious syndrome is characterized by bilateral but asymmetrical facial weakness (Figure 181.2). The facial nucleus may also be affected by cerebrovascular accidents and by tumors. More about...164

Intrapontine lesions of the facial nerve fascicles are strictly unilateral. In addition to facial musculature involvement, they produce: (1) ipsilateral sixth cranial nerve palsy; (2) ipsilateral Horner syndrome and hypohydrosis and vasodilatation of the ipsilateral body; (3) ipsilateral decreased tearing; and (4) contralateral upper motor neuron

hemiparesis. Magnetic resonance imaging is the study of choice to

evaluate the facial nucleus and intrapontine fibers.

A B

Figure 181.2— Moebious syndrome. [A] At rest, no asymmetry is noted. [B] During crying the facial asymmetry becomes obvious.



TUMORS

Central nervous system tumors in the neonatal period may occur in the brain and spine.

Brain tumors may be supratentorial or infratentorial. Brain tumors may produce obstetrical complications due to severe macrocephaly, or may present in the neonatal period as hydrocephalus, focal neurological

findings, or massive bleeding. Supratentorial tumors in neonates occur more often than infratentorial tumors. Magnetic resonance imaging is the study of choice for neonates with suspected brain or spinal cord tumor. Teratomas, astrocytomas, choroid plexus papilloma, and primitive neuroectodermal tumors are the most frequent brain tumors in neonates.

Teratomas constitute about one-third of all neonatal tumors (Figure 257.1).

A B C

Figure 257.1.— MRI of the brain demonstrating a large teratoma. The tumor involves the left optic nerve (A) and extends beyond the skull (B and C). Calcification (B).

Astrocytomas also occur frequently. Astrocytic tumors may occur in neonates with tuberous sclerosis. Choroid plexus papillomas are usually in the lateral ventricles and produce hydrocephalus. Choroid plexus papillomas have been described in neonates with Aicardi syndrome and

melanocytic nevus. Choroid plexus papillomas have the best prognosis of all neonatal brain tumors. Primitive neuroectodermal tumors are highly

aggressive tumors that metastasize widely within the cerebrospinal fluid (Figure 257.2). Neonates with rhabdoid tumors of the liver or Wilms tumor have a higher incidence of primitive neuroectodermal tumors. Optic gliomas may occur in neonates with neurofibromatosis type I. More about... 46, 288

A B

Figure 256.2.— Primary neuroectodermal tumor. [A] Contrast enhanced lesion obstructing the left foramina of Monro. [B] T1- transverse view demonstrates a hypointense mass obstructing the left foramina of Monro.

Tumors in the spinal cord usually present as lower extremity diplegia.

The most frequent spinal cord tumor is neuroblastoma (Figure 257.3).

Astrocytomas and teratomas may also occur.

Figure 257.3.— MRI of the spine demonstrating a neuroblastoma compressing the spine.

ABSCESS

Central nervous system absceseses in the neonatal period may occur in the brain and spine. Two-thirds of brain abscesses occur in association with meningitis. The most common organisms are Citrobacter diversus, Proteus, and Pseudomonas. Every neonate with gram-negative bacterial meningitis should be evaluated for the possibility of an abscess. Absceseses are usually multiple. Seizures, signs of sepsis, and increasing head circumference are the most common clinical manifestations. Magnetic resonance imaging of the brain is the study of choice to diagnose brain abcess (Figure 257.4). Well-formed absceseses should be drained. In most cases surgical aspiration should be attempted. If surgical aspiration fails to collapse the abscess, open surgical drainage is recommended. Antibiotic therapy should be adjusted based on the cerebrospinal fluid findings or preferably on the findings in the material collected from the

abscess.

Figure 257.4.— MRI of the brain demonstrating a brain abscess with surrounding edema producing ventricular compression. In addition, there are multiple isolated areas of increased signal.

PORENCEPHALY

Porencephaly may present as hemiparesis, seizures or both. Porencephaly refers to an intraparenchymal cavity that is isointense to the cerebrospinal fluid in all MRI sequences. It can be distinguished from schizencephaly because the cavity is not lined by a cortex-like band. The

cause of porencephaly is local ischemia after the 26 weeks gestational

age. The evaluation of a neonate with porencephaly should be similar to the evaluation of a neonate with an ischemic arterial infarct.

SCHIZENCEPHALY

Schizencephaly is usually clinically silent in the neonatal period but it may present as hemiparesis, seizures or both. Schizencephaly can be diagnosed by CT or MRI of the brain (Figure 257.4 [A] [B]). Schizencephaly refers to a cavity lined by a cortex-like band that is isointense to the cerebrospinal fluid in all MRI sequences (Figure 257.4 [B]). The cavity may be so narrow that the cortex-like bands appear adjacent to each other (closed lips) (Figure 257.4 [A]) or so wide that the cortex-like bands are very far from each other (open lips) (Figure 257.4

[B]). Schizencephaly may be sporadic or familial.

A B

Figure 257.4.— [A] CT of the brain demonstrating closed-lip schizoencephaly. [B] MRI of the brain demonstrating open-lip schizoencephaly.

Schizencephaly may be associated with other central nervous system malformations. Neonates with schizencephaly should have a neuro-ophthalmological evaluation. Schizencephaly may be associated with de Morsier's syndrome (Figure 257.5).

A B

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Focal Nervous System Lesions

Figure 257.5.— MRI of the brain in a patient with the association of DeMorsier's syndrome (bilateral optic nerve atrophy) and schizencephaly.

de Morsier's syndrome consists of atrophic optic nerves (Figure 257.6) and endocrine problems. More about... 46

A B

Figure 257.6.— [A] Atrophic optic nerve: lack of sharp borders, and increased vessels-size to disc-size relation. [B] Normal optic nerve: sharp borders, and normal vessels-size to disc-size relation.



Neurocutaneous Disorders


NEONATAL ABUSE

Abuse is rare in the neonatal period. Linear cutaneous equimosis may be a cutaneous sign of trauma (Figure 308.1). The suspicion of child abuse warrants a very careful clinical evaluation including ophthalmological evaluation for retinal bleeding (Fgure 308.1), bone survey, and a social worker consultation. The differential diagnosis of neonatal abuse includes cutis mamorata telangelactica, congenital reticulated vascular pattern, epidermolysis bullosa simplex, epidermolysis bullosa (scalded skin), and

osteogenesis imperfecta.

A B

Figure 308.1.— Neonatal abuse. [A] Cutaneous lesions in an abused neonate. Linear bruises over the skin. [B] Retinal hemorrhages.


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The Motor-Sensory Unit System


ALPHA MOTOR NEURON DISEASES

Alpha motor neuron diseases are usually referred to as spinal atrophies. The latter term downplays the fact that this group of diseases also affect the alpha motor neuron in the cranial nerve motor nucleus. Alpha motor neuron diseases produce hypotonia with decreased dynamic tone.

Electromyogram may show fibrillations and sometimes fasciculation

potentials and large-amplitude, long-duration polyphasic motor units.

Muscle biopsy is abnormal. Sensory and motor nerve conductions are

normal. Alpha motor neuron diseases in the neonatal period may be

caused by dysgenetic, destructive, and degenerative processes. Dysgenetic processes result from disruption in the number or migration of the alpha motor neurons. They are nonprogressive and are usually not associated with fasciculation potentials in the EMG.

Destructive processes are intrauterine hypoxia and infections (poliomyelitis). They are nonprogressive and are usually associated with fasciculation potentials.

Degenerative disorders include Werdnig-Hoffmann disease, Pompe disease (acid maltase deficiency), neonatal adrenoleukodystrophy, and incontinentia pigmenti. The most frequent alpha motor neuron disease in the United states is Werdnig-Hoffmann disease. Neonatal poliomyelitis is very rare in the United States but it occurs more frequently in other parts of the world. Degenerative processes are progressive and may be associated with fasciculation potentials. Nevertheless, progression in degenerative alpha motor neuron disorders may not occur in the neonatal period.



Figure 124.1.— Salient features of alpha motor neuron disease. Arrow indicates the anatomical location of the injury. The arrow pointing to the yellow rectangle indicates involvement of the alpha motor neuron in the spinal cord. The arrows pointing to the gray and yellow rectangles indicate involvement of the motor neuron in the spinal cord and brainstem. DEG: degenerative; DYS: dysgenesis; DES: destruction; Diag: diagnosis; D: deficiency. The illustrations below Werdnig Hoffmann disease indicate a small tongue and a small heart. The illustrations below Pompe disease indicate a large tongue and a large heart.





The diagnosis of Werdnig-Hoffmann disease is confirmed by DNA

study. The genetic abnormality is at the 5q 11.2-13.2 site. Neonates with the clinical findings of Werdnig-Hoffmann disease and a negative DNA study should undergo EMG, nerve conduction, tensilon trial, and muscle biopsy to exclude the possibility of other causes of hypotonia with decreased dynamic tone. The EMG of a neonate with Werdnig-Hoffmann

disease shows fibrillation potentials. Fasciculations are rare. Occasionally a peculiar pattern of spontaneous bicouple discharges may be present. Muscle biopsy may show panfascicular atrophy and type I fiber hypertrophy. The loss of checkerboard appearance and the presence of type grouping that is characteristic of Werdnig-Hoffmann disease during childhood is not present in most neonates with Werdnig-Hoffmann disease. The only treatment for neonates with Werdnig-Hoffmann disease is supportive.

Pompe Disease Pompe disease or acid maltase deficiency occurs less frequently than

Werdnig-Hoffmann disease. The gene locus is at 17q 23-25 site. Pompe disease is an autosomal recessive disorder caused by alpha-glucosidase

deficiency. Alpha-glucosidase deficiency leads to increased glycogen deposition in lysosomes of many different tissues, including the anterior horn motor neurons and muscle. The most common clinical manifestations are hypotonia with decreased dynamic tone (without the typical distribution of Werdnig-Hoffmann disease), congestive heart failure, a large tongue, bulky muscles, and a firm liver. The deposition of glycogen in the cardiac muscle lysosomes leads to a large heart with shortened PR intervals, elevated R-waves, and inverted T-waves. Muscle biopsy reveals large amounts of periodic acid Schiff (PAS)-positive material. The enzymatic defect can be demonstrated in leukocytes and fibroblasts.

Prenatal diagnosis from amniotic fluid fibroblasts is possible. There is no specific treatment. Death due to cardiac failure often occurs at a young

age.



Causes and Treatments of Seizures


DISORDERS OF CITRIC ACID CYCLE

Two disorders involving the citric acid cycle produce neonatal coma: fumarase deficiency and dihydrolipoyl dehydrogenase deficiency (Figure 79.1 B). Comatose neonates with disorders of the citric acid cycle have elevated lactate and pyruvate, and a lactate-to-pyruvate ratio above 35. Fumarase deficiency is associated with a characteristic urine organic acid pattern that consists of elevated fumaric and succinic acids. Treatment consists of a high carbohydrate diet and aspartic acid

supplementation. Dihydrolipoyl dehydrogenase deficiency was previously described. More about... 73

Figure 79.1.— Metabolic pathways involved in branched chain amino acid disorders. A: maple syrup urine disease; B: dihydrolipoyl dehydrogenase deficiency; C: isovaleric acidemia; D: glutaric acidemia type II; E: multiple carboxylase deficiency; F: HMG-CoA lyase deficiency.



UREA CYCLE DEFECT

The urea cycle takes 2 moles of ammonia and, in the presence of N-acetylglutamate (an allosteric activator of carbomoylphosphate synthetase) and normal urea cycle enzymes activity and after a turn in the 5-step cycle, produces 1 mole of urea. The urea cycle defects that present in the neonatal period are carbamyl phosphate synthetase deficiency, ornithine transcarbamylase deficiency, citrullinemia, and argininosuccinic aciduria. All urea cycle defects are autosomal recessive disorders except ornithine transcarbamylase deficiency. Ornithine transcarbamylase deficiency is an X-linked disorder. The hallmark of a urea cycle defect is hyperammonemia. A normal serum ammonia level excludes all urea cycle defects that occur in neonates. The metabolic profile of each urea cycle defect occurs as the result of an elevation of the amino acids prior to the enzymatic block within the cycle and their alternate pathways. The alternate pathways are the production of glycine, glutamate, and orotic acid. Neonatal hyperammonemia also occurs with severe liver failure, severe perinatal asphyxia, total parenteral nutrition, isovaleric acidemia, propionic acidemia, methylmalonic acidemia, multiple carboxylase deficiency, pyruvate dehydrogenase deficiency, carboxylase complex deficiency, N-acetylglutamic acid synthetase deficiency, Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, and glutaric acidemia type II. These causes of neonatal hyperammonemia are distinguished from urea cycle defects by the presence of metabolic acidosis, abnormal liver function tests, and specific amino acid profile.



Macrocephaly


BRAIN PARENCHYMA

Parenchymal space enlargement occurs in neurocutaneous disorders, Soto syndrome, metabolic megalencephalies, and some degenerative disorders.

Neurocutaneous Disorders The possibility of a neurocutaneous disorder should be considered in

every neonate with macrocephaly. The evaluation of every neonate with macrocephaly should include a careful cutaneous examination. The two neurocutaneous disorders most often associated with macrocephaly are hypomelanosis of Ito and linear nevus sebacceous syndrome.

Soto Syndrome Neonates with Soto syndrome are born with borderline macrocephaly.

The diagnosis of this disorder is established by the presence of a growth spurt beyond the normal range during the first 3 years of life. This excessive growth spurt causes the infant to become larger than normal, especially the head. Plasma somatomedin levels are usually elevated during the growth spurt. Soto syndrome is usually a sporadic condition, although familial cases have been reported. Estrogen may reduce growth

in girls.

Metabolic Megalencephalies

Metabolic megalencephalies do not usually present in the neonatal period. The exceptions to this are glutaric acidemia type I, Canavan disease, and Alexander disease.





Isovaleric-CoA dehydrogenase deficiency

A block in the leucine pathway due to isovaleric-CoA dehydrogenase deficiency occurs in isovaleric acidemia (Figure 74.1 C) and multiple acyl-CoA dehydrogenase deficiency. Multiple acyl-CoA dehydrogenase

deficiency is also called glutaric acidemia type II (Figure 74.1 D). Clinical findings that may suggest these disorders in a neonate are: (1) an offensive sweat odor in the urine, (2) mild facial dysmorphism, and (3) rocket-bottom feet. Neonates with multiple acyl-CoA dehydrogenase deficiency may have anterior muscular abdominal wall defects and abnormal genitalia.

Figure 74.1.— Leucine pathway showing different enzymatic blocks and the amino acids that increase as a result of the block. A: maple syrup urine disease; B: dihydrolipoyl dehydrogenase deficiency; C: isovaleric acidemia; D: glutaric acidemia type II; E: multiple carboxylase deficiency; F: HMG-CoA lyase deficiency.



The metabolic profiles of isovaleric acidemia and glutaric acidemia type II are different even though the enzyme block in the leucine pathway is the same (Figure 74.1 [C,D]).

Isovaleric acidemia

The metabolic profile of isovaleric acidemia is more complex than would be expected from a single pathway-specific enzyme deficiency (Figure 74.2 C). This complex profile occurs because high levels of isovaleric acid produce carnitine deficiency and disruption of: (1) pyruvate dehydrogenase complex, producing lactic acidosis; (2) glycine cleavage system, producing hyperglycemia; and (3) carbamyl phosphate synthetase, producing hyperammonemia.






ERRORS OF PROTEIN METABOLISM THAT DO NOT INVOLVE THE LEUCINE PATHWAY

Errors of protein metabolism that do not involve the leucine pathway include glycine encephalopathy, propionic and methylmalonic acidemias, sulfite oxidase deficiency, and pyruvate metabolism disorders. Propionic and methylmalonic acidemias are also known as organic acidemias.

Glycine encephalopathy Glycine encephalopathy is diagnosed by finding elevated glycine in the

blood, urine, or cerebrospinal fluid in the absence of: (1) ketosis, (2) abnormal serum amino profile, and (3) abnormal urine organic acid profile. The cerebrospinal fluid to plasma glycine ratio is above 0.09 (in normal circumstances and in secondary hyperglycemia it is below 0.04). The diagnosis is only excluded by finding a normal cerebrospinal fluid glycine level. Three findings may suggest glycine encephalopathy: (1) hiccups; (2) an EEG with a burst suppression pattern; and (3) a brain imaging study with white matter hypodensity and partial or total absence of the corpus callosum. There is no satisfactory pathophysiologic treatment. Seizures should be treated with diazepam. The prognosis of glycine encephalopathy is very poor in most cases, although a transient

variety with good prognosis also occurs. Elevated levels of glycine are also found in inborn errors of metabolism that have an increase in coenzyme-A derivatives including tiglyl-CoA, propionyl-CoA, methylmalonyl-CoA, and isovaleryl-CoA. The disorders produced by these enzyme deficiencies are denominated secondary

hyperglycinemia.

Propionic and methylmalonic acidemias Coma due to propionic and methylmalonic acidemias lack specific

clinical characteristics. These disorders should be considered in neonates with urine pH below 5.5 and if the calculated anion gap (Na - [Cl +

HCO3]) is in excess of 20 mmol/L.

The metabolic profile of propionic acidemia consists of the accumulation of propionyl-CoA and its metabolites in urine: methylcitrate and 3-hydroxypropionate. In addition, the metabolic profile reflects dysfunction of the citric acid cycle (lactic acidosis), pyruvate



dehydrogenase complex (lactic acidosis), N-acetylglutamate synthetase (hyperammonemia), and glycine cleavage (hyperglycinemia).





DIFFERENTIATING COMA FROM HYPOTONIA

The clinical appearances of a severely hypotonic neonate with cranial nerve involvement and a comatose neonate are very similar. The only neonatal disease that produces this degree of hypotonia is botulism. Botulism is characterized by a history of constipation preceding the absence of limb movements and a history of normal mental status as weakness develops. Peripheral nerve stimulation in neonates with botulism does not produce muscle twitching due to myoneural junction block. Patients with botulism usually have normal EEGs unless there is superimposed hypoxia due to respiratory failure or hyponatremia due to inappropriate secretion of antidiuretic hormone. Neonates with botulism and hypoxia or hyponatremia may present with EEG background abnormalities and electroencephalographic seizures.

ETIOLOGY

There are many causes of coma. Most causes of coma are readily identified from the initial clinical evaluation and laboratory findings while others require a high index of suspicion and special laboratory investigations.

ASPHYXIA

Coma due to asphyxia is associated with profound metabolic or mixed acidemia (pH < 7.00) at the time of the event or shortly after. Evidence of multi-organ system failure is often present. Lactic acid is elevated but ketosis is not present. The absence of ketosis distinguishes lactic acidosis due to asphyxia from lactic acidosis due to an inborn error of

metabolism. The mechanisms of asphyxia during labor, delivery, and immediate postpartum are: (1) an interruption of the umbilical circulation; (2) altered placental gas exchange; (3) inadequate perfusion of the maternal side of the placenta, (4) impaired maternal oxygenation; or (5)

failure of the neonate to accomplish lung inflation.




Pyruvate metabolism disorders

Pyruvate metabolism disorders are usually considered when the blood lactate is elevated. Pyruvate metabolism abnormalities may be due to: (1) an isolated defect in the pyruvate metabolism, (2) a defect that produces dysfunction of pyruvate metabolism and at the same time involves other metabolic pathways, and (3) secondary involvement of the pyruvate metabolic pathway by high concentration of an abnormal amino or organic acid. Isolated pyruvate metabolic disorders are pyruvate dehydrogenase complex deficiency and pyruvate carboxylase deficiency.

Pyruvate dehydrogenase complex deficiency

Pyruvate dehydrogenase complex deficiency should be suspected in a comatose neonate with elevated serum lactate and pyruvate and a lactate-to-pyruvate ratio below 25. It can only be excluded by the presence of a normal cerebrospinal fluid lactate. Dysmorphic facial features (frontal bossing, upturned nose, thin upper lip, and low-set ears), short fingers and nails, simian creases, and hypospadia may be present. Neonates with pyruvate dehydrogenase deficiency have an appearance similar to that of neonates with fetal alcohol syndrome. Brain imaging may show evidence of prenatal brain damage. The diagnosis is established by finding decreased activity of one or more of the pyruvate dehydrogenase complex enzymes in cultured fibroblasts, liver tissue, skeletal muscle, lymphocytes, or brain tissue. Multiple tissues may have to be analyzed to establish the correct diagnosis since the enzyme deficiency may not be detected in all tissues. Treatment, in addition to metabolic support, consists of a high-fat (to introduce compounds to the citric acid cycle bypassing pyruvate), low-carbohydrate diet, thiamine, lipoic acid, carnitine, and dichloroacetate. Pyruvate dehydrogenase complex deficiency has an autosomal-recessive or a sex-linked inheritance. Pyruvate dehydrogenase complex deficiency may also occur in isovaleric acidemia and in dihydrolipoyl dehydrogenase

deficiency.

Pyruvate carboxylase deficiency

Pyruvate carboxylase deficiency in a comatose neonate is characterized by high serum ketones, pyruvate, and lactate, and a lactate-to-pyruvate ratio above 35. Brain imaging shows evidence of prenatal damage. The complex metabolic findings in a patient with pyruvate carboxylase are due



to high levels of acetyl-CoA and low levels of oxaloacetate. High levels of acetyl-CoA produce ketosis. Low levels of oxaloacetate cause low levels of aspartate. Low aspartate prevents nicotinamide adenine dinucleotide from entering the mitochondria. An excess of nicotinamide adenine dinucleotide in the cytosol increases the conversion of pyruvate to lactic acid. It is this increase in the conversion of pyruvate to lactic acid that leads to a lactate-to-pyruvate ratio above 35. Low oxaloacetate also impairs the citric acid cycle, glycine cleavage system, and the urea cycle. The diagnosis is established by finding decreased pyruvate carboxylase activity in cultured fibroblasts. Treatment consists of metabolic support and a diet low in fat and high in carbohydrates and protein. Aspartic acid and biotin should be added. Pyruvate carboxylase deficiency also occurs in

multiple carboxylase deficiency. Prognosis is dismal.





DISORDERS OF FATTY ACID METABOLISM

Neonatal coma due to a disorder of fatty acid oxidation may occur with any of the following conditions: (1) deficiency of short-chain, medium-chain, or long-chain acyl-CoA dehydrogenases; (2) multiple acyl-CoA dehydrogenase deficiency (glutaric acidemia II); (3) hydroxymethylglutaryl-CoA dehydrogenase deficiency; and (4) carnitine cycle defects. The characteristic features of fatty acid oxidation disorders are mild metabolic acidosis, nonketotic hypoglycemia, low or normal total carnitine blood levels, dicarboxylic aciduria. Mild hyperammonemia and slight elevation of liver transaminases may also be present with fatty acid oxidase disorders. Final diagnosis is established by demonstration of the enzymatic defect in leukocytes and fibroblasts. Treatment consists of stopping fat intake, correcting hypoglycemia with glucose, and providing oral carnitine at 100 mg/kg per day. Riboflavin at 50 to 750 mg daily is

recommended. Fasting should be avoided.

DISORDERS OF CARBOHYDRATE METABOLISM

Coma due to an inborn error in the metabolism of carbohydrates occurs in fructose-1-6 diphosphate deficiency and in fructose-1-phosphate aldolase deficiency (hereditary fructose intolerance). Fructose-1-6 diphosphate deficiency produces accumulation of lactic and pyruvic acids, increased ketosis, and hypoglycemia. Treatment consists of continuous glucose supplementation to avoid gluconeogenesis. Hereditary fructose intolerance presents with vomiting after the introduction of fruit juice or table sugar to the neonatal diet. Continuous vomiting leads to coma. Carbohydrate abnormalities are diagnosed by finding reduced enzyme activity in the liver. Treatment consists of eliminating fructose from the

diet and correcting hypoglycemia.

EVALUATION OF A NEONATE WITH A SUSPECTED

METABOLIC DISORDER

To help establish a prompt diagnosis of a metabolic disorder in a



neonate with a suspected metabolic disorder, group them according to the results of the most readily available blood test: blood pH, glucose, lactate and ammonia, and urine ketones. Neonates with ketoacidosis and hypoglycemia are likely to have a metabolic error that involves the leucine pathway, propionic or methylmalonic acidemias, or a disorder of carbohydrate metabolism. Neonates with hyperammonemia and respiratory alkalosis usually have a urea cycle defect. Neonates with low urinary ketones and hypoglycemia usually have a disorder of mitochondrial fatty acid oxidation. Neonates with lactic acidosis are likely to have pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency, or a respiratory chain enzyme defect, but other disorders are frequently occurs in this group. The evaluation of neonates with lactic acidosis is complicated since elevated lactic acids frequently occur in a large number of disorders.

Inborn errors of metabolism that present with lactic acidosis in neonates can be grouped according to the results of the urine organic acids. Lactic acidosis and organic aciduria occur with fatty acid oxidative defects, biotinidase and multiple carboxylase deficiencies and in organic acidemias. Lactic acidosis without organic aciduria occurs in pyruvate dehydrogenase, glucogenic enzymes, pyruvate carboxylase, and respiratory chain defects.

Inborn errors of metabolism that present with lactic acidosis without organic acidemia can be further grouped according to the lactate/pyruvate ratio and the pyruvate concentration. The normal lactate (0.8 to 2.2 mmol/L) to pyruvate (0.04 to 0.01 mmol/L) blood concentration ratio is less than 25 (lactate 25: pyruvate 1). The lactate/pyruvate ratio depends on the state of tissue oxygenation (lactate = pyruvate multiplied by the state of tissue oxygenation [x]). The state of tissue oxygenation x depends on the amount of NADH2 and NAD in the cytosol (NADH2/NAD). So a metabolic disorder associated with lactic acidosis and a high number in x will have a high serum lactate level despite low serum pyruvate levels (increased lactate/pyruvate ratio [lactate >35: pyruvate 1]); whereas diseases with lactic acidosis and a lower x will have a high serum lactate level at the expense of a high pyruvate level (low lactate/pyruvate level [lactate <25:

pyruvate 1]).





HYPERBILIRUBINEMIA

Coma due to hyperbilirubinemia is rare. It usually presents in the first days of life with jaundice, hypotonia, and poor suck. Fever and hypertonia with retrocollis and opisthotonos may follow. Double volume exchange transfusion should be tried if phototherapy fails to keep bilirubin below 18

mg/dL. Bilirubin-albumin displacing substances should be avoided

and potentially bilirubin-albumin displacing substances should be used at the lowest therapeutic concentrations. Premature neonates may require exchange transfusion at a lower level. Neonates with generalized glutathione synthetase deficiency are predisposed to hyperbilirubinemia. Glutathione synthetase deficiency is an autosomal disease. Low glutathione renders erythrocytes more vulnerable to oxidative damage. Neonates with glutathione synthetase deficiency may have partial albinism (Figure 67.1).

Figure 67.1.— Partial albinism in a patient with glutathione synthetase deficiency. The color of the patient's skin contrasts with the mother's skin (holding patient at the waist).

MENINGITIS

Bacterial meningitis is most often caused by group B streptococcus,

Escherichia coli, Listeria monocytogenes, or Haemophilus influenzae. Early onset meningitis has a fulminant course. Signs of systemic failure, such as poor perfusion, hypothermia, and coma, occur simultaneously. Late onset meningitis has a more protracted course. Feeding problems and irritability precede coma by several hours. Seizures and a bulging fontanel are common. Neck rigidity is usually not present. The typical



cerebrospinal fluid findings are white blood cell count above 32 cells/

mm, protein concentration above 90 mg/dL, and a cerebrospinal fluid to blood glucose ratio of less than 2:3. Nevertheless, a comatose neonate with cerebrospinal fluid white blood cell count of more than 10 cells/mm should be treated with antibiotics pending the results of the cerebrospinal fluid culture. Gram-stained smear and antigen detection, if positive, can be used to diagnose meningitis and to identify the organism. However, in most cases the diagnosis of bacterial meningitis depends on the identification of the organism in cerebrospinal fluid culture.





A positive polymerase chain reaction for herpes in the cerebrospinal

fluid usually establishes the diagnosis of herpetic meningitis. A negative polymerase chain reaction makes the diagnosis of herpetic meningitis very unlikely. Viral cultures from the affected brain tissue remain the most reliable diagnostic method but they are seldom done because of the inherent risk of brain biopsy. MRI of the brain may reveal typical changes depending on the time of diagnosis (Figure 69.1). Acyclovir 20 mg/kg every 8 hours for 21 days is the treatment of choice in term neonates with normal renal function.

A B C

Figure 69.1.— Evolution of MRI changes in a patient with herpetic meningitis. [A] First MR, T1 axial: temporal pole asymmetry; [B] MRI contrast T1 axial, seven days later: white matter and vascular interhemisphere asymmetry; and [C] MRI T1 axial image one month after the first MRI: hypointensity in the right temporal pole.

SEPSIS

Sepsis may cause coma in neonates even without evidence of meningitis. The exact mechanism for encephalopathy is not clear. Fever, metabolic alterations, and hypotension are contributing factors. Sepsis is diagnosed on clinical grounds and confirmed by blood culture.

INTRACRANIAL HEMATOMA



Intraparenchymal, subdural, and epidural hematomas may produce coma in neonates. The mechanisms of coma are transtentorial and subfalcial herniations with supratentorial hematomas and direct brainstem compression with infratentorial hematomas. Infratentorial (Figure 69.2) and supratentorial hematomas are diagnosed by CT scan of the brain. Intraparenchymal bleeding most often occurs in the cerebral hemispheres. Coagulation disorders are the most frequent cause of intraparenchymal bleeding. Correction of the bleeding diathesis is imperative. Evacuation of the intraparenchymal hematoma is seldom possible or needed. Subdural and epidural hemorrhages are due to trauma or coagulation disorders. Subdural and epidural supratentorial hematomas are due to a tear in a meningeal artery or cerebral bridging vein. Eye deviation responsive to caloric testing and focal seizures may be present. Supratentorial subdural and epidural hematomas are treated by evacuation if they are considered clinically significant. Infratentorial subdural hematomas are usually due to tentorial lacerations or occipital osteodiastasis due to difficult deliveries.

Figure 69.2.— T1 axial MRI of the brain demonstrates an infratentorial subdural hematoma.



Upper Motor Neuron System Hypotonia


Degenerative disorders with visceral storage include GM1 gangliosidosis (lysosomal deficiency of beta galactosidase), Sandhoff disease (lysosomal deficiency of hexosaminidase A and B), Farber disease (lysosomal deficiency of ceramidase), sialidosis (lysosomal deficiency of alpha neuroaminidase without the presence of alpha neuroaminidase in the cytosol), infantile sialic acid storage disease (lysosomal deficiency of alpha neuroaminidase with excessive cytosol alpha neuroaminidase due to the production of alpha neuroaminidase without the marker that guides it to the lysosomes), Zellweger syndrome or cerebrohepatorenal syndrome (peroxisomal disease characterized by peroxisomal organelles without enzymes), and neonatal adrenoleukodystrophy (peroxisomal disease characterized by peroxisomal organelles with a decreased amount of enzymes). The diagnosis of these disorders is established by enzymatic studies in fibroblasts or leukocytes, except for sialidosis, infantile sialic acid storage disease, Zellweger syndrome, and neonatal adrenoleukodystrophy. The diagnosis of sialidosis requires fibroblast studies for the deficient enzyme. Studies of leukocytes are not revealing. Neonates with sialidosis may have hydrops fetalis. In infantile sialic acid storage disease, no enzyme deficiency has been found. Infantile sialic acid storage disease is diagnosed by the presence of excessive sialic acid in plasma and urine in the presence of normal alpha-neuroaminidase activity in fibroblasts. Neonates with infantile sialic acid storage disease usually have thin white hair. Zellweger syndrome and neonatal adrenoleukodystrophy are diagnosed by liver biopsy or microscopic evaluation of cultured fibroblasts. Electron microscopy of liver tissue or fibroblasts of patients with Zellweger syndrome and neonatal adrenoleukodystrophy reveals the presence of peroxisomes that are empty of enzymes in Zellweger syndrome and have very little enzymes in

neonatal adrenoleukodystrophy.



Microcephaly


Aicardi Syndrome

Aicardi syndrome occurs in females. Aicardi syndrome consists of the

association of agenesis of the corpus callosum, lacunar chorioretinopathy (Figure 281.1), and periventricular heterotopias. Aicardi syndrome usually manifests with seizures in the neonatal period. The EEG in most neonates shows a burst-suppression pattern arising independently and asynchronous from each hemisphere. Severe mental retardation, infantile spasms, and hypsarrhythmia usually develop during the first months of life. It is an X-linked dominant disorder that is lethal in

males. More about... 52

A B C

Figure 281.1.— MRI of the brain in a neonate with Aicardi syndrome: [A] agenesis of the corpus callosum and interhemispheric cyst; [B] colpocephaly and interhemispheric cyst; [C] lacunar chorioretinopathy.

Microlissencephaly

Microlissencephaly results from severe cerebral and cerebellar hypoplasia. Microcephaly is severe. These patients usually die during the neonatal period. Craniofacial dysmorphism, genitalia anomalies, and arthrogryposis may occur. Microlissencephaly results from an abnormal neuronal and glial proliferation. An autosomal recessive inheritance has been suggested. The diagnosis is established by MRI of the brain. The MRI of the brain shows a smooth cerebral surface, agenesis of the corpus

callosum, and cerebellar dysgenesis.


Microcephaly

Agenesis of the corpus callosum

Agenesis of the corpus callosum may be associated with microcephaly. The diagnosis of agenesis of the corpus callosum is detected by brain ultrasound and confirmed by MRI of the brain. Agenesis of the corpus callosum may be associated with cortical abnormalities. The EEG usually shows interhemispheric asynchrony. The corpus callosum can be

recognized by fetal ultrasound by around 18 to 22 weeks of conception.

Figure 281.2.— Characteristic ultrasonographic features of agenesis of the corpus callosum. Top row: brain ultrasound; bottom row: MRI.



Facial Weakness


Facial Nerve Branch Lesions

Facial nerve branch lesions may involve one branch or a combination of the five major branches. The branch most often involved is the mandibular branch (Figure 184.1).

A B

Figure 184.1.— Mandibular branch lesion. [A] Asymmetrical facial grimacing involving the lower facial quadrant. [B] No asymmetry during sleep.

Mandibular branch deficits produce complete weakness of the depressor labii inferioris, mentalis, and transversus menti muscles, and incomplete weakness of the depressor anguli oris muscle (Figure 184.2). The depressor anguli oris muscle is innervated by two branches: the mandibular branch and

the buccal branch (Figure 184.2). In a mandibular branch lesion the lips will deviate to the opposite side when crying. The lips stay closer together on the side of the lesion than on the normal side. Mandibular branch deficits may be difficult to distinguish from absence of the depressor angularis oris but usually with mandibular branch injury other signs of trauma are present (Figure 184.1) and often the asymmetry improves in a few days.


Facial Weakness

Figure 184.2.— Anatomical localizations of injuries in the facial motor system. T: thalamus; IAC: internal auditory canal; FC: facial canal; SMO: styloidmastoid orifice; BB: buccal branch; MB: mandibular branch; TB: temporal branch; OOM: orbicularis oculi muscle; RM: risorius muscle; DAOM: depressor angularis oris muscle; BM: buccinator muscle; MM: mentoris muscle. Light blue line indicates components of the facial nerve that has ipsilateral (hence bilateral) cortical innervation; dark blue line indicates components of the facial nerve that have contralateral innervation. A: cerebral lesion above the thalamus; B: cerebral lesion below the thalamus and above the pons; C: pontine lesion; D: facial nerve; E: mandibular branch lesion; F: depressor angularis oris muscle.

Temporal branch deficits produce facial upper quadrant weakness. The

weakness is only apparent when the neonate cries.

A B


Facial Weakness

Figure 184.3.— Temporal branch lesion. [A] No asymmetry during sleep. [B] Asymmetrical facial grimacing involving the upper facial quadrant.

Facial nerve branch lesions may be associated with brachial plexus

injury and signs of facial trauma. The diagnosis is confirmed by finding fibrillations and positive sharp waves in the affected muscles 12 to 14 days after the injury. Facial nerve branch lesions also produce delayed conduction or a conduction block in the affected branch with normal findings in other

muscles innervated by other branches. Facial nerve branch lesions are due to trauma and usually do not require treatment.





Lissencephaly

Neonates with lissencephaly may present with seizures. The brain of a patient with lissencephaly shows a smooth cortical surface. Pathological examination of the brain surface in patients with lissencephaly may show agyria (absence of gyri) or pachygyria (few broad and flat gyri) or polymicroglia. Lissencephaly are classified into types I, II, III, and IV,

based on the morphology of the brain and associated brain anomalies. The only common finding among the different types of lissencephaly is that the brain surface looks smooth. Lissencephaly is diagnosed by CT or MRI of the brain. Magnetic resonance imaging is the study of choice.

Lissencephaly type I

Lissencephaly type I results from a complete arrest of cortical neuronal migration between 12- and 16-weeks gestation (Figure 47.1 [A]). The MRI of the brain has a figure-8 appearance on axial images (Figure 47.1 [A]). This appearance results from the smooth brain surface, the large and vertically placed Sylvian fissure, the hypoplastic operculum, and enlarged ventricles. The MRI of the brain also shows that the cerebral cortex has 2 bands of cortical gray matter (Figure 47.1 [A]), an outer layer that is thin and an inner layer that is thick. The outer and inner layers are separated by a zone of white matter. Cerebral anomalies often associated with lyssencephaly type I are hypoplasia of the corpus callosum, colpocephaly (enlargement of the occipital horns of the lateral ventricles), and brainstem

hypoplasia. The cerebellum and third and fourth ventricles are normal. Neonates with lissencephaly type I do not have ocular or muscle abnormalities.

Lyssencephaly type I may occur as: (1) isolated lissencephaly syndrome (no specific dysmorphysm); (2) Miller-Dieker syndrome (specific dysmorphysm and deletion of the distal part of the short arm of chromosome 17); and (3) Norman-Robert syndrome (dysmorphic features but no chromosome 17 abnormality). Miller-Dieker syndrome is probably the most common.

Miller-Dieker syndrome

Neonates with Miller-Dieker syndrome have characteristic facial features: microcephaly with bitemporal narrowing, vertical ridging and furrowing in the central forehead (especially when crying), small nose



with antiverted nostrils, upslanting palpebral fissures, protuberant upper lip, thin vermilion border of upper lip, and micrognathia (Figure 47.1 [B]).

A deletion in the p13 region of chromosome 17 is present in patients

with Miller-Dieker syndrome. Parents of patients with Miller-Dieker syndrome should undergo genetic evaluation to determine whether they are carriers of a balance translocation of the terminal fragment of chromosome 17 onto a chromosome in the 13-15 group.

A B

Figure 47.1.— Miller-Dieker syndrome. [A] T1-weighted MRI axial image demonstrates the typical figure-8 appearance. The cortical surface is smooth with no secondary sulci. Thin outer cortical band separated from a thick inner cortical band by a zone of white matter (best appreciated in the regions of the sylvian groove). [B] Facial characteristics of Miller-Dieker syndrome.





Aicardi syndrome occurs only in females and consists of absence of the

corpus callosum, subcortical and periventricular heterotopias, and lacunar chorioretinopathy (Figure 52.1). Neonates with seizures due to neuronal heterotopia should be treated with antiepileptic drugs. Surgical treatment should be considered if neuronal heterotopia is localized. More about...281

A B C

Figure 52.1.— Aicardi syndrome. [A] Midline T1 sagittal MRI of the brain demonstrates agenesis of the corpus callosum, interhemispheric cyst, large occipital ventricle; [B] T1 axial MRI of the brain demonstrates colpocephaly and loculated interhemispheric cyst; [C] lacunar chorioretinopathy (no hyperpigmentation spot inside the punched out-white-yellow areas).

Intracranial Hemorrhage

Intracranial hemorrhage may produce seizures. Intracranial hemorrhage may be due to trauma, infarct, coagulation disturbances, vascular defects, or cerebral tumors. Coagulation studies, including CBC with differential and platelets, prothrombin time, partial thromboplastin time, fibrinogen index, and proteins S and C levels, should be performed. Intracranial hemorrhages are classified according to the location of the largest amount of blood as subdural, subarachnoid, parenchymal, and intraventricular. The age of the hematoma can be determined by analyzing the MRI appearance of the blood collection (Figure 52.2).



Figure 52.2.— MRI appearance of hemorrhage. This pattern of changes varies with location, source, pulse sequence, and field strength.



Macrocephaly


Glutaric aciduria type I Glutaric aciduria type I is a rare disorder. It is produced by glutaryl-coenzyme

A dehydrogenase deficiency. The deficiency of this enzyme leads to an error in the catabolism of lysine, hydroxylysine, and tryptophan. Glutaric acidemia has an autosomal recessive inheritance. Megalencephaly is usually present from birth. Most neonates with glutaric aciduria type I do not present with any neurological deficit. The neurological manifestations of glutaric acidemia type I consist of an acute encephalitis-like illness characterized by somnolence, irritability, and excessive sweating followed by slowly progressive signs of cerebral deterioration. In some patients, these acute manifestations do not occur. Instead, the disease starts as a slowly progressive central nervous system deterioration. Urine organic acid chromatogram shows an increase in glutaric acids (3-hydroxyglutaric and 3-hydroxybutyric) and acetoacetic acids. The diagnosis is

established by glutaryl-coenzyme A dehydrogenase deficiency in fibroblasts.

Canavan disease Canavan disease usually presents with rapid head growth during the first

weeks of life, marked hypotonia, and nystagmus. The diagnosis is suspected by finding increased levels of N-acetylaspartic acid in urine and is confirmed by

demonstrating decreased aspartoacetylcase activity in cultured fibroblasts.

Alexander disease Alexander disease may present with macrocephaly in the neonatal period. The

disease should be suspected if MRI of the brain shows white matter disease with frontal predominance. Brain biopsy shows fibrillary astrocytes with eosinophilic deposits (Rosenthal fibers).

Brain Tumors The most common neonatal tumors are teratomas (Figure 288.1),

astrocytomas, and choroid plexus papilloma. Most neonatal brain tumors are midline and supratentorial. Brain tumors may produce macrocephaly due to their large size or due to hydrocephalus. Hydrocephalus may be noncommunicating due to obstruction of cerebrospinal fluid flow inside the ventricular system, or communicating due to excessive production of cerebrospinal fluid in choroid plexus papilloma. In addition to macrocephaly, brain tumors in neonates may present with lethargy, feeding difficulty, vomiting, bulging anterior fontanelle, hemiparesis, and seizures. Seizures usually imply that bleeding has occurred.


Macrocephaly

Brain tumors are more frequent in neonates with neurofibromatosis type I (optic gliomas), tuberous sclerosis (giant cell astrocytoma), or with hepatic and renal tumors (primitive neuroectodermal tumor) than in the general population. More about... 46, 257

A B C

Figure 288.1.— MRI of the brain demonstrating a large teratoma. The tumor involves the left optic nerve.





ERRORS OF PROTEIN METABOLISM THAT INVOLVE THE

LEUCINE PATHWAY

The errors of protein metabolism that involve the leucine pathway are: (1) maple syrup urine disease (MSUD), (2) dihydrolipoyl dehydrogenase deficiency, (3) isovaleric acidemia, (4) glutaric acidemia type II, (5) multiple carboxylase deficiency, and (6) hydroxymethylglutarate-CoA lyase.

Branched chain beta-keto acid dehydrogenase deficiency

A block in the metabolism of leucine due to branched chain beta-keto acid dehydrogenase deficiency occurs in MSUD and in dihydrolipoyl dehydrogenase deficiency (Figure 72.1 A, B).

Figure 72.1.— Leucine pathway showing different enzymatic blocks and the amino acids that increase as a result of the block. A: maple syrup urine disease; B: dihydrolipoyl dehydrogenase deficiency; C: isovaleric acidemia; D: glutaric acidemia type II; E: multiple carboxylase



deficiency; F: HMG-CoA lyase deficiency.

Maple syrup urine disease

Maple syrup urine disease combines a block in leucine metabolism with blocks in the metabolism of isoleucine and valine (Figure 72.2 A).


Three findings may suggest MSUD prior to the serum amino acid result: (1) a burnt sugar smell in the urine; (2) an interictal EEG with runs of 5 to 7 Hz monophasic, central, or parasagittal negative activity during awake or

sleep ; or (3) a brain imaging study showing dorsal brainstem edema (Figure 72.3).

A B



Figure 72.3.— MRI demonstrating brainstem edema in a neonate with maple syrup urine disease.



Generalized hypotonia


CAUSES OF HYPOTONIA

Generalized hypotonia occurs with neuromuscular disorders, systemic illnesses, and connective tissue abnormalities.

Neuromuscular Disorders Neuromuscular disorders are the most frequent causes of generalized

hypotonia. Neuromuscular disorders produce generalized hypotonia by decreasing the spring-like properties of the striated muscle fiber. A decrease in the spring-like properties of the striated muscle fiber results from a physical or functional disruption of the contractile elements of the muscle fiber (muscle pathology) or from abnormal neurological input to the muscle contractile elements (nervous system pathology).

Nervous system pathology localized at different levels of the neuroaxis may produce hypotonia. Nervous system pathology involves structures that either convey information to the alpha motor neurons, convey information from the alpha motor neurons to the muscles, or both.

The axons of the alpha motor neurons become the motor nerve fibers that ultimately synapse with the striated muscle fibers at the myoneural junction. The term lower motor neuron (Figure 92.1) will be used to refer to the alpha motor neurons in the anterior horn of the spinal cord and in cranial nerve motor nuclei, their axons, and terminal endings (presynaptic region of the myoneural junction). The terms alpha motor neuron and lower motor neuron are interchangeable.

Figure 92.1.— Schematic representation of the lower motor neuron. 1: alpha motor neuron; 2: axon; 3: presynaptic region of the myoneural junction.



The term motor unit refers to the lower motor neuron and the muscle fibers (extrafusal) that it innervates (Figure 92.2).

Figure 92.2.— Schematic representation of the motor unit. 1: alpha motor neuron; 2: axon; 3: presynaptic region of the myoneural junction; 4: extrafusal muscle fiber.





The sites of pathology in neonates with hypotonia and decreased

dynamic tone are the brain, brainstem, cerebellum, rostral spinal cord, anterior horn cell, nerve, presynaptic-myoneural junction, postsynaptic-myoneural junction, muscle, or a combination of these sites (Figure 99.1). The distinction among them can sometimes be made based on associated neurological findings: seizures, weakness of facial muscles, increased facial dynamic tone, parasympathetic pupil abnormalities, lack of bowel movements, and anal sphincter weakness.

Figure 99.1.— Schematic representation of the possible sites of neuromuscular involvement in neonates with hypotonia and decreased or normal dynamic tone: (1) brain; (2) brainstem; (3) rostral spinal cord; (4) lower cervical spinal cord (5) cerebellum; (6) alpha motor neuron; (7) nerve; (8) presynaptic-myoneural junction; (9) postsynaptic-myoneural junction; (10) muscle. Green broken line implies myelin of Scwann cell origin. Orange-yellow broken line implies myelin of oligodendrocite origin.

Neonates with hypotonia and normal dynamic tone are likely to have an upper motor neuron system dysfunction but certain diseases of the motor-



sensory unit, such as myasthenia gravis and some myopathies, have normal dynamic tone.





ERRORS OF PROTEIN METABOLISM

The cornerstone of the diagnosis of most of the inborn errors of protein metabolism that occur in neonates is knowing the metabolic pathway of leucine and remembering the amino acids that become elevated after each metabolic block (Figure 71.1). If all the metabolites of the leucine pathway are within normal limits, six of the most common inborn errors of protein metabolism that produce coma in the neonatal period can be excluded. The errors of protein metabolism that involve the leucine pathway are: (1) maple syrup urine disease (MSUD), (2) dihydrolipoyl dehydrogenase deficiency, (3) isovaleric acidemia, (4) glutaric acidemia type II, (5) multiple carboxylase deficiency, and (6) hydroxymethylglutarate-CoA lyase. Glycine encephalopathy, propionic and methylmalonic acidemia, and sulfite oxidase deficiency can occur in the neonatal period but they do not involve the leucine pathway and cannot be excluded by evaluating leucine metabolism. They are excluded if cerebrospinal fluid amino acids, blood amino and organic acids, urine organic acids, and urine sulfite are

normal.



Figure 71.1.— Leucine pathway showing different enzymatic blocks and the amino acids that increase as a result of the block. A: maple syrup urine disease; B: dihydrolipoyl dehydrogenase deficiency; C: isovaleric acidemia; D: glutaric acidemia type II; E: multiple carboxylase deficiency; F: hydroxymethylglutarate (HMG)-CoA lyase deficiency.





AMNIOTIC BANDS

Amniotic bands may involve the brachial plexus although more frequently they affect the peripheral nerves. Physical examination should include separating the skin folds to search for amniotic bands. The possibility of surgical intervention should be considered if there is a conduction block under the amniotic band.

HEMANGIOMA INVOLVING THE BRACHIAL PLEXUS

Neonatal hemangiomatosis may be associated with brachial plexus palsy. Brachial plexus palsy results from compression of the brachial

plexus by a hemangioma.

HUMERAL OSTEOMYELITIS

Brachial plexus palsy is a rare presentation of late-onset group-Β streptococcal osteomyelitis. Evidence of brachial plexus involvement has been documented by electromyographic findings. The mechanism of injury is probably ischemia. Weakness resolves with treatment of the

infection.

COSTAL EXOSTOSIS

Exostosis of the first rib is an unusual cause of brachial plexus palsy in the neonatal period. The mechanism of injury is probably compression of

the brachial plexus by the bone tumor.

NECK COMPRESSION

Brachial plexus palsy may result from compression of the brachial plexus at the level of the neck by a positive pressure apparatus.

TUMOR

Brachial plexus palsy may be due to neoplastic involvement of the plexus. In the two reported cases, weakness was noted a few days after



birth and had a progressive course. A mass at the level of the neck was present in one patient. The tumor was considered a rhabdomyosarcoma

(Figure 265.1) in one patient and a plexiform neuroma in the other.

A B

Figure 265.1.— [A] Large neck mass. [B] MRI of the cervical spine demonstrating a large mass compressing the plexus.

CAUDA EQUINA LESION

Lesions in the cauda equina region are caused by tumors or spinal dysraphysm. Magnetic resonance imaging is the investigation of choice for this area (Figure 265.2). Spinal cord dysraphysms are usually associated with cutaneous stigmata.

Figure 265.2— MRI of the spine demonstrates a lipoma of the conus medullaris and the cauda equina.



Arthrogryposis Multiplex Congenita


Marden-Walker Syndrome

Marden-Walker syndrome or cerebro-oculo-facio-skeletal syndrome is characterized by the presence of a fixed facial expression, blepharophinosis, micrognathia, and multiple joint contractures from birth. Brain and posterior fossa malformations are frequent. Dandy-Walker abnormality and brainstem hypotonia may occur. It is an autosomal

recessive condition.

SPINAL CORD

Amyoplasia Congenita Neonates with amyoplasia congenita are fullterm and of average weight.

They appear healthy. They may have a round face, short upturned nostrils, and micrognathia (Figure 162.1 [A]). A midface capillary hemangioma is often present. They have multiple symmetrical fixed joints with typical positions and distribution. The limbs are cylindrical and fingers are slender. The upper extremity position is most characteristic. The shoulders are adducted and medially rotated, elbows are extended or flexed, forearm is pronated, wrists are flexed and have ulnar deviation, and the fingers are flexed. The upper extremity posture, except in neonates with flexed elbows, resembles that which occurs in patients with brachial plexus palsy involving the upper trunk. The lower extremities are less frequently involved. When involved, the lower extremities are flexed at the hips, knees are flexed or extended, and the feet are in equinovarus or calcaneovalgus positions (Figure 162.1 [B]).

A B

Figure 162.1— Amyoplasia congenita. [A] Typical facial appearance. [B]



Abnormal position of the limbs.





Antley-Bixler Syndrome

Antley-Bixler syndrome should be considered in a neonate with dysmorphic facial features (Figure 154.1 [A]), especially if they cannot breathe through the nose (choanal atresia). The diagnosis is confirmed by conventional radiographs demonstrating bony abnormalities, especially in the presence of radiohumeral synostosis and femoral bowing. Arthrogryposis involves the fingers, wrist, elbows (Figure 154.1 [B]), hips, and ankles. Patients with Antley-Bixler syndrome may die during the neonatal period because of choanal atresia. Survivors have normal intelligence. Contractures improve with age. This syndrome is probably an

autosomal recessive disorder.

A B

Figure 154.1.— Antley-Bixler syndrome. [A] Facial features: brachycephaly, prominent frontal bossing, dysplastic ears, midfacial hypoplasia, depressed nasal bridge, and proptosis; [B] arthrogryposis of the elbows.

Diastrophic dysplasia

Diastrophic means crooked. Neonates with diastrophic dysplasia are short and the limbs are crooked (Figure 154.2). Diastrophic dysplasia may be associated with respiratory obstruction due to laryngeal stenosis. Death may occur due to obstructive apnea.



Figure 154.2.— Diastrophic dysplasia. Arthrogryposis of both feet.





CAUSES OF SEIZURES THAT REQUIRE ANTIEPILEPTIC DRUGS

Bacterial Meningitis The presence of bacterial meningitis is suspected on clinical grounds.

Bacterial meningitis is tentatively diagnosed by an abnormal cerebrospinal fluid cell count, sugar level, and protein concentration, and the detection of antigen in the cerebrospinal fluid. Bacterial meningitis is conclusively diagnosed by cerebrospinal fluid Gram-stained smear and culture. Meningitis usually occurs with late-onset (after 7 days) sepsis. Seizures may be the first sign of meningitis. Neonates with bacterial meningitis are usually lethargic after the seizures. The anterior fontanel may be bulging. Neck rigidity may be present. Seizures in neonates with meningitis are usually due to microscopic or macroscopic ischemic vascular parenchymal lesions but the possibility of hypocalcemia, hypoglycemia, hyponatremia, abscess, and subdural empyema should be considered. The organisms usually associated with bacterial meningitis are group B streptococcus, Escherichia coli, Listeria monocytogenes, Staphylococcus aureus, and

Pseudomonas aeruginosa.

The tentative diagnosis of bacterial meningitis should be made in neonates with seizures if the cerebrospinal fluid shows less than 100 red blood cells per cubic millimeter and more than 11 white blood cells per cubic millimeter (90% of neonates without meningitis have 11 white blood

cells per cubic millimeter or less) or if organisms are present in the Gram-stained smear. Neonates with seizures having any of these parameters should be treated with antibiotics while awaiting the results of the CSF culture. These patients should undergo a careful physical examination searching for a primary source of infection such as otitis media, arthritis, or skin infection.

For practical purposes, a negative cerebrospinal fluid culture eliminates the possibility of bacterial meningitis if the Gram-stained smear is also negative and the patient did not receive antibiotics before the lumbar puncture. If a cerebrospinal fluid culture is negative but the Gram-stained smear is positive, or the patient received antibiotic treatment before the lumbar puncture was done, a full course of antibiotics should be administered.



An MRI of the brain should be performed when the patient is stable or if deterioration occurs after initiation of treatment or fever persists after several days of the appropriate antibiotic treatment. Deterioration raises the possibility of localized intracranial infection. Localized intracranial

infections include brain abcesses, subdural empyema, and ventriculitis.

The choice of antibiotics depends on the type of organism isolated and its sensitivity. Prior to isolation of the organism, treatment should be initiated with ampicillin and gentamicin.

Ampicillin is given at a dose of 100 to 150 mg/kg every 12 hours in the first 7 days of life and 150 to 200 mg/kg every 8 hours thereafter.



Microcephaly


Neonates with fetal alcohol syndrome are usually jittery. Seizures are

not frequent except in neonates with midline prosencephalic abnormalities. Midline prosencephalic abnormalities are agenesis of the corpus callosum, septo-optic dysplasia, and holoprosencephaly. Other brain malformations that occur in fetal alcohol syndrome are errors in neuronal and glial proliferation and neuronal migration. Intelligence quotient tends to correlate with dysmorphic features—the more dysmorphic, the more delayed. An EEG pattern characterized by excessive hypersynchronicity has been reported. Cardiac septal defect occurs in about half of these

patients.

Anticonvulsant Fetal Syndrome The maternal use of anticonvulsant drugs during pregnancy, especially

phenytoin, phenobarbital, or primidone, may produce congenital microcephaly. Carbamezapine and valproic acid have been involved in producing fetal malformation syndromes, but microcephaly is not one of their major features. Neonates with fetal exposure to anticonvulsant drugs often have characteristic facies. Their most salient features include large fontanelles, metopic suture ridging, ocular hypertelorism, epicanthal folds, broad nasal bridge, and hypoplasia of the distal phalanges and nails. Bifid or shawl scrotum, cardiac abnormalities, and cleft lip and palate may also occur. The teratogenic effect of these drugs may be related to their conversion to their epoxide compounds and the inability of the fetal liver to transform them. Patients with fetal anticonvulsant syndrome are developmentally delayed. The diagnosis is made by maternal history of

anticonvulsant drug intake during pregnancy.





Benign Nonfamilial Neonatal Convulsions

The diagnosis of benign nonfamilial neonatal convulsions should be reserved for neonates with characteristics similar to those listed for benign familial convulsions but without a positive family history.

Cryptogenic Neonatal Seizures Cryptogenic neonatal seizures is a term used for seizures that occur in a

neonate with an abnormal neurological examination but with no established cause for the seizures. Many neonates with cryptogenic seizures demonstrate a characteristic EEG pattern that consists of bursts of high-voltage activity followed by periods of attenuation. The diagnosis of Otahara syndrome is given to neonates with seizures and this characteristic EEG pattern. Neonates with Otahara syndrome may have cryptogenic neonatal seizures or seizures with a demonstrable etiology. The possibility of migrational errors or obscure metabolic diseases should be considered in neonates with Otahara syndrome.

ANTIEPILEPTIC TREATMENT OF CONVULSIONS

Antiepileptic drugs and etiological treatment stop seizures by preventing massive repetitive and synchronous neuronal depolarization. During depolarization, the voltage-dependent sodium channels open and sodium enters the cell driven by its concentration (there is more sodium outside the cell than inside the cell) and electrical gradients (there are more negative charges than positive charges adjacent to the inner surface of the membrane). When the inner side of the membrane is flooded with enough positive ions to decrease its normal negativity above the threshold of the voltage-dependent sodium channels, these channels will open. Medications that maintain the inner membrane surface and prevent it from reaching the threshold of the voltage-dependent sodium channel prevent seizures.





BRAIN ARTERIAL INFARCTS

Brain arterial infarcts are produced by hypoperfusion, embolic or thrombotic phenomena, or vasospasm (pathogenesis).

Arterial infarcts due to cerebral hypoperfusion Cerebral hypoperfusion is the most frequent cause of cerebral arterial

infarcts. Cerebral hypoperfusion is due to systemic hypotension. Episodes of systemic hypotension lead to ischemia in the distribution of a given arterial territory. The local ischemia leads to cerebral infarct. Cerebral hypoperfusion produces border zone infarcts in premature and fullterm neonates.

Arterial infarcts due to cerebral embolism

Cerebral embolic infarcts are more common than thrombotic infarcts. The embolic material may arise from the placenta, heart, carotid artery (Figure 245.1), or from the vein in the lower extremities in neonates with

right-to-left shunt.

A B C

Figure 245.1.— [A] MRI of the brain demonstrating a large infarct in the distribution of the left middle cerebral artery; [B] B-mode ultrasonography demonstrating a thrombus at the origin of the internal carotid artery; [C] MRA of the brain demonstrating a narrow internal carotid artery and absence of the middle cerebral artery.



Arterial infarcts due to cerebral artery thrombosis

Thrombotic arterial infarcts may occur with hypercoagulation states such as proteins C and S deficiencies, antithrombin III deficiency, or the presence of Factor V-Leiden, anticardiolipins, and antiphospholipids antibodies. Protein C is a glycoprotein that inhibits factors V and VIII. Protein S is a glycoprotein that serves as a cofactor for protein C. The excess of factors V and VIII that occurs with proteins C and S deficiencies, and the excess of thrombin that occurs with antithrombin III deficiency,

leads to thromboembolic phenomena. Factor V-Leiden is a mutated Factor V. The mutation consists of the substitution of the right aminoacid at a key position by the wrong aminoacid. The consequence of this substitution is that it renders Factor V (called Factor V-Leiden) resistant to

protein C inactivation. The mechanism of thrombosis in neonates with anticardiolipins and antiphospholipids is not known. Polycythemia and dehydration can also produce thrombotic arterial infarcts.

Arterial infarcts due to cerebral vasospasmodic phenomena

Vasospasmodic arterial infarcts occur in neonates exposed to cocaine and maternal hypertension during pregnancy.





APLASIA CUTIS CONGENITA

The hallmark of aplasia cutis congenita in the neonatal period is the presence of a solitary well-demarcated skin punch-out lesion (Figure 305.1). Multiple lesions may also occur. Aplasia cutis congenita must be differentiated from traumatic cutaneous lesions (fetal monitor injuries). Aplasia cutis congenita may be isolated or it may occur with Trisomy 13, 4p-syndrome, ectodermal dysplasia, and amniotic bands. Aplasia cutis in the hair whirl area is usually a benign finding. Neonates with aplasia cutis congenita in the craniofacial and lumbosacral regions should have an MRI or ultrasound to evaluate the central nervous system structures below it. Isolated aplasia cutis congenita is usually sporadic.

Figure 305.1.— Typical punch-out lesion of aplasia cutis congenita in the lumbar region.



Apnea


Pathological respiratory consequences are hypoxia manifested by a drop in oxygen saturation below 80% (Figure 17.1) and hypercapnia. Pathological cardiovascular changes are bradycardia manifested by a 20% drop below baseline (Figure 17.1), tachycardia, arrhythmia, asystole, and arterial hypotension or hypertension. Pathological neurological findings are lethargy, seizures, and hypotonia.

Obstructive-central respiratory pauses are not usually seen in normal neonates, hence they are considered apnea regarless of the absence of any other parameter.

Respiratory pauses without pathological consequence lasting from 10 to 19 seconds in a premature infant, or from 10 to 15 seconds in a fullterm neonate are considered apnea if they add up to more than 2 minutes per hour.

Periodic breathing refers to respiratory pauses lasting from 3 to 10 seconds without pathological consequences, interrupted by at least 5 periods of normal breathing lasting less than 5 seconds each. Periodic breathing is abnormal if it occupies more than 3% of the recording time in a fullterm infant.


Apnea

Figure 17.1.— Central apnea (cessation of airflow at the nose and mouth, and absence of thoracic and abdominal movements). Sleep stage: quiet sleep (tracé alternant and regular respiration), bradycardia and desaturation.



Apnea


Apnea of prematurity is diagnosed based on clinical grounds in

premature neonates after systemic and pulmonary causes of apnea have been excluded. Auditory brainstem evoked responses are delayed in a large number of premature neonates with apnea. A brainstem conduction showing a III to V interpeak latency below 5.6 milliseconds usually

coincides with resolution of apnea in neonates. Treatment of apnea of prematurity includes stimulation, pharmacologic intervention (caffeine or theophylline), continuous positive airway pressure, and mechanical ventilation. The usual loading dose of caffeine citrate is 20 mg/kg followed by a maintenance dose of 5 mg/kg per day beginning 24 hours after the loading dose. The usual loading dose of theophylline is 5 mg/kg followed

by 1.5 to 2 mg/kg every 8 hours.

Congenital hypoventilation syndrome produces hypoxemia, especially during quiet sleep, even in the absence of apnea. Apnea is central and occurs predominantly during quiet sleep. Congenital central hypoventilation syndrome is a diagnosis of exclusion. Congenital hypoventilation syndrome may be associated with Hirshprung disease. The diagnosis is supported by the presence of sustained hypoxia during quiet

sleep. Central hypoventilation syndrome may improve with doxapram but tracheostomy with mechanical ventilation or a

diaphragmatic pacemaker are usually requiered.

Apnea in startle disease (hyperekplexia) occurs during spontaneous or provoked episodes of generalized stiffening. Episodes of stiffening may be provoked by noise or touch. Tapping the nose is particularly likely to produce an apneic episode in neonates with startle disease. Apnea in neonates with startle disease stops with forced flexion of the neck and legs

towards the trunk.

Feeding apnea is diagnosed clinically. Feeding apnea may be central, obstructive, or mixed. It occurs during feeding in preterm and term neonates and is controlled by frequent interruption during feeding. Feeding apnea is probably due to lack of coordination between breathing and

swallowing mechanisms in the brainstem.



Apnea


Neuropathies are rare in neonates. A bilateral lesion involving either

cranial nerve V or XII may produce obstructive apnea. Bilateral phrenic nerve injuries produce central apnea. Bilateral phrenic nerve injury may occur with bilateral brachial plexus injuries.

Myoneural junction disorders are common in the neonatal period. Botulism and transient myasthenia gravis are the most common neuromuscular disorders that affect the myoneural junction in neonates. Botulism affects the presynaptic area preventing the normal release of acetylcholine. Botulism produces signs of smooth and striated muscle dysfunction. Smooth muscle dysfunction leads to constipation and pupillary abnormalities. Striated muscle dysfunction leads to weakness and hypotonia. Myasthenia gravis is a postsynaptic disease. It affects the nicotinic receptors of the striated muscle. Myasthenia gravis presents with weakness and hypotonia but no evidence of autonomic dysfunction.

Muscle disease may produce apnea. Neonates with myotonic dystrophy often need prolonged respiratory support in the neonatal period because of frequent apnea. Myotonic dystrophy is diagnosed by shaking hands with the mother. A mother with myotonic dystrophy has difficulty performing maneuvers that require muscle relaxation after a muscle contraction such

as releasing one’s hand after a handshake.

NONNEUROLOGICAL CAUSES OF APNEA

Apneic episodes of nonneurological cause are more frequent than apnea of neurologic origin. Nonneurologic causes of apnea are gastroesophageal reflux, upper airway abnormality, systemic illness, and pulmonary disease.



Apnea


INDICATIONS FOR MONITORING

The use of apnea monitors decreases mortality in high-

risk infants. There are no indisputable indications for the use of monitors in neonates. We suggest to send the following neonates home on apnea monitors: (1) those with an apparent or confirmed life-threatening episode if the etiology is unknown, unresolved, or likely to recur; (2) those with a sibling who died of sudden infant death syndrome; (3) premature neonates with persistent apnea at the time of discharge; and (4) those who go home on respiratory stimulants, medications for gastroesophageal reflux, oxygen for chronic lung disease, or with a tracheostomy. The use of monitors for premature neonates without apnea or with few apneic episodes shortly after birth is controversial. Some neurologists believe that all premature neonates should go home on a monitor while others believe that if no apnea occurs for 1 week prior to discharge they should go home without a monitor. The latter position is supported by a consensus

statement from the National Institutes of Health.

Regarding the duration of the monitoring period, we suggest that: (1) neonates with an apparent or confirmed life-threatening episode should be monitored until they are free of events for at least 3 months and are at least 6 months of age; (2) siblings of infants who died of sudden infant death syndrome should be monitored for at least 6 months and until 1 month after the age at which the sibling died; (3) infants with apnea of prematurity should be monitored until their conceptional age is at least 52 weeks and they have not had apnea for at least 1 month after all respiratory stimulants and gastroesophageal reflux medications have been stopped.

The apnea alarm is set at 20 seconds for all ages. The high heart rate alarm is set at 230 beats per minute. The setting of the low heart rate alarm will change according to conceptional age. The low heart rate alarm for neonates less than 40 weeks conceptional age is set at 80 beats per minute; for neonates between 40 and 48 weeks conceptional age, 70 beats per minute; and for neonates older than 48 weeks conceptional age, 60 beats per minute.



Apnea


Apnea Due to Systemic Illness Apnea is a frequent complication of systemic illness in neonates.

Infections, anemia, patent ductus arteriosus, inborn errors of metabolism, hypoglycemia, hypermagnesemia, and many other conditions may present with apnea in the neonatal period. Systemic illnesses usually produce central apnea.

Apnea Due to Pulmonary Disease Pulmonary disease may produce prolonged expiratory apnea. Prolonged

expiratory apnea is characterized by absence of airflow into the lungs in the absence of upper airway obstruction despite effective inspiratory and expiratory chest and abdominal movements judged by esophageal pressure changes. The apnea occurs during wakefulness (crying and feeding) or

during sleep. The apnea as it appears on polysomnogram is obstructive. Bilateral pneumothorax and pneumonia may be associated with apnea.



Apnea


The diagnosis of Dandy-Walker malformation is established by MRI of the brain (Figure 29.1). The fourth ventricle is markedly dilated. The vermis is small and compressed by the dilated fourth ventricle. The posterior fossa is large, the occipital bone protrudes backwards, and the tentorium is raised. Brainstem hypoplasia is present. Dandy-Walker malformation may be associated with dysgenesis of the corpus callosum, neuronal migration abnormalities, and other central nervous system anomalies. Treatment of Dandy-Walker malformation is surgical.

A B

Figure 29.1.— [A] Large posterior fossa with ventral compression of the brainstem; [B] absence of the cerebellar vermis.


Apnea

Miller-Dieker syndrome usually presents with seizures. Apnea may

occur during a seizure or because of brainstem abnormalities.

Microscopic or Functional Brainstem Abnormality Neonates with microscopic or functional brainstem abnormalities do not

show evidence of brainstem abnormalities on MRI, yet the pathology is suspected to be in the brainstem. These abnormalities include apnea of prematurity, idiopathic hypoventilation syndrome, startle disease, and feeding apneas.

Apnea of prematurity is a common entity. Neonates with apnea of

prematurity usually have signs of global immaturity. Apnea occurs most frequently during active sleep. The apnea may be central, obstructive, or

mixed. Excessive periodic breathing is usually present.



Apnea


Mixed apnea has the polysomnographic characteristics of central and obstructive apnea in the same event (Figure 21.1). Mixed apnea is usually central-obstructive. Obstructive-central apnea is very rare, except as terminal events.

Figure 21.1.— Mixed (central-obstructive) apnea . Left-sided electroencephalographic seizure. The apnea is associated with tachycardia and desaturation.

The type of apnea does not have a strong correlation with the cause of the apnea nor with the location of the pathology. Neonates with myasthenia gravis may have central apnea if the diaphragmatic involvement predominates, or obstructive apnea if upper airway muscle involvement predominates. The apnea type offers a window to the pathophysiology of the apnea that, when analyzed in conjunction with other clinical and laboratory findings, contributes to the differentiation between neurological and nonneurological causes of apnea and among the different possible sites of neurological involvement.


Apnea


TYPE OF APNEA

Apnea may be central, obstructive, or mixed based on polysomnographic findings. This classification contributes to determine the possible sites of nervous system involvement (Figure 18.1). The classification is based on two factors: (1) nasal and oral airflow, and (2) chest and abdominal movements.

Figure 18.1— Sites of possible lesions producing central apnea. A: chemoreceptor; B: respiratory groups; C: cervico-medullary junction; D: anterior horn cells of the phrenic nerve; E: phrenic nerve; F: myoneural junction; G: diaphragm.



Apnea


Apnea Due to Gastroesophageal Reflux

Gastroesophageal reflux may produce apnea by causing a laryngospasm or by a reflex mechanism that involves the esophageal mucosa, the

superior laryngeal nerve, and the respiratory centers in the brainstem.

Laryngospasm should be suspected in an awake or asleep neonate with an obstructive episode within one hour of feeding. The episode consists of staring, rigid or opisthotonic posturing, and plethora followed by hypotonia and cyanosis or pallor. There is no coughing, choking, or gagging during the episode. The reflex-mediated apnea produced by gastroesophageal reflux is central, occurs during swallowing, and is associated with bradycardia.

Diagnosis of gastroesophageal reflux-induced apnea requires polysomnogram and pH probe. It is established by documenting pathological gastroesophageal reflux by pH probe recordings temporally associated with the apnea or by documenting that apnea only occurs during periods of low esophageal pH. A decrease in frequency of apnea after successful gastroesophageal reflux treatment confirms the diagnosis. Treatment consists of positioning the neonate upright while feeding, administration of oral antacid, and the use of sphincter-augmenting agents (metoclopramide). Thickening formula and frequent feeding are of

questionable value in neonates. Surgical treatment may be warranted.

Apnea Due to Upper Airway Abnormality Air on its way to the alveoli travels through the nose, pharynx, larynx,

and trachea. A structural obstruction at any level in this trajectory may produce apnea. Choanal atresia is an infrequent cause of apnea. It is easily diagnosed by finding no mist on the surface of a glass held close to the nostrils. Narrowing of the upper airway produces increased airflow turbulence resulting in excessive negative pressure that may collapse the

pharynx. Narrowing of the upper airway occurs with micrognathia (Figure 34.1), macroglossia, or even by mild anatomical upper-airway

abnormalities. Plexiform neuroblastoma should be considered in

neonates with narrow upper airway if café au lait spots are present.


Apnea

Figure 34.1.— Micrognathia.

The typical clinical presentation consists of noisy or laborious respirations preceding apnea. Facial dysmorphism may be present. Apnea due to upper airway abnormalities is obstructive, except for apnea due to choanal atresia which is central.



Macrocephaly


Aqueductal Stenosis The aqueduct of Sylvius is a narrow structure that allows

communication between the third and fourth ventricles. The cerebrospinal fluid produced in the choroid plexus of the lateral ventricles and the roof of the third ventricle travels through the aqueduct of Sylvius to reach the fourth ventricle on its way to the subarachnoid space. Congenital aqueduct of Sylvius stenosis or atresia may be sporadic or of X-linked inheritance. X-linked inheritance (Bickers-Adams syndrome) accounts for 2% of patients with aqueductal stenosis. Boys with Bickers-Adams syndrome

often have flexus adductus thumb deformity (Figure 293.1).

A B

Figure 293.1.— Bickers-Adams syndrome. [A] Macrocephaly due to aqueduct of Sylvius stenosis with bilateral cortical thumbs; [B] flexus adductus thumb deformity.

The head of patients with congenital aqueduct of Sylvius stenosis or

atresia is large from birth (Figure 293.2 [A]). Cesarean section is often required to because of cephalopelvic disproportion. There is usually frontal bossing, dilated scalp veins, and splitting of the sutures. Transillumination is positive in severe cases (Figure 293.2 [B]). The eyes may deviate downward. The diagnosis is established by MRI of the brain.

A B


Macrocephaly

Figure 293.2.— [A] Macrocephaly due to aqueduct of Sylvius stenosis; [B] transillumination of the same patient.

Aqueduct of Sylvius stenosis may also accur with meningitis.

Dandy-Walker Malformation Patients with Dandy-Walker malformation may present with

macrocephaly during the neonatal period. Macrocephaly during the neonatal period usually results from an enlarged posterior fossa (Figure 293.3).

A B

Figure 293.3.— [A] Large posterior fossa with ventral compression of the brainstem; [B] absence of the cerebellar vermis.

The large posterior fossa results in a dolichocephalic appearance which should be differentiated from dolichocephaly and bathrocephaly. Dolichocephaly (keel-shaped head) is due to sagittal suture synostosis. In neonates with premature closure of the sagittal suture synostosis most of the dolichocephalic appearance of the head is due to frontal prominence.


Macrocephaly

Bathrocephaly (step in the head) is a normal finding in the neonatal skull that disappears after a few months. Bathrocephaly is characterized by bulging of the interparietal part of the occipital bone. (Figure 293.4).

A B

Figure 293.4.— Bathrocephaly. [A] Lateral skull film demonstrating step-like elongation of the posterior aspect of the skull. [B] The occipital bone protrudes more posterior than the parietal bone.



Arm


The musculocutaneous nerves innervate the biceps brachialis,

brachialis, and coracobrachialis muscles. The main function of the biceps and brachialis muscles is to flex the forearm at the elbow (C5-C6). The median and the ulnar nerves innervate the muscles that flex the wrist and fingers. The median nerve innervates most of the flexors of the wrist except for the flexor carpi ulnaris. The flexor carpi ulnaris is innervated by the ulnar nerve. Flexion of the fifth and fourth fingers is carried out by muscles innervated by the ulnar nerve. Flexion of the second and middle fingers is carried out by the action of the median nerve. All intrinsic muscles of the hand, including the thumbs, are innervated by the ulnar nerve except for the abductor pollicis brevis, flexor pollicis brevis, opponent pollicis, and lumbricales I and II. These muscles are innervated by the median nerve. The radial nerve innervates the extensors of the forearms, wrist, and fingers (C5-C8). The radial nerve also innervates the brachioradialis muscle (C5-C6). The brachioradialis muscle flexes the forearm when the forearm is midposition between pronation and supination. The radial nerve innervates most of the muscles that supinate the forearm (C6-C7). The median nerve innervates the muscles that pronate the forearm (C6-C8).

The evaluation of a neonate with arm monoparesis follows the principles of neurological diagnosis: anatomical diagnosis followed by pathological diagnosis followed by etiological diagnosis. The anatomical diagnosis is made by determining if the weakness is due to an upper or lower motor neuron disorder. Pivotal to this distinction is the differentiation between spastic and flaccid arm weakness. Spastic arm monoparesis refers to a decreased frequency and strength of movements with increased stretch muscle reflexes and an exaggerated Moro reflex. Flaccid arm monoparesis refers to decreased frequency and strength of movement with decreased stretch muscle reflexes and diminished Moro response. Neonates with arm monoparesis, normal stretch muscle reflexes, and normal Moro reflex are likely to develop signs of spasticity. They should be evaluated as if they had spastic arm monoparesis.





Neonates with arthrogryposis multiplex congenita may have facial

dysmorphysm. Facial dysmorphysm and arthrogryposis multiplex congenita occur in many disorders including trisomy 13 and 18 syndromes, Pena-Shokeir I and II syndromes, Antley-Bixer syndrome, Sheldon-Fremann syndrome, Beals syndrome, Smith-Lemli-Opitz syndrome, and Zellweger syndrome.

Arthrogryposis may be caused by neurological or nonneurological causes. Neurological arthrogryposis multiplex congenita may be due to central or peripheral abnormalities. Nonneurological arthrogryposis multiplex congenita may be due to cartilaginous abnormalities or physical constraint from movement.

CARTILAGINOUS ABNORMALITIES

Cartilaginous abnormalities should be considered the cause of arthrogryposis multiplex congenita in neonates with any of the following characteristics: (1) long for gestational age, (2) hyperextensible and transparent skin, (3) blue sclera, (4) abnormal earlobe shape, and (5)

craniosynostosis. Intelligence is usually normal in patients with arthrogryposis multiplex congenita due to cartilaginous abnormalities. The mechanism that leads to arthrogryposis in patients with cartilaginous abnormalities is joint hyperelasticity combined with the normal restriction from movement imposed by intrauterine life. Arthrogryposis multiplex congenita improves with time. The most common entities that present arthrogryposis multiplex congenita due to cartilaginous abnormalities in the neonatal period are: (1) Beals syndrome, (2) Antley-Bixer syndrome, (3) diastrophic dysplasia, and (4) distal arthrogryposis.

Beals Syndrome Beals syndrome is a connective tissue disorder linked to a fibrillin locus

on chromosome 5q23-31 (FBN2). The most distinguishing features of Beals syndrome are crumpled ears and long slim limbs with long fingers. Patients with Beals syndrome may also have frontal bossing, short necks, spinal deformities, hypoplasia of the calf muscle, metatarsus varus, and talipes equinovarus. Arthrogryposis primarily involves the knees, elbows, and hands. Patients with Beals syndrome are neurologically normal. Beals

syndrome is an autosomal dominant entity.




BRAIN

Trisomy 13 Syndrome Trisomy 13 syndrome is characterized by microcephaly, posterior scalp

lesions, microphthalmia, cleft lip (Figure 157.1 [A]), coloboma of the iris, low-set dysplastic ears, deafness, cleft palate, polydactyly, typical trisomy 18 hands (Figure 157.1 [B]), prominent heels, cryptorchidism, and abnormal scrotum.

A B

Figure 157.1.— Trisomy 13 syndrome. [A] Typical facial features of trysomy 13 syndrome and [B] typical positions hands position of distal athrogryposis.

The most frequent central nervous system anomaly is holoprosencephaly (Figure 157.3). Holoprosencephaly may be alobar (fused thalami, no third ventricle, no interhemispheric fissure, no corpus callosum, an anteriorly displaced pancake-like mass of tissue, and a cresent-shaped holoventricle continuous with a large dorsal cyst), semilobar (partially separated thalami, small third ventricle, interhemispheric fissure present posteriorly, posterior corpus callosum present, normal occipital or temporal lobes, and a telencephalic ventricle that is continuous with a dorsal cyst) or lobar (hypoplastic anterior falx, hypoplastic frontal lobes, absence of the septum pellucidum but separated thalami, normal third ventricle, and present interhemispheric fissure and posterior corpus callosum). Full trisomy 13 occurs more often in neonates



born to older mothers. Translocation of chromosome 13 material produces a similar phenotype. The parents of an infant with translocation should have chromosomal studies because they may be asymptomatic carriers of a balance translocation. The chance of recurrence is higher if either parent is

a carrier of a balance translocation.

Figure 157.2.— CT scan of the brain demonstrates holoprosencephaly. Partially fused frontal lobes, partially formed interhemispheric fissure, and no third ventricle.





PHYSICAL CONSTRAINT FROM MOVEMENT

Arthrogryposis multiplex congenita due to physical constraint occurs when the capacity of the uterine cavity is small and asymmetric or when the fetus is affected by cutaneous bands that restrict limb movements. The capacity of the uterus may be restricted by oligohydramnios, anatomic malformations, amniotic bands, or uterine tumors. Thick cutaneous bands

that restrict fetal joint movements occur in Escobar syndrome.

Oligohydramnios sequence Oligohydramnios is the most frequent cause of arthrogryposis multiplex

due to physical constraint. A reduced uterine capacity places the fetus at risk for multiple anomalies in addition to arthrogryposis. The constellation of findings that occur as the result of decreased amniotic fluid is called oligohydramnios sequence. The characteristic features of oligohydramnios sequence are wrinkled skin; skin folds that extend from the inner canthus to the upper cheek; squashed nose; large, low-set and posteriorly rotated ears; short neck; and large wrinkled hands. Arthrogryposis usually involves the knees and the feet. The most frequent causes of oligohydramnios are placental insufficiency and premature rupture of membranes. Bilateral renal agenesis is a rare but severe cause of oligohydramnios often associated with arthrogryposis.

Escobar syndrome Escobar syndrome or multiple pterygia syndrome is characterized by

thick skin folds that produce an unusual appearance and keep the joints in a fixed position. The skin folds are usually in the neck, axilla, antecubital, popliteal, and digital areas. The thick skin folds reduce joint motility in utero and lead to arthrogryposis multiplex congenita. Arthrogryposis is especially marked in the hands. Intelligence is normal. Scoliosis often develops by five years of age. Escobar syndrome is an autosomal recessive condition. Surgical treatment of the pterygium may be necessary.

NEUROLOGICAL ABNORMALITIES

Neurological disorders should be suspected in any neonate without signs that suggest a cartilaginous abnormality, oligohydramnios sequence, or Escobar syndrome. Neurological abnormalities can be classified based



on the region of the nervous system most affected.





Mural or arterial wall abnormalities are due to vascular malformations,

thickening of the intima, or obliterative arteritis. Obliterative arteritis is probably the cause of cerebral infarcts in infants of cocaine-addicted mothers. Extramural abnormalities such as neoplasms can produce cerebral infarcts but they most frequently produce intracranial bleeding. Asphyxia may produce cerebral infarcts by a combination of endomural and mural factors. Neonates with cerebral infarct should be evaluated by obtaining MRI and MRA of the brain, carotid ultrasonogram, echocardiogram, EKG, CBC with differential and platelets, prothrombin time, partial thromboplastin time, fibrinogen splitting products, proteins S and C activity levels, antithrombine-III activity, antiphospholipid

antibody, urine for homocysteine, and factor-V Leiden polymerase chain

reaction (PCR). More about... 244

Hypoxic-Ischemic Encephalopathy The diagnosis of hypoxic-ischemic encephalopathy should be based on

clinical evidence of encephalopathy and perinatal asphyxia. Perinatal asphyxia is diagnosed in the presence of 3 or more of the following findings: (1) intrapartum distress (bradycardia with a heart rate of less than 100 beats per minute, late decelerations, or absence of beat-to-beat variability); (2) thick meconium-stained amniotic fluid, (3) an APGAR score of 6 or less at 5 minutes, (4) a need for resuscitation for more than 1 minute with positive pressure ventilation and oxygen immediately after birth, and (5) an arterial pH value of 7.20 or less or a base deficit of at least

14 mmol per liter within the first hour after birth. A minimal degree of encephalopathy produces lethargy and mild hypotonia with superimposed jitteriness. These findings, if lasting less than 24 hours, are very common after a traumatic delivery. Severe hypoxic-ischemic encephalopathies manifest as coma. Neonates with severe hypoxic-ischemic encephalopathies are hypotonic and have evidence of brainstem dysfunction. Asphyxia should be diagnosed if an event of hypotension and hypoxia is documented by clinical or laboratory findings. The presence of multi-organ involvement (high blood-urea nitrogen, creatine, and creatine phosphokinase) is often present in asphyxiated neonates. The degree of acidemia reflects the severity of the asphyxia. Computed tomography or MRI of the brain may initially demonstrate brain edema and, after 14 days, laminar cortical necrosis and status marmoratus (Figure 55.1).



A B

Figure 55.1.— Hypoxic ischemic encephalopathy. [A] T1- weighted sagittal image of the brain demonstrates laminar necrosis and diffuse hyperintensity of the basal ganglia and thalami. [B] T1- weighted axial image of the brain demonstrates laminar necrosis (especially in the occipital region) and diffuse hyperintensity of the thalami.



Microcephaly


Herpes Simplex Congenital microcephaly can occur due to transplacental transmission

of herpes simplex early during pregnancy. Neonates with congenital herpes simplex infection tend to be premature and often have chorioretinitis, microphthalmia, multicystic encephalomalacia, and cerebral calcifications. The diagnosis may be established by specific detection of viral DNA or by IgM-enzyme-linked immunosorbent assay. Viral DNA detection techniques using polymerase chain reaction to amplify small amounts of DNA has improved the accuracy of viral DNA

detection. Viral DNA detection is more reliable than IgM-enzyme-linked inmunosorbent assay because early infection may not produce an IgM reaction.

NEONATES WITH NORMAL FACIES AND NORMAL SERUM IgM

Autosomal Dominant Microcephaly Neonates with autosomal dominant microcephaly have features that are

not distinct enough to be considered dysmorphic, yet some of these neonates have upslanting palpebral fissures, slanting forehead, and prominent ears. Pathological studies have not been reported in patients with autosomal dominant microcephaly. The diagnosis is established by measuring the head circumference of the parents and finding that one of

them is microcephalic.





Neonatal Poliomyelitis

Neonatal poliomyelitis is extremely rare in the United States. It is caused by polio virus infection. Neonates may be infected by exposure to a

recently vaccinated sibling. Polio virus has affinity for the alpha motor neurons of the anterior horn of the spinal cord and cranial nerve motor nucleus.

Weakness and hypotonia are diffuse but usually asymmetrical. Dynamic tone is decreased. Pleocytosis and increased protein are usually present in the cerebrospinal fluid. The diagnosis is established by viral

isolation from the stool.

PERIPHERAL NERVE

Hypotonia due to nerve involvement has few distinguishing characteristics (Figure 134.1). Dynamic tone is usually decreased. Hypotonia and weakness occur to a similar degree (Figure 134.1). Large thick nerves (auricular nerve hypertrophy) may be present. Signs of peripheral nervous system sympathetic autonomic dysfunction may be present. Laboratory investigations are often needed to diagnose hypotonia due to nerve problems. Nerve conduction velocity, especially sensory

nerve conduction velocity, may be decreased. H-reflex may demonstrate slow proximal nerve conduction prior to the presence of distal slow nerve conduction velocity in routine nerve conduction studies. Slow sensory nerve conduction velocity is the major electrophysiologic clue to the diagnosis of peripheral nerve disease but it is not always present. Electromyography shows fibrillations. Motor unit potentials tend to be normal or slightly prolonged and large. Cerebrospinal fluid protein may be elevated. Autonomic responses to electrical and chemical stimulation may be abnormal. Nerve biopsy shows myelin or axonal abnormalities or both.



Figure 134.1.— Salient features of generalized hypotonia due to nerve disease. Arrow indicates the anatomical location of the injury; S & M: sensory and motor; SNAP: sensory nerve action potentials; EMG: electromyogram; CSF: cerebrospinal fluid; PR: protein; WBC: white blood cells; IC: intracutaneous.

Diseases that involve the peripheral nerve in the neonatal period are: (1) neuronal-axonal disease not associated with Werdnig-Hoffmann disease, (2) giant axonal neuropathy, (3) infantile porphyria, (4) congenital sensory neuropathy with anihidrosis, (5) congenital hypomyelinative neuropathy, (6) Riley-Day syndrome, (7) acute polyneuropathy, (8) chronic inflammatory demyelinating polyneuropathy, and (9) congenital sensory neuropathy. Neuropathy can be classified as axonal, hypomyelinative, or demyelinating, and as sensory, motor, sensory-motor,

or sensory-autonomic.

Five axonal neuropathies occur in the newborn period: giant axonal neuropathy, axonal polyneuropathy not associated with Werdnig-Hoffmann disease, the neuropathy that accompanies infantile porphyria, congenital sensory neuropathy with anhidrosis, and Riley-Day syndrome. All the neonatal neuropathies that affect myelin involve the thick myelinated fibers and produce slow sensory nerve conduction velocities. Sensory neuropathies apparently produce hypotonia by damaging the sensory fibers that feed information to the alpha motor neurons.


Paroxysmal Motor Events


Behavioral Movements

Behavioral movements occur in neurologically normal and abnormal neonates. They are characterized by truncal, facial, and limb movements

that occur during sleep or while awake. They consist of hiccups, crying, grimaces, sucking, and localized or generalized jerks (click on clips). They also include repetitive or erratic and fragmentary movements that represent normal movements that take on unusual qualities because

they occur in encephalopathic neonates. They do not produce central nervous system damage or cardiovascular compromise, nor do they have the characteristics of primitive reflexes (fatiguability, spatial and temporal summation, and variability with changes in position). Behavioral movements are not associated with electroencephalographic seizures. Interictal electroencephalographic background activity may be normal or abnormal.

Physiologic Reflex Activity

The Moro reflex, rooting, and sucking are physiological reflexes. They do not warrant any neurological investigations.

Benign Jitteriness Benign jitteriness is a syndrome that consists of stereotypic movements

occurring in a healthy fullterm neonate with normal serum glucose and calcium and no historical risk factors for central nervous system pathology. The movements are characterized by equal, low-amplitude, high-frequency, rhythmic bilateral tremors (click on clip). Benign jitteriness usually occurs in the first two weeks of life. Benign jitteriness can be triggered by stimuli, but may also occur without apparent stimulation. Jitteriness diminishes in response to passive flexion. Benign jitteriness may occur during sleep or quiet awake, but it is especially prominent during crying. Jitteriness can be stopped by passive restraints.





Benign jitteriness has the characteristics of a primitive reflex. Minor increases in heart rate may occur during the event. The EEG background

activity is normal and there are no changes during the event.

Neonates with benign jitteriness may be more inattentive and harder to console than other healthy neonates. In the presence of typical findings, it is not necessary to obtain an EEG or imaging study. No treatment is

required.






The glucose level in neonates with hypoxic-ischemic encephalopathy

should be kept at 75 to 100 mg/dL. Blood pressure should be kept within the normal limits for age. The urinary output should be maintained at 65 mL/kg per day. The head of the bed should be elevated 30 to 45 degrees. Mannitol 0.25 g/kg every 6 hours, furosemide 2 mg/kg every 8 hours, and corticosteroids during the first 24 hours after the insult have been suggested but are not routinely used. Neonatal convulsions should be

controlled with antiepileptic drugs.

The treatment of hypoxic-ischemic encephalopathy consists of correcting metabolic derangements, maintaining vital functions with careful consideration to the cardiac and renal status, managing cerebral edema, and controlling seizures. Hypothermia looks promising in preliminary reports. Hypoglycemia and hypocalcemia are frequent in asphyxiated neonates and should be considered as a possible cause of seizures in all neonates with hypoxic-ischemic encephalopathy. More about... 40, 110

Benign Familial Neonatal Convulsions The diagnosis of benign familial neonatal convulsions should be

reserved for patients with convulsions during the first week of life who also have: (1) normal physical and neurological examinations; (2) no detectable cause for the convulsions; (3) normal EEG; (4) normal development; and (5) a positive family history of one or more relatives with neonatal convulsions who have subsequently developed normally. The seizures may manifest as tonic or tonic-clonic convulsions with or without apnea. There is not a specific clinical electroencephalographic

pattern that is diagnostic of benign familial neonatal convulsions. Benign familial neonatal convulsions are linked to chromosomes 20 and 8.

The likelihood of these patients having seizures as adults is 14%.





Pyridoxine Dependency Pyridoxine dependency should be suspected in neonates with

continuous seizures without an apparent cause. A history of unusual fetal movements (intrauterine convulsions) and meconium stained amniotic fluid is often present. An EEG pattern characterized by generalized bursts of synchronous high-voltage 1- to 4-Hz spike and wave complexes has been described.

The seizures in neonates with pyridoxine dependency are probably caused by low concentrations of gamma-aminobutyric acid (GABA). Gamma-aminobutyric acid is an inhibitory neurotransmitter in the central nervous system. The lack of pyridoxine decreases the activity of glutamate decarboxylase; the low activity of glutamate decarboxylase decreases the

conversion of glutamic acid to GABA. The diagnosis of pyridoxine dependency is made on the basis of the response to intravenous pyridoxine or low levels of pyridoxal-5-phosphate in the CSF.

Treatment consists of pyridoxine 100 mg intravenously. The convulsions and abnormal electroencephalographic seizure pattern usually

stop immediately. Neonates should be monitored during, and for about one hour, after the infusion of pyridoxine because hypotonia and apnea may occur in neonates with pyridoxine dependency. This first-dose effect of pyridoxine in patients with pyridoxine dependency is probably due to a burst of GABA synthesis that results from sudden activation of glutamate

decarboxylase.

Folinic Acid Responsive Seizures Neonates with onset of seizures during the first week of life and no

explanation for seizures may have folinic acid responsive seizures. This type of seizure may be associated with an abnormal peak in the CSF electrophoresis. Treatment with folinic acid 2.5 to 5 mg twice daily stops

the seizures.

Biotinidase deficiency Biotinidase is the enzyme that cleaves biotin from biocytin and byotinyl

peptides. Biotin is needed for the activation of mitochondrial carboxylases (propionyl-CoA carboxylase, pyruvate carboxylase, and beta methylcrotonyl-CoA carboxylase). No biotinidase leads to no biotin. No biotin leads to no activity of the previously mentioned carboxylases. Lack



of activity of the mitochondrial carboxylases leads to metabolic derangement and to seizures. Neonates with seizures due to biotinidase deficiency usually have skin rash, total or partial alopecia, and persistent

conjunctivitis. Treatment consists of biotin 5 to 20 mg orally each day.

Disorder of glucose transport Glucose is transported across the blood brain barrier by facilitative

diffusion. A defect in this mechanism leads to low cerebrospinal fluid glucose and lactate. The possibility of a disorder of glucose transport should be considered when the cerebrospinal fluid glucose concentration is less than about 50% of the serum glucose concentration and the CSF lactic

is low. Treatment with a ketogenic diet controls seizures and prevents

neurological deficit.





INCONTINENTIA PIGMENTI

The hallmark of incontinentia pigmenti (Bloch-Sulzberger syndrome) in the neonatal period is the presence of an erythematous vesicular rash. The rash may be present at birth or may develop shortly after, usually during the first 2 weeks of life. The vesicles usually form a linear pattern following the Blaschko lines but isolated lesions with no particular pattern may also occur (Figure 298.1). The evolutive changes that characterize incontinentia pigmenti (verrucous eruption and hypopigmented lesions) do not usually occur in the neonatal period. The most important entity to differentiate from incontinentia pigmenti is herpes simplex encephalitis. They both may produce seizures and have skin vesicles. The distinction is based on the location and cytology of the vesicles. The vesicles in herpes simplex infection tend to occur on the scalp or presenting body part (sites of trauma) and the scrapings from the base of the vesicles show multinucleated giant cells with intranuclear inclusion (Sank smear). The vesicles in incontinentia pigmenti tend to occur on the limbs or lateral trunk, and the scrapings from the base of the vesicles show large numbers of eosinophils. Neonates with incontinentia pigmenti have leukocytosis and a high blood eosinophils count.

Figure 298.1.— Vesicular rash. Typical cutaneous manifestation of incontinentia pigmenti in neonates.

Neonates with incontinentia pigmenti should undergo ophthalmological

evaluation for retinal dysplasia, uveitis, keratitis, cataracts, and retrolental dysplasia. Incontinentia pigmenti occurs in females. Incontinentia



pigmenti is transmitted as an X-linked trait and is lethal in homozygous males. The gene loci are Xp11 (sporadic) and Xp28 (familial). Prenatal diagnosis is possible by DNA analysis. Males born with lesions of incontinentia pigmenti should have chromosomal studies to determine if

an XXY karyotype is present.





Decreased generalized movements due to pain is a very rare condition. It occurs in patients with pseudoparalysis of Parrot, osteogenesis imperfecta, and in victims of child abuse. Pseudoparalysis of Parrot is due to syphilitic infiltration of bone tissue. Neonates with congenital syphilis are likely to have hepatomegaly, skin rash (Figure 91.1[A]), and nasal discharge (Figure 91.1 [B]). The diagnosis of congenital syphilis is definite if: (1) the organism is identified on dark-field or direct observation in a pathological specimen; (2) there is a four-fold increase in venereal disease research laboratory test (VDRL) or rapid plasma reagin with positive treponemal antibody test in asymptomatic patients; (3) a reactive serum VDRL or treponemal hemagglutination test occurs in the presence of sniffles, condylomata lata, or osseous lesions; or (4) a reactive VDRL or

rapid plasma reagin is present in the cerebrospinal fluid.

A B

Figure 91.1.— Congenital syphilis. [A] Nasal discharge and scalded skin (left shoulder). [B] Skin rash on the palms.

Osteogenesis imperfecta is a hereditary disorder of connective tissue. Osteogenesis imperfecta produces decreased movements due to multiple

bone fractures (Figure 91.2 [A]). Osteogenesis imperfecta is diagnosed based on a positive family history, multiple fractures on radiographic bone

survey (Figure 91.2 [B]), and blue sclera. Fracture of the ear bones produces deafness.

A B



Figure 91.2.— Osteogenesis imperfecta. [A] Typical posture of a neonate with osteogenesis imperfecta due to limb deformities. [B] Radiographic evidence of multiple fractures.

Child abuse may produce generalized decreased movements in

neonates with multiple fractures. Neonates suffering from child abuse usually have cutaneous (Figure 91.3 [B]) and retinal changes (Figure 91.3 [B]) suggestive of abuse.

A B

Figure 91.3.— Neonatal abuse. [A] Cutaneous lesions in an abused neonate. Lineal bruises over the skin. [B] Retinal hemorrhages.





PRESYNAPTIC MYONEURAL JUNCTION DISORDERS

Hypotonia due to presynaptic myoneural junction disorders may result from destructive, metabolic, or dysgenetic problems (Figure 138.1).

Figure 138.1.— Salient features of generalized hypotonia due to presynaptic myoneural junction dysfunction. Arrow indicates the anatomical location of the injury (presynaptic myoneural junction); SNST: slow nerve stimulation test; RNST: rapid nerve stimulation test; C: Clostridium; DES: destructive; MET: metabolism; DYS: dysgenesis.

Infantile Botulism

Infantile botulism results from an intestinal infection by Clostridium botulinum. Frequent sources of C botulinum are honey (neonates and infants should not be given honey), soil, and dust. Infants are especially



vulnerable to colonization by C botulinum the first week after breast milk is stopped.

The toxin produced by this organism alters the presynaptic component of the myoneural junction. This alteration results in failure of acetylcholine release. Failure of acetylcholine release affects the nicotinic (striated muscle) and muscarinic (smooth muscle) myoneural junctions. The clinical presentation of botulism is characterized by the onset of constipation and feeding difficulty in a previously healthy neonate. This is followed by hypotonia with decreased dynamic tone. The hypotonia involves the facial and bulbar muscles first. Pupillary reaction is usually absent or, if present, is weak. Pupillary reaction may get progressively stronger with repetitive stimulation if the light is turned on and off at a fast rate (over 20 times per second) or progressively weaker if the light is turned on and off at a slow rate (2 to 3 times per minute). This phenomena occurs because of two physiologic factors: (1) acetylcholine has a duration of action of 100 milliseconds in the synaptic cleft, and (2) the number of quanta of acethylcholine released progressively decreases with each stimulation.



Arm


Arm movements are influenced by the cerebellum and brainstem

neurons. Cerebellum neurons influence upper extremity movements through their ascending cortical connections. Brainstem neurons influence arm movements through their descending pathways to the brachial somatic motor center. These subcortical fibers (from cerebellum and brainstem) are concerned with regulating the automatic component of movements.

Figure 203.1.— Schematic representation of the motor systems of the face, arms, and legs, and central and peripheral nervous systems structures involved in limb movements. The colored rectangles indicate the location of weakness produced by damage to the different components of the somatic motor system. U: upper motor neurons; V: ventricles; T: thalamus; UQ: upper quadrant; FN: facial nerve; LQ: lower quadrant; L: lower motor neurons; BP: brachial plexus; LSP: lumbosacral plexus.

The brachial somatic motor center is located in the cervical

enlargement of the spinal cord. The brachial somatic motor center or brachial center consists of a pair of anterior horn motor neuron columns


Arm

extending from C5 to T1 spinal segments. The axons of these neurons exit through the ventral surface of the spinal cord forming the ventral roots (Figure 203.2). The ventral roots travel for a short distance to join the dorsal roots. The dorsal roots are made of the central and peripheral axons of the dorsal ganglia neurons. The union of the ventral and dorsal roots form the spinal nerves. The spinal nerves are very short. The spinal nerves exit the spinal canal through the intervertebral foramina and split into dorsal and ventral rami. The dorsal rami innervate the paraspinal muscles and the sensory receptors of the dorsal torso. The ventral rami form the

brachial plexus (Figure 203.2).

Figure 203.2.— Schematic representation of the formation of the spinal nerves and their relation to the ventral and dorsal roots and dorsal and ventral rami.



Arm


Flaccid Arm Monoplegia Due to Lower Motor Neuron Lesions A lower motor neuron lesion may occur at the: (1) brachial center of the

spinal cord; (2) roots and spinal nerves that arise from the spinal segments C5 to T1; (3) brachial plexus; or (4) peripheral nerves (Figure 214.1 D through G). Lesions in the brachial center, roots, and spinal nerves usually occur together with brachial plexus lesions.

Figure 214.1.— Sites of possible nervous system injury that can produce arm monoparesis. A: brain to midbrain; B: upper pons; C: lower pons and medulla; D: rostral spinal cord; E: brachial center; F: brachial plexus; G: peripheral nerves; V: ventricles; T: thalamus; UQ: upper quadrant; FN: facial nerve; LQ: lower quadrant; BP: brachial plexus; LSP: lumbosacral plexus. The colored rectangles indicate the location of weakness produced by damage to the different components of the somatic motor system.

Brachial Plexus Palsy


Arm

The brachial plexus is the most common site of injury in neonates with flaccid arm weakness. A brachial plexus lesion may present as complete or

segmental flaccid weakness. Complete brachial plexus injury refers to weakness of the whole arm. Segmental arm monoparesis due to brachial plexus injury in the neonate has four clinical presentations: (1) Duchenne-Erb palsy; (2) upper-middle trunk syndrome, (3) Klumpke palsy, and (4) fascicular syndromes. Brachial plexus palsy must be differentiated from flaccid arm monoparesis due to an upper motor neuron lesion and from peripheral nerve damage.





BRACHIAL PLEXUS

The most common causes of brachial plexus palsy in neonates are intrauterine trauma, chicken pox infection, soft tumors of the brachial plexus or surrounding structures, extrauterine trauma, and bony exostosis.

TRAUMA

Intrauterine trauma is the most common cause of brachial plexus injury. Trauma may occur during pregnancy or at the time of delivery (obstetrical brachial plexus injury). Obstetrical brachial plexus injury is more frequent

than brachial plexus palsy due to intrauterine trauma. Obstetrical brachial plexus injury occurs because the brachial plexus is pulled in a direction that causes one of the angles formed by the spinal cord and the plexus to increase beyond the stretching capacity of the nerve fibers. Traumatic injuries during pregnancy are probably due to persistent intrauterine compression of the brachial plexus. Neonates with brachial plexus palsy due to intrauterine compression usually have a fixed

anatomical deformity. Bone abnormalities may be present. Fibrillation potentials are found on the affected muscles. These three findings help to distinguish intrauterine compression from obstetrical brachial plexus injury. Management consists of clinical and radiological evaluation of the extremity, physical therapy, and orthopedic evaluation if necessary.

Obstetrical brachial plexus injury is due to acute trauma as witnessed by the presence of swelling of the brachial plexus on MRI for several days after the injury (Figure 260.1). Evidence of trauma in other areas may be present. Frequent structures involved are the scalp (caput

cephalohematoma), facial and hypoglossal nerves, phrenic nerve (diaphragmatic paralysis), oculosympathetic nerve fibers (Horner syndrome), clavicle (fracture), shoulder (posterior dislocation of the head

of the humerus), and humerus (fracture). Specific investigations may be required to diagnose these injuries.

The cornerstone of the treatment of obstetrical brachial plexus injury is to avoid muscular atrophy in the affected muscles and contractures of the healthy muscles. Atrophy of the affected muscles renders them unsuitable for reinnervation. Contracture of the healthy muscles produces muscle group imbalance and joint deformities. Muscular atrophy is prevented with



physical therapy. Physical therapy involving the shoulder is recommended after 7 to 10 days of age. The waiting period is recommended to avoid stretching the plexus during a time when the plexus is vulnerable to further injury. Physical therapy should include active and passive exercises. Splinting is generally contraindicated unless low-weight splints are used, and only to arrest or reverse deformities. Some authors recommend

electrical stimulation.

Figure 260.1.— MRI of the brachial plexus showing edema in the area of the left brachial plexus.



Microcephaly


GENETIC MICROCEPHALY

Genetic microcephaly includes multiple syndromes that usually have normal chromosomal studies but are presumed to have a genetic origin on the basis of a positive family history, or proven to have a genetic origin on the basis of DNA testing. Some patients considered to have genetic microcephaly may show chromosomal abnormalities when prometaphase chromosome studies are performed. Nevertheless, these patients are still classified as having a genetic microcephaly because a normal prometaphase chromosomal study does not exclude their diagnosis. Once a genetic syndrome is diagnosed, the family should be referred to a geneticist for counseling. The following are the most common genetic syndromes.

Brachmann-de Lange Syndrome Neonates with Brachmann-de Lange syndrome have typical facies.

They are microcephalic, with bushy eyebrows and synophrys, long curly eyelashes, depressed nasal bridge, upturned nose, long philtrum, thin upper lip, and down-turned angle of the mouth. In addition to characteristic facial features, neonates with Brachmann-de Lange syndrome may have flexion contracture of the elbows, hypoplastic nipples and umbilicus, low-set thumb, brachydactyly or syndactyly of the second and third toes, hallux valgus, and sometimes absence of the third toe. Prometaphase chromosome studies should be done in all neonates with Brachman-de Lange syndrome. A duplication of the q26-q27 band region of chromosome 3 is present in some patients with Brachman-de Lange

syndrome.

Williams Syndrome The diagnosis of Williams syndrome is based on the typical facies and

cardiac abnormalities. The facies is characterized by prominent lips and subcutaneous tissue around the eyes. The irises are often blue and have a stellate pattern. Neonates with Williams syndrome may also present with cardiac abnormalities with or without the characteristic facies. The cardiac abnormalities include supravalvular aortic stenosis, valvular aortic stenosis, aortic stenosis, coarctation of the aorta, and pulmonary stenosis. Musculoskeletal malformations, including arthrogryposis, may occur. Hypercalcemia is usually present. The diagnosis may be established by


Microcephaly

fluorescent in situ hybridization studies. Inherited and sporadic cases show deletion of chromosome subunit 7q11.23.5. Most cases are sporadic. Williams syndrome is a connective tissue disorder. The 7q11 site

constitutes the elastin gene.



Apnea


BRAINSTEM

Brainstem lesions produce apnea by disrupting multiple respiratory structures localized to the pons and medulla (Figure 25.1). Brainstem involvement occurs with posterior fossa tumors, developmental abnormalities, and microscopic or functional abnormalities. Brainstem lesions in neonates can produce any type of apnea (obstructive, central, or mixed) during any behavioral state except in idiopathic hypoventilation syndrome. Neonates with idiopathic hypoventilation syndrome have central apnea usually during quiet sleep. Neonates with apnea due to brainstem abnormalities often have cranial nerve dysfunction. The diagnosis of brainstem pathology in a neonate with apnea is based on clinical impression, polysomnogram interpretation, MRI and CT findings, and brainstem auditory and somatosensory evoked responses.

Figure 25.1— Possible respiratory structures involved in brainstem lesions between black lines. Pontine respiratory centers are not represented.




Brain Tumors Seizures may be the presenting sign of neonatal brain tumor. Seizures

occur in about 14% to 20% of newborns with brain tumors. Brain tumors in neonates are more often supratentorial than infratentorial. Teratomas are the most frequent supratentorial tumors in neonates. They are usually present at the time of birth. Magnetic resonance imaging is the method of choice to diagnose brain tumors. Treatment is surgical. Chemotherapy is sometimes used. Radiotherapy is seldom used because of its deleterious

effects on future neurological development. More about... 257, 288

Schizencephaly Schizencephaly consists of a canal, surrounded by cerebral cortex, that

allows communication between the subarachnoid space and the ventricles. Schizencephaly is diagnosed by CT or preferably by MRI. The MRI appearance of schizencephaly is very characteristic. It consists of a thin or wide canal that extends from the cerebral cortex to the ventricles. Schizencephaly is unilateral or bilateral. The walls of the clefts or lips exhibit abnormal cortex with frequent neuronal heterotropia. The lips may be adjacent or distant from each other. Schizencephaly occurs most often in the regions of the Rolandic and Sylvian fissures. Schizencephaly may be associated with optic nerve hypoplasia and absence of the septum pellucidum.

Neonates with closed-lip schizencephaly have a better prognosis than those with open-lip schizencephaly. Neonates with unilateral schizencephaly have a better prognosis than those with bilateral schizencephaly. Convulsions are treated with antiepileptic drugs. Hemiparesis and mental retardation may occur. Hemiparesis is seldom present in the neonatal period. The possibility of surgical treatment for medically uncontrollable epilepsy should be considered in neonates with schizencephaly. More about... 257





CHROMOSOMAL DISORDERS

Chromosomal disorders are diseases associated with abnormal karyotyping. Karyotyping should be performed with chromosomes in metaphase in order to detect subtle abnormalities. Hypotonia occurs with a significant number of chromosomal abnormalities. Down syndrome is the most common chromosomal abnormality associated with hypotonia during the neonatal period.

Down Syndrome The diagnosis of Down syndrome is usually obvious. Neonates with

Down syndrome have brachycephaly, flat occiput, upward-slanting palpebral fissures, epicanthal folds, Brushfield spots, fissures on the tongue, low-set ears with prominent antihelix, angular overlapping helix, brachydactyly, clinodactyly, simian creases, small middle phalanx of the second and fifth fingers, and a wide space between the first and second toes (Figure 111.1). Neonates with Down syndrome have hypotonia with decreased dynamic tone. Lax ligaments contribute to hypotonia. Seizures occur in less than 10% of patients with Down syndrome. Endocardial cushion defects may be present. Duodenal atresia, anal atresia and megacolon are less frequent. Upper cervical vertebral abnormality may lead to atlantoaxial dislocation. Atlantoaxial dislocation may produce apnea and quadriparesis. Down syndrome is due to trisomy of all, or a large part, of chromosome 21. Trisomy 21 has a recurrence of 1%. D/G and G/G translocations are rare but they should be considered because they have significant genetic implications. Parents of infants with a translocation may be carriers of a balance translocation, therefore they are more likely to have other children with Down syndrome than parents who are not carriers of a balance translocation. The diagnosis is established by

karyotyping. More about... 275

A B C



Figure 111.1.— Characteristic findings in neonates with Down syndrome. [A] Upward-slanting palpebral features, [B] simian crease, [C] wide space between the first and second toes.

GENETIC DISORDERS

Genetic disorders are a group of syndromes with normal karyotype but with abnormal genes detected using DNA testing or a family history that suggests a genetic origin. Prader-Willi and Lowe syndromes are frequent causes of neonatal hypotonia. They course with hypotonia and decreased dynamic tone.

Prader-Willi Syndrome Neonates with Prader-Willi syndrome usually have bitemporal

narrowing, prominent forehead, almond-shaped eyes, strabismus, dysmorphic ears with narrow external canal, triangular mouth, poor sucking and swallowing reflexes at birth, small hands and feet, small penis, and cryptorchidism. Most patients have a paternally transmitted deletion of chromosome 15 (15q11-12). Prader-Willi syndrome should be suspected in all neonates with central hypotonia. The diagnosis is established by DNA testing. Fluorescent in situ hybridization for Prader-Willi syndrome is negative in about one-third of neonates with Prader-

Willi syndrome.

A B C



Figure 111.2— Prader-Willi syndrome. [A] Bitemporal narrowing, prominent forehead, almond-shaped eyes, triangular mouth, and poor sucking and swallowing reflexes at birth; [B] penis; and [C] cryptorchidism.

Lowe Syndrome Lowe syndrome or oculocerebrorenal syndrome is characterized by

cataracts, megalocornea, buphthalmos, glaucoma, prominent forehead, protruding tongue, thin sparse hair, proteinuria, metabolic acidosis, amino aciduria, and defective acidification of urine. Cryptorchidism is common. Lowe syndrome is transmitted by X-linked, recessive inheritance. Mothers of infants with Lowe syndrome may have minor lenticular opacities. Diagnosis is established by the presence of hypotonia, ocular abnormality,

and laboratory evidence of renal involvement.





Degenerative disorders without evidence of visceral storage include

infantile neuroaxonal dystrophy (a neurofilament disorder diagnosed by finding spheroid bodies in nerve biopsy), Canavan disease (diagnosed by decreased N-acetylaspartase activity in fibroblasts and by DNA study), metachromatic leukodystrophy (diagnosed by decreased arylsulfatase activity in leukocytes and fibroblasts), leukodystrophy with cerebral calcifications (no confirmatory diagnostic test is available), Menkes disease (diagnosed by the combination of decreased serum copper, decreased serum ceruloplasmin, and an elevated ratio of

dihydroxyphenylalanine to dihydroxyphenylglycol; or an increased uptake of labeled copper by cultured fibroblasts), and Tay-Sachs disease (diagnosed by decreased hexosaminidase A activity in leukocytes and

fibroblasts).

Infantile neuroaxonal dystrophy, Canavan disease, leukodystrophy with cerebral calcifications, and Menkes disease can be suspected but not excluded based on MRI findings. Infantile neuroaxonal dystrophy is associated with cerebellar atrophy with a hyperintense cortex on T2-weighted images. Canavan disease is associated with swollen gyri and increased signal on T2-weighted images of subcortical white matter (U-fibers), external and internal capsule, and thalamus. Leukodystrophy with cerebral calcification is associated with diffuse hyperintensity of cerebral white matter on T2-weighted images and areas of decreased signal intensity (calcification) close to the ventricles. Menkes disease is associated with cerebellar atrophy with subdural hygromas, infarctions demonstrated by MRI of the brain, and tortuous vessels demonstrated by MRA of the brain.

Urine evaluation may be helpful in the diagnosis of degenerative central nervous system disorders with and without visceral storage. Sialic acid containing oligosaccharides and glycoprotein may be present in sialidosis. Free sialic acid may be present in infantile sialic acid storage disease. Urinary level of N-acetylaspartate is increased in Canavan disease. The urine of neonates with metachromatic leukodystrophy shows decreased arylsulfatase activity. Mucopolysaccharides may be elevated in GM1 gangliosidosis.

Blood tests are also helpful in the diagnosis of degenerative central nervous system disorders. Plasma sialic acid is increased in infantile sialic acid storage disease. High serum concentration of very-long-chain fatty acids (>22 carbons) occurs in Zellweger syndrome and neonatal adrenoleukodystrophy. Serum N-acetylaspartate is increased in Canavan



disease. Copper and ceruloplasmin may be low in neonates and the ratio of dihydroxyphenylalanine to dihydroxyphenylglycol is elevated in Menkes

disease.





The immediate treatment of a urea cycle defect is to stop all protein

intake and to provide enough glucose to maintain normal glucose levels. Arginine 2 mmol/kg, and sodium benzoate (3% solution) 250 mg/kg

should be given over 2 hours. After the 2-hour period, arginine 2 mmol/

kg per day, carnitine 150 mg/kg per day, and sodium benzoate infusion (3 % solution) 350 to 500 mg/kg per day should be provided while monitoring plasma benzoate level and sodium. Later, protein 1.2 g/kg per

day with 50% as essential amino acids is added. Hemodialysis is superior to peritoneal dialysis to remove excessive ammonia.

The most frequent inherited metabolic causes of hyperammonemia in the neonatal period that primarily involve the urea cycle are: carbamyl phosphate synthetase deficiency, ornithine transcarbamylase deficiency, argininosuccinic acid synthetase deficiency, or citrullinemia. N-acetylglutamic acid synthetase deficiency and hyperornithinemia-hyperammonemia-homocitrullinuria syndrome will also be considered in this section, since they produce hyperammonemia and do not produce ketosis. Hyperammonemia with ketosis suggests a branched-chain amino

acid or an organic acid defect. Transient hyperammonemia of the preterm infant will also be considered in this section.

Carbamyl phosphate synthetase deficiency

The gene for carbamyl phosphate synthetase deficiency has been cloned and mapped to chromosome 2p. Serum glycine and glutamate are high because they are produced in the alternate pathways for ammonia disposal. Serum arginine and citruline are low because they are not being produced. Urinary orotic acid is low. Low urinary orotic acid helps differentiate carbamyl phosphate synthetase deficiency from ornithine-transcarbamylase (OTC) deficiency. The diagnosis is established by liver biopsy. Prenatal diagnosis is possible.

Ornithine-transcarbamylase deficiency Ornithine transcarbamylase deficiency is the only X-linked urea cycle

defect. Ornithine transcarbamylase deficiency in the neonatal period only affects boys. Urinary orotic acid is elevated. The diagnosis is confirmed by liver or intestinal mucosa biopsy. The prognosis of ornithine

transcarbamylase deficiency is poor.

Argininosuccinic acid synthetase deficiency



Argininosuccinic acid synthetase deficiency or citrullinemia has been mapped to chromosome 9q34. Serum citruline are high. The diagnosis may be confirmed by cultured skin fibroblasts and leukocytes studies. Prenatal diagnosis can be made by assay of citrulline in the amniotic fluid or enzymatic activity assay in cultured amniotic cells or chorionic villus material.

N-acetylglutamic acid synthetase deficiency N-acetylglutamic acid synthetase catalyzes the formation of N-

acetylglutamate. N-acetylglutamate is an allosteric activator of carbamoyl phosphate synthetase. Carbamoyl phosphate synthetase is the first enzyme in the urea cycle. The metabolic profile is similar to carbamyl phosphate synthetase deficiency. The diagnosis is confirmed by liver biopsy. Treatment consists of carbamylglutamate supplementation and low protein diet.

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome is due to impaired transport of ornithine across the inner mitochondrial enzyme. The urea cycle takes place in the cytosol and in the mitochondrion. There are two amino acids that must cross the cytosol-mitochondrion border: citrulline and ornithine. Citrulline normally crosses from the mitochondrion to the cytosol. Ornithine normally crosses from the cytosol to the mitochondrion.

Transient hyperammonemia of the preterm infant Transient hyperammonemia of the preterm infant occurs in

symptomatic and asymptomatic forms. The symptomatic form presents with seizures, coma, and evidence of significant brain stem dysfunction. Hyaline membrane disease is often present. The cause is not known. Treatment with exchange transfusion may require controlling hyperammonemia. The asymptomatic form is arginine-responsive. Arginine is needed to activate the synthesis of N-acylglutamate. N-acylglutamate is necessary for carbamyl phosphate synthetase activity. Treated or not treated neonates with asymptomatic hyperammonemia do

well.

MITOCHONDRIAL RESPIRATORY CHAIN DISORDERS

Coma in neonates with mitochondrial electron chain disorder occurs in NADH-coenzyme Q reductase (Complex I), cytochrome C oxidase (Complex IV), and in multiple acyl-CoA dehydrogenase deficiency (glutaric acidemia type II). Complex I and IV deficiencies present with



overwhelming lactic acidosis. Cardiomyopathy may be present. Lactate-to-pyruvate ratio is above 35. The diagnosis is established by finding NADH-Co Q reductase deficiency or cytochrome C oxidase deficiency in muscle. Treatment consists of riboflavin and succinate sodium administration in Complex I deficiency. There is no effective treatment for Complex IV

deficiency.





Carbohydrate-Deficient Glycoprotein Syndrome

Carbohydrate-deficient glycoprotein syndrome presents in the neonatal period with hypotonia and limb wasting. The skin is puffy and uneven. Trunk hypotonia may be more pronounced than limb hypotonia. Magnetic resonance imaging shows pontocerebellar atrophy. The diagnosis of carbohydrate-deficient glycoprotein syndrome is established by an abnormal transferrin isoform. It can be demonstrated by serum

carbohydrate-deficient transferrin assay.

Congenital Pontocerebellar Hypoplasia

Neonates with congenital pontocerebellar hypoplasia may be hypotonic at birth. Congenital pontocerebellar hypoplasia may have an autosomal dominant or recessive inheritance. Magnetic resonance imaging of the brain is diagnostic (Figure 123.1). Pontocerebellar hypoplasia may occur

in association with spinal muscular atrophy.

A B

Figure 123.1— Congenital pontocerebellar hypoplasia. [A] T1-weighted sagittal image demonstrates brainstem atrophy and cerebellar hypoplasia. [B] T1-weighted axial image demonstrates an empty posterior fossa.




Disorders of Lipid Metabolism

Carnitine deficiency produces myopathy. Carnitine deficiency may be systemic or restricted to the muscles. Systemic carnitine deficiency produces hypotonia, weakness, hepatomegaly, and encephalopathy. Serum carnitine is low. Carnitine deficiency restricted to the muscle produces weakness and hypotonia. Serum carnitine is normal. Carnitine deficiency restricted to the muscle can only be diagnosed by muscle biopsy. Treatment of carnitine deficiency consists of carnitine supplements and a diet rich in medium-chain triglycerides and low in long-chain

triglycerides.

REFERENCES

Aihara M, Tanabe Y, Kato K. Serial MRI in Fukuyama type congenital muscular dystrophy. Neuroradiology. 1992;34:396-398. Al-Qudah AA, Shahar E, Logan WJ, et al. Neonatal Guillain-Barre syndrome. Pediatr Neurol. 1988;4:255-256. Bergeisen GH, Baumann RJ, Gilmore RL. Neonatal paralytic poliomyelitis. A case report. Arch Neurol. 1986;43:192-194. Brzustowicz LM, Lehner T, Castilla LH. Genetic mapping of childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3. Nature. 1990;344:540-541. Cornblath DR. Disorders of neuromuscular transmission in infants and children. Muscle Nerve. 1986;9:606-611. Dyken PR, Harper PS. Congenital dystrophia myotonica. Neurology. 1973;23:465-473. Egger J, Kendall BE, Erdohazi M, et al. Involvement of the central nervous system in congenital muscular dystrophies. Dev Med Child Neurol. 1983;25:32-42. Fenichel GM. Clinical syndromes of myasthenia in infancy and childhood. Arch Neurol. 1978;35:97-103. Greer M, Schotland M. Myasthenia gravis in the newborn. Pediatrics. 1960;26:101-198.





Head Trauma Head trauma in the neonatal period usually occurs during delivery.

Physical abuse by a caretaker is infrequent in neonates. The possibility of spinal injury should be considered in every neonate with head trauma.

The hypotonia that results from head injury is initially associated with decreased dynamic tone, but after a few weeks dynamic tone increases. Clinical features that suggest head trauma are scalp bruises and equimosis, caput succedaneum (Figure 106.1 [A]), subgaleal hemorrhage (Figure 106.1 [B]), cephalohematoma, and linear and depressed skull fractures. Caput succedaneum refers to edematous or hemorrhagic swelling under the skin and above the galea aponeurosis. The mass is soft and indents with pressure. Caput succedaneum are usually located at the vertex and cross the sutures lines. They resolve rapidly and require no treatment. Subgaleal hemorrhages are localized between the galea aponeurosis and the external periosteum. They produce a mass that, as in caput succedaneum, crosses the suture lines, but unlike caput succedaneum, the mass feels tense and fluctuates with pressure. Subgaleal hemorrhages may

dissect over a large area of the skull. No treatment is necessary unless blood loss into the subgaleal space produces anemia and jaundice. Anemia and jaundice should be treated if their severity warrants it.

A B



Figure 106.1.— [A] Magnetic resonance imaging showing subgaleal hemorrhage. [B] Computed tomography of the brain demonstrating caput succedaneum.





Minimal Change Myopathy Minimal change myopathy is a term reserved for neonates with

generalized hypotonia, elevated serum creatine phosphokinase, brief and small motor unit potentials, and variation in muscle fiber size in muscle

biopsy.

Congenital Myopathy with Typical Light Microscopic Findings Congenital myopathy with typical light microscopic findings is a

heterogeneous group of disorders. They are grouped together because, when appropriately stained, light microscopy shows a typical recognizable pattern. Electromyogram may be normal or may show small-amplitude, brief-duration motor potentials. These disorders are not associated with elevated serum creatine phosphokinase. They include central core disease (NADH-tetrazoline stain reveals central or pericentral round clear zones due to absence of mitochondria primarily in type I muscle fibers), nemaline myopathy (Gomori trichrome stain reveals rodlike structures constituted by concentration of actin filaments with predominantly subsarcolemmal location in smaller and atrophic type I muscle fibers), myotubular myopathy (ATP-ase pH 9.4 stain reveals central or pericentral round clear zones in type I and II fibers that result from failure of the immature central nucleus and mitochondria to migrate peripherally), and congenital fiber-type disproportion (hematoxylin-eosin stain shows a predominance of small type I fibers).



Macrocephaly


Cephalohematoma

Cephalohematoma presents as a localized mass that does not cross suture lines. It is usually unilateral and over the parietal bone. The blood collects between the external periosteum and the bone. The mass is firm, tense, and confined to an individual bone. The edge of the mass may feel like a ridge. Underlying linear fracture is detected in 10% to 25% of cases. Cephalohematoma is produced by forces that tend to separate the periosteum from the bone. Complications are hyperbilirubinemia, late onset anemia, and osteomyelitis. Cephalohematomas require no treatment.

Complications should be treated accordingly.

SKULL

Increased thickness of the skull can occur with osteopetrosis. Osteopetrosis is a disorder characterized by overgrowth of brittle bones. This results in thick, dense, and fragile bones. The bony tissue overgrowth results in encroachments of the: (1) bone marrow leading to anemia, (2) cranial nerves foramina leading to deafness, blindness, or other signs of cranial nerve dysfunction, (3) Pacchioni bodies producing communicating hydrocephalus and macrocephaly. Osteopetrosis may be an autosomal recessive or an autosomal dominant disorder but only the autosomal recessive form occurs during the neonatal period.

Neonates with osteopetrosis may present with hypocalcemic seizures. Hepatomegaly is not usually present in the neonatal period. Alkaline phosphatase is increased. This condition is diagnosed by obtaining whole-body radiographs. Radiographs show dense bones, anterior notching up the vertebral bodies, thick ribs, and a bone-within-bone appearance of the

hands.





The diagnosis of this syndrome in females is very difficult because the

most characteristic features (cryptorchidism and hypospadia) are not present. Brain and brainstem malformations may be present. Arthrogryposis is more prominent in the hands. Smith-Lemli-Opitz syndrome is due to a severe defect in cholesterol biosynthesis. The defective enzyme is 7-dehydrocholesterol reductase. This defect leads to a high level of the cholesterol precursor 7-dehydrocholesterol and low cholesterol levels. The low cholesterol levels lead to abnormalities of mitochondrial function, hormone synthesis, myelinization and bile acid and vitamin D metabolism. Smith-Lemli-Opitz syndrome can be diagnosed prenatally or postnatally by measuring 7-dehydrocholesterol using chromatographic assay. Most patients with Smith-Lemli-Opitz syndrome die during the neonatal period. Survivors are severely mentally retarded. Smith-Lemli-Opitz syndrome is an autosomal recessive

condition.

Zellweger Syndrome Zellweger syndrome or cerebrohepatorenal syndrome is characterized

by severe hypotonia, brachycephaly, widely open fontanels and sutures, hepatomegaly, hypospadias and cryptorchidism in males (Figure 160.1), and clitoral hypertrophy in females. Patients with Zellweger syndrome have a prominent forehead, flat occiput, round face, micrognathia, anteverted nares, low-set dysplastic ears, hypertelorism, puffy eyelids, epicanthal folds, glaucoma, cataracts, corneal clouding, and Brushfield spots. Hepatomegaly may not be present at birth but develops during the first month of life. Arthrogryposis primarily involves distal joints. Bone radiograph may reveal calcified stippling of the patella and acetabulum. Magnetic resonance imaging may show: (1) hypomyelination, (2) perisylvian and perirolandic cortical malformation, and (3) germinolytic

cysts. Zellweger syndrome is associated with increased serum

concentrations of very-long-chain fatty acids in plasma.

A B



Figure 160.1.— [A] Cherry red spot in a patient with GM1-gangliosidosis. [B] Hepatosplenomegaly in a patient with Zellweger syndrome.





In full term neonates, gentamicin is given at a dose of 2.5 mg/kg every

12 hours during the first 7 days of life and 2.5 mg/kg/dose every 8 hours thereafter. In premature neonates, gentamicin is given at a dose of 2.5 mg/kg every 18 hours and, if the weight is less than 1000 grams, gentamicin is given at a dose of 2.5 mg/kg every 24 hours. Gentamicin blood levels should be monitored. Once the organism is determined, treatment is tailored to it. A repeat spinal tap should be done several days after initiation of treatment. Treatment should be continued for 2 weeks after cerebrospinal fluid is sterile. The mortality and neurological morbidity

associated with bacterial meningitis are high.

Herpetic Meningitis Herpetic meningitis is less common than bacterial meningitis. Seizures

are often the first sign of herpetic meningitis. The clinical and cerebrospinal fluid findings associated with herpetic meningitis are similar to those found in bacterial meningitis. The decision to start antiviral therapy relies on finding cerebrospinal fluid parameters similar to those seen in bacterial meningitis but with a negative Gram-stained smear, historical evidence of genital or labial herpes in the mother, or the presence of cutaneous vesicles in the patient. The drug of choice is acyclovir. The recommended dose in patients with normal renal function is 20 mg/kg every 8 hours for neonates over 33 weeks conceptional age and 20 mg/kg every 12 hours for neonates less than 33 weeks conceptional age. Treatment should be continued for 21 days unless the cerebrospinal fluid polymerase chain reaction and culture for herpes are negative, the vesicular fluid evaluation does not reveal herpes simplex, an alternative

explanation for the convulsion is present, and there is no evidence of

systemic herpes simplex infection.

Inborn Errors of Metabolism

Inborn errors of metabolism produce seizures by altering the brain metabolic milieu. The clinical presentation of inborn errors of metabolism is dominated by coma. Seizures in neonates with inborn errors of metabolism may be produced by a metabolic derangement amiable to etiological treatment and therefore may not require the use of antiepileptic drugs. This situation is rare because in most cases the metabolic abnormalities producing seizures can not be readily corrected by etiological treatment. More about... 71




ROSTRAL CERVICAL SPINAL CORD

Hypotonia due to rostral cervical spinal cord lesions may have increased or decreased dynamic tone. Neonates with acute cervical spinal cord injury present with hypotonia and decreased dynamic tone. Increased dynamic tone develops after several weeks. Generalized hypotonia due to rostral cervical spinal cord involvement is usually associated with apnea and

bowel and bladder incontinence (Figure 124.1).

Figure 124.1.— Salient features of rostral spinal cord hypotonia. Arrow indicates the anatomical location of the injury (upper cervical spinal cord); C: cervical; MRI: magnetic resonance imaging; SSER: somatosensory evoked response.

Cranial nerve functions are normal unless the spinal component of cranial nerve XI or cranial nerve XII or its motor nucleus are damaged. The spinal component of cranial nerve XI can be damaged in the spinal canal as its fibers (that arise from the lateral aspect of the cervical spine) travel up to enter the cranial vault through the foramen magnum. The



cranial nerve XII nucleus and nerve are located very low in the medulla and can be damaged during rostral cervical spinal cord injury. The most common cause of rostral cervical spinal cord injury is trauma. Spinal cord injury is readily detectable by MRI of the spine (Figure 124.2) and somatosensory evoked potentials.

A B

Figure 124.2.— Median sagittal cervical spinal cord images. [A] T1-

weighted image demonstrates an infarct in the cervical spine as an area of increased ecogenicity. [B] T2-weighted image demonstrates an infarct in the cervical spine as an area of increased ecogenicity.

LOWER CERVICAL SPINAL CORD

Generalized hypotonia due to lower cervical spinal cord lesions usually have increased dynamic tone of the lower extremities and decreased dynamic tone of the upper extremities (Figure 124.3). Neonates with acute lower cervical spinal cord injury present with hypotonia and decreased dynamic tone in all extremities. Increased dynamic tone of the lower extremities develops after several weeks. The most common cause of lower cervical spinal cord lesions is trauma. Spinal cord injury is readily detectable by MRI of the spine and somatosensory evoked potentials.



Figure 124.3.— Salient features of lower cervical spinal cord hypotonia. Arrow indicates the anatomical location of the injury (lower cervical spinal cord). C: cervical; MRI: magnetic resonance imaging.



Apnea


Rostral Spinal Cord

Rostral spinal cord injuries (C1 to C2 level) are usually traumatic. They produce apnea by interrupting the fibers that conduct the impulses from the ventral and dorsal respiratory groups to the phrenic center and the

intercostal alpha motor neurons. It is usually diagnosed by MRI (Figure 31.1). Cervical spine radiography may demonstrate a C1-2 subluxation.

Figure 31.1.— MRI of the brain demonstrating cervico-medullary junction atrophy.

The classic clinical presentation of rostral spinal cord injury consists of

absence of movements of the upper and lower extremities in an alert neonate with normal midbrain, pontine, and medullary cranial nerve functions. This classic presentation is not always present because: (1) trauma, the most frequent cause of spinal cord injury, often involves the brain and leads to coma; (2) damage to the fibers of cranial nerve XI as they ascend in the spinal canal produces head tilt; and (3) damage to the hypoglossal motor nuclei or nerve in the lower medulla produces a weak tongue.

Rostral spinal cord injury produces central, obstructive, and mixed apnea. Central apnea occurs because of disconnection of the dorsal and ventral respiratory groups from the phrenic center. Obstructive and mixed


Apnea

apnea may also occur due to hypoglossal motor nuclei and nerve damage, or due to lack of temporal coordination between upper airway muscles and diaphragmatic contractions. The latter occurs as a result of delay in signal transmission from the ventral and dorsal respiratory groups to the phrenic motor center.

The diagnosis of rostral spinal cord injury is established by MRI and radiography. They may show vertebral fracture, C1-C2 subluxation,

extraaxial hematoma, parenchymal lesion, or atrophy. Pathological findings may reveal a hemorrhagic discoloration of the rostral cervical cord (Figure 31.2). Treatment of the primary disease may be surgical. Tracheostomy with mechanical ventilation and diaphragmatic pacemaker are usually needed.

Figure 31.2.— Rostral cervical cord showing dark gray-blue discoloration.





Prevention should be considered for all pregnant women, but especially

for women with a previous child with brachial plexus injury, because 14% of siblings are likely to be affected. Preventive measures include avoidance of the following: weight gain during pregnancy, heavy sedation during delivery, and prolonged stage two labor. In addition, a mother with a child with an obstetric brachial plexus lesion should be evaluated for uterine deformities. Delivery by cesarean section helps to avoid obstetrical brachial plexus palsy by preventing shoulder dystocia; nevertheless, 3.6% to 11.4% of patients with obstetrical brachial plexus palsy are born by

elective or emergency cesarean section.

CONGENITAL CHICKENPOX

Congenital chickenpox infection may produce brachial plexus

damage. The damage usually involves the cervical anterior horn motor neurons. Other central nervous system areas may be involved. Clinical manifestations include arm monoparesis and cutaneous scarring (Figure 264.1). Horner syndrome may also be present. Congenital chickenpox is the result of fetal infection by the varicella virus during early pregnancy. No specific treatment is available. Physical therapy is recommended. Surgical treatment of limb deformities and tendon transplant can be

attempted when the patient is older.

A B

Figure 264.1.— Intrauterine chickenpox infection. [A] Left Horner



syndrome, atrophy of the left arm and absence of the left thumb. [B] Scar formation in shoulder region.





Congenital Hypomyelinative Neuropathy

Congenital hypomyelinative neuropathy has a presentation in many ways similar to Werdnig-Hoffmann disease. A sensory deficit is present but is usually clinically undetectable in neonates. The first clue to the diagnosis of hypomyelinative neuropathy is a very slow motor nerve conduction or the presence of elevated cerebrospinal fluid protein in the presence of a normal white blood cell count.

The diagnosis is established by sural nerve biopsy. The biopsy shows little or no myelin sheath around the axons and no evidence of demyelination or onion bulb formation in sural nerve biopsy. This entity may occur sporadically or follow an autosomal recessive or dominant

pattern of inheritance. In most instances, this disease is not progressive.

Acute Polyneuropathy Acute polyneuropathy or Guillain-Barre syndrome may occur in the

neonatal period and should be considered if a previously healthy neonate develops hypotonia with decreased dynamic tone after an apparent viral illness. Cerebrospinal fluid proteins are increased and motor nerve conduction is very slow after 2 weeks. These patients usually recover. This entity is very rare. Immunoglobulin is the treatment of choice for acute

polyneuropathy. The effectiveness of immunoglobulin in the neonatal period is unknown.

Chronic Inflammatory Demyelinating Polyneuropathy Chronic inflammatory demyelinating polyneuropathy presents very

much like acute polyneuropathy in a newborn. It is the history of chronicity or recurrence as the patient gets older that raises the possibility of this diagnosis. Nerve conduction is decreased. Nerve biopsy shows a decreased myelin, evidence of segmental demyelination and remyelination, and subperineural and endoneural edema with inflammatory cells. The diagnosis is established by sural nerve biopsy.

Treatment with steroids is effective.



Apnea


Posterior fossa extraaxial hematoma may result from small tentorium

tears, ruptures of bridging veins, or due to occipital diathesis. A history of birth trauma is often present. Posterior fossa hematoma may present with coma, eye deviation (not altered by lateral head rotation to provoke the doll's head phenomenon or cold caloric testing), and pupillary abnormalities. This presentation may occur after a symptom-free period or immediately after birth. The neonate may develop retrocollis or opisthotonos. Bradycardia and apnea are usually terminal events. Posterior fossa hematoma is diagnosed by CT or MRI of the brain. Treatment is surgical.

Other posterior fossa lesions that may present with signs of mass effects are pontine gliomas and brainstem hemorrhage. They are diagnosed by MRI of the brain. Treatment is dictated by the cause.

Developmental Abnormalities Cleland-Chiari malformation has three major elements: brainstem

displacement, cerebellar dysplasia, and elongation of the fourth ventricles. This anomaly may be associated with myelomeningocele and hydrocephalus. Cleland-Chiari malformation is characterized by feeding difficulties and a weak cry due to medullary dysfunction. Frequent episodes of crying and apnea may occur. Laryngeal stridor may occur during crying and feeding. The diagnosis is established by MRI of the brain (Figure 27.1).

Figure 27.1.— Cleland-Chiari malformation. Elongation of the brainstem and beaking of the posterior midbrain.




SIMPLIFIED MODEL OF THE LOWER MOTOR NEURON SYSTEM

The lower motor neuron system is housed in the central and peripheral nervous system (97.1 [A,B]).

The parts of the lower motor neuron system housed in the central nervous system are the bodies of the lower motor neuron and the small segment of their axons. The bodies of the lower motor neurons are housed in the brainstem and in the spinal cord. Their axons travel briefly in the central nervous system and then exit. The segment of the axons of the lower motor neurons travel in the central nervous system and are surrounded by myelin of oligodendrite origin.

The part of the lower motor neuron system in the peripheral nervous system are the nerve, myoneural junction, the muscle sensory apparatus, and muscle. The nerves are formed by the myelinated (Schwann cell origin) axons from the lower motor neurons and the axons from the sensory and autonomic neurons. The myoneural junction is the area of functional contact between the nerve and muscle. The muscle sensory apparatus consists of the neuron bodies of the propioceptive sensory neuron in the dorsal spinal ganglion, their axons, and the intrafusal muscle fibers. The axon of the propioceptive sensory unipolar neuron of the dorsal spinal ganglion sends one arm toward the spinal cord. This arm of the axon enters the spinal cord (SC), and makes a loop in the spinal cord to contact with the lower motor neuron body (Figure 97.1 [A]. The other arm travels toward the muscle and innervates the muscle spindle. The muscle spindle is the tension sensor of the muscle.

A B



Figure 97.1.— Schematic representation of the lower motor neuron system [A]. The relation between relevant regions of the central nervous system and the lower motor neuron system [B]. The lower motor neuron is represented in blue. The sensory neuron is represented in dark orange. SC: spinal cord; LMN: lower motor neuron; MNJ: myoneural junction. Green squares represent myelin of Schwann cell origin. Light brown squares represent myelin of oligodendroglia origin.

LOCALIZAING THE SITE OF DAMAGE USING A SIMPLIFIED MODEL IN NEONATES WITH NEUROMUSCULAR HYPOTONIA

The possible site of neuromuscular dysfunction (Figure 97.2) is determined by analyzing the clinical findings and is confirmed by neurophysiological testing or imaging studies. There are 10 possible sites.

Figure 97.2.— Schematic representation of the possible sites of



neuromuscular involvement in neonates with hypotonia: (1) brain; (2) brainstem; (3) rostral spinal cord; (4) brachial plexus area of the spinal area; (5) cerebellum; (6) alpha motor neuron; (7) nerve; (8) presynaptic-myoneural junction; (9) postsynaptic-myoneural junction; (10) muscle. Green squares represent myelin of Schwann cell origin. Light brown squares represent myelin of oligodendroglia origin.





If examined just prior to a schedule feeding a normal arousal response

in a neonate more than 34 weeks gestational age is usually triggered by gently shaking the thorax, and the arousal is sustained for at least 5 to 10 minutes. Normal neonates born between 28 and 33 weeks gestation require more vigorous stimulation and are seldom able to sustain an arousal for longer than 5 minutes. Neonates from 25 to 27 weeks gestation require vigorous and frequent stimulation to arouse and the arousal is very

brief.

If examined just after a feeding a healthy fullterm neonates when asleep may require painful stimuli to be arouse. Once aroused, they do not remain awake for long, even if continuously stimulated. Premature neonates often go through a similar period after gavage feeding. A history of recent feeding prior to the examination and the transient nature of postprandial sleep distinguishes sleep from coma in these cases.

DIFFERENTIATING COMA FROM DEATH

A comatose neonate has a heartbeat and does not meet brain death criteria. Brain death criteria in the United States has only been established for fullterm neonates after 7 days of age (Figure 63.1).

Figure 63.1.— Brain death criteria for fullterm neonates from 7 to 30 days of age. 1: no brain flow for 10 minutes; 2: two EEG flat 48 hours



appart; 3: two neurological examination showing no clinical evidence of cortical or brainstem functions 48 hours appart; 4: no movements other than spinal movements for 48 hours; 5: no brainstem activity for 48 hours; H: hours.





Brain death criteria in the United States includes: (1) no wakefulness or

movements other than spinal reflexes for a 48-hour observation period; (2) neurological examinations at the beginning and at the end of the observation period showing no clinical evidence of brain or brainstem functions; and (3) either no electroencephalographic cortical activity at the time of the neurological examination or no cerebral blood flow within the

observation period (Figure 64.1).

Figure 64.1.— Cerebral blood flow study demonstrating absence of cerebral blood flow.

DIFFERENTIATING COMA FROM STATUS EPILEPTICUS

Partial and generalized electroencephalographic status epilepticus may be associated with a state of altered mental status clinically similar to coma. The distinction is based on EEG findings. The distinction between status epilepticus and coma is important because status epilepticus is a hyperexcitable neuronal state that requires treatment with antiepileptic drugs whereas coma is a hypoexcitable neuronal state that does not require

antiepileptic treatment.




Normal or low lactate/pyruvate ratio (<25) and increased pyruvate

concentration occurs in defects of pyruvate dehydrogenase (not associated with hypoglycemia), glucogenic enzymes deficiencies (associated with hypoglycemia), and partial pyruvate carboxylase deficiency (this form of pyruvate carboxylase deficiency usually does not occur in neonates). High lactate/pyruvate ratio (usually >35) and decreased or normal pyruvate occurs with total pyruvate carboxylase deficiency (the usual form that presents in neonates) or respiratory chain defects. Respiratory chain defects are associated with an increased ratio (normally 2:1 or less) of 3-hydroxybutyrate to acetoacetate. More about... 45

MANAGEMENT OF THE COMATOSE NEONATE

Evaluation and treatment of a comatose neonate must be carried out simultaneously in order to prevent further brain damage. Further brain damage is avoided by preventing and correcting systemic and neurological causes of secondary brain damage while simultaneously treating the primary insult if it is still present.

TREATMENT OF SYSTEMIC CAUSES OF SECONDARY

DAMAGE

Oxygen by hood, mechanical ventilation, or extracorporeal membrane oxygenation should be used to keep arterial oxygen saturation above 95% or arterial pO2 above 70 torr. Levels of pCO2 should be kept between 35 to 45 mm Hg. Mean blood pressure should be kept at about 50 mm Hg. Serum blood sugar should be kept above 75 mg/dL. Respiratory acidosis is corrected by increasing the positive end expiratory pressure or the ventilatory rate. Metabolic acidosis should be corrected when arterial base deficit exceeds 7 mEq/L. Sodium bicarbonate should be used at a dose of 2 to 5 mEq/kg over 5 to 10 minutes and repeated if necessary to maintain blood pH above 7.20. Hemodialysis is an effective method of correcting persistent metabolic acidosis.

TREATMENT OF NEUROLOGICAL CAUSES OF SECONDARY CEREBRAL DAMAGE



Continuous EEG monitoring should be used to detect electroencephalographic seizures without concomitant clinical manifestations and to determine if some clinical manifestations are epileptic. Electroencephalographic seizures with and without concomitant clinical manifestations should be treated. The antiepileptic drug of choice is phenobarbital. Diazepam, lorazepam, phosphenytoin, and valproic acid may also be used. The only contraindication for complete electroencephalographic and electroclinical seizure control is if the systemic effects of high antiepileptic drugs are deemed unacceptable. Brain swelling is managed by fluid restriction and placing the patient's head midline and mildly elevated. The use of mannitol and diuretics may offer some benefit but are not routinely used. Mannitol 0.25 g/kg intravenously (onset of action in 15 minutes) may be given every 6 hours during the first day.



Facial Weakness


COMMON OCULOMOTOR SYSTEM

During the active awake state, the primary muscles used to open the eyes are the levator palpebrae muscles (Figure 188.1 [B]). The levator palpebrae muscles are innervated by the common ocular motor nerve (Figure 188.1). The oculomotor nucleus complex is located in the dorsal midbrain and receives bilateral cortical innervation. The oculomotor nucleus complex has two single midline structures and four bilateral structures. The midline structures are the nucleus for the levator palpebrae and the Edinger-Westphal nucleus. The axons from the neurons in these nuclei split into two bundles. One bundle goes to the right to innervate the right palpebrae muscle and the right pupillary sphincter and the other goes to the left to innervate the left palpebrae muscle and the left pupillary sphincter. These bundles join the axons from the four bilateral neuronal structures destined to innervate the superior, inferior, and medial recti, and the inferior oblique muscles. The fibers for the superior rectus arise from the contralateral nucleus (the neurons for the right superior rectus arise from the left oculomotor nucleus complex). The fibers for the inferior and medial recti and inferior oblique arise from the ipsilateral oculomotor nucleus.


Facial Weakness

Figure 188.1.— RN: red nucleus; CN: cranial nerve; CS: cavernous sinus; PT: pyramidal tract; SR: superior rectus; IR: inferior rectus; MR: medial rectus; IO: inferior oblique; SM: sphincter muscle; LPM: levator palpebral muscle; LPMN: nucleus of the levator palpebral muscle; CN III N: cranial nerve III nucleus; EWN: Edinger-Westphal nucleus. A, B: common sites of injury.



Facial Weakness


The fascicles formed by the axons of the third cranial nerve nucleus complex travel across the midbrain crossing through the red nuclei and the pyramidal tracts (Figure 189.1). They leave the brainstem anteriorly and advance in the subarachnoid space (Figure 189.1 [A]), go through the cavernous sinus, and enter into the orbits through the superior orbital fissure. In the orbits it splits into two groups to innervate the muscles of the eyes.

Figure 189.1.— RN: red nucleus; CN: cranial nerve; CS: cavernous sinus; PT: pyramidal tract; SR: superior rectus; IR: inferior rectus; MR: medial rectus; IO: inferior oblique; SM: sphincter muscle; LPM: levator palpebral muscle; LPMN: nucleus of the levator palpebral muscle; CN III N: cranial nerve III nucleus; EWN: Edinger-Westphal nucleus. A, B: common sites of injury.

Lesions to the oculomotor system usually occur in the subarachnoid

space prior to the cavernous sinus (Figure 189.1 A) or at the levator palpebrae muscle (Figure 189.1 B). Oculomotor system involvement at these sites produces a droopy eyelid when the other eye is wide open. The


Facial Weakness

asymmetry is not present when the patient cries or sleeps. The asymmetry is only apparent when the patient is in a quiet awake state and it only involves the upper quadrant of the face (Figure 189.2). Damage to the

common oculomotor system is rare in neonates. Usually, no cause is found.

A B

Figure 189.2.— Common oculomotor nerve lesion. [A] No asymmetry during crying. [B] Asymmetry present during quiet awake, involving only the upper half of the face. Left eye deviates down and out.





BRAINSTEM

The brainstem houses the motor neurons of the cranial nerve, their fibers, and several of the nuclei and pathways that make direct and indirect contact with the brainstem and spinal cord motor neurons (Figure 121.1). Hypotonia due to a brainstem lesion affects the brainstem motor nuclei, their fibers, and the fibers of the upper motor neuron systems. Apnea is frequent. Cranial nerve abnormalities may occur due to involvement of the cranial nerve fibers as they travel in the brainstem. Somatosensory and auditory evoked responses and MRI of the brain help localize the pathology to the brainstem.

Figure 121.1.— Salient features of brainstem hypotonia. Arrow indicates site of injury (brainstem). GAZE PREFERENCE (symbol: indicates that gaze preference is not overcome by cold caloric)POST. F US: posterior fontanelle ultrasound; SSER: somatosensory evoked responses; BEAR: brain evoked auditory responses.



The brainstem disorders that present with hypotonia in the neonatal period are Cleland-Chiari malformation, pontocerebellar degeneration, and carbohydrate deficient glycoprotein syndromes. Pontocerebellar degeneration and carbohydrate deficient glycoprotein syndromes involve the brainstem and the cerebellum. These neonates may also have signs of cerebellar involvement.

Cleland-Chiari Malformation

This anomaly consists of downward herniation of the cerebellar vermis through the foramen magnum. Spina bifida is usually present. Cleland-Chiari malformation in the neonatal period manifests with hypotonia and findings related to the spina bifida. The spinal bifida is usually located in the lumbosacral region and produces paraparesis.





CONGENITAL VARICELLA SYNDROME

The hallmark of congenital varicella syndrome (chikenpox) in the neonatal period is the presence of cutaneous scars (Figure 306.1). Neonates with congenital varicella may present with brachial plexus palsy, limb hypoplasia, Horner syndrome, or seizures. These presentations result from invasion of the nervous system by the varicella virus. Congenital varicella syndrome occurs in infants exposed to maternal varicella between 8 and 20 weeks gestation. The incidence of congenital varicella syndrome in a mother infected with varicella prior to 20 weeks of pregnancy is 1% to

2%.

Figure 306.1.— Typical cutaneous scars in the shoulder area due to congenital chickenpox infection.





Neuronal-Axonal Disease Not Associated with Werdnig-Hoffmann Disease

Neuronal-axonal disease not associated with Werdnig-Hoffmann disease is a rare condition that primarly involves the axons. Neuronal-axonal disease not associated with Werdnig-Hoffmann disease refers to a group of peripheral neuropathies in which the axon is the primary structure involved. Nerve conduction is normal or only moderately slow. It is diagnosed by sural nerve biopsy. The biopsy shows sphered bodies in the axons, particularly in the presynaptic region. It is important to diagnose this entity because neonates with this disorder may not deteriorate and may

even improve with time. The disease has a sporadic or autosomal-dominant inheritance.

Giant Axonal Neuropathy

Giant axonal neuropathy is a rare condition that involves the central and peripheral nervous systems. It should be suspected when the patient has tightly curled, kinky, poorly pigmented scalp hair. Motor and sensory nerve conduction velocity may not be decreased. The diagnosis is established by finding greatly enlarged axons filled with disarrayed neurofilaments in sural nerve biopsy. The cause is probably an error of

metabolism affecting the formation of neurofilaments.

Infantile Porphyria Infantile porphyria may produce neonatal hypotonia. The clinical course

is characterized by recurrent polyneuropathy. Nerve conduction velocity is normal. The characteristic findings are increased urine delta-aminolevulinic acid and coproporphyrin levels and decreased erythrocyte

aminolevulinic acid synthetase activity.

Congenital sensory neuropathy with anhidrosis Congenital sensory neuropathy with anhidrosis may produce neonatal

hypotonia. It should be suspected in hypotonic neonates with anhidrosis, no tears and episodes of unexplained fever. Nerve conduction velocity is normal. Autonomic dysfunction is present. Evidence of autonomic dysfunction can be proven by intracutaneous injection of 0.01 mL of histamine phosphate (1:10,000) and installation of 2.5% methacholine into the conjunctival sac. In a patient with normal autonomic function the intracutaneous injection of histamine produces a wheal with surrounding



erythema, and the installation of diluted methacholine into the conjunctiva sac does not produce miosis. In neonates with autonomic dysfunction, the intracutaneous injection of histamine produces a wheal with a surrounding erythema and the installation of diluted methacholine into the conjunctival sac evokes a rapid miosis. The diagnosis is established by sural biopsy. Sural biopsy in patients with congenital sensory neuropathy with anhidrosis shows a reduction or absence of small myelinated and

unmyelinated fibers.

Riley-Day syndrome Riley-Day syndrome or familial dysautonomia may produce neonatal

hypotonia. It should be suspected in hypotonic neonates of Ashkenazi Jewish parents with episodes of unexplained fevers or hypothermia, excessive sweating, and irritability. Fungiform papillae are absent. Abnormal rolling tongue movements, retrocollis and opisthotonus are usually present. There is no response to pain, and corneal responses and deep tendon reflexes are absent. Sensory nerve action potentials are absent. Evidence of autonomic dysfunction can be proven by intracutaneous injection of 0.01 mL of histamine phosphate (1:10,000) and installation of 2.5% methacholine into the conjunctival sac. In neonates with normal autonomic function the intracutaneous injection of histamine produces a wheal with surrounding erythema, and the installation of diluted methacholine into the conjunctiva sac does not produce miosis. In neonates with autonomic dysfunction, the intracutaneous injection of histamine produces a wheal with a surrounding erythema and the installation of diluted methacholine into the conjunctiva sac evokes a rapid miosis. The diagnosis is established DNA testing. In the past the diagnosis was stablished by the combination of ancestry, excessive sweating, and sural biopsy. Sural biopsy in patients with Riley-Day syndrome shows a

reduction or absence of small myelinated and unmyelinated fibers.





In neonates with myotonic dystrophy, EMG may show myotonic

discharges. These discharges may occur spontaneously or be elicited by moving the recording needle or percussion on the muscle. Muscle biopsy shows an arrest of fetal muscle maturation. Mothers with myotonic dystrophy have characteristic facies, clinical or EMG myotonic responses, and a minimal degree of mental delay may be present. Clinical myotonia is readily elicited in the mother (inability to open eyes quickly after they have been briefly closed or inability to extend the fingers after a handshake). The diagnosis is established by DNA testing. The abnormal site is at 19q13.3. The likelihood of giving birth to another infant with neonatal myotonia in subsequent pregnancy is about 30%. Treatment is supportive. Arthrogryposis should be managed nonsurgically in the neonatal period. Surgical management of joint deformities may be

necessary later on.

Neonatal Fascioscapular Humeral Dystrophy

Neonatal fascioscapular humeral dystrophy is a rare condition. It is encountered in two situations: (1) in a neonate who has weakness and hypotonia that spares the extraocular movements and the lower extremities, who also has a family history of facioscapular humeral dystrophy; or (2) in a patient with facial and shoulder girdle weakness and a muscle biopsy that exhibits inflammatory changes. Serum creatine phosphokinase is moderately elevated. Treatment is supportive.

Congenital Muscular Dystrophy

Congenital muscular dystrophies are a group of disorders that affect the muscles. They produce elevated serum creatine phosphokinase and a characteristic muscle biopsy pattern. The characteristic muscle biopsy changes are replacement of muscle by fat and connective tissue and evidence of muscle fiber necrosis and regeneration.





Congenital Muscular Dystrophy

Neonates with congenital muscular dystrophy are hypotonic, weak, and may have distal arthrogryposis. Serum concentration of creatine kinase may be normal or elevated. Electromyographic findings are consistent with

a myopathic process (brief, small, and abundant motor unit potentials). Muscle biopsy shows variation in fiber size, central nucleus, and replacement of muscle tissue by fibrosis and proliferation of adipose tissue. Merosin deficiency is present in some cases. Every patient with congenital muscular dystrophy should undergo MRI of the brain. The MRI of the brain of patients with Fukuyama type congenital muscular dystrophy shows migrational errors (polymicrogyria, lissencephaly, and

heterotopia) and hypomyelination of the centrum semiovale.

Myotubular Myopathy

Neonates with myotubular myopathy present with facial weakness, ptosis, ophthalmoplegia, generalized weakness and hypotonia, and, at times, with arthrogryposis. The severe form of myotubular myopathy courses with severe respiratory compromise which may lead to asphyxia. This malignant form occurs in males (X-linked inheritance). Myotubular myopathy is diagnosed based on muscle biopsy. Muscle biopsy with ATP-ase stain shows muscle fibers with one or more central nucleus, surrounded by a clear halo (area devoid of myofibrils). Prenatal diagnosis of the X-linked recessive form is accomplished by chorionic villus biopsy

and DNA marker studies of the Xq28 region.

Craniocarpotarsal Dysplasia Craniocarpotarsal dysplasia, Freeman-Sheldon syndrome, and whistling

face syndrome are synonyms. Craniocarpotarsal dysplasia is characterized by very peculiar facial features: a flat face with a crying-like expression, long philtrum, and a puckered mouth (as if ready to whistle). They have an H- or V-shaped groove on the chin (Figure 166.1 [A] [B]). Arthrogryposis is more marked in the upper extremities than in the lower extremities. Feeding problems are frequent. Patients with craniocarpotarsal dysplasia usually have normal intelligence. Craniocarpotarsal dysplasia is usually transmitted as an autosomal dominant disorder but autosomal recessive inheritance occurs in some families. The nature of this disease is not known. Muscle biopsy of the buccinator muscle reveals fibrous connective

tissue replacing the muscle bundles.



A B

Figure 166.1.— Freeman-Sheldon syndrome. [A] Typical facial characteristics; [B] distal arthrogryposis.

Schwartz-Jampel syndrome Schwartz-Jampel syndrome is a recessively inherited heterogenous

condition defined by myotonia, short stature, and bone dysplasia. Arthrogryposis occurs in a significant number of patients with Schawart-Jampel syndrome. There is no genetic test to diagnose Schwartz-Jampel syndrome. The diagnosis of Schwartz-Jampel syndrome in the neontal period requires the presence of myotonia during EMG. Myotonia is characterized by spontaneous, continuous high frequency, low voltage discharges or low voltage wax and wane discharges (that make a diver bomber sound). These discharges occur at rest and are triggered by needle movements (myotonia). The diagnosis of Schwartz-Jampel syndrome also requires short-limb bone dysplasia. Bone abnormality in neonates with Schwartz-Jampel syndrome can also result from bone remodeling because of abnormal muscle traction. The changes due to bone remodeling, as a result continuous muscle contraction are: flat face, hypognathium, pectus excavatum, pectus carinatum, bowing or external rotation of the femora, coxa vara or valga, dysplasia of luxation of the hips; retrocurvation of the knees; talipes valgus or planus, arthrogryposis, and osteoporosis. The differential diagnosis of Schwartz-Jampel syndrome includes other conditions that present with neonatal myotonia and arthrogryposis. These conditions are: (1) sodium-channel myotonia, which is a dominantly inherited condition and is not associated with bone dysplasia; and (2)

myotonic dystrophy.




The diagnosis of these conditions should be suspected if EMG

evaluation shows small-amplitude, brief-duration motor unit potentials with or without denervation potentials. Distinction among them can not be made on clinical grounds, although some features may suggest a particular condition. Skeletal anomalies (high arch palate, long dysmorphic face, and pectum excavatum or pectum carinatum) may occur in nemaline myopathy. The presence of ptosis, ophthalmoplegia, and facial weakness suggests myotubular myopathy. Nemaline and myotubular myopathy may produce severe neonatal weakness and hypotonia. Facial muscle is usually not affected in central core disease. Fibrillations are more frequent in myotubular and nemaline myopathies. The congenital myopathies with typical microscopic findings include disorders with autosomal dominant, autosomal recessive, or X-linked inheritance. Treatment is

supportive.

Mitochondrial Myopathy Mitochondrial myopathy could well be classified with the above group

of congenital myopathies with typical light microscopic findings because muscles stained with Gomori trichrome show red material (ragged red) within the muscle fibers. Electromyogram is normal. Macrosomia and Toni-Fanconi-Debre renal syndrome may be present. Some mitochondrial myopathies are due to cytochrome C oxidase deficiency (a specific mitochondrial defect). Lactic acidosis and pyruvate elevation are constant

features.

Myopathies Due to Glycogen Metabolism Abnormalities

Myopathies due to glycogen metabolism abnormalities produce hepatomegaly and hypoglycemia (debrancher enzyme deficiency), hepatomegaly, large heart, prominent muscles, and large tongue (Pompe’s disease is also called alpha-glucosidase deficiency), or arthrogryposis (McArdle disease is also called muscle phosphoylase deficiency). Myopathies due to disorders of glycogen metabolism are recognized by the presence of PAS-positive subsarcolemmal vacuoles on muscle biopsy.

Biochemical studies show absence of the specific enzyme.




Neuromuscular Blockers

The neuromuscular blockers used in neonates are vecuronium and pancuronium. They act on the nicotinic receptors and produce competitive nondepolarizing blockage. Neuromuscular blockers have an expected duration of action. The action of vecuronium lasts for 25 to 40 minutes in older patients. In neonates, the action of pancuronium usually lasts for 35 to 55 minutes. The action of neuromuscular blockers sometimes lasts longer than anticipated in neonates, leading to persistent hypotonia. This possibility should be considered prior to embarking on a complete neurophysiological evaluation in neonates that have previously received neuromuscular blockers.

MUSCLES

Hypotonia due to muscle involvement is associated with normal or decreased dynamic tone. Cranial nerves are usually involved. Myopathic hypotonia may course with elevated serum creatine phosphokinase. Electromyography pattern in muscle disease is characterized by low amplitude, brief duration, abundant motor unit potentials. Muscle biopsy may be normal or may show dystrophic, inflammatory, or structural

changes.



Figure 142.1.— Salient features of generalized hypotonia due to muscle disease. Arrow indicates the anatomical location of the injury (muscle); CPK: creatinine phophokinase; EMG: electromyogram; MUP: motor unit potencials.





MUSCLE

Congenital Myotonic Dystrophy Neonates with congenital myotonic dystrophy have marked body and

facial hypotonia. They usually do not appear alert. Arthrogryposis tends to be more common in the lower than in the upper extremities (Figure 165.1). The distal joints are more involved than the proximal joints. The only distinguishing facial feature is temporal muscle atrophy but this feature is seldom present at birth. The head is usually large. Magnetic resonance imaging of the brain may show ventricular dilation. The prognosis is poor. Mental retardation is usually noted as the patients get older. Congenital myotonic dystrophy is diagnosed by demonstrating the presence of myotonia in the mother and is confirmed by DNA testing. The disorder is caused by expansion in the number of trinucleotide repeats at chromosome region 19q13.3. It is an autosomal dominant disorder but the neonatal form

only occurs if the mother is the affected parent.

Figure 165.1.— Distal arthrogryposis in a neonate with congenital myotonic dystrophy.





Congenital Sensory Neuropathy

Congenital sensory neuropathy produces significant feeding difficulty. It is demonstrated by finding a slow sensory nerve conduction in the presence of normal motor conduction. The diagnosis is confirmed by sural nerve biopsy. It shows an increased ratio of small unmyelinated fibers to

normal-to-large myelinated fibers.

MYONEURAL JUNCTION DISORDERS

Hypotonia due to myoneural involvement has different characteristics depending on the site of the myoneural junction involved (animation below). Myoneural junction disorders may involve presynaptic or postsynaptic areas. The presynaptic area is involved in infantile botulism, hypermagnesemia, and some of the congenital myasthenic syndromes. Aminoglycosides combines presynaptic and postsynaptic blocks. The postsynaptic area is involved in transient myasthenia gravis and most

congenital myasthenia gravis syndromes.




Movement Arousals

Movement arousals occur in neonates with normal or abnormal neurological examinations. They are characterized by single jerks or briefly sustained postures during sleep. They are associated with EEG stage changes or transient flattening of the background activity (click on clips). The periods of EEG flattening may last for up to one minute. These periods of flattening occur more frequently during the first transition from

active to quiet sleep and may be bilateral or unilateral. It is important not to mistake this electroencephalographic pattern with those that occur during some electroencephalographic seizures. The interictal electroencephalographic background activity may or may not be normal. No significant changes in cardiac changes occur. They require no treatment.

ABNORMAL PAROXYSMAL MOTOR EVENTS

Convulsions

Convulsions are paroxysmal motor events characterized by increased motor activity that is believed to be a seizure based on clinical observation or proven to be a seizure by its association with an electroencephalographic seizure. Convulsions may occur in neurologically normal or abnormal neonates. A paroxysmal motor event is clinically considered a convulsion if it is not triggered by stimulation or stops upon arousal and is characterized by either: (1) focal tonic limb postures; (2) focal or multifocal clonic limb movements; or (3) repetitive facial twitches (click on clips, below). Nevertheless, many of the events considered to be convulsions based on these criteria are proven not to be so when studied by continuous EEG recording and single photon emission computed tomography.

Any paroxysmal motor event with increased motor activity associated with an electroencephalographic seizure is a convulsion. Convulsions are associated with increased focal hemispheric cerebral perfusion on single photon emission computed





tomography. Convulsions can be produced by disorders that require etiologic or antiepileptic treatment, or both.







The absence of scalp-recorded-electroencephalographic seizures during a paroxysmal motor event excludes a convulsion unless the events consist of paroxysmal giggling and smiling. Paroxysmal giggling and smiling in a neonate may be signs of gelastic epilepsy. Gelastic epilepsy is a rare and peculiar type of convulsion associated with hypothalamic hamartomas in neonates. The clinical manifestations of an event of gelastic epilepsy consist of a burst of hyperpnea, followed by repeated cooing, giggling, and smiling (laughing seizures). Limbs jerks may also be present. The convulsions usually last for 20 to 30 seconds and occur in clusters lasting from 1 to 3 minutes. The convulsions do not interfere with normal neonatal activities and may be present from birth. Scalp electroencephalographic recordings do not demonstrate

electroencephalographic seizures during gelastic convulsions. In one patient with gelastic seizures, an ictal single photon emission computed tomography demonstrated increased uptake in the area of the tumor, whereas the interictal single photon emission computed tomography did

not.

Pathological Reflexes

Pathological reflexes occur in encephalopathic neonates with significantly depressed EEG background activity (Figure 9.1) or in neonates with hyperexcitability syndrome.

Pathological reflexes in encephalopathic neonates with significantly depressed EEG background activity are also called subcortical release phenomena or brainstem release phenomena. They consist of paroxysmal motor events that show fatiguability, spatial and temporal summation, and variability with positioning, and do not have characteristics of physiologic reflexes nor meet the criteria for benign jitteriness. These paroxysmal motor events are characterized by repetitive eye or eyelid movements, pedaling or stepping, jitteriness, rolling arm movements, decorticated and decerebrated postures, and trunk or head writhing, or both(click on clips, below).



They are not associated with concomitant electroencephalographic

seizures (Figure 9.1[A]), nor with focal increase in cerebral hemispheric perfusion by single photon emission computed tomography (Figure 9.1

[B]).

A B

Figure 9.1— [A] EEG: depressed electroencephalographic background and no electroencephalographic seizure pattern. Clinical: pathological reflex activity characterized by raising both arms while isotope for single photon emission computed tomography is being injected; [B] Single photon emission computed tomography demonstrating no focal increase hemispheric perfusion.








METABOLIC DISORDERS

Many metabolic disorders can produce hypotonia. Electrolyte abnormalities, inborn errors of metabolism, and hepatic and renal encephalopathy usually produce transient hypotonia that resolves when the primary disorder improves. They are diagnosed by the appropriate laboratory investigations. Hypotonia with decreased dynamic tone usually occurs initially. After several weeks, if permanent damage results from brain swelling, hypotonia with increased dynamic tone appears. The two most frequent metabolic disorders that produce hypotonia are hypoxic-ischemic encephalopathy and hypothyroidism.

Hypoxic-ischemic encephalopathy Hypoxic-ischemic encephalopathy is probably the most frequent cause

of hypotonia during the neonatal period. Mild hypoxic encephalopathy produces a transient generalized hypotonia with decreased dynamic tone that lasts for a few days. Severe hypoxic ischemic encephalopathy initially produces hypotonia with decreased dynamic tone followed several weeks later by hypotonia with increased dynamic tone. A hypotonic neonate with increased dynamic tone at birth did not suffer asphyxia during labor. Hypoxic-ischemic encephalopathy often involves the brain and the brainstem. Very severe hypoxic-ischemic encephalopathy (Sarnat Stage

III ) may involve the brain, brainstem (Figure 110.1), spinal cord, and muscle. Magnetic resonance imaging of the brain in neonates with hypotonia due to hypoxic-ischemic encephalopathy shows loss of gray-

white matter interface, cortical necrosis, or status marmoratus of the basal ganglia and thalamus. More about... 40, 56, 66



Figure 110.1.— Cerebral and brainstem hypotonia. Top rectangle

identifies neurological characteristics of combined cerebral and brainstem hypotonia. Arrows indicate the anatomical location of involvement. Green rectangle identifies frequent findings associated with combined cerebral and brainstem hypotonia. SIADH: increased antidiuretic hormone secretion; GAZE PREFERENCE with symbol: symbol implies that the gaze prefernece is not overcome by cold caloric testing; SCRP: subcortical release phenomena; Purple cube: tests often abnormal in combined cerebral and brainstem hypotonia. US: ultrasound; EEG: electroencephalogram; VER: visual evoked responses; CT: computerized tomography; MRI: magnetic resonance imaging.

Congenital hypothyroidism

Congenital hypothyroidism is an infrequent but important cause of generalized hypotonia. Symptoms of hypothyroidism may be difficult to detect at birth. Neonates with congenital hypothyroidism are usually post-term and heavy. Jaundice is prolonged, anterior and posterior fontanelle are large, skin is mottled, and umbilical hernia and hoarse cry may be present. Congenital hypothyroidism is diagnosed by determining serum

thyroxine and thyroid stimulating hormone levels. Radiographs show delayed bone maturation in only 50% of cases and therefore are not a reliable method of excluding the possibility of hypothyroidism. Treatment

consists of thyroid hormone supplementation.


Microcephaly


Trisomy 18 Syndrome

Trisomy 18 syndrome is characterized by microcephaly and distal arthrogryposis especially involving the hands. The position of the hands is characterized by overlapping of the third finger by the index finger and of the fourth finger by the fifth finger. The position of the hand is so characteristic that the term “trisomy 18 hand position” is commonly used to describe them. Neonates with trisomy 18 often have a prominent occiput. Chromosome studies are indicated. Ten percent of patients of neonates with trisomy 18 syndrome have translocation. Parents with balance translocations are more likely to have offspring with trisomy 18

syndrome than parents who are not carriers of the translocation. More about... 158

Trisomy 13 Syndrome Trisomy 13 syndrome is characterized by microcephaly,

holoprosencephaly, facial abnormalities ranging from hypertelorism to cyclopia, cleft palate and lip, polydactyly, narrow hyperconvex finger nails, prominent heels, and cutis aplasia in the posterior scalp. The skin lesions are very characteristic but they are not always present. Chromosomal studies are indicated to confirm the diagnosis and to detect translocations. Parents with balance translocations are more likely to have other offspring with Trisomy 13 syndrome than parents who are not

carriers of the translocation. More about... 157

5p- Syndrome or Cri-du-chat Syndrome 5p- syndrome is characterized by a peculiar catlike cry. The peculiar

quality of this sound is probably due to larynx and vocal cord malformations. Microcephaly, prominent epicanthal folds, and down-slanting palpebral fissures are common features. The chromosomal region involved in the larynx and vocal cord malformations is at 5p15.3. The

affected chromosome in 5p- syndrome is paternal in 80% of the cases.



Microcephaly


NEONATES WITH NORMAL FACIES AND ELEVATED SERUM

IgM

Cytomegalovirus Infection

Cytomegalovirus (CMV) is usually transmitted to the fetus during a primary maternal infection. Fetuses of women with preexisting seroimmunity are usually protected. Central nervous system involvement occurs with infection in the first and second trimester of pregnancy.

Microcephaly and seizures are common manifestations of congenital cytomegalovirus infection. Microcephaly and seizures result from brain damage due to meningoencephalitis in the developing brain (Figure 277.1 [A]). Cytomegalovirus meningoencephalitis produces damage to the fetal brain due to its destructive effects on the proliferating and migrating neurons. Cytomegalovirus is associated with several migrational disturbances including polymicrogyria (most frequent), lissencephaly, pachygyria, and neuronal heterotopias. Central nervous system manifestations of CMV infection also include porencephaly, hydranencephaly, hydrocephalus, and cerebellar hypoplasia.

Neurological signs are the sole manifestations of congenital CMV infection in about 30% of cases. Neonates with congenital CMV infection often have hepatomegaly, petechiae, or other manifestations of reticuloendothelial system involvement. Chorioretinitis also occurs. Computed tomography of the brain often shows periventricular calcifications (Figure 277.1[B]).

A B

Figure 277.1— [A] Microcephaly. [B] Computed tomography of the brain showing evidence of periventricular calcifications.


Apnea


Somatosensory evoked potentials in patients with Cleland-Chiari

malformation may show a conduction block in the upper cervical region or a delayed conduction between the upper cervical region and the cerebral cortex. If hydrocephalus is not present, the treatment of choice is posterior fossa decompression. If hydrocephalus is present, the initial treatment of choice is shunting followed by posterior fossa decompression if apnea reoccurs. Myelomeningocele should be treated shortly after birth.

Joubert syndrome presents in the neonatal period with hyperpnea alternating with apnea. Abnormal eye movements may be present. These neonates also have flaccid hypotonia. The diagnosis is established by MRI. The MRI shows complete or partial absence of the cerebellar vermis and a normal or small posterior fossa.

Dandy-Walker malformation in the neonatal period usually presents with macrocephaly. The head is particularly enlarged in the occipital area. Apnea is an infrequent presentation of Dandy-Walker syndrome in the neonatal period.





The most common cerebellar lesions that cause neonatal hypotonia are

Dandy-Walker syndrome, Joubert syndrome, and rhomboencephaloclasis. Cerebellar atrophy may also occur with fetal alcohol syndrome,

cytomegalovirus infection, and hypothyroidism.

Dandy-Walker Malformation Dandy-Walker malformation is most likely due to slow flow of

cerebrospinal fluid from the fourth ventricle to the cisterna magna. Dandy-Walker malformation is characterized by agenesis or hypoplasia of the

cerebellar vermis and cystic dilation of the posterior fossa (Figure 117.1).

Figure 117.1.— Schematic representation of Dandy-Walker malformation. Large posterior fossa due to a large cisterna magna and hypoplasia or agenesis of the cerebellar vermis.

The tentorium is positioned high because of the large size of the posterior fossa (Figure 117.2). Apneic spells and nystagmus may occur. Macrocephaly with prominent occiput may be present. Other congenital brain abnormalities that occur in association with Dandy-Walker syndrome are agenesis of the corpus callosum, neuronal heterotopia, and aqueductal stenosis. Hydrocephalus is not present at birth but usually develops after 3 months of age. Magnetic resonance imaging of the brain is diagnostic (Figure 117.2).

A B



Figure 117.2.— Dandy-Walker malformation. [A] T1-weighted axial image demonstrates wide communication between the suspected region of the fourth ventricle and the large posterior fossa cyst. The cerebellar hemispheres are hypoplastic. [B] T1-weighted sagittal image demonstrates a large posterior fossa, superiorly rotated superior vermis, high-positioned tentorium and torcula.



Decreased Limb Movements


WEAKNESS

Decreased limb movements due to weakness—regardless of its degree—will be referred to as paresis, thus avoiding the need to use paresis and plegia to imply different degrees of weakness. Limb weakness implies a neurological deficit. The neurological deficit results from a lesion in the central or peripheral nervous system (Figure 197.1).

Figure 197.1.— Schematic representation of the central and peripheral nervous systems involved in patients with weakness. The colored rectangles indicate the location of weakness produced by damage to the different components of the somatic motor system. V: ventricles; T: thalamus; UQ: upper quadrant; FN: facial nerve; LQ: lower quadrant; BP: brachial plexus; LSP: lumbosacral plexus.




DEGENERATIVE DISORDERS

The possibility of a degenerative disorder should be considered in a hypotonic neonate with a family history of a neurodegenerative disorder, or if the neonate has a cherry red spot (Figure 112.1 [A]), hepatosplenomegaly (Figure 112.1 [B]), dysmorphic features, swollen joints, hyperplastic gums, bone dysplasia, or evidence of white matter

disease on MRI of the brain. The usual history of neurodevelopmental regression is not present during the neonatal period. Degenerative disorders that affect the newborn can be divided into those that have

evidence of visceral storage and those that do not. Signs of visceral storage are hepatomegaly, cherry red spot, facial dysmorphism, swollen joints, hypertrophic gums, and bone dysplasia.

A B

Figure 112.1.— [A] Cherry red spot in a patient with GM1-gangliosidosis. [B] Hepatosplenomegaly in a patient with Zellweger syndrome.





LUMBOSACRAL "BLEMISH"

A cutaneous abnormality or "blemish" overlying the spine indicates the possibility of occult spinal dysraphism. They are especially frequent in the lumbosacral area (Figure 307.1). Neonates with a subcutaneous fatty pad, angiomatous patch, a hairy tuft, or a dermal sinus in the lumbosacral region should have ultrasound or MRI of this area.

Figure 307.1.— Lumbar sinus. A spinal MRI showed an intraspinal lipoma.

Neonates with angiomatous patch may have Cobb syndrome. Cobb syndrome consists of the association of cutaneous angiomatosis and angiomatosis of the spinal cord, the adjacent meninges, or both (Figure 307.2).

A B C



Figure 307.2.— Cobb syndrome. [A] Angiomatous patch with prominent fat component; [B] MRI showing the patch and intramedullary pathology; [C] MRA showing the vascularity of the lesion.

Imaging studies detect the position of the conus medullaris, the presence of a tethered cord, and associated central nervous system malformations. Neonates with lumbosacral blemish should undego an ultrasound of the lumbosacral region (Figure 307.3) except those who have a superficial pit over the sacrococcygeal region (within the intragluteal fold) with a well-defined bottom, no oozing, no associated skin abnormalities, and no

neurological deficits.

A B

Figure 307.3.— [A] Normal conus medullaris: lowest portion rests between L1 and L2 (arrow); roots are not straight (between arrow heads). [B] Abnormal conus medullaris: lowest portion rests between L4 and L5 (arrow); roots are straight (between arrow heads).




If convulsions do not stop after the second dose of phenobarbital,

phosphenytoin is used. Phosphenytoin is a prodrug of phenytoin. Plasma phosphatase enzymes cleave phenytoin from phosphenytoin. Phosphenytoin acts on sodium current. The loading dose is 10 mg/kg. It should be infused intravenously at a rate no faster than 1 mg/kg per minute (same as phenobarbital). If the seizure persists after 10 minutes, a second dose of phosphenytoin of 10 mg/kg should be administered. If the seizure stops, no further antiepileptic medication is given and a phenytoin level is taken after 6 hours. The maintenance dose of intravenous phosphenytoin is 3 to 5 mg/kg per day divided in two doses. Phosphenytoin is as cardiotoxic as phenytoin. The advantage of phosphenytoin is that it is water soluble and has less toxicity at the site of infusion.

If phenobarbital and phosphenytoin do not stop the seizures, the patient should be placed on continuous EEG recording and 0.1 mg/kg intravenous lorazepan should be administered. The same dose of lorazepan may be repeated in 10 minutes if the seizure persists. Another option in patients unresponsive to phenobarbital and phosphenytoin is to use intravenous valproic acid. Intravenous valproic acid may be useful to achieve a therapeutic level quickly. The intravenous dose of valproic acid can be calculated by considering that each 1 mg/kg of valproic acid given intravenously raises the serum concentration by about 3 micrograms per

milliliter. Elevation of serum ammonia may occur with intravenous

valproic acid.

Oral antiepileptic drugs are used as soon as possible if seizures stop or are relatively controlled. Phenobarbital, phenytoin, valproic acid, carbamezapine and lamotragine can be used. The dose of carbamezapine is 5 mg/kg every 12 hours. No loading dose is necessary. Carbamezapine acts on sodium current. The loading dose of oral valproic acid is 20 to 26

mg/kg. The maintenance dose of oral valproic acid is 5 to 10 mg/kg. Valproic acid acts on sodium current and GABA receptors. Carbamezapine and valproic acid levels should be monitored and kept within the usual therapeutic range. Lamotrigine at a dose of 4.4 mg/kg per day can be used as a single dose for 3 days and then divided in two

doses. Brain surgery should be considered in cases of focal pathology.

The cessation of clinical seizures must be followed by an EEG looking for clinically silent electroencephalographic seizures. If electroencephalographic seizures are present, our current approach is to maintain phenobarbital and phosphenytoin levels in a high therapeutic



range and to use lorazepan intermittently to stop the long electroencephalographic seizures. In a recent report phenobarbital did not stop seizures in 57% of neonates, phenytoin did not stop seizures in 55% of neonates, and when used simultaneously, they did not stop seizures in 40% of neonates. Eighty percent reduction in seizure frequency was not achieved in about 25% of neonates despite the combination of

phenobarbital and phenytoin.

We discontinue antiepileptic drugs in neonates with proven or suspected hypoxic-ischemic encephalopathy, acute cerebrovascular accidents, or correctable metabolic disorders after 48 hours without clinical and electroencephalographic seizures. If more than one antiepileptic drug is being used, the first antiepileptic drug used is stopped first. If seizures recur after 48 hours, antiepileptic drugs are restarted and used for one month. All neonates with abnormal brain development and seizures are usually treated for about 1 month.



Facial Weakness


AGENESIS OF THE DEPRESSOR ANGULARIS ORIS MUSCLE

The depressor angularis oris muscle (DAOM) originates from the oblique line of the mandible and extends upward and medially to the orbicularis oris. It attaches to the skin and the mucous membrane of the

lower lip. The DAOM draws the lower corner of the mouth downward and everts the lower lip. The cause for agenesis of the muscle is unknown. The absence or hypoplasia of the DAOM produces characteristic findings (Figure 185.1). The lower lip on the affected side looks thinner because of the lack of eversion and feels thinner because of the muscle agenesis. When crying, the corner of the mouth on the affected side is displaced toward the normal side and the lower lip on the normal side moves downward and outward (Figure 185.1). These patients have symmetrical forehead wrinkling, eye closure, and nasolabial fold depth. The diagnosis may be confirmed by electrophysiologic studies. The facial nerve conduction time to the mentalis and orbicularis oris muscle are normal. There is no fibrillation in the area normally occupied by the

DAOM. Motor units are decreased or absent in the same area.

Agenesis of the DAOM can occur as an isolated anomaly but it has also been reported in association with cardiovascular, musculoskeletal,

genitourinary, and respiratory defects. Our approach to these patients is to assume no associated anomaly is present if the rest of the clinical examination is normal. No treatment is required since the asymmetry will not be noted when the patient grows older.

A B


Facial Weakness

Figure 185.1.— Absence of the depressor angularis oris muscle. [A] No facial asymmetry is present during quiet awake. [B] The asymmetry becomes apparent when crying.



Arm


Neonates with Duchenne-Erb palsy may also have facial, diaphragmatic,

or hypoglossal paralysis. Facial paralysis occurs because of concomitant traumatic facial nerve lesions (Figure 218.1). Facial weakness involves the upper and lower quadrants and it is minimal or not present when the neonate is quiet or asleep but very noticeable when the neonate is crying (Figure 218.1).

A B

Figure 218.1.— Facial nerve injury in a neonate with Duchenne-Erb palsy. [A] When quiet, the face looks symmetrical. [B] When crying, there is a facial asymmetry that involves the lower and the upper quadrants of the face. The facial asymmetry is on the side opposite from the arm weakness.

Unilateral diaphragmatic paralysis is usually asymptomatic but it should be considered if a neonate with Duchenne-Erb palsy can not be removed from the respirator. Bilateral diaphragmatic paralysis produces inability to sustain effective respiration. Diaphragmatic paralysis is usually diagnosed by inspiratory and expiratory chest radiographs (Figure 218.2 [A and B]) or fluoroscopy. Phrenic nerve conduction studies may be necessary in certain cases (Figure 218.2 [C]). The phrenic nerve arises from the anterior roots of C3-C5 spinal segments. The phrenic nerve becomes a single nerve over the brachial plexus and progresses caudally toward the diaphragm. Injuries to the phrenic nerve often occur at the level of the roots or over the brachial plexus. Unilateral diaphragmatic paralysis usually resolves spontaneously in 6 to 12 months. The only necessary management is clinical follow-up.


Arm

Bilateral diaphragmatic paralysis may require surgical treatment if it persists

for more than 2 months. Respiratory support is usually needed from birth. Tongue weakness due to hypoglossal nerve injury may occur. Clavicular fractures often occur with Duchenne-Erb palsy. They may not be noted clinically or by radiographs during the first 10 days. A lump in the clavicle is usually felt after 10 days.

A B C

Figure 218.2.— Unilateral phrenic nerve injury. [A] Expiration film does not show diaphragmatic paralysis. [B] Inspiratory film demonstrates the presence of a nonfunctional left diaphragm. [C] Decreased amplitude of diaphragmatic contraction during phrenic nerve conduction.





Common causes of hypocalcemia after the first week of life are

DiGeorge sequence (lateral displacement of the inner canthi, short palpebral fissures, short philtrum, micrognathia, ear and cardiovascular anomalies, absent parathyroid, and a defect in cell-mediated immunity that

results from a primary defect of the fourth bronchial arch), hyperphosphatemic states, magnesium deficiency, and osteopetrosis. Neonates on furosemide, bicarbonate therapy, or undergoing transfusion of citrated blood may develop hypocalcemia.

Neonates with hypocalcemia tend to look healthy between seizures. A clue to the diagnosis of hypocalcemia is a Q-oTC interval (measured from the beginning of the Q to the beginning of the T) greater than 0.2 seconds (prolonged). The immediate treatment of hypocalcemic seizures is calcium gluconate 10% at a dose of 1 to 2 mL/kg intravenously at an infusion rate of less than 1 mL per minute. Calcium gluconate should not be mixed with sodium bicarbonate. The initial dose should be repeated in 10 minutes if seizures continue or reccur. If seizures continue after the second dose and the Q-oTC interval is still greater than 0.2 seconds, hypomagnesemia should be suspected. If seizures continue but the Q-oTC is shorter than 0.2 seconds, phenobarbital should be used. The maintenance dose of calcium should be adjusted for each patient. The daily dose is usually 5 to 10 mL/

kg of 10% calcium gluconate solution.

Hypomagnesemia Total serum magnesium under 1.5 mg/dL may induce seizures.

Hypomagnesemia should be considered in neonates with hypocalcemia that persists after two appropriate doses of intravenous calcium. The immediate treatment of hypomagnesemia consists of 0.1 to 0.2 mL/kg of 50% magnesium sulfate solution intravenously or intramuscularly. Magnesium sulfate, if given intravenously, should be infused slowly over 10 minutes. If seizures continue and hypocalcemia is not present, antiepileptic drugs are indicated. The usual maintenance dose of magnesium sulfate 50% solution is 0.2 mL/kg per day administered orally

or intravenously.



Microcephaly


Autosomal Recessive Microcephaly Vera The diagnosis of autosomal recessive microcephaly vera is based on the

absence of any systemic anomaly and a history of microcephaly in the maternal or paternal families. Facial features that suggest autosomal recessive microcephaly vera are receding frontal hair, upward slanting palpebral fissures, and relatively large protruding ears. Magnetic resonance

imaging shows a small well-formed brain.

NEONATE WITH DYSMORPHIC FACIES AND ABNORMAL CHROMOSOMES

Microcephaly occurs in a large number of chromosomal syndromes. Trisomy 13, 18, and 21, and 4p-, 5p-, 13q-, 18p-, and 18q-deletions are

associated with microcephaly.

Down Syndrome

Down syndrome is characterized by typical facial features: epicanthal folds, prominent furrowed tongue, a flat nasal bridge, and oblique palpebral fissures with a flat occiput (Figure 275.1). Neonates with Down syndrome have a predisposition for duodenal atresia, congenital heart disease (particularly endocardial cushion defects), and leukemia. Chromosomal studies are indicated to confirm the diagnosis and to detect translocations. Parents with balance translocations are more likely to have other offspring with Down syndrome than parents who are not carriers of

the translocation. More about... 111

A B C


Microcephaly

Figure 275.1.— Characteristic findings in neonates with Down syndrome. [A] Upward slanting palpebral features, [B] simian crease, [C] wide space between the first and second toes.



Arm


Duchenne-Erb Palsy

The most striking manifestation of Duchenne-Erb palsy is the abnormal posture of the affected upper extremity when the neonate is moving the healthy arm (Figure 216.1). This posture consists of adduction and internal rotation of the shoulder, extension of the elbow, pronation of the forearm,

and flexion of the wrist and fingers. There is minimal weakness of the extensors of the wrist and no finger weakness.

A B

Figure 216.1.— Typical posture of a neonate with Duchenne-Erb palsy [A and B]. The posture consists of arm adduction and internal rotation, extended elbow, forearm pronation, palmar flexion of the wrist, and good finger movements. The presence of wrist flexion indicates minimal or no involvement of C7.

Duchenne-Erb palsy indicates involvement of C5 and C6 spinal segment fibers. The most frequent site of involvement of these fibers is at the upper trunk prior to the origin of the suprascapular nerve (Figure 216.2 B) but more proximal damage can also occur (Figures 216.2 A). The clinical manifestations of Duchenne-Erb palsy are so typical that it can not be confused with a lesion at any other location.


Arm

Figure 216.2.— Schematic representation of the brachial plexus and its nerves and muscles. Site of injury. A: C5 root and C6 spinal nerve; B: upper trunk; (PS): paraspinal muscles; (R): rhomboid muscle; DS: dorsoscapular nerve; LT: long thoracic nerve; (SA): serratus anterior muscle; (SS): supraspinal muscle; (IS): infraspinal muscle; SPS: suprascapular nerve; PL: pectoral lateralis nerve; (P): pectoralis muscle; PM: pectoralis medialis nerve; SF: sympathetic fibers to the eyes; (M of M): muscle of Müller; (DP): dilator pupillary muscle; (TM): teres major muscle; (SBS): subscapularis muscle; SBS: subscapularis nerves; TD: thoracodorsal nerve; (LD): latissimus dorsi muscle; MC: musculocutaneous nerve; (Bi): biceps muscle; (Br): brachialis muscle; M: median nerve; U: ulnar nerve; A: axillary nerve; (TMi): teres minor muscle; (D): deltoid muscle; R: radial nerve.





The upper motor neuron system can be simplified as having three

neurons: an upper motor neuron and two upper motor neuron helpers (Figure 96.1). The upper motor neuron is housed in the cerebral cortex and makes direct contact with the alpha motor neuron (pyramidal tract). The two upper motor neuron helpers differ in their site of origin and type of connections (extrapyramidal component). One upper motor neuron helper (#1) makes direct contact with the alpha motor neuron but it differs from the upper motor neuron because it is housed in the brainstem rather than in the cortex. The other upper motor neuron helper is housed in the cerebellum (#2) and does not make contact with the lower motor neuron. This second upper motor neuron helper is housed in the cerebellum and makes contact with the upper motor neuron through a neuron housed in the brainstem.

Figure 96.1.— Schematic representation of the different neurons that make the upper motor neuron system.

For the purpose of remembering the possible sites of pathology in neonates with generalized hypotonia it is not necessary to account for the upper motor neuron helper #1. However, it is important to understand the relation between the upper motor neuron and the upper motor neuron helper #2, and the regions of the central nervous system they occupy (Figure 96.2).



Figure 96.2.— Schematic representation of the relation between relevant regions of the central nervous system and the upper motor neuron system in generalized hypotonia. The axons of the upper motor neurons cross to the opposite side; those for the cranial nerve muscles cross at the upper levels of the brainstem whereas those for the spinal nerve muscle cross at the lower medulla. The neurons and axons of the upper motor neuron system are represented by the red area and lines. Also represented in this figure is the upper motor neuron helper #2 illustrated as dark pink squares in the cerebellum.





Neostigmine has maximal effect in 15 to 30 minutes and it lasts for 1 to

3 hours. Edrophonium has maximal effects in 3 to 5 minutes and it lasts for 10 to 15 minutes. Neostigmine is usually preferred. These tests should be performed after choosing a quantifiable clinical sign and atropine must be readily available to eliminate the possible side-effects of neostigmine and edrophonium (bradycardia, diarrhea, and profuse tracheal secretions). Serum creatine phophokinase and cerebrospinal fluid are normal. Repetitive nerve stimulation at 10 impulses per second results in 40% decrease in motor unit potential amplitude within 1 second. These findings can be corrected by neostigmine and edrophonium. The treatment of neonatal transient myasthenia gravis consists of nasogastric feeding and respiratory support when necessary, and the use of anticholinesterase therapy. Therapy should be started with intramuscular neostigmine 0.1 mg/kg approximately 30 minutes before feeding. Once stable and swallowing well, oral neostigmine should be started at a dose of 1 mg/kg. This oral dose should be given about 1 to 2 hours prior to feeding. Neostigmine

treatment is usually needed for about one month.

Hereditary Myasthenia Gravis Syndromes Hereditary myasthenia gravis refers to a group of congenital disorders

that affect the myoneural junction. They may be presynaptic or postsynaptic. Hereditary myasthenia gravis syndromes may present with sustained weakness from birth or with episodic weakness starting a few days after birth. In the latter situation, weakness usually starts several hours after waking up from sleep. Two syndromes are recognized in the neonatal period: familial infantile myasthenia gravis and congenital myasthenia gravis. Cranial nerve dysfunction is prominent in both. Signs of medullary and facial cranial nerve dysfunction predominate in familial infantile myasthenia gravis. Ocular findings predominate in congenital myasthenia gravis. Hereditary myasthenia gravis syndromes are diagnosed by observation of the response to parenteral anticholinesterase medication and a pathological decremental or incremental response to repetitive nerve stimulation.

The hereditary myasthenia gravis syndromes have autosomal recessive inheritance in most cases. They are treated with neostigmine. The dose and timing of neostigmine should be similar to that used for transient myasthenia gravis. Treatment should be continued for at least 1 year even

if symptoms disappear.




Connective Tissue Abnormalities

Connective tissue abnormalities produce hypotonia by decreasing the spring-like properties of the collagen fibers. The hallmark of connective tissue abnormalities is the presence of lax joints. Lax joints can be assessed by gently bending the joints and observing their maximal angulation. Lax joints bend farther than normal joints. Dynamic muscle tone is not significantly affected by connective tissue abnormalities. Several connective tissue diseases may produce hypotonia in the neonatal period. Ehlers-Danlos syndrome is the most frequent. Ehlers-Danlos syndrome type I is a hereditary (autosomal dominant) connective tissue disorder.

Neonates with Ehlers-Danlos syndrome type I are usually born prematurely due to friability of the amniotic sack. Evidence of collagen dysfunction is especially noticeable in the skin, blood vessels, and tendons. Neonates with Ehlers-Danlos syndrome type I usually have signs of joint

hyperelasticity, bilateral hip dislocation, and hyperextensible skin.





ENCEPHALOCELE

Encephaloceles are due to failure of the anterior neuropore to close. In the general population, about 75% of the encephalocele are located in the occipital region (Figure 258.1). The diagnosis of an occipital encephalocele is usually obvious (Figure 258.1), but occasionally it requires a high index of suspicion (Figure 258.2).

A B

Figure 258.1.— [A] Large occipital encephalocele. [B] CT of the brain showing brain tissue protruding through an occipital bone opening.

Subtle occipital encephalocele (Figure 258.2) may increase in size during the neonatal period. In high occipital encephalocele, other central nervous system abnormalities are usually not present. In low occipital encephalocele, there may be associated cerebellar and brainstem abnormalities.

Meckel-Gruber syndrome is characterized by posterior encephalocele, microcephaly with sloping forehead, cerebral and cerebellar hypoplasia, polydactyly, polycystic kidney, and cryptorchidism. Meckel-Gruber syndrome has an autosomal recessive inheritance.

A B



Figure 258.2.— [A] Small encephalocele high in the occipital region characterized by a patch of dark hair and small bold area with a red

protruding mass. [B] MRI of the brain demonstrating the location of the encephalocele.

Anterior encephaloceles are more common than posterior encephaloceles among neonates of oriental ancestry. The possibility of an anterior nasal encephalocele should be considered in any neonate with an apparent clonal atresia. Parietal encephaloceles are rare.

Magnetic resonance imaging or CT are the studies of choice in neonates with encephalocele (Figures 258.1,2,3). The point of origin of the occipital encephalocele is determined by observation. The point of origin of anterior encephalocele may be difficult to determine, especially if it is in the nasal or oral region. Determining the origin of the encepalocele in these patients may require special MRI or CT views. In addition to the origin of the encephalocele, MRI and CT of the brain usually demonstrate the presence of associated brain and brainstem anomalies. The treatment of encephalocele is surgical.

A B

Figure 258.3.— [A] Posterior parietal encephalocele; [B] MRI of the brain demonstrating the encephalocele and hydrocephalus.

MENINGOMYELOCELE



Meningomyeloceles are a type of spina bifida [Types of spina bifida? ]. Meningomyeloceles usually occur in the lumbosacral region (Figure 258.4). Lumbar myelomeningoceles are due to failure of the posterior neuropore to close. Myelomeningoceles that involve the lumbar region are more likely to be associated with hydrocephalus than myelomeningoceles at any other level of the spinal cord. Signs of hydrocephalus are full anterior fontanelle, wide sagittal sutures, and a large head. Signs of hydrocephalus usually occur by 6 weeks of age. Treatment of myeolomeningocele is surgery as soon as possible. If the myeolomeningocele is not covered by skin, the sack should be kept moist and sterile prior to surgery. Endoscopic coverage of fetal myelomeningocele in utero may prevent damage to the spinal cord by avoiding the exposure of the spinal cord to the urea-rich amniotic fluid

produced late in pregnancy. Echocardiograms are warranted in neonates with myelomeningocele since cardiac malformation occurs in 39% of

these patients.

Figure 258.4.— Lumbar myelomenigocele with a partially skin-covered sac.





ENCEPHALOCRANIOCUTANEOUS LIPOMATOSIS

The hallmark of encephalocraniocutaneous lipomatosis is the presence of a large, soft, unilateral, slightly protuberant mass in the craniofacial region (Figure 304.1). The skin above the mass is devoid of hair. A fleshy pterygium-like lesion is usually present on the sclera.

Neonates with encephalocraniocutaneous lipomatosis may present with seizures and hypotonia. Hydrocephalus may develop later. Magnetic resonance imaging usually shows cerebral atrophy ipsilateral to the cutaneous lesions, porencephalic cysts, intracranial lipomas, and vascular malformations. Spinal cord involvement (lipomas) may occur in encephalocraniocutaneous lipomatosis. Encephalocraniocutaneous

lipomatosis is a sporadic disorder.

Figure 304.1.— Large soft protuberant mass under the bald area in a patient with encephalocraniocutaneous lipomatosis.





Tentorial laceration may produce a tear in the vein of Galen, straight sinus, or transverse sinus. Occipital osteodiastasis consists of a separation between the squama occipitalis and the lateral portion of the occipital bone. Occipital osteodiastasis may result in rupture of the occipital sinus. Infratentorial subdural hematoma may present clinically 2 to 4 days after birth in a previously normal neonate. Signs of brainstem dysfunction, increased intracranial pressure, and nuchal rigidity may be present. The most frequent signs of brainstem dysfunction are skew deviation unchanged by caloric testing, asymmetric pupils, and bradycardia.

ERRORS OF METABOLISM

An inborn error of metabolism should be suspected in every comatose neonate. The level of suspicion should be raised if the neonate has: (1) a peculiar odor; (2) a combination of truncal hypotonia and limb hypertonia; (3) brainstem dysfunction; (4) signs of increased intracranial pressure; (5) stimulus-sensitive myoclonus; (6) abnormal respirations in the absence of cardiac or respiratory disease; or (7) a family history of unexplained death, metabolic disease, or parental consanguinity. A symptom-free interval lasting for a few days after birth may occur with some inborn errors of metabolism.

The blood, urine, and cerebrospinal fluid investigations that should be performed in a patient suspected of having an inborn error of metabolism include: (1) venous blood for CBC and platelets, liver function tests, glucose, lactate, pyruvate, ammonia, total and acyl-carnitine, uric acid, biotinidase, and amino acids; (2) arterial pH; (3) urine for ketones, sulfite, and organic acids; and (4) cerebrospinal fluid for amino acids (especially

glycine) and lactate.

Coma due to an inborn error of metabolism is produced by enzymatic defects in the metabolism of proteins, fats, carbohydrates, and pyruvate, or abnormalities of the citric cycle, mitochondrial respiratory chain, and urea cycle. These disorders can not be clinically distinguished from each other. Their diagnoses depend on specific laboratory findings.





Hypotonic neonates suspected to have a traumatic brain injury should have an MRI or CT of the brain. In neonates with traumatic brain injury, MRI or CT may show evidence of intracranial bleeding, cerebral contusion, or both (Figure 108.1). Intracranial blood may be found in the

epidural, subdural, or arachnoid spaces; parenchyma; or ventricles. Epidural hematoma refers to blood between the inner surface of the bone and the periosteum. Epidural hematomas are confined to the individual bone because the blood collection is restricted by the periosteum attachment to each bone. They appear as convex masses on neuroimaging studies (Figure 108.1 [A]). The blood does not enter into the sulci or fissures of the brain. Subdural hematoma refers to blood between the dura and the arachnoid. The hematoma is not confined to an individual bone. The subdural hematoma collection appears as a concave mass on imaging studies. The blood does not enter into the sulci or fissures of the brain in neonates with epidural and subdural hematomas.

A B C

Figure 108.1.— [A] Epidural bleeding, small intraparenchymal bleed on the opposite frontal hemisphere. [B] Intraventricular hemorrhage around the ventricles, intraparenchymal blood, and cerebromalacia in the right occipital lobes. [C] Intraventricular blood in the occipital horns of the lateral ventricles.




HEMORRHAGES AND HEMATOMAS

Central nervous system hemorrhages and hematomas may occur in any

area of the brain, brainstem, cerebellum, or spinal cord. Bleeding in the CNS is classified according to its relation to the piamater. Bleeding that occurs in areas external to the piamater are referred to as extra-axial hematomas or hemorrhages. Bleeding that occurs in areas internal to the piamater are referred to as intra-axial hematomas. Intra-axial hematomas occur in the parenchyma, choroid plexus, and ventricles.

EXTRA-AXIAL HEMORRHAGES AND HEMATOMAS

Extra-axial hematomas may be localized to the epidural, subdural, and arachnoid/subarachnoid spaces. The distinction between epidural and subdural hematomas is not always anatomically possible because both compartments may be simultaneously involved.

EPIDURAL HEMATOMAS

Epidural hematomas are located between the bone and the internal periosteum. They may occur in the anterior, medial, and posterior fossi, and in the spinal canal. Epidural hematomas are usually produced by trauma but the possibility of a clotting disorder should be considered. Epidural hematomas tend to produce paroxysmal clinical events, decreased limb movements (monoparesis, hemiparesis, paraparesis, upper extremity diplegia, and quadriparesis), facial weakness, or coma. The study of choice to diagnose epidural hematoma in the cranial vault is CT of the brain. The study of choice to diagnose epidural hematoma in the spinal canal is MRI of the spine. The blood in epidural hematomas does not cross the bone sutures (convex inner surface is convex) nor does it enter into the fissures and sulci (Figure 250.1 [A]). The convexity of the inner surface occurs because the blood pools in the center area of each bone since the periosteum is limited to each bone and tightly attached to the bone edges. The treatment of epidural hematomas is dictated by their clinical manifestations. Drainage of the blood collection is necessary if symptoms are progressive or there are signs of impending herniation.



SUBDURAL HEMATOMAS

Subdural hematomas are localized between the periosteum and the arachnoid. Subdural hematomas are usually produced by trauma but the possibility of a clotting disorder should be considered. Subdural hematomas may be asymptomatic. Small subdural hematomas of the falx cerebri and the tentorium cerebri are frequently present after vaginal delivery in asymptomatic neonates. Most neonates with small subdural

hematomas have normal neurological development. Large subdural hematomas may produce paroxysmal clinical events, decreased limb movements (monoparesis, hemiparesis, paraparesis, upper extremity diplegia, and quadriparesis), facial weakness, or coma. The study of choice to diagnose subdural hematoma in the cranial vault is CT of the brain. The study of choice to diagnose subdural hematoma in the spinal canal is MRI of the spine. The blood in subdural hematomas crosses the bone sutures (concave inner surface is convex) but does not enter into the fissures and sulci (Figure 250.1 [B]). The collection of blood is concave because it is not restricted by the individual periosteum of each bone. The treatment of subdural hematomas is dictated by the clinical manifestations. Drainage of the blood collection is necessary if symptoms are progressive or there are signs of impending herniation. Treatment of anemia and hyperbilirubinemia may be necessary. More about... 53, 286

A B

Figure 250.1.— [A] CT of the brain demonstrating epidural hematoma, subarachnoid hematoma, and intraparenchymal punctate hemorrhages. [B] MRI of the brain demonstrating bilateral subdural hematomas.



Facial Weakness


Facial Molding

Facial molding is a musculoskeletal deformation (Figure 171.1). It is usually due to compression of the face against the walls of the uterus or the neonate’s own shoulder. Although the area involved by the asymmetry may vary, the jaw is the area most often involved. Marked malocclusion of the alveolar process may occur with jaw deformities. Treatment is usually

not needed. The deformity is usually not noticeable by one year of age.

A B

Figure 171.1.— Facial molding. The right jaw appears sharper while the left is fuller. The facial asymmetry is present during [A] crying and [B] quiet awake.

Plagiocephaly

Plagiocephaly or asymmetrical craniosynostosis may produce an asymmetrical face (Figure 171.2).

A B C


Facial Weakness

Figure 171.2— Asymmetrical face due to plagiocephaly. The asymmetry is present while asleep [A], awake [B], and when crying [C].

Unilateral lambdoid and coronal sutures (Figure 171.3) synostosis are frequent causes of facial asymmetry. Plagiocephaly should be corrected surgically by 4 to 6 months of age.

A B C

Figura 171.3— Right coronal sutures synostosis. [A] Deviation of the sagittal suture and abnormal shape of the anterior fontanelle; the orbits are of different sizes. [B] Coronal suture synostosis. [C] Normal coronal suture.

Facial Tumors Facial tumors in the neonate are rare. The distribution of the asymmetry

is related to the location and size of the tumor. In most cases there is an obvious mass. The asymmetry may change with action but it will never disappear (Figure 171.4).

A B


Facial Weakness

Figure 171.4.— Facial hemangioma. The facial asymmetry is less apparent during [A] quiet awake than when [B] crying .

The most frequent tumors in the facial region are teratomas,

adenocarcinomas, and carcinomas arising in the area of the parotid and salivary glands. Lymphangiomas (cystic hygromas) of the neck may grow large enough to produce facial distortion (Figure 171.5). Facial tumors

usually require surgery.

Figure 171.5.— Large neck lymphangioma producing facial asymmetry.



Facial Weakness


The facial motor system is a two-motor neuron system (Figure 175.1). The facial upper motor neuron component arises from cortical neurons in the lower third of the precentral gyrus. The axons of these neurons travel ipsilaterally in the centrum semiovale, genu of the internal capsule, and midbrain. At the level of the upper pons, they cross to the opposite side and make contact with the motor neurons located in the facial nerve motor nucleus. These motor neurons constitute the second component of the two-motor neuron system. The motor neurons in these nuclei destined to innervate the upper facial quadrant also receive ipsilateral innervation, while those destined to innervate the lower quadrant facial muscles only receive contralateral innervation.

Figure 175.1.— Facial motor system. T: thalamus; AC: internal auditory canal; FC: facial canal; SMO: stylomastoid orifice; BB: buccal branch; MB: mandibular branch; TB: temporal branch; OOM:


Facial Weakness

orbicularis oculi muscle; RM: risorius muscle; DAOM: depressor angularis oris muscle; BM: buccinator muscle; MM: mentoris muscle. Llight blue line indicates components of the facial nerve that have ipsilateral (hence bilateral) cortical innervation; dark blue line indicates components of the facial nerve that have contralateral innervation.



Facial Weakness


Facial nerve malformation

Damage to the facial nerve may occur with or without petrous bone malformation. (Figure 183.1) Facial nerve damage is often associated with deafness and abnormal ears.

A B

Figure 183.1.— Lower motor neuron facial weakness. [A] Asymmetrical facial grimacing. [B] Brain CT demonstrating an abnormal left petrous bone.

Facial nerve damage with or without radiological evidence of petrous bone malformation occurs in CHARGE association (Figure 183.2). CHARGE stands for C-coloboma, H-heart disease, A-atresia choanae, R-retarded growth and retarded development, G-genital hypolasia, E-ear anomalies. In a large series, facial palsy occurred in 38% of patients with

CHARGE syndrome.

A B


Facial Weakness

Figure 184.2.—CHARGE association. [A] Asymmetrical facial grimacing and cleft palate. [B] Ear abnormality.

Facial nerve damage due to parotid gland tumor Tumors of the parotid gland may involve the facial nerve (Figure

183.3). Nonneurological findings associated with facial nerve damage include evidence of facial trauma, hemotympanum, skull fracture, and

signs of infection or hemangioma of the parotid gland (Figure 183.2).

A B C

Figure 183.3— Facial asymmetry due to parotid gland hemangioma. The asymmetry is present [A] while crying but [B] not during quiet awake. [C] The parotid hemangioma creates a bluish mass behind the ear.

Nonneurological findings associated with facial nerve damage include evidence of facial trauma, hemotympanum, skull fracture, and signs of

infection or hemangioma of the parotid gland (Figure 183.2).


Facial Weakness

The diagnosis of a facial nerve lesion may be confirmed by electrodiagnostic studies. Nerve conduction studies determine threshhold, latency, and amplitude of the compound muscle potential in the normal and the affected side. Electromyography shows fibrillations and positive sharp waves 12 to 14 days after the injury. An EMG abnormality in the first 48 hours of life implies that the injury occurred before delivery. Computed tomography of the petrous bone may be used to evaluate the

osseous facial nerve canal and the middle ear.

The temporal evolution of peripheral facial nerve deficit depends on whether the damage is transient, permanent, or progressive. Transient deficits improve starting with the forehead and periocular

muscle. Permanent deficits remain unchanged. Deterioration implies a complication requiring neurodiagnostic studies to determine its cause.

A facial nerve lesion is distinguished from an intrapontine facial lesion by the absence of signs of involvement of the central sympathetic tract, cranial nerve VI, and upper motor neuron limb weakness. Treatment is dictated by the etiology. At an older age, nerve grafting and muscle transplantation may be performed in selected cases. Tumors may require surgery. Congenital petrous bone abnormalities do not have specific

treatment. Traumatic cases usually do not require treatment.



Arm


SPASTIC ARM MONOPARESIS

Spastic arm monoparesis is characterized by increased muscle stretch reflexes in the biceps, brachioradialis, and triceps, and exaggerated Moro reflex. The weak arm moves as much or more than the normal arm during a Moro reflex (Figure 208.1).

A B

Figure 208.1— Neonate with spastic right arm monoparesis. [A] At rest, the right arm does not move. [B] During Moro reflex, the right arm motion is appropriate. This neonate had left hemispherectomy for the control of seizures. He was born with left hemimegalencephaly.

Spastic arm monoparesis does not develop until 1 or 2 weeks after an acute injury. The site of injury of the upper motor neuron may be at the brain, midbrain, pons, medulla, or rostal spinal cord (Figure 208.2 A-D). The distinction among the different possible sites of central nervous system injury is based on the distribution of weakness in the arm, the presence and characteristics of facial weakness, and the associated neurological and nonneurological findings.


Arm

Figure 208.2.— Sites of possible nervous system injury that can produce arm monoparesis. A: brain to midbrain; B: upper pons; C: lower pons and medulla; D: rostal spinal cord; E: brachial center; F: brachial plexus; G: peripheral nerves; V: ventricles; T: thalamus; UQ: upper quadrant; FN: facial nerve; LQ: lower quadrant; BP: brachial plexus; LSP: lumbosacral plexus. The colored rectangles indicate the location of weakness produced by damage to the different components of the somatic motor system.





FOCAL PERIPHERAL NERVOUS SYSTEM LESIONS

FACIAL NERVE

Trauma Facial nerve damage in the neonate is usually traumatic. Trauma usually

occurs just after the facial nerve exits from the facial canal through the stylomastoid orifice. Intracanalicular trauma is much less frequent. Petrous bone fractures may be present with traumatic facial nerve injury. Petrous bone fractures are often associated with hemotympanum. Petrous fractures

are better detected by CT than by MRI.

Congenital Anomalies Anomalies of the facial nerve canal may occur with or without

associated inner ear anomalies. Computed tomography of the petrous bone may show anomalies of the inner ear (Figure 259.1) or just a narrow

canal.

A B

Figure 259.1.— [A] Left facial palsy. [B] CT of the petrous bone demonstrates evidence of left inner-ear malformation.



Tumors

Tumors in the parotid glands may produce facial nerve palsy. The most common tumors in this area are lymphangiomas and hemangiomas (Figure

259.2).

A B

Figure 259.2.— [A] Right facial nerve lesion. [B] Hemangioma of the parotid gland.

SYMPATHETIC FIBERS

Tumors

Neuroblastoma of the cervical sympathetic chain may produce Horner syndrome. Vanillylmandelic acids and homovanillic acid may be elevated

in the urine.



Arm


Horner syndrome may be present in Klumpke palsy. Horner syndrome occur

in neonates with Klumpke palsy when the anterior root, spinal nerve, and proximal region of the ventral ramus are affected. This is so because these structures carry the sympathetic fibers that innervate the constrictor muscle of the iris and the muscle of Müller. Horner syndrome does not occurs with Kumpke palsy, which occur as the result of an injury beyond the ventral ramus because the sympathetic fibers leave the brachial plexus at this level (Figure 221.1).

Figure 221.1.— Site of injury in Klumpke palsy. [A] Root of T1 and spinal nerve of C8. [B] Lower trunk. The green lines at T1 represent the most frequent origin of sympathetic fibers for the eyes. (PS): paraspinal muscles; (R): rhomboid muscle; DS: dorsoscapular nerve; LT: long thoracic nerve; (SA): serratus anterior muscle; (SS): supraspinal muscle; (IS): infraspinal muscle; SPS: suprascapular nerve; PL: pectoral lateralis nerve; (P): pectoralis muscle; PM: pectoralis medialis nerve; SF: sympathetic fibers to the eyes; (M of M): muscle of Müller; (DP): dilator pupillary muscle; (TM): teres major muscle; (SBS): subscapularis muscle; SBS: subscapularis nerves; TD: thoracodorsal nerve; (LD): latissimus dorsi muscle; MC: musculocutaneous nerve; (Bi): biceps muscle; (Br): brachialis muscle; M:


Arm

median nerve; U: ulnar nerve; A: axillary nerve; (TMi): teres minor muscle; (D): deltoid muscle; R: radial nerve.

Horner syndrome manifests by ipsilateral ptosis and miosis. The eyelid asymmetry is not present when the patient cries or is asleep (Figure 221.2). The lack of pigmentation in the affected eye leads to a different color of the iris. This color difference is not noted in the immediate neonatal period nor is it noticeable in all patients. The color difference is noted if and when the iris of the eye not affected by the Horner syndrome becomes darker as the result of normal pigmentation. In the absence of Horner syndrome or the classical Klumpke posture of the arm, weakness restricted to the hand raises the possibility of a cortical lesion in the region of the hand. An MRI of the brain may be necessary to eliminate this possibility.

A B

Figure 221.2.— Horner syndrome. [A] The right eye opening is smaller than the left when the patient is awake. [B] The asymmetric eye opening is not present when the neonate is crying.



Microcephaly


Fetal Hyperphenylalaninemia Syndrome

Mothers with hyperphenylalaninemia may give birth to neonates with microcephaly. Phenylalanine levels are higher in the fetus than in the mother (at a ratio of about 3:2). Mothers with hyperphenylalaninemia may have a history of phenylketonuria or may be unaware of their condition. In addition to microcephaly, neonates with hyperphenylalaninemia syndrome may have: a round face with prominent glabella and epicanthal folds, short palpebral fissures, poorly developed but long philtrum, thin upper lip, and small upturned nose. Cardiac anomalies may be present. These characteristics are not present in all neonates with intrauterine exposure to hyperphenylalaninemia; therefore, fetal hyperphenylalaninemia syndrome should be considered in all neonates with unexplained microcephaly. The diagnosis is confirmed by finding an elevated phenylalanine level in maternal blood. Future pregnancies should be closely monitored. A maternal phenylalanine level should be kept between 120 and 360 mmol/L (2 to 6 mg/dL) before conception and during pregnancy. Women with elevated phenylalanine levels should also take multivitamins including

B12 and folic acid.

Fetal Alcohol Syndrome

Alcohol exposure during early pregnancy is a common cause of mental retardation. The earlier the exposure and the larger the amount of alcohol ingested, the more likely it is for fetal alcohol syndrome to occur. Microcephaly is one of the most consistent features in fetal alcohol syndrome in neonates. In addition, neonates are shorter and thinner than normal and have characteristic facial features. The characteristic facial features are short palpebral fissures, epicanthal folds, midfacial hypoplasia, low nasal bridge with short upturned nose, long hypoplastic philtrum, and a long upper lip with a narrow vermilion border. Limb abnormalities occur less often than facial abnormalities. The limb abnormalities include palmar crease abnormalities and joint contractures.



Arm


Other neurological findings that may help to localize the lesion in a patient with spastic arm weakness are the presence of seizures and gaze preference. Seizures are more common with cortical or subcortical lesions than with lesions below these areas. Convulsions usually involve the weak arm and may become generalized. Gaze preference may occur with spastic arm weakness.

Spastic arm weakness is due to a focal central nervous system lesion. The evaluation of a neonate with spastic arm weakness should include MRI and MRA of the brain. Magnetic resonance imaging and angiography of the brain usually localize the lesion. If MRI and MRA are normal, an MRI of the upper cervical spine should be done.

FLACCID ARM MONOPLEGIA

Neonates with flaccid arm monoplegia have decreased frequency and strength of movement of the affected limb (Figure 211.1 [A]). They also show absence or decreased movement during the Moro reflex (Figure 211.1 [B]) and decreased biceps, brachioradialis, and triceps muscle stretch reflexes. The location of the lesion in a neonate with flaccid weakness may be in the upper motor neuron or in the lower motor neuron.

A B

Figure 211.1.— Flaccid arm monoparesis. [A] The left arm rests motionless. [B] The Moro reflex does not elicit movement of the weak arm.


Leg Monoparesis, Hemiparesis, Paraparesis, and Bilateral Arm Weakness


FLACCID LEG MONOPARESIS

Flaccid leg monoparesis may occur with any lesion in the central or peripheral components of the lumbosacral somatic motor system. Flaccid leg monoparesis may occur with: (1) recent lesions in the central component of the somatic lumbosacral motor system at sites similar to those that produce spastic leg monoparesis (Figure 235.1 [A-E]); (2) cerebellar lesions; and (3) lesions in the peripheral component lumbosacral somatic motor system (lumbosacral center (Figure 235.1 [F]), cauda equina (Figure 235.1 [G]), lumbosacral plexus (Figure 235.1 [LSP]), or peripheral nerves.

Figure 235.1.— Schematic representation of the cortical component of the somatic motor system and sites of possible injuries causing leg monoparesis. The colored rectangles indicate the location of weakness produced by damage to the different components of the somatic motor system. V: ventricles; T: thalamus; UQ: upper quadrant; LQ: lower



quadrant; BP: brachial plexus; LSP: lumbosacral plexus. A: brain and midbrain; B: upper pons; C: lower pons and medulla; D: upper spinal cord above the brachial center; E: lower spinal cord below the brachial center but the above the lumbosacral plexus; F: lumbosacral motor center; G: lumbosacral plexus; H: lower extremity peripheral nerves.





Patients with amyoplasia congenita do not have evidence of brain,

cardiac, or genitourinary tract abnormality. Bowel atresia and gastroschisis have been reported. The cause of amyoplasia congenita is unknown. Fetal spinal cord disruption due to systemic hypotension producing anterior horn cell ischemia is the most likely explanation. Amyoplasia congenita is a sporadic condition. This is an important condition to recognize since the chances of recurrence are low and the prognosis is good. Muscle biopsies may show evidence of myopathy and neuropathy. Amyoplasia congenita is the final diagnosis in about one-third of neonates with arthrogryposis.

Spinal Cord Abnormalities

Traumatic spinal cord injury usually occurs during delivery. It should be suspected if no cause for arthrogryposis is found and there are no signs of brain or brainstem involvement. Magnetic resonance imaging of the spine is indicated. Arthrogryposis of the lower extremities has been reported with lumbosacral meningocele (Figure 163.1) and with sacral

agenesis.

A B

Figure 163.1.— [A] Arthrogryposis of the lower extremities (after

surgery). [B] MRI of the spine demonstrating a lumbosacral meningocele.

ALPHA MOTOR NEURON



Infantile Spinal Muscular Atrophy

Arthrogryposis multiplex congenita occurs in 10% to 20% of neonates

with infantile spinal muscular atrophy. Deoxyribonucleic acid studies for infantile spinal muscular atrophy should be performed in neonates with unexplained arthrogryposis. The prognosis of arthrogryposis due to infantile spinal muscular atrophy is poor. Autosomal recessive and X-linked inheritance have been reported.

Infantile Neuronal Degeneration Infantile neuronal degeneration can only be diagnosed by performing an

autopsy. The autopsy findings reveal anterior horn motor neuron atrophy and degenerative changes in the Clarke’s column; corticospinal tracts; spinocerebellar and spinothalamic tracts; Purkinje cell layer; and dentate and ventral thalamic nuclei. It presents with EMG findings of infantile spinal muscular atrophy and delayed sensory and motor conduction. Deoxyribonucleic acid study for Werdnig-Hoffmann disease is

normal.

Focal Spinal Muscular Atrophy

Arthrogryposis multiplex involving only the upper or the lower extremities occurs with congenital focal cervical or lumbar spinal

atrophy.





When both the upper motor unit system and the motor-sensory unit are

involved, signs of one or the other tend to predominate. In general, signs of upper motor neuron system dysfunction predominate early, while those of the motor-sensory unit predominate later.

Diseases of the upper motor neuron should be further localized to one of the following anatomical structures: brain, brainstem, cerebellum, or spinal cord. Although these structures may be involved simultaneously, one tends to predominate in most cases. Localization is pivotal in determining the most likely pathological process involved and the most likely etiology.

BRAIN

Brain lesions may produce generalized hypotonia with decreased or increased dynamic tone. The findings associated with cerebral hypotonia in neonates are seizures, lethargy, subcortical release phenomena, myoclonus, irritability, gaze preference, evidence of inappropriate antidiuretic hormone secretion, hypothermia, abnormal retinal findings, microcephaly, macrocephaly, facial dysmorphism, skull fracture, and abnormalities in EEG, visual evoked response, and brain imaging (Figure 105.1). The pathological processes that affect the brain are trauma, metabolic disorders, chromosomal and genetic abnormalities, and degenerative diseases.



Figure 105.1.— Cerebral hypotonia. Red arrow indicates the anatomical location of involvement. IADH: increased antidiuretic hormone secretion; Symbol by the side of GAZE PREFERENCE indicates that it may be overcome by cold caloric testing; SCRP: subcortical release phenomena; Purple cube: tests often abnormal in cerebral hypotonia; US: ultrasound; EEG: electroencephalogram; VER: visual evoked responses; CT: computerized tomography; MRI: magnetic resonance imaging;





Hypotonia with decreased or normal dynamic tone is generalized,

proximal more than distal, and particularly involves the face and neck muscles. Dysphagia and respiratory compromise are less common. Extraocular movements are usually normal. The disease is always progressive but an apparent initial improvement in muscle strength sometimes occurs during the neonatal period. Some patients with congenital muscular dystrophy have associated brain anomalies. Fukuyama congenital muscular dystrophy is associated with cerebral and cerebellar gyral abnormalities (migrational errors) and occasionally white matter hypodensity on CT. Congenital muscular dystrophy with white matter hypodensity on CT, but without gyral abnormalities, have been reported. Walker-Warburg syndrome consists of congenital muscular dystrophy with cerebral and cerebellar gyral abnormalities, white matter hypodensity on CT, and ocular abnormalities (congenital glaucoma, retinal and optic nerve hypoplasia, and cataracts). The absence of brain malformation on CT or MRI is highly indicative of normal intellect.

Treatment of all congenital muscular dystrophies is supportive.

Polymyositis Polymyositis produces marked hypotonia with decreased dynamic tone

(especially in neck muscles), weak cry, and poor sucking and feeding ability. Serum creatine phosphokinase is very elevated. Electromyography shows fibrillations and brief and small motor unit potentials. Muscle biopsy shows muscle destruction with lymphocytic infiltration. Steroid

treatment is beneficial.



Microcephaly


Periventricular calcifications are not pathognomonic of cytomegalovirus. Periventricular calcifications occur because CMV has a predilection for the germinal matrix tissue, causing necrosis of the

ependyma. Migration errors are best diagnosed by MRI of the brain. The diagnosis of congenital CMV central nervous system infection is established by detecting CMV DNA in urine by polymerase chain reaction or CMV-specific IgM detection. Placentitis should be present on pathological evaluation. Brain auditory evoked potentials should be performed in all neonates suspected of CMV exposure. Sensorineural hearing loss may be the sole manifestation of congenital CMV infection. Sensorineural hearing loss may be progressive.

Ganciclovir has been used to treat congenital central nervous system CMV infection. It does not change neurological outcome, since most damage is done prior to birth. Ganciclovir may prevent progression of

sensorineural hearing loss.

Toxoplasmosis Congenital toxoplasmosis is produced by Toxoplasma gondii. This

protozoan parasite is more likely to cross the placenta in the last trimester of pregnancy; nevertheless, central nervous system and ocular manifestations are more frequent in fetuses infected during the first trimester. Microcephaly may occur in neonates with central nervous system toxoplasmosis infection but macrocephaly due to hydrocephalus as a result of aqueductal stenosis may also occur. Seizures often occur. Toxoplasmosis produces parenchymatous and periventricular calcifications (Figure 278.1). Porencephaly and hydranencephaly may also occur. Cerebrospinal fluid pleocytosis is often present.


Microcephaly

Figure 278.1.— Computed tomography of the brain in a neonate with toxoplasmosis demonstrating many intraparenchymal and periventricular calcifications.

Chorioretinitis is present in most neonates with central nervous system involvement (Figure 278.2). Chorioretinitis is usually bilateral and involves the macular region. Hepatomegaly, hyperbilirubinemia, and anemia are systemic manifestations of congenital toxoplasmosis.

Figure 278.2.— Typical appearance of toxoplasma chorioretinitis.





Bacterial meningitis can only be excluded in the presence of a negative

cerebrospinal fluid culture if antibiotics were not previously used and there is an alternative explanation for coma. The initial choice of antibiotic therapy, prior to organism identification, varies greatly. Our choice is a combination of ampicillin (300 mg/kg per day divided in 2 doses in the first 7 days of life and 300 mg/kg per day divided in 3 doses thereafter) and gentamicin. In full term neonates, gentamicin is given at a dose of 2.5 mg/kg every 12 hours during the first 7 days of life and 2.5 mg/kg per dose every 8 hours thereafter. In premature neonates over 1000 grams, gentamicin is given at a dose of 2.5 mg/kg every 18 hours; in premature neonates weighing less than 1000 grams, gentamicin is given at a dose of 2.5 mg/kg every 24 hours. Gentamicin blood levels should be monitored. The final choice of antibiotics is determined from the results of CSF culture growth and sensitivity.

Herpes simplex encephalitis is usually caused by herpes simplex virus type 2 and occasionally type 1. The initial symptoms of encephalitis are irritability and seizure followed by coma. Encephalitis may present in an otherwise healthy-looking neonate or in a neonate with overt clinical evidence of systemic herpes simplex infection. Conjunctivitis and a vesicular eruption on the scalp or buttocks may be present. Giemsa staining of the scraping from the base of the vesicles reveals multinucleated giant cells with intranuclear inclusion (Figure 68.1). Viral antigens may also be detected from the vesicles smear by immunofluorescence. A periodic pattern of slow-wave or spike discharges

is often seen on EEG. Cerebrospinal fluid shows polynuclear or mononuclear pleocytosis, increased protein, and an increased number of red cells if hemorrhagic necrosis of the brain parenchyma has occurred.

Figure 68.1.— Giemsa stain showing multinucleated giant cells.




The previously described scheme may avoid the need for ventriculoperitoneal shunting in some patients (Figure 254.1). Stabilization of head growth and decreased ventricular size are signs that serial lumbar punctures with or without medication are effective.

Figure 255.1.— Ultrasonographic findings in a patient with resolution of progressive hydrocephalus treated with serial lumbar punctures. Sizes of the head circumference are at the top or the bottom of each ultrasound. Days of age are in the corners of each study. The first lumbar puncture was done at 14 days and the last at 32 days.

Failure of serial lumbar punctures is usually reflected by an increase in ventricular size and increased head growth (Figure 255.2). An increase in head circumference alone is not a good indication of progressive ventriculomegaly since the head circumference of healthy neonates may grow at a rate of 1 cm per week shortly after their general condition improves.



Figure 255.2.— Ultrasonographic findings in a patient with progressive hydrocephalus that required ventroperitoneal shunting despite serial lumbar punctures and medication. Sizes of the head circumference are at the top or the bottom of each ultrasound. Days of age are in the corner of each ultrasound. The first lumbar puncture was done at 16 days and the last at 38 days.

Progression of ganglionic germinal matrix bleed to periventricular hemorrhagic infarction

Germinal matrix bleed may progress to periventricular hemorrhagic infarction (Figure 255.3). Periventricular hemorrhagic infarction may be confined to the area drained by the medullary veins or may involve a wider distribution.



Figure 255.3.— Progression of germinal matrix hemorrhage.

Periventricular hemorrhagic infarction is usually asymptomatic during the neonatal period. Longterm neurological sequela are spastic hemiparesis (or asymmetrical quadriparesis) and intellectual deficits. The diagnosis of periventricular hemorrhagic infarction is made by ultrasonography. (Figure 255.4).

Figure 255.4.— Ultrasonographic findings in a patient with



periventricular hemorrhagic infarction. Brain ultrasound at 7 days of age (7 D) is normal; at 14 days of age (14 D) shows a left germinal matrix hemorrhage (GMH); at 20 days of age (20 D) shows bilateral germinal matrix hemorrhages and a left periventricular hemorrhagic infarction; at 34 days of age shows a cyst in the area of the left germinal matrix hemorrhage and resolution of the periventricular hemorrhagic infarction.





Carnitine deficiency occurs because isovaleric acid combines readily

with carnitine, forming a compound that is excreted in the urine. Hyperglycinemia is mild because glycine combines with isovaleric acid to form isovalerylglycine, which is rapidly cleared in the urine. Treatment of isovaleric acidemia consists of correction of hypoglycemia, acidosis, and other metabolic abnormalities. Glycine 250 mg/kg per day should be used to promote the formation of isovalerylglycine.

Glutaric acidemia type II

Glutaric acidemia type II is an autosomal recessive inborn error of metabolism due to a mitochondrial respiratory electron chain transport defect. Glutaric acidemia type II results from impaired flavin-mediated transfer of electrons between the mitochondrial matrix and the electron transport chain. The metabolic profile of multiple acyl-CoA dehydrogenase deficiency, also called glutaric acidemia type II, combines the metabolic features of isovaleric acidemia with those that occur as a result of a block in lysine metabolism (elevated levels of glutarylglycine and glutarylcarnitine), and fatty acid metabolism (hypoglycemia, hypoketonemia, and dicarboxylic acidemia) (Figure 75.1 D). Glutaric acidemia type II is often associated with temporal lobe atrophy and agenesis of the cerebellar vermis. Administration of carnitine and

riboflavin should be tried. The prognosis is dismal.




Beta-methylcrotonyl-CoA carboxylase deficiency

A block in the leucine pathway due to beta-methylcrotonyl-CoA carboxylase deficiency occurs in multiple carboxylase deficiency (Figure 75.2 E). The block in the leucine pathway leads to accumulation of many metabolites (Figure 75.2).




Multiple carboxylase deficiency

The metabolic profile of multiple carboxylase deficiency is characterized by the accumulation of metabolites that reflect the block in the leucine pathway (Figure 75.2 E), and in other nonleucine pathways (Figure 75.1 E). These nonleucine pathway involvements produce: (1) lactic acidosis with an increased lactate-to-pyruvate ratio due to a defect in pyruvate metabolism, (2) propionic acidemia due to a defect in propionic metabolism, and (3) decreased fatty acid formation due to a defect in acetyl-CoA metabolism. Multiple carboxylase deficiency may be due to holocarboxylase deficiency (normal serum biotinidase level but low enzyme activity in leukocytes or cultured fibroblasts) or biotinidase deficiency (low serum biotinidase level). Treatment of these disorders consists of correction of metabolic abnormalities and large doses of

biotin.

Hydroxymethylglutaryl-CoA (HMG-CoA) lyase deficiency

A block in the leucine pathway due to a defect of hydroxymethylglutaryl-CoA (HMG-CoA) lyase occurs in HMG-CoA lyase deficiency (Figure 75.1 F). The metabolic profile is characterized by



the accumulation of the metabolites prior to the leucine pathway block (Figure 75.2 F), and hypoglycemia and hypoketonemia due to a defect in fatty acid metabolism (Figure 75.1 F).





SUBARACHNOID HEMORRHAGES

Subarachnoid hemorrhage refers to blood between the arachnoid layer and the piamater. Unlike epidural and subdural hematomas, the blood in the subarachnoid hemorrhages gets into the sulci and fissures of the CNS. Subarachnoid hemorrhages are very common in the neonatal period. Subarachnoid hemorrhages are usually asymptomatic but they may be associated with paroxysmal clinical events, decreased limb movements or facial weakness. Subarachnoid hemorrhages often occur after vaginal delivery. Extensive subarachnoid hemorrhages probably warrant a coagulation work-up. Subarachnoid hemorrhages do not require any treatment. More about... 53

INTRA-AXIAL HEMORRHAGES AND HEMATOMAS

Intra-axial hemorrhages or hematomas may involve the brain (Figure 251.1) or the spinal cord. Intracranial intra-axial hemorrhages or hematomas may be localized to the parenchyma, ventricles, and choroid plexus. Intra-axial spinal cord hemorrhages are very rare.

A B

Figure 251.1.— Intra-axial hemorrhages. [A] Intraventricular hemorrhage. [B] Choroid plexus and intraparenchymal hemorrhages.



PARENCHYMAL HEMORRHAGES

Parenchymal hemorrhages have very different presentations in premature and full-term neonates. Parenchymal hemorrhages occur more often in premature than in full-term neonates.

Parenchymal hemorrhage in premature neonates

The most common site of parenchymal bleeding in the premature neonate is the germinal matrix. The germinal matrix is in the subventricular area. The germinal matrix is what is left of the germinal layer after the pluripotential cells stop dividing and producing neurons and glia cells. The germinal matrix is prone to bleeds because as the pluripotential cells of the germinal matrix disappear so does the vasculature, and in the process of disappearing the vessels walls become fragile.

Germinal matrix bleeds may involve the extraganglionic or the ganglionic germinal matrix. Bleeding from extraganglionic germinal matrix is more frequent before 32 weeks gestation. Extraganglionic bleeding tends to be massive and to produce acute hemorrhagic hydrocephalus. The acute hemorrhagic hydrocephalus results from obstruction of the cerebrospinal fluid flow within the ventricular system (Figure 251.2).

Figure 251.2.— Progression of a germinal matrix bleed to intraparenchymal hemorrhage and acute hydrocephalus. GMH: germinal matrix hemorrhage; D: days; IPH: intraparenchymal hemorrhage.



Ganglionic germinal matrix is the most common site for germinal

matrix hemorrhage after about 32 weeks gestation. The ganglionic germinal matrix is localized adjacent to the head of the caudate nucleus. The ganglionic germinal matrix is the most frequent site of bleeding because the venous blood flow at the level of the ganglionic germinal matrix makes a U-turn, producing an area of high mechanical stress in the venous vessel wall. This high pressure venous system renders the capillary-venous junction vulnerable to ischemic reperfusion injury. Germinal matrix hemorrhages occur when a vulnerable capillary-venous system junction in the mechanically stressed venous walls is further stressed by events that cause an increase in venous pressure. Pneumothorax is a frequent cause of increased venous pressure.



Facial Weakness


Hemifacial Hypertrophy

Hemifacial hypertrophy may occur either isolated or associated with one of several syndromes. Syndromes associated with facial hemihypertrophy are Proteus syndrome, Klippel-Trenaunay-Weber syndrome, and other neurocutaneous diseases.

Hemifacial hypertrophy usually involves the cheek and is limited rostally by the orbits and caudally by the jaw (Figure 172.1 [A]). Hemifacial hypertrophy may be accompanied by hemimegalencephaly (Figure 172.1 [B]). Hemimegalencephaly is characterized by hypertrophy of one cerebral hemisphere with ipsilateral ventricular dilatation. More about... 49

A B

Figure 172.1.— Hemifacial hypertrophy. [A] Hypertrophic tissue on the right cheek prevents the face from moving in the direction of the hemifacial hypertrophy. [B] MRI of the face and brain show hypertrophic facial tissue and hemimegalencephaly on the same side.





The initial step in the evaluation of a neonate with limb weakness is to determine the site of the lesion in the nervous system. The most important step to establish the site of neurological damage is to determine the distribution of the weakness. Decreased limb movements when limited to an extremity (monoparesis) or to two extremities in the same side (hemiparesis) produce asymmetrical limb movements. Decreased limb movements of both upper (upper extremity diparesis) and lower extremities (paraparesis) produce a discrepancy between upper and lower limb movement. This discrepancy may be difficult to detect because in neonates upper extremity movements are normally more prominent than lower extremity movements as a result of the physiologic rostocaudal maturational pattern of the central nervous system. The physiologic rostocaudal maturational pattern and the quick speed of progression of some disorders during the neonatal period often leads to a changing distribution of weakness during the neonatal period. Neonates with apparent upper extremity monoparesis may later be detected to have hemiparesis. Neonates with bilateral upper extremities weakness often develop quadriparesis as infants.





Flaccid leg monoparesis is rarely of central nervous system origin.

Flaccid leg monoparesis is usually due to peripheral nervous system damage. The clinical manifestation of flaccid leg monoparesis is foot drop. Foot drop due to peripheral nerve system damage occurs with involvement of the L5 root fibers at any level of the peripheral lumbosacral somatic motor system. Lesions in the cauda equina usually occur in association with meningocele (Figure 236.1). Lesions of the cauda equina and lumbosacral plexus usually produce, in addition to foot drop, weakness of hip flexion and leg adduction.

A B

Figure 236.1.— Neonate with a left foot drop at rest [A]. During action he is unable to lift the left foot up [B]. The patient had a lumbar meningocele and a lipoma of the phylum terminalis.

Sciatic nerve (Figure 236.2 [SN]) lesions may be complete or fascicular. A complete sciatic nerve lesion produces foot drop but unlike a lumbosacral plexus lesion it spares hip movements (iliopsoas nerve), knee extension (femoral nerve), and adduction (obturator) of the leg. A complete sciatic nerve lesion involves all muscles of the thigh. Fascicular sciatic nerve lesions are more frequent than complete sciatic nerve lesions. Fascicular lesions of the sciatic nerve may involve the lateral or the medial fascicles. Lateral fascicle sciatic nerve injury occurs more frequently than medial fascicle sciatic nerve injury. Lateral fascicles sciatic nerve injury spares all the muscles of the thigh except the short head of the biceps (Figure 236.2 [BshM]). This finding (the sparing or involvement of the short head of the biceps) is an important EMG finding to distinguish lateral fascicle sciatic nerve injury from common peroneal nerve lesion



(both present with foot drop). A neonate with a lateral fascicular sciatic nerve lesion shows evidence of denervation of the short head of the biceps femoralis, whereas a neonate with a common peroneal nerve lesion does not.

Common peroneal nerve (Figure 236.2 [PN]) lesions produce foot drop. Common peroneal nerve lesions spare all the muscles of the thigh, including the short head of the biceps, and the muscles innervated by the tibial nerve. Peroneal nerve lesions produce weakness of the tibialis anterior muscles.

Tibial nerve (Figure 236.2 [TN]) lesions are extremely rare in neonates. Tibial nerve damage produces plantar flexion weakness. Tibial nerve injury does not produce foot drop. Obturator nerve (Figure 236.2 [ON]) lesions produce inability to adduct the thigh. Femoral nerve (Figure 236.2 [FN]) lesions produce inability to extend the knee. Femoral and obturator nerve lesions do not produce foot drop.

Figure 236.2.— Schematic representation of the lumbosacral plexus and most important intermedial nerves. IPN: iliopsoas nerve; SGN: superior gluteal nerve; IGN: inferior gluteal nerve; ON: obturator nerve; FN: femoral nerve; LST: lumbosacral trunk; SN: sciatic nerve; TN: tibial nerve; CPN: common peroneal nerve; AdM: adductor muscle of the thigh; HSM: hamstring muscles; PostTM: posterior tibialis muscle; B(sh)M: short head of the biceps femoralis muscle; PlNs: plantar nerves; DPN: deep peroneal nerve; SPN: superficial peroneal nerve.




Lissencephaly types III and IV present with microcephaly. In type III

lissencephaly the cortex is thin. Lissencephaly type IV is also called radial microbrain. The cortex is thick. Lissencephaly type IV occurs in neonates with cytomegalovirus infection.

Polymicrogyria Polymicrogyria is a disorder of neuronal organization. The neurons

reach the cortex but do not organize well, leading to the formation of multiple small gyri. Polymicrogyria is diagnosed by MRI. Polymicrogyria may be an isolated finding or may be associated with other brain abnormalities. Polymicrogyria may be associated with degenerative central nervous system disorders (Zellweger disease or neonatal adrenoleukodystrophy), central nervous system infections (cytomegalovirus infection), or developmental disorders (Aicardi syndrome). Neonates with polymicrogyria and clinical suspicion of cytomegalovirus infection or periventricular cysts, calcifications (often periventricular), or cerebellar hypoplasia should have their cerebrospinal fluid studied for the possibility of cytomegalovirus infection. Treatment of cytomegalovirus infection with ganciclovir stops the excretion of virus in the urine. The possibility that treatment with ganciclovir may arrest further progression of brain damage has been raised. Seizures in patients with polymicrogyria are treated with antiepileptic drugs. Surgical treatment

should be considered.

Hemimegalencephaly Hemimegalencephaly refers to enlargement of one cerebral hemisphere

(Figure 49.1). Magnetic resonance imaging of the brain is the study of choice to establish the diagnosis. Unilateral hemimegalencephaly occurs because of hamartomatous overgrowth of one hemisphere. The cortex is dysplastic and the white matter is abnormal. The lateral ventricle in the enlarged hemisphere is enlarged in proportion to the lateral ventricle of the smaller hemisphere. The anterior aspect of the lateral ventricle on the

larger hemisphere points superiorly and anteriorly.



Figure 49.1.— Hemimegalencephaly. CT of the brain with contrast demonstrates enlarged left lateral ventricle and pachygyric left posterior cerebral cortex.



Apnea


NEUROLOGICAL CAUSES OF APNEA

There are many neurological disorders that can produce apnea. The neurological disorders that can produce apnea may involve the neuroaxis at different levels. Apnea may occur due to lesions in the brain, brainstem,

spinal cord, or phrenic and upper airway muscle motor units.

BRAIN

Brain lesions produce apnea by two mechanisms: seizures and transtentorial herniation.

Seizures

Electroencephalographic seizures are an important cause of apnea in neonates (Figure 22.1). Apnea due to seizures may be associated with other clinical manifestations, such as paroxysmal motor events, or it may occur without any associated clinical manifestations.

Figure 22.1.— Mixed (central-obstructive) apnea. Left-sided


Apnea

electroencephalographic seizure. The apnea is associated with tachycardia and desaturation.

The seizure may be due to a metabolic problem (hypoglycemia or

hypocalcemia) or structural supratentorial lesions. The most frequent supratentorial causes of apneic seizures are hemorrhage (Figure 23.1) and herpetic encephalitis involving the temporal lobes. The clinical presentation encountered in neonates with apnea due to seizures depends on the cause of the seizures. Apnea triggered by seizures occur during any behavioral state, are not associated with bradycardia unless longer than

one minute, and can be either central or mixed.

Figure 22.2.— MRI of the brain demonstrating left temporal lobe hemorrhage.

During apnea triggered by seizures, the EEG recording will show an electroencephalographic seizure. The origin of the electroencephalographic seizure is usually the temporal lobe. The EEG pattern that usually occurs with apneic seizures consists of rhythmic alpha

activity. Neonates with apneic seizures should undergo MRI of the brain because of the possibility of a structural brain lesion, and a metabolic evaluation because of the possibility of a metabolic disorder.




Hemimegalencephaly may occur in association with an established syndrome or may be an isolated finding. The most frequent syndrome associated with hemimegalencephaly is probably linear nevus sebaceous syndrome. Isolated hemimegalencephaly may occur with or without unilateral overgrowth of the body. Isolated hemimegalencephaly with unilateral overgrowth of the body may be associated with Wilms tumor or

adrenal or hepatic tumors. Isolated hemimegalencephaly without unilateral overgrowth of the body often produces intractable seizures. Hemispherectomy may be needed to control the seizures. More about... 172

Neuronal Heterotopias Heterotopia results from an arrest of neuronal radial migration.

Neuronal heterotopias are diagnosed by MRI of the brain. The MRI shows gray matter where there should be white matter (Figure 50.1). Heterotopias are classified based on the location of the heterotopic neurons as subependymal, subcortical, or diffuse.

Figure 50.1.— Heterotopia. T1-weighted coronal image demonstrates band heterotopia of the left hemisphere.




Subependymal heterotopia appears as smooth, sometimes pedunculated, nonenhancing gray matter-like ventricular masses. Seizures do not usually occur in neonates with subependymal heterotopia unless cortical abnormalities are also present. Subcortical focal heterotopia appears as islands of gray matter within the white matter. Subcortical focal heterotopia may be difficult to detect during the neonatal period because the signal intensities of the white and gray matter in the neonate are similar. Diffuse gray matter heterotopia appears as a band of gray matter within the white matter. Subcortical focal hetereotopia and diffuse gray

matter heterotopia often produce seizures in the neonatal period.

Heterotopias may occur as isolated anomalies or as part of a syndrome. Isolated neuronal heterotopia is more frequent. Neuronal heterotopia may be associated with metabolic disorders (Zellweger syndrome, neonatal adrenoleukodystrophy, glutaric aciduria type II, nonketotic hyperglycinemia, Menkes disease, and GM2-gangliosidosis), neurocutaneous syndromes (neurofibromatosis, tuberous sclerosis, incontinentia pigmenti, hypomelanosis of Ito, and linear nevus sebaceous syndrome), dysmorphic syndromes (Smith-Lemli-Opitz syndrome, de Lange syndrome, oro-facial-digital syndrome, Meckel-Gruber syndrome, Coffin-Siris syndrome), chromosomal abnormalities (Trisomy 13, Trisomy 18, Trisomy 21, 4p-syndrome), fetal toxic exposure (carbon monoxide, isotretinoic acid, ethanol, organic mercury), congenital myotonic dystrophy, and Aicardi syndrome.





HYPOMELANOSIS OF ITO

The hallmark of hypomelanosis of Ito or incontinentia pigmenti acromians is the presence of a well-defined area of hypopigmented skin along the lines of Blaschko (Figure 309.1 [A]). The hypopigmented areas may involve any body parts (large or small, linear, vorticose, or square). Wood lamp examination may be needed to demonstrate the hypopigmented areas. The skin histopathological findings are similar to those encountered in tuberous sclerosis. Hypomelanosis of Ito may be associated with nervous system, ocular, musculoskeletal, and vascular abnormalities. The most frequent neurological problems in the neonatal period are seizures and hypotonia, but arthrogryposis may also occur. Magnetic resonance imaging of the brain may reveal hydrocepahlus (Figure 309.1 [B]) or atrophy. Hypomelanosis of Ito appears to be an etiologically hetereogenous physical finding. Karyotyping of the affected skin is indicated because of the possibility of chromosomal

mosaicism.

A B

Figure 309.1.— Hypomelanosis of Ito. [A] Well-delineated hypopigmented area and arthrogryposis of the arms. [B] Magnetic resonance imaging of the same patient demonstrating significant hydrocephalus.


Facial Weakness


Lower Motor Facial Asymmetry

Lower motor facial asymmetry occurs with a lesion at the: (1) pons [Figure 180.1 C]; (2) facial nerve [Figure 180.1 D]; (3) facial nerve branches [Figure 180.1 D]; or (4) depressor angularis oris muscle [Figure

180.1 F].

Figure 180.1.— Anatomical localizations of injuries in the facial motor system. T: thalamus; AC: internal auditory canal; FC: facial canal; SMO: styloidmastoid orifice; BB: buccal branch; MB: mandibular branch; TB: temporal branch; OOM: orbicularis oculi muscle; RM: risorius muscle; DAOM: depressor angularis oris muscle; BM: buccinator muscle; MM: mentoris muscle. Light blue line indicates components of the facial nerve that have ipsilateral (hence bilateral) cortical innervation; dark blue line


Facial Weakness

indicates components of the facial nerve that has contralateral innervation. A: cerebral lesion above the thalamus; B: cerebral lesion below the thalamus and above the pons; C: pontine lesion; D: facial nerve; E: mandibular branch lesion; F: depressor angularis oris muscle.



Arm


Complete Brachial Plexus Palsy Weakness involving the whole arm (Figure 215.1) is the initial

presentation in most neonates with brachial plexus injury. Most neonates with total arm monoparesis immediately after a brachial plexus trauma will later develop a segmental syndrome. Neonates with transient weakness of the whole arm usually begin to improve within one week of the injury.

A B

Figure 215.1.— [A] Total brachial plexus palsy with thumb amputation and cutaneous scars in the shoulder areas. [B] Left Horner syndrome. The mother had chickenpox during pregnancy.

Complete brachial plexus palsy may be associated with Horner

syndrome (Figure 215.1) or facial nerve palsy. The presence of Horner syndrome in a neonate with flacid arm weakness localizes the lesion to the brachial plexus. The presence of total flaccid arm monoparesis and ipsilateral facial weakness raises the possibility of an upper motor neuron lesion. Neonates with total flaccid arm monoparesis and ipsilateral, predominantly lower quadrant facial weakness should probably have an MRI of the brain because of the possibility of a central nervous system lesion. Neonates with total arm monoparesis and contralateral lower quadrant facial weakness are likely to have a facial nerve branch injury in conjunction with a brachial plexus lesion. Neonates with total arm


Arm

monoparesis and encephalopathy, seizures, or gaze preference should have an MRI of the brain because of the possibility of a central nervous system lesion.

Peripheral nerve lesions are unlikely to produce total arm weakness. Nevertheless, the possibility of a circular amniotic band high in the arm should always be considered in a neonate with total arm monoparesis and every skin fold in the arm should be scrutinized for this possibility. A circular amniotic band may compress the musculocutaneous, radial, ulnar, and medial nerves and produce clinical findings similar to those of a complete brachial plexus palsy but without involvement of brachial plexus proximal nerves.



Macrocephaly


Hydrocephalus Hydrocephalus may be communicating or noncommunicating. In

communicating hydrocephalus, the lumbar subarachnoid space shares the increased pressure with the ventricular space. In noncommunicating hydrocephalus, the increased pressure of the ventricular space is not accompanied by increased pressure of the lumbar subarachnoid space.

Communicating hydrocephalus occurs secondary to: (1) an obstruction in the subarachnoid space in the convexity of the cranium that prevents the cerebrospinal fluid from reaching corpuscles of Pachioni; (2) an obstruction at the level of the corpuscle of Pachioni that blocks the absorption of cerebrospinal fluid; or (3) an anatomical or functional obstruction at the level of the sinuses that prevents drainage of cerebrospinal fluid. A functional obstruction of the sinus results from increased venous pressure inside the sinus that raises the threshold of intracranial pressure needed to open the “valves” of the corpuscles of Pachioni. The most common cause of communicating hydrocephalus in the neonatal period is intraventricular hemorrhage. Intraventricular hemorrhage produces an obliterative arachnoiditis of the posterior fosa.

Noncommunicating hydrocephalus is due to an obstruction at the foramen of Monro, aqueduct of Sylvius, or at the foramina of Luschka and Magendie. Obstruction at any of these orifices may occur due to blood clot, tumor, congenital narrowing, or scar tissue proliferation.



Macrocephaly


Posthemorrhagic Hydrocephalus

Posthemorrhagic hydrocephalus is the most common type of hydrocephalus in the neonatal period. Posthemorrhagic hydrocephalus may be communicating or noncommunicating. It is usually the consequence of intraventricular hemorrhage. Intraventricular hemorrhage usually occurs as a consequence of germinal matrix hemorrhage. Germinal matrix hemorrhages are unusual after 34 weeks gestational age. Germinal matrix hemorrhages are classified based on brain ultrasound in four grades. Grade I intraventricular hemorrhage refers to the presence of subependymal bleed; Grade II intraventricular hemorrhage refers to extension of the subependymal bleed into the ventricles but without ventricular dilatation; Grade III intraventricular hemorrhage refers to subependymal bleed with extension of the bleed into the ventricles and hydrocephalus; and Grade IV intraventricular hemorrhage refers to subependymal bleed with extension

of the bleed into the parenchyma as a result of venous infarcts.

Hydrocephalus following intraventricular hemorrhage can occur within days of a bleed (acute), more than a week later (subacute), or as late as 3 months after the bleeding (chronic).

Acute hydrocephalus may be communicating or noncommunicating. Acute communicating hydrocephalus occurs with large intraventricular hemorrhages due to obstruction of the arachnoid villi by blood clots. Acute noncommunicating hydrocephalus is due to obstruction by blood clots of the ventricular system at any of its narrow passages.

Subacute hydrocephalus (the term posthemorrhagic hydrocephalus is often reserved for this type of hydrocephalus) is usually communicating. It occurs with small and large hemorrhages. It is due to obstruction of the subarachnoid space. The obastruction occurs at the tentorial notch. The arachnoid adhesions block the normal flow of cerebrospinal fluid to the convexity of the brain.

Chronic hydrocephalus may be communicating or noncommunicating. It occurs with small and large hemorrhages. Communicating hydrocephalus results from permanent scarring of the corpuscle of Pachioni. Noncommunicating hydrocephalus results from disrupted ependyma or reactive gliosis. The blood clot or reactive gliosis obstructs the ventricular system at any of its narrow passages.

The diagnosis of hydrocephalus in the premature newborn is made by ultrasound. Computed tomography and MRI of the brain offer additional information that may help to define the site of obstruction. There is no general consensus regarding the best way to manage these patients. Serial


Macrocephaly

lumbar punctures do not prevent hydrocephalus. They are used because they delay the need for ventricular drainage, thus allowing time for spontaneous resolution of the blockage. Fibrinolytic therapy is promising but its use is not recommended. Neonates with posthemorrhagic hydrocephalus may present with: (1) excessive increase in head circumference (>1 cm/week); (2) excessive increase in head circumference associated with a tense fontanelle; (3) ultrasonographic evidence of increased ventricular size without any other signs; (4) neurological signs of increased intracranial pressure such as encephalopathy or increased musculoskeletal reflexes; or (5) cardiovascular signs of increased intracranial pressure such as tachycardia and hypotension. The latter two presentations are infrequent.





Posthemorrhagic hydrocephalus Posthemorrhagic hydrocephalus results from obstruction of the

cerebrospinal fluid flow at the posterior fossa cisterns. The cerebrospinal fluid exits the ventricular systems through the orifices of Luschka and Magendie. These orifices are in the region of the medulla oblongata. The fluid from this area must flow from the base of the cranium (posterior fossa) to the convexity to drain through the Pachioni corpuscles. The obstruction at the posterior fossa is due to obliterative arachnoiditis.

The clinical manifestations of progressive posthemorrhagic hydrocephalus usually include an abnormal increase in head circumference and a full fontanelle. Clinical manifestations may not be present despite significant ventriculomegaly.

The diagnosis of posthemorrhagic hydrocephalus is based on the presence of large ventricles and no signs of cerebral atrophy. The distinction between ventricular distension due to hydrocephalus and ventricular enlargement due to cerebral atrophy can often be made based brain ultrasound (Figure 253.1). Computed tomography or MRI may be needed to demonstrate atrophy or hydrocephalus.



Figure 253.1.— Characteristic ultrasonographic findings in brain atrophy [A] and hydrocephalus [B]. The two ultrasounds on top demonstrate typical atrophic changes: large subarachoid spaces (green arrows), prominent sulci (pink arrows), angular frontal horn of the lateral ventricles (blue arrows), moderate to mild lateral ventricular enlargement of the frontal horns (tan arrows), no enlargement of the temporal horn of the lateral ventricle or third or fourth ventricle. The two ultrasounds on the bottom demonstrate typical findings of posthemorrhagic hydrocephalus: no subarachnoid space, thin sulci (pink arrows), round frontal horns of the lateral ventricles (blue arrows), large ventricles (tan arrows), periventricular echogenicity (yellow arrows), large third and temporal horns of the lateral ventricles (red arrows).

Treatment of posthemorrhagic hydrocephalus

Posthemorrhagic hydeocephalus has no treatment. Intraventricular fibrinolytic agents such as urokinase, streptokinase, and tissue plasminogen activator are not currently recommended. Posthemorrhagic hydrocephalus may require shunting depending on its evolution.

Evolution of posthemorrhagic hydrocephalus

Posthemorrhagic hydrocephalus can arrest or become progressive. An arrested hydrocephalus implies that the size of the ventricle remained the same from one ultrasound to the next. Progressive hydrocephalus implies that the ventricle increased in size from one ultrasound to the next. An arrested hydrocephalus may become progressive and a progressive hydrocephalus may arrest.

When to conclude that arrested hydrocephalus will not progress?

There is no data supporting an answer to this question. Two ultrasounds one week apart that demonstrate no increase in ventricular size probably implies that no further ventricular size increase will occur.

When to conclude that progressive hydrocephalus will not spontaneously arrest before producing brain damage?

There is no data supporting an answer to this question. Probably, clinically silent, slowly progressive hydrocephalus for one month or rapidly progressive hydrocephalus for one week may produce brain damage. Hydrocephalus producing clinical manifestation is also likely to produce brain damage. Human studies using near-infrared-spectroscopy and Doppler ultrasound, have shown that even relatively small and slowly progressive increases in ventricular size negatively affect brain metabolism



in the periventricular area. In animals, it has been documented that ventricular distension results in periventricular damage (hypoperfusion,

anaerobic metabolism, and loss of high-energy phosphates.)



Macrocephaly


Neonates with posthemorrhagic hydrocephalus require close follow-up, and may require lumbar punctures, acetozolamide, ventricular drainage, or ventriculoperitoneal shunt. Close follow-up consists of daily head circumference measurements and assessment of fontanelle tension and interparietal suture distance. Lumbar puncture should be performed at the L2-L3 or L3-L4 intervertebral space. The neck of the neonate should not be flexed. The amount of fluid to be extracted should be 10 to 15 cc/kg. The cerebrospinal fluid should be studied for cell count, glucose, protein, and bacterial cultures. The success of a lumbar puncture is judged by the amount of cerebrospinal fluid removed and the comparison of the fontanelle tension and ventricular size by brain ultrasound before and after the lumbar puncture. A lumbar puncture is considered successful if the fluid removed is 10 cc/kg or more, and if the fontanelle tension and ventricular size decrease after the procedure. Acetozolamide decreases the production of cerebrospinal fluid. The dose is 100 mg/kg per day in 2 doses. Ventricular drainage may be performed by multiple ventricular taps or by placing a continuous reservoir. Ventriculoperitoneal shunt is the treatment of choice for nonarrested hydrocephalus. Ventriculoperitoneal shunt should be performed when the neonate weighs over 1500 grams, the cerebrospinal fluid has less than 1000 red cells per cubic centimeter, the protein concentration is less than 500 mg/dL, and the patient is clinically stable. A CT of the brain prior to placement of the ventroperitoneal shunt is recommended.





Neonates with pathological reflexes require the same evaluation as neonates with convulsions. The causes of subcortical release phenomena or brainstem release phenomena are the same as those that produce seizures. The most frequent cause of pathological reflexes is hypoxic-ischemic encephalopathy. Pathological reflexes do not require treatment with antiepileptic drugs. Pathologic reflexes originate either from a transient cortical dysfunction producing a release of normally inhibited preprogrammed brainstem activity or an intrinsic irritability of the brainstem structures. Pathological reflexes do not originate from electroencephalographic seizures and are not associated with scalp or

nasopharyngeal electroencephalographic seizures.

Pathological reflexes also occur in neonates with hyperexcitability syndrome. The triad of signs referred as hyperexcitability syndrome consists of coarse tremor, brisk deep tendon reflexes, and a low threshold for Moro reflex. Hyperexcitability syndrome may be associated with hypermotility and increased resistance to passive movements of the limbs. Local anesthetic intoxication and withdrawal from opiates may produce

hyperexcitability syndrome.

Startle Disease

Startle disease or hyperekplexia is characterized by a pathological

intensification of the startle response. Startle disease is due to glycine receptor abnormalities in the spine and brainstem reticular neurons. It is transmitted as an autosomal recessive trait mapped to chromosome 5. The clinical manifestations of startle disease are tonic contraction of all four extremities and massive myoclonic jerks (click on clips, below). Tonic contraction may be associated with apnea. There are no changes in EEG activity during the episodes, except for slowing secondary to hypoxia if apnea is prolonged. Startle may be triggered by tactile stimulation, especially of the face and nose, or may occur spontaneously. Forced flexion of the head and legs toward the trunk ends the episode of tonic contraction and apnea (click on clips, below). Heart rate initially increases at the onset of the event and then decreases after a few minutes if a

prolonged apnea occurs. Clonazepan may help.



Extrapyramidal movements Extrapyramidal movements may be seen at 2 to 3 months of age in

premature neonates with bronchopulmonary dysplasia. Extrapyramidal movements are characterized by oral-buccal-lingual, limb, neck, and trunk repetitive movements. Oral-buccal-lingual movements often interfere with

feeding. Clonazepan may help.



http://pediatricneuro.com/alfonso/Clip3.mpg.mpg




Progressively stronger pupillary constriction occurs with very frequent

stimulations because of the additive effect of acetylcholine at the postsynaptic region. This additive effect occurs when the interval between the release of acetylcholine is significantly less than the time it takes for acetylcholine to be destroyed in the cleft. Progressively weaker pupillary constriction occurs with infrequent stimulation because repetitive stimulation at a slow rate does not have this additive effect.

Seizures may occur in neonates with botulism and are often due to hyponatremia (which results from inappropriate secretion of antidiuretic hormone) or asphyxia. Classic electrodiagnostic findings are an incremental response in muscle action potential produced by very frequent repetitive nerve stimulation (20 to 50 Hz) and abundant brief and small polyphasic motor unit and fibrillation potentials. These findings are not present in all cases, therefore, their absence does not exclude infantile botulism. The diagnosis of botulism rests on finding C botulinum in the stools. Treatment is supportive. Infantile botulism is a self-limiting disease

that lasts from 2 to 8 weeks.

Hypermagnesemia

Hypermagnesemia produces hypotonia, weakness, abdominal distention, absent bowel sounds, and constipation. It usually occurs in newborns after the mother has received a large amount of intravenous magnesium sulfate. It is a presynaptic defect. The diagnosis is confirmed by a serum magnesium level above 4.5 mEq/L. Treatment is supportive.

Exchange transfusion may help in very severe cases.

Aminoglycosides Therapy Aminoglycosides produce weakness, hypotonia, dilated pupils, atonic

bladder, and paralytic ileus. Treatment consists of elimination of antibiotics and support. Hypotonia due to aminoglycoside therapy occurs more frequently in neonates with other disorders that affect the myoneural junction; therefore, the use of aminoglycosides in a neonate with a disorder of myoneural junction involvement should be avoided.





Hyponatremia

Serum sodium under 120 mEq/L may produce seizures. Hyponatremia occurs in neonates with inappropriate antidiuretic hormone secretion syndrome, congenital adrenal hyperplasia, and those receiving hypo-osmolar formula. Inappropriate antidiuretic hormone secretion syndrome should be suspected in a neonate with decreased urinary output and high urinary osmolarity. The immediate treatment of hyponatremic seizures in neonates consists of providing enough sodium in a 10-minute period to elevate the serum sodium level to 125 mEq/L by using 3% normal saline solution (contains 513 mEq of sodium/L). The amount of sodium required is calculated using the following formula:

(125 -?) x (0.6) x (wt kg) = X mEq

where ? represents the patient’s serum sodium, 0.6 is the dilution constant, and X represents the number of mEq needed to correct the sodium level to 125 mEq. Neonates with the inappropriate antidiuretic hormone secretion syndrome should also be given furosemide 1 mg/kg intravenously, followed by replacing urinary sodium milliequivalent for milliequivalent with 3% normal saline solution. Neonates with congenital adrenal hyperplasia and those receiving diluted formulas do not require furosemide. Antiepileptic drugs should be used if seizures persist after the

infusion of 3% normal saline solution or if it is not available.

Central pontine myelinolysis may occur due to rapid correction of hyponatremia. Central pontine myelinolysis should be suspected in a neonate with hyponatremia that in the course of correction of the hyponatremia develops cranial nerve dysfunction and quadriparesis. MRI is the study of choice (Figure 42.1).

A B



Figure 42.1.— Central pontine myelinolysis. [A] MRI of the brain (T1-weighted image) demonstrating a round lesion in the central pontine area. [B] MRI of the brain (T2-weighted image) demonstrating a oval lesion in the central pontine area.

Hypernatremia Serum sodium above 150 mEq/L may produce seizures. Hypernatremia

occurs in neonates who have received excessive sodium orally (by mistakenly trying to sweeten formula with salt) or intravenously (miscalculating the sodium in hyperalimentations or not accounting for the sodium in sodium bicarbonate when it is used to correct acidosis). Signs of dehydration may or may not be present.

The correct treatment of hypernatremic seizures in a neonate is uncertain. Some advocate blood volume correction using 5% albumin followed by forced diuresis (furosemide 1 mg/kg) and replacement of the urine volume with a 10% dextrose solution. Others advocate using D5W 0.2 normal saline solution at 100 to 150 cc/kg per day according to the gestational age of the neonate. Once seizures stop, serum sodium should be measured and further correction should aim at decreasing serum sodium by 10 mEq a day. Serum potassium and blood calcium should be

monitored carefully. Antiepileptic drugs may be necessary.

Local anesthetic intoxication Local anesthetic intoxication should be considered as a possible cause

of seizures in neonates with scalp puncture wounds and in neonates that in the first 6 hours have dilated and fixed pupils, and absence of extraocular movements. The usual offenders are mepivacaine and lidocaine. The half-life of these drugs is about 8 to 10 hours. Treatment consists of diuresis with acidification of urine and vital signs support. Antiepileptic drugs are

of questionable value.




CEREBELLAR, BRAINSTEM, AND SPINAL CORD ARTERIAL INFARCTS

Cerebellar, brainstem, and spinal cord arterial infarcts are rare in the

neonatal period. Cerebellar and brainstem arterial infarcts involve the posterior cerebral circulation. Thrombosis is the most frequent mechanism of arterial infarcts in these areas. Spinal cord arterial infarcts usually occur in the distribution of the artery of Adamkiewicz or the artery of the cervical enlargement. The artery of Adamkiewicz supplies the thoracolumbar spine. Occlusion of the artery of Adamkiewicz produces paraparesis. Occlusion of the artery of the cervical enlargement (Figure

248.1) produces quadriparesis, but it occasionally produces diplegia of the upper limbs. The most common mechanism of spinal cord arterial infarct is probably thrombosis or hypoperfusion.

A B

Figure 248.1.— Median sagittal cervical spinal cord images. [A] T1-

weighted image demonstrates an infarct in the cervical spine as an area of increased ecogenicity. [B] T2-weighted image demonstrates an infarct in the cervical spine as an area of increased ecogenicity.

Umbilical arterial placement has traditionally been associated with spinal

infarcts but the association may not be causal.



VENOUS INFARCTS

Venous infarct in the neonatal period usually involves the brain. Venous infarcts in the brainstem, cerebellum, and spinal cord are very rare.

BRAIN, CEREBELLAR, BRAINSTEM, AND SPINAL CORD VENOUS INFARCTS

Central nervous system venous infarcts are produced by thrombotic phenomena (pathogenesis). The clinical manifestations of CNS venous infarcts vary according to the anatomical site involved. Venous infarcts in the brain usually produce seizures or paresis. Venous infarcts in other areas usually produce paresis.

The mechanism of cerebral venous infarct is thrombosis. Thrombotic venous infarcts may occur with hypercoagulation states such as proteins C and S deficiencies, antithrombin III deficiency, or the presence of Factor V-Leiden, anticardiolipins, and antiphospholipids antibodies. Protein C is a glycoprotein that inhibits factors V and VIII. Protein S is a glycoprotein that serves as a cofactor for protein C. The excess of factors V and VIII that occurs with protein C and S deficiencies and the excess of thrombin that occurs with antithrombin III deficiency leads to thromboembolic

phenomena. Factor V-Leiden is a mutated Factor V. The mutation consists of the substitution of the right aminoacid at a key position by the wrong aminoacid. The consequence of this substitution is that it renders

Factor V (called Factor V-Leiden) resistant to protein C inactivation. The mechanism of thrombosis in neonates with anticardiolipins and antiphospholipids is not known. Polycythemia, sepsis, and dehydration can also produce thrombotic venous infarcts. Venous thrombosis due to compression occurs in premature neonates when the terminal vein is compressed by a ganglionic germinal matrix bleed. The presence of increased venous pressure contributes to the production of venous infarcts.





The prognosis for independent breathing for patients with lesions above

C4 is poor, especially if they do not breathe during the first 24 hours of life.

Infarcts Spinal cord infarcts are rare. They usually occur in newborns with

umbilical artery catheterization in whom the catheter tip is placed too high in the umbilical artery. They rarely occur in premature neonates without an apparent predisposing problem. Placing the tip of the catheter at or above T10 and T12 may lead to obstruction of the artery of Adamkiewicz. This artery is the major segmental artery of the spinal cord. Spinal infarct due to obstruction of the artery of Adamkiewicz initially produces generalized hypotonia with decreased dynamic tone followed by spastic paraparesis as a result of damage to the corticospinal fibers destined to innervate the

lumbosacral motor neurons.

REFERENCES

Aicardi J. Diseases of the Nervous System in Childhood. Oxford: Blackwell Scientific; 1992. Anderson JS, Gorey MT, Pasternak JF, et al. Joubert's syndrome and prenatal hydrocephalus. Pediatr Neurol. 1999;20:403-405. Barkovich AJ. Pediatric Neuroimaging. New York, NY: Raven Press; 1995. Butler MG. Prader-Willi syndrome: current understanding of cause and diagnosis. Am J Med Genet. 1990;35:319-332. Fareber EN. CNS magnetic resonance in infants and children. Clinics in Developmental Medicine. High Holborn, London: Mac Kieth Press; 1995. Fenichel GM. Neonatal Neurology. New York, NY: Churchill Livingstone; 1990. Hirsch JF, Pierre-Kahn A, Renier D, et al. The Dandy-Walker malformation: a review of 40 cases. J Neurosurg. 1984;61:512-522.





The term idiopathic subarachnoid hemorrhage implies a primary

subarachnoid hemorrhage without a known cause. Secondary subarachnoid hemorrhage results from a spill of blood into the arachnoid space from a brain parenchymal hemorrhage, an intraventricular hemorrhage, or a hemorrhagic infarct. The term secondary subarachnoid hemorrhage is also used for hemorrhages in the subarachnoid space if the cause is known. Seizures are the most common manifestations. They usually occur after the first day of life. The clinical presentation of secondary subarachnoid hemorrhage is often dominated by the cause of the subarachnoid hemorrhage. In cases of idiopathic subarachnoid hemorrhage, the neonate appears healthy. The diagnosis is established by CT or MRI of the brain. In a neonate with seizures and subarachnoid hemorrhage, other causes for the seizures should be considered. The prognosis of a neonate with idiopathic subarachnoid hemorrhage is good. Subarachnoid hemorrhages require no treatment but careful follow-up is necessary due to the possibility of hydrocephalus. Seizures should be treated with antiepileptic drugs. More about... 251

Intraventricular and Intraparenchymal Hemorrhages Intraventricular hemorrhage usually presents as lethargy or irritability.

Seizures are uncommon but other types of pathological paroxysmal motor events often occur. Intraparenchymal hemorrhages are more frequent than intraventricular hemorrhages in neonates born at term. Seizures are a frequent presentation of intraparenchymal hemorrhages in fullterm neonates. More about... 251-255

Cerebral Infarction

Convulsions are the most common presenting sign of cerebral infarction in neonates. Focal motor deficit often persists after the convulsion stops. Cerebral arterial infarction may occur because of endomural, mural, or extramural abnormalities affecting a vessel. Endomural occlusions are either embolic or thrombotic. The source of the emboli is usually the heart or the placenta. Embolic strokes are

frequent in neonates with cyanotic heart disease because the venous blood bypasses the lungs (natural filter). Thrombosis results from trauma, coagulopathies (proteins C and S deficiencies), or polycythemia.




A posterior fossa cyst in the region of the cisterna magna is a cerebrospinal

space cavity within the single layer of the arachnoid space. Posterior fossa cysts may or may not compress the brainstem and the cerebellum.

The distinction between a posterior fossa cyst in the region of the cisterna magna and a megacisterna magna is not possible and clinically unnecessary unless the cyst contains blood or is compressing the brainstem and the cerebellum. Posterior fossa cysts that compress the brainstem and the

cerebellum may require surgery.

Joubert Syndrome

Joubert syndrome may present with hypotonia and decreased dynamic tone, hyperventilation alternating with apnea, and abnormal eye movements during the neonatal period. Joubert syndrome is characterized by agenesis or hypoplasia of the cerebellar vermis. The posterior fossa is normal or small in size (Figure 119.1). The tentorium is not high. Other central nervous system abnormalities that often present with Joubert syndrome are dysplasia or heterotopia of the cerebellar nuclei, absence of the pyramidal decussation, and histological abnormalities of the inferior olivary nuclei, trigeminal tract,

solitary fascicle, and dorsal column nuclei.

Figure 119.1.— Schematic representation of Joubert syndrome. Hypoplasia or agenesis of the cerebellar vermis and small cisterna magna.





KLIPPEL-TRENAUNAY SYNDROME

The hallmark of Klippel-Trenaunay syndrome is the presence of cutaneous abnormalities in the limbs or trunk associated with underlying soft tissue hypertrophy. Cutaneous abnormalities include capillary angiomatosis, cavernous hemangiomas, pigmented verrucous lesions, hyperhidrosis, and hypertrichosis. The soft tissue hypertrophy results from vascular abnormalities including varicose veins, phlebectasias, lymphangiomas, and arteriovenous malformations. The neurological manifestations of Klippel-Trenaunay syndrome result from intraspinal and intracranial angiomas. Neurological manifestations are infrequent in the neonatal period. Klippel-Trenaunay syndrome has a sporadic

occurrence.

Figure 297.1.— Typical appearance of Klippel-Trenaunay syndrome. Extensive nevus and soft tissue hypertrophy involving the right leg. Lumbosacral hemangioma.



Arm


Klumpke Palsy Klumpke palsy may produce several abnormal postures. Classically, it

produces flexion and supination of the elbow, extension of the wrist, hyperextension of the metacarpophalangeal joints, and flexion of the

interphalangeal joints with the “claw hand” posture. This presentation is rarely seen in the newborn period. Klumpke syndrome usually manifests in the newborn period as weakness restricted to the hand (Figure 220.1).

There are no reflex or spontaneous movements of the intrinsic hand muscles.

Figure 220.1.— Weakness of wrist and finger extension. EMG evidence of triceps denervation.

The most frequent sites of involvement are the lower trunk (Figure 220.2 [B]) or a combination of T1 roots and C8 ventral ramus (Figure 220.2 [A]).


Arm

Figure 220.2.— Site of injury in Klumpke palsy. [A] Root of T1 and spinal nerve of C8. [B] Lower trunk. The green lines at T1 represent the most frequent origin of sympathetic fibers for the eyes. (PS): paraspinal muscles; (R): rhomboid muscle; DS: dorsoscapular nerve; LT: long thoracic nerve; (SA): serratus anterior muscle; (SS): supraspinal muscle; (IS): infraspinal muscle; SPS: suprascapular nerve; PL: pectoral lateralis nerve; (P): pectoralis muscle; PM: pectoralis medialis nerve; SF: sympathetic fibers to the eyes; (M of M): muscle of Müller; (DP): dilator pupillary muscle; (TM): teres major muscle; (SBS): subscapularis muscle; SBS: subscapularis nerves; TD: thoracodorsal nerve; (LD): latissimus dorsi muscle; MC: musculocutaneous nerve; (Bi): biceps muscle; (Br): brachialis muscle; M: median nerve; U: ulnar nerve; A: axillary nerve; (TMi): teres minor muscle; (D): deltoid muscle; R: radial nerve.





Arterial border zone infarcts in premature neonates lead to periventricular leukomalacia. Periventricular leukomalacia is diagnosed by demonstrating increased echogenicity by brain ultrasound that persists for more than 7 days or is associated with cavitation. The increased echogenicity is best appreciated in the peritrigonal area. Cavitation occurs 2 to 6 weeks after the hypoperfusion episode (Figure 247.1).

Figure 247.1.— Diagnosis and evolution of periventricular leukomalacia. Increased ecogenicity in the lateral angles of the lateral ventricles and in the peritrigonal region (yellow arrows) at 7 days of age (7 D); cavitation (green arrows) best seen at the frontal region at 20 days (20 D) and 37 days (37 D).

Cavitation may be very extensive. Cavitation is better delineated by MRI of the brain than by ultrasound (Figure 247.2). Periventricular leukomalacia may also occur in neonates with ventriculitis, metabolic

disorders, and hydrocephalus. Periventricular leukomalacia is usually asymptomatic during the neonatal period.



Figure 247.2.— MRI of the brain demonstrating extensive periventricular leukomalacia.

Border zone infarct in fullterm neonates

Arterial border zone infarctions are less common in fullterm neonates. Arterial border zone infarcts in fullterm neonates usually occur in the parasagittal region because the irrigation of this zone is provided by the terminal branches of the anterior, middle, and posterior cerebral arteries. Periventricular leukomalacia, the typical findings in arterial border zone infarct in premature neonates, can also occur in term neonates. The pathogenesis and radiological findings of periventricular leukomalacia are similar.

Single artery brain infarct

Single artery cerebral infarct occurs more frequently in the distribution of the middle cerebral artery (Figure 247.3). The left hemisphere is more frequently involved than the right hemisphere. Patients who have undergone extracorporeal circulatory support are at risk for single artery brain infarcts.

A B



Figure 247.3.— [A] CT of the brain demonstrating a large infarct in the distribution of the middle cerebral artery. [B] MRI of the brain (T2-weighted image) demonstrating a small posterior limb infarct in the internal capsule.

Multiple artery brain infarcts

Multiple artery brain infarcts are less frequent than single artery brain infarcts. Meningitis should be considered as a possible cause.





LINEAR NEVUS SEBACEOUS SYNDROME

The hallmark of linear nevus sebaceous syndrome in the neonatal period is the presence of linear nevus sebaceous in the craniofacial region. Linear nevus sebaceous lesions have raised borders and yellowish color (Figure 302.1). Linear nevus sebaceous is a type of epidermal nevi. Other types of epidermal nevi are nevus unius lateralis, ichthyosis hystrix, and localized pigmented papilloma.

A B

Figure 302.1.— Linear nevus sebaceous syndrome. [A] Coloboma of the left eye and nevus sebaceous of the jaw; [B] linear nevus sebaceous.

Seizures and ocular abnormalities are usually present in the neonatal period. Magnetic resonance imaging of the brain may show ventricular dilatation, cerebral and cerebellar hypoplasia, and hamartomatous brain changes. Ocular calcification may be visualized by CT of the orbits (Figure 302.2). Linear nevus sebaceous syndrome is a sporadic

disorder.

A B



Figure 302.2.— Linear nevus sebaceous syndrome. [A] Fundus calcification; [B] bilateral retinal calcification.





TREATMENT OF THE PRIMARY INSULT

Treatment of the primary insult may be carried out on the basis of a firm diagnosis or on suspicion. Treatment of comatose neonates with a firm diagnosis was briefly discussed under each etiology. The need for empirical treatment arises when the suspected primary insult warrants immediate treatment and its confirmation requires a potentially dangerous procedure, transportation, or a laboratory test whose results will not be immediately available.

Meningitis is diagnosed by performing a lumbar puncture. A lumbar puncture is not a risk-free procedure. Transtentorial herniation or clinical deterioration without apparent herniation may occur after lumbar puncture in patients with open fontanels. They appear to be related to forceful flexion of the neck during the lumbar puncture rather than to the extraction

of the cerebrospinal fluid. Our approach is to perform a lumbar puncture with the neonate in the horizontal position without attempting to curve the neck in all comatose neonates if: (1) the fontanel is not bulging, and (2) there are no signs of brainstem damage. If the fontanel is bulging or signs of brainstem damage are present, empirical antibacterial and antiviral treatments are warranted. Empirical treatment of this condition should also be initiated if the lumbar puncture is unsuccessful or the results are not conclusive. Our approach in cases with no or inconclusive cerebrospinal fluid results is to initiate treatment with ampicillin and gentamicin and add acyclovir if the EEG shows multifocal periodic activity or electroencephalographic seizures. We also consider the presence of a positive polymerase chain reaction for amplification of

herpes virus DNA an indication for acyclovir.

Subdural bleeds are diagnosed by CT scan of the brain. Computed tomography scanning requires transporting the neonate. The risk of transportation often raises the possibility of performing a subdural tap in neonates with a suspected subdural collection. Our approach is to not perform a subdural tap based on suspicion. The only exception is in cases when brain ultrasound shows midline shift and lateral brain hemisphere displacement.




The lumbosacral somatic motor center is located at the lumbosacral

enlargement of the spinal cord. This center consists of a pair of anterior horn motor neuron columns extending from L2 to S3 spinal segments. The axons of these neurons exit through the ventral spinal surface of the cord. These axons form the ventral roots which travel for a long distance in the spinal canal before joining the dorsal roots just before the intervertebral foramina. The dorsal roots are composed of the central axons of the

sensory neuron located in the dorsal ganglia.

The dorsal ganglia is located just before the union of the ventral and dorsal roots. The cauda equina is the structure created by the ventral and dorsal roots as they travel the distance from the spinal cord to their

corresponding intervertebral foramina inside the spinal canal. The cauda equina extends from the twelfth thoracic vertebral body to the fifth sacral vertebral foramina. The spinal nerves are formed by the union of the dorsal and ventral roots. The spinal nerves exit through the intervertebral foramina and shortly after split into the dorsal and ventral rami (Figure 229.1). The dorsal rami innervate the skin and musculature of the lower trunk. The ventral rami form the lumbosacral plexus.

Figure 229.1.— Schematic representation of the formation of the lumbosacral plexus. The spinal cord, ventral and dorsal roots, and the dorsal ganglion form the cauda equina.





LUMBOSACRAL PLEXUS DAMAGE

Lumbosacral plexus lesions are usually due to obstetrical trauma. They are usually associated with breech presentation. Evidence of trauma in other areas may be present.

PERIPHERAL NERVE DAMAGE

Peripheral nerve damage is usually due to local nerve trauma. Radial nerve damage has been associated with fracture of the humerus, restricted uterine positions, difficult delivery, or the use of blood pressure

cuffs. An area of cutaneous discoloration in the trajectory of the radial nerve or in the posterior interosseous branch may be present.

Median nerve injury in the antecubital fossa is usually due to brachial

artery puncture. Median nerve injury is more common in small neonates.

Sciatic nerve injury occurs after injection to the buttocks, prolonged pressure on the buttocks, or infusion of drugs into the umbilical artery. The mechanism of injury with injections to the buttocks is the inflammation associated with the injected substance and not trauma to the nerve by the needle stick as was initially considered. Necrosis of the buttocks may be associated with thrombosis of the inferior gluteal artery. The mechanism of sciatic nerve injury due to infusion of drugs into the umbilical artery is probably thrombosis of the inferior gluteal artery. This artery irrigates the

sciatic nerve.

Peroneal nerve injury may be due to compression by uterine bands (Figure 266.1), an ill-applied foot board, or intravenous fluid

infiltration.



Figure 266.1.— Amniotic band affecting the leg above the ankle.

Injuries to the peripheral nerves do not have any specific treatment other

than discontinuing the mechanism of injury if possible. Most neonates with peripheral nerve injuries recuperate with physical and occupational therapy.



Arm


Median Nerve

Median nerve damage produces inability to flex the index finger and, to

a lesser degree, the middle fingers. Flexion of the distal phalanx of the thumb and opposition of the thumb are weak. Forearm pronation is also weak. Efforts to make a fist produces a typical hand posture that has the appearance of a priest giving benediction. This posture is due to the inability to flex the index and middle fingers (benediction hand). Long-standing intrauterine median nerve lesions may produce an abnormal appearance called “simian hand” or “ape hand” due to atrophy of the median nerve innervated thumb muscles and the unopposed action of the extensor pollicis longus (radial nerve) and the adductor pollicis (ulnar

nerve).





Dandy-Walker malformation must be differentiated from a subarachnoid cyst in the posterior fossa because both are associated with a large cisterna magna.

Patients with Dandy-Walker malformation have an elevated tentorium, while patients with megacisterna magna and posterior fossa arachnoid cysts in the region of the cisterna magna have a normally placed tentorium. Megacisterna magna refers to a primary bone abnormality that leads to a large cisterna magna (Figure 118.1) and, therefore, central nervous system structures within the posterior fossa are normal.

Figure 118.1.— Schematic representation of a megacisterna magna. All neurological structures are within normal limits. There is no compression of the cerebellar vermis or hemispheres.





Lissencephaly type II

Lissencephaly type II probably results from a defect that involves the external basal lamina and the external layer of the cortex. It is believed that the external basal lamina and the external layer of the cortex normally function as a boundary that prevents the fusion of adjacent gyri and keeps the cortical layer from invading the meninges. A defect in these structures leads to penetration of the cortical tissue into the meninges and fusion of

the adjacent gyri.

The MRI of the brain shows smooth brain surfaces but the typical figure-8 appearance and the 2-band appearance of the cortex that are characteristic of type I lissencephaly are less prominent or not present. The cerebral cortex of a neonate with lissencephaly type II shows a very irregular gray-white matter junction. Lissencephaly type II is often associated with cerebellar abnormalities, hydrocephalus, hypoplasia of the corpus callosum, and hypomyelination. Neonates with lissencephaly type II have ocular anomalies and congenital muscular dystrophy.

Lyssencephaly type II may occur with: (1) Walker-Warburg syndrome (Figure 48.1), and (2) Fukuyama congenital muscular dystrophy. Fukuyama congenital muscular dystrophy has more hypomyelination and

more muscular involvement than Walker-Warburg syndrome.

A B C

Figure 48.1.— Walker-Warburg syndrome. [A] Microphthalmia, [B] lissencephaly, and [C] agenesis of the cerebellar vermis.


Microcephaly


Roberts SC Phocomelia Syndrome Roberts SC Phocomelia syndrome is characterized by facial and limb

abnormalities. Limb abnormalities consist of tetraphocomelia and abnormal thumb position. The craniofacial features include sparse hair, hypertelorism, exophthalmus, coloboma of the eyelids, corneal opacity, cataracts, and dysplastic ears. Prominent clitoris or penis has been reported. Other systemic abnormalities, especially kidney abnormalities, may be present. About 80% of patients with Roberts SC Phocomelia syndrome have premature separation of centromeric heterochromatin in

many chromosomes.

Miller-Dieker Syndrome The possibility of Miller-Dieker syndrome is considered in the presence

of a peculiar facies and typical findings on MRI of the brain. A most characteristic feature (although not always present nor specific for this entity) is furrowing of the forehead. Furrowing is especially prominent when crying. Magnetic resonance imaging of the brain shows a smooth cerebral surface, large vertical Sylvian fissures, and hypoplasia of the operculum. These abnormalities give the brain a “figure 8” configuration. The cerebral cortex is thick. Electroencephalogram typically shows a burst-suppression or hypsarhythmic pattern. Genetic diagnosis is available. Some patients will show abnormalities on prometaphase chromosome study. These abnormalities consist of ring chromosome or terminal deletion of chromosome 17. Most patients with Miller-Dieker syndrome have a deletion at 17p13.3 that can be demonstrated with the use of

fluorescent in situ hybridization. More about... 48





POSTSYNAPTIC MYONEURAL JUNCTION DISORDERS

Hypotonia due to postsynaptic myoneural junction disorders may result from destructive, metabolic, or dysgenetic problems (Figure 140.1).

Figure 140.1.— Salient features of generalized hypotonia due to presynaptic myoneural junction dysfunction. Arrow indicates the anatomical location of the injury (postsynaptic myoneural junction); SNST: slow nerve stimulation test; RNST: rapid nerve stimulation test; C: Clostridium; DES: destructive; MET: metabolism; DYS: dysgenesis.

Neonatal Transient Myasthenia Gravis Neonatal transient myasthenia gravis occurs in 10% to 20% of neonates

born to symptomatic or asymptomatic myasthenic mothers. Neonatal



transient myasthenia gravis is due to a decreased number of available nicotine acetylcholine receptors at the postsynaptic striated muscle membrane. This occurs because maternal antibodies cross the placenta and bind to the receptor. It is still unclear why all neonates of myasthenic mothers do not develop transient myasthenia gravis since the antibodies always cross the placenta. Neonatal transient myasthenia gravis presents in the first week of life, usually immediately after birth. Limb and axial hypotonia and weakness is overshadowed by the signs of pontine and medullar cranial nerve musculature dysfunction (Figure 140.1). Fatigability is the hallmark of myasthenia gravis. Muscle stretch reflexes are normal. Neonatal transient myasthenia gravis is diagnosed by using neostigmine 0.15 mg/kg administered intramuscularly or edrophonium at a dose of 0.15 mg/kg intramuscularly or subcutaneously or 0.1 mg/kg intravenously.





The posterior fossa findings of Cleland-Chiari malformation probably

result from a normal size cerebellum developing in a small posterior fossa with low tentorial attachment. The consequence of this discrepancy is that the cerebellum encroaches on other posterior fossa structures and is “squeezed” out of the posterior fossa as it grows. The cerebellum protrudes through the tentorial incisure and the foramen magnum as it wraps around the brainstem. The pons, medulla, and cervical spine are stretched inferiorly. The inferior displacement of the cervical spine is limited by the dentate ligaments. The characteristic cerebromedullary kink occurs as the medulla is stretched down farther than the dentate ligaments will allow the cervical spine to move inferiorly. The tectum is stuck below the tentorium and takes the shape of a beak. These posterior fossa abnormalities influence supratentorial development. The splenium of the corpus callosum is thin or absent and neuronal migrational errors are often present. Hydrocephalus occurs because of a combination of diminished

fourth ventricular foramina outflow and aqueductal stenosis. Magnetic resonance imaging of the brain is diagnostic (Figure 122.1). Treatment consists of closure of the myelomeningocele. Ventriculoperitoneal shunt is usually required.

Figure 122.1.— Cleland-Chiari malformation. T1-weighted sagittal image demonstrates large massa intermedia, beaked tectum, towering cerebellum, elongated fourth ventricle, and inferior extension of the cerebellum.

An entity related to Cleland-Chiari malformation is Chiari III. Chiari



type III malformation is characterized by the displacement of the posterior fossa content (brainstem and cerebellum) through a C1-C2 spina bifida (Figure 122.2).

A B C

Figure 122.2.— Chiari type III malformation. [A] Lateral view; [B]

posterior view; [C] MRI showing displacement of the posterior fossa content into th cervical area.





NEUROFIBROMATOSIS

The hallmark of neurofibromatosis type I in the neonatal period is the presence of cafe au lait spots (Figure 301.1). The presence of six or more cafe au lait spots larger than 1 cm in diameter establishes the diagnosis in young children. Neonates with less than six spots, even if smaller than 1 cm, may have neurofobromatosis because the number and size of the cafe au lait spots increases after birth.

Figure 301.1.— Two cafe au lait spots in a neonate with neurofibromatosis.

Neurofibromatosis does not usually produce neurological manifestations in the neonatal period. Nevertheless, the possibility of dysplastic tumor of the central or peripheral nervous system should be considered in any patient with neurofibromatosis who develops a neurological deficit. Careful ophthalmological evaluation should be performed and, if inconclusive or if an optical disc abnormality is found, an MRI of the brain should be done to exclude the possibility of optic glioma. Lisch nodules of the iris and axillary freckling are usually not present in the neonate. Neurofibromatosis is an autosomal dominant disorder with 100% penetrance but variable expression. Spontaneous

mutations are frequent. The gene locus is 17q11.2.




NEUROCUTANEOUS MELANOSIS

The hallmark of neurocutaneous melanosis in the neonatal period is the presence of a large bilateral hairy dark nevus with satellite nevi over the trunk and neck (Figure 303.1). The diagnosis should be considered in neonates with large pigmented nevi and in those with more than three hairy dark nevi regardless of their size. Neonates with neurocutaneous melanosis are at risk of developing neurological problems. The neurological complications of neurocutaneous melanosis are hydrocephalus, seizures, cranial nerve dysfunction, and signs of spinal cord and root involvement.

Hydrocephalus may have different causes. The most frequent cause of hydrocephalus is obstruction of the cerebrospinal fluid flow at the base of the skull due to thickening of the meninges (communicating hydrocephalus). This phenomenon occurs in neonates with a pigmented nevus in the distribution of the neck. Thickening of the meninges results from melanocytic infiltration of the arachnoid. Noncommunicating hydrocephalus due to aqueductal stenosis may also occur.

Magnetic resonance imaging of the area underlying the nevus or guided by the neurological findings is the study of choice in neonates with neurocutaneous melanosis. The most frequent MRI finding is the presence of areas of increased signal on T1. These areas of increased signal represent accumulation of melanocytic cells (Figure 303.1 B). The most frequent areas of melanocytic cell infiltration are the anterior temporal region, close to the amygdala, and the cerebellum. Malignant transformation of these areas is suggested by the presence of necrosis, hemorrhages, edema, growth, or contrast enhancement by CT.

The cerebrospinal fluid of neonates with neurocutaneous melanosis may reveal increased protein, decreased sugar, and a normal cell count. Melanin-filled cells are sometimes found in the cerebrospinal fluid.

Neurocutaneous melanosis is a sporadic condition.

A B



Figure 303.1.— Neurocutaneous melanosis. [A] Hyperpigmented nevus; [B] MRI findings showing bilateral increased signal from deep brain regions and the left mesial temporal lobe.



Facial Weakness


Ocular Pterygium

Ocular pterygium refers to a patch of hypertrophied bulbar subconjunctival tissue. This tissue may anchor the eyelid to the sclera, thus preventing the opening of the eye. Ocular pterygium will be noticeable during quiet wakefulness when both eyes are supposed to be wide open (Figure 173.1). The diagnosis is established by direct observation of the affected eye. Ocular pterygium may occur as an isolated finding or as a component of a syndrome. Ocular pterygium often occurs with linear nevus sebaceous syndrome. The treatment of ocular pterygium is surgical.

A B

Figure 173.1.— Neonate with linear nevus sebaceous syndrome. [A] Facial asymmetry is hardly noticeable when both eyes are closed. [B] Facial asymmetry becomes very noticeable when attempting to open the eyes.



Facial Weakness


NEONATAL FACIAL ASYMMETRY THAT IS WORSE WHEN

CRYING

Oculosympathetic Motor System Dysfunction During the active awake state, the muscles of Müller helps to keep the

upper and lower eyelids apart. This muscle is innervated by the oculosympathetic system. The oculosympathetic system is a 3-neuron

system. The first group of neurons are in the posterior hypothalamus (Figure 186.1 [1]). The second group of neurons are at the Budge ciliospinal center (Figure 186.1 [2]). The third group of neurons, those that innervate the muscles of Müller, are at the superior cervical ganglion (Figure 186.1 [3]). The fibers from the sympathetic neurons in the posterior hypothalamus form the central sympathetic tract. This tract travels caudally in the brainstem and the rostral cervical spinal cord until it reaches the spinal cord segments C8 and T1.

Figure 186.1.— Oculosympathetic pathway. MM: muscle of Müller; CS: cavernous sinus; ECA: external carotid artery; ICA: internal carotid artery; CCA: common carotid artery; BP: brachial plexus; T1: thoracic 1


Facial Weakness

spinal segment; C8: cervical 8 spinal segment; BCSC: Budge cilospinal center; CST: central sympathetic tract; A: common site of injury.





HEMIPARESIS

Hemiparesis refers to motor weakness involving the arm and leg on the same side of the body. Hemiparesis may occur with a lesion in the brain, brainstem, cerebellum, or upper cervical spine (Figure 237.1 A-D). Hemiplegia, whether spastic or flaccid, always implies a central nervous system lesion. Hemiplegia does not occur as a consequence of peripheral nervous system involvement.

Unilateral lesions in the cortex, centrum semiovale, internal capsule, midbrain, and upper pons may produce contralateral hemiparesis and facial weakness (Figure 237.1 A).

Unilateral cerebellar lesions may produce hemiparesis on the same side of the cerebellar lesion. The face is usually spared.

Unilateral pontine lesions produce contralateral hemiparesis and ipsilateral facial weakness (Figure 237.1 B). The involvement of the face on the same side as the lesion (on the side opposite from the hemiparesis) is due to direct damage to the facial motor nucleus or its fibers. The sparing of the face on the side of the hemiparesis occurs because the fibers innervating the facial musculature of the opposite side cross to the other side at the level of the midbrain. The presence of contralateral hemiparesis and ipsilateral facial weakness is referred to as cross-hemiplegia.

Unilateral upper medullary lesions may produce contralateral hemiplegia with sparing of the facial musculature (Figure 237.1 C). Medullary lesions more commonly produce paraparesis. They damage the pyramidal system as their left and right fibers cross to the other side.

A unilateral upper spinal cord lesion may produce ipsilateral hemiplegia with sparing of the facial musculature (Figure 237.1 D).



Figure 237.1.— Possible sites of anatomical injury producing hemiparesis. A: brain and midbrain; B: upper pons; C: lower pons and medulla; D: rostral spinal cervical cord; V: ventricles; T: thalamus; UQ: upper quadrant; LQ: lower quadrant; BP: brachial plexus; LSP: lumbosacral plexus. The colored rectangles indicate the location of weakness produced by damage to the different components of the somatic motor system.





Trisomy 18 Syndrome

Trisomy 18 syndrome is characterized by having a narrow bifrontal head diameter with a prominent occiput, epicanthal folds, small mouth, a short upper lip, micrognathia, low-set dysplastic ears, shield chest, short sternum, limited hip abduction, and hand and feet arthrogryposis. The position of the hands are typical in most cases. The feet anomalies are characterized by talipes calcaneovalgus, short dorsiflexed big hallux, and prominent heels. The central nervous system is affected in neonates with trisomy 18 syndrome. The most frequent anomalies are abnormal myelinization, microgyria, cerebellar hypoplasia, agenesis of the corpus callosum, hydrocephalus, and meningomyelocele. Neonates with trisomy 18 syndrome often die because of apnea. If they survive the neonatal period, they may require respiratory support and nasogastric feedings. The overall survival rate is very low and those that survive are severely mentally retarded. Limitation of extraordinary medical means for prolonging life should be considered.

Most neonates with trisomy 18 syndrome phenotype have trisomy. Full trisomy 18 occurs more frequently in neonates born to older mothers. The risk of recurrence of trisomy 18 in the same family is probably less than one percent. Translocation of chromosome 18 material produces a similar phenotype. The parents of an infant with translocation may be asymptomatic carriers of a balance translocation. The chance of recurrence translocation of chromosime 18 material is higher if either parent is a

carrier of a balance translocation.

Pena-Shokeir I Syndrome Pena-Shokeir I syndrome is characterized by hypertelorism,

micrognathia, depressed tip of the nose, low-set deformed ears, hypoplastic dermal ridges, hypoplastic lungs, cryptorchidism, and club feet (Figure 158.1). They are often stillborn or die within the first year of life.



Figure 158.1.— Pena-Shokeir I syndrome. Distal arthrogryposis and lung hypoplasia.





Arthrogryposis is especially prominent in the hands. Arthrogryposis

also involves the hips and the knees. Central and peripheral nervous system abnormalities are present. Pathologic findings reported in these patients include neurogenic atrophic muscle changes, and spinal cord and cerebellar histological abnormalities. Pulmonary hypoplasia results from decreased diaphragmatic motility. Neonates with Pena-Shokeir I syndrome are premature or small for gestational age. Pena-Shokeir I syndrome has been considered an autosomal recessive condition but more likely represents a typical phenotype that occurs as a consequence of decreased

fetal movements at a particular gestational age.

Pena-Shokeir II Syndrome Pena-Shokeir II syndrome, also known as cerebro-ocular-facio-skeletal

syndrome, is characterized by cerebral, ocular, and skeletal abnormalities and characteristic facial features. The cerebral abnormalities consist of microcephaly, calcification of the lenticular nuclei and hemispheric white matter, focal gliosis of the third ventricle, focal microgyria, and hypoplasia of the optic tract and chiasm. The ocular abnormalities include cataracts, blepharophimosis, and microphthalmia. Skeletal abnormalities include camptodactyly, prominent heels, rocket-bottom feet, and a longitudinal groove on the sole. Arthrogryposis primarily involves the elbows and knees. Radiographs of the lower extremities show shallow acetabular angle, coxa valga, posteriorly placed second metatarsal, and vertical talus. The characteristic facial features are thick scalp hair, large ears, prominent root of the nose, prominent upper lip that overlaps the lower, and micrognathia. Pena-Shokeir II syndrome is an autosomal recessive

disorder.

Opitz Trigonocephaly Syndrome Opitz trigonocephaly syndrome is characterized by trigonocephaly,

upslanting palpebral fissures, hypoplastic nasal root, wide alveolar ridges, anomalous and posteriorly angulated ears, loose skin, heart anomaly, and arthrogryposis (distal). The head size is normal at birth but fails to grow postnatally. Mental retardation is constant. Opitz trigonocephaly syndrome is possibly an autosomal recessive disorder. Chromosomal anomalies (specially chromosome 3), Frydman trigonocephaly syndrome and Say-

Meyer trigonocephaly syndrome need to be excluded.



A B C

Figure 159.1— Opitz trigonocephaly syndrome. [A] trigonocephaly and hypoplastic nasal root; [B] 3-D CT demonstrating metopic and coronal suture synostosis; [C] CT brain demonstrating abnormal skull configuration and prominent subarachnoid space.

Smith-Lemli-Opitz Syndrome Smith-Lemli-Opitz syndrome is characterized by microcephaly with a

narrow frontal area, slanted or low-set ears, ptosis, anteverted nostrils, cryptorchidism, and hypospadias. The most important distinguishing features in males are cryptorchidism and hypospadias.





PRESENTATIONS OF VENOUS CNS INFARCTS

Venous brain infarcts may involve the veins or the venous sinuses. Venous brain infarcts occur more often in premature neonates than in fullterm neonates. Venous infarcts in premature neonates occur due to compression of the terminal vein by the mass effect of blood from germinal matrix bleeds. Venous infarct may be localized to the area drained by the medullary veins or may be more extensive and involve the areas drained by the medullary, thalamostriate, and choroidal veins (Figure 249.1). Venous brain infarcts are often hemorrhagic (see intraparenchymal hemorrhage). In fullterm neonates, venous infarcts usually occur with dehydration and hypercoagulation states and they involve the sinuses.

Figure 249.1.— Schematic representation of the brain (Gestational age: 34-38 weeks) demonstarting angles on an axial cut (B-B: sagittal) and (C-C: coronal). The ventricles are represented in blue; the choroid plexus in pink. 1: medullary veins; 2: terminal vein; 3: internal cerebral vein; 4:



vein of Galen; 5: straight sinus; 6: thalamostriate vein; 7: choroidal vein; 8: Heubner's artery; 9: striated branches of the middle cerebral aftery; 10: frontal poles; 11: frontal horn of the left lateral ventricle; 12: germinal matrix; 13: foramen of Monro; 14: third ventricle; 15: occipital poles.

A venous CNS infarct should be considered in patients with focal CNS deficits, abnormal movements or seizures, and in patients with predisposing conditions for venous or venous sinus involvements. Central nervous system deficits that should raise suspecion of the possibility of an infarct in a neonate are: monoparesis, hemiparesis, paraparesis, upper extremity diplegia, and quadriparesis. Conditions that predispose to a venous infarct are increased intracranial pressure, polycythemia, dehydration, hypotension, or a hypercoagulopathy.

The study of choice to diagnose infarcts varies. Brain ultrasonography is the study of choice in premature neonates with suspected brain venous infarct. Brain ultrasonography is highly effective in diagnosing periventricular infarcts due to terminal vein compression because the infarcts are directly beneath the fontanelle and often hemorrhagic. On coronal projection, periventricular infarcts due to terminal vein compression often appear as asymmetrical globular or triangular-shaped echodensities irradiating from the external angle of the lateral ventricle. Periventricular infarcts due to terminal vein compression often resolve with or without cystic formation (Figure 249.2).

Figure 249.2.— Brain ultrasound demonstrating evolution of periventricular infarction. D: days of age; GMH: germinal matrix hemorrhage; PVHI: periventricular hemorrhagic infarct; B GMH:



bilateral germinal matrix hemorrhage. There is a cyst in the area of the germinal matrix bleed.

In fullterm neonates suspected of having a venous infarct the studies of choice are MRI, magnetic resonance venogram (MRV), or CT of the area in question (Figure 249.3). The study should be performed as soon as possible after the onset of clinical manifestations. Nevertheless, a normal MRI or CT within the first 24 hours after the onset of clinical manifestations does not eliminate the possibility of an ischemic venous infarct because ischemic central nervous system parenchymal changes may not be detected by MRI or CT studies during this period. Power Doppler ultrasound and MRV may demonstrate the flow abnormality earlier than MRI or CT. Power Doppler ultrasound imaging is probably the study of

choice to diagnose cerebral venous sinus thrombosis.

A B

Figure 249.3.— [A] MRI and [B] MRV demonstrating a left transverse sinus thrombosis (complication of beta-streptococcal meningitis). TS: transverse sinus; IJV: internal jugular vein.





Seizures develop when a massive number of neurons depolarize

repetitively. Specific drugs stop and prevent seizures by avoiding the factors that initiate the chain reaction that ultimately leads to repetitive massive neuronal depolarization. Antiepileptic drugs act at different levels of the chain reaction that leads to neuronal depolarization. Antiepileptic drugs act by: (1) preventing the sodium channel from opening; (2) facilitating the passage of chloride ions into the cell; (3) inhibiting T-calcium currents; and (4) antagonizing one or more types of glutamate receptors. Glutamate receptors are N-methyl-D-aspartate [NMDA], alpha-amino-3-hydroxy-methyl-4-isoxazole-propionic acid [AMPA], or kainite.

Thse receptors facilitate the passage of calcium and sodium into the cell.

Antiepileptic drugs are not indicated in all neonates with convulsions. Convulsions that stop with etiology-specific therapy and those that are brief and infrequent may not warrant antiepileptic drugs. The following factors should be considered prior to the initiation of antiepileptic drugs in neonates with seizures without etiology-specific therapy: (1) clinical consequences, and duration and frequency of the seizure; (2) natural history of the disorder; and (3) possible side effects of the seizures and the antiepileptic drugs.

The decision to use antiepileptic drugs is even more uncertain in the absence of electroencephalographic-confirmed seizures. Most physicians tend to use antiepileptic drugs for prolonged and recurrent focal and clonic paroxysmal motor events, and avoid using antiepileptic drugs for myoclonus provoked by stimulation or for generalized tonic posturing or automatisms provoked by stimulation or suppressed by restraint. The use of antiepileptic drugs for brief and infrequent myoclonus, focal clonic and tonic paroxysmal motor events, or generalized tonic posturing or

automatisms is controversial.

Phenobarbital is the drug of choice to treat convulsions in neonates. Phenobarbital acts on sodium current and GABA receptors. The loading dose is 20 mg/kg. It should be infused intravenously at a rate no faster than 1 mg/kg per minute. If the seizure persists 10 minutes after completing the loading dose, a second dose of 20 mg/kg should be administered. If the seizure stops, no further antiepileptic medication is given and a phenobarbital level is taken after 6 hours or if seizures recur. The maintenance dose of phenobarbital is 3 to 5 mg/kg per day.




Treatment of progressive posthemorrhagic hydrocephalus

When to to treat progressive hydrocephalus? The treatment of hydrocephalus has risk. The benefit versus risk must

be considered in each patient. Treatment is probably indicated for symptomatic hydrocephalus and for clinically silent hydrocephalus if associated with: (1) a significant increase in ventricular size between two ultrasounds; (2) a slowly progressive ventriculomegaly as detected by ultrasound during a 4-week period; and (3) a moderately increased ventricular size as detected by ultrasound during a 2-week period.

How to treat progressive hydrocephalus? The treatment options for progressive hydrocephalus are: (1)

medications that decrease cerebrospinal fluid production; (2) serial lumbar punctures; (3) direct ventricular drain; and (4) ventroperitoneal shunt.

Drugs that decrease CSF production

Acetazolamide (100 mg/kg per day) reduces cerebrospinal fluid production by 50%. The combination of acetazolamide and furosamide reduces CSF production by 100%. Neonates on acetazolamide should have

serial renal ultrasounds because of the possibility of nephrocalcinosis. The potential toxic effects of acetazolamide on myelination should be discussed with parents before the initiation of treatment. A recent trial

demonstrated the use of these drugs to be ineffective.

Serial lumbar puncture

Serial lumbar punctures probably work by creating a conduit between the lumbar subarachnoid space and the subcutaneous space. Cerebrospinal fluid leaks through the conduit and is reabsorbed in the subcutaneous space. The risk of serial lumbar puncture is infection.

Direct ventricular drain

Direct ventricular drain can be achieved by ventricular taps or the



introduction of a catheter in the ventricle. Ventricular taps are seldom done because of the high risk of infection and tissue injury due to multiple taps. Ventricular shunt to an external container is preferred to ventricular taps when direct ventricular drain is needed.

Ventriculoperitoneal shunt

Ventroperitoneal shunt is the definite treatment of progressive posthemorrhagic hydrocephalus. The major risk is infection and shunt malfunction. Ventriculoperitoneal shunt is probably contraindicated until a neonate weighs more than 1500 grams or if a previous lumbar puncture demonstrates cerebrospinal fluid with an increased level of protein (>300 mg), red cells (>1000 cells/mm), or evidence of infection. These treatment options for progressive hydrocephalus are often combined to achieve maximal benefit (Figure 254.1).

Figure 254.1.— Management scheme for progressive posthemorrhagic hydrocephalus. CSF: cerebrospinal fluid; LP: lumbar puncture; BU: brain ultrasound; VENT.: ventricular; WT: weight; DV: direct ventricular; VP: ventriculoperitoneal.



Apnea


Posterior Fossa Tumors

Medulloblastoma is the most frequent infratentorial tumor in neonates. Medulloblastomas are usually midline and arise from primitive neurons in the posterior medullary velum. They may compress and infiltrate the brainstem. They present with signs of brainstem dysfunction and increased intracranial pressure. Apnea may be the first sign of medulloblastoma.

Posterior fossa arachnoid cysts can produce apnea by brainstem compression (Figure 26.1). Apnea is more likely to occur with ventrally located cysts. The treatment for posterior fossa arachnoid cysts producing apnea is surgical decompression.

A B

Figure 26.1.— [A] Ventrally located posterior fossa arachnoid cyst compressing the brainstem. [B] Decompressed posterior fossa arachnoid cyst. The apnea in this patient ceased after treatment.





Neonates with significant asphyxia during the perinatal period have

umbilical artery pH less than 7 and Apgar scores of 0 to 3 at 5 minutes. The mechanisms of asphyxia after the immediate postpartum period are severe respiratory disease or cardiac arrest. The diagnosis of coma due to asphyxia can not be established if the mechanism for asphyxia can not be determined. The current treatment for coma due to asphyxia is supportive. More about it...110

HYPERTENSION

Coma due to hypertensive encephalopathy in neonates usually occurs when systolic blood pressure is greater than 106 mm Hg. Treatment of hypertensive encephalopathy consists of hydralazine 1 mg/kg per dose, followed by diazoxide 2 mg/kg and nitroprusside 0.25 to 0.5 mg/kg per

minute if necessary. The etiology of the hypertension should be determined and corrected if possible.

HYPOGLYCEMIA

Coma due to hypoglycemia is diagnosed if serum glucose is below 40 mg/dL. Patients with hypoglycemic coma present with hypotonia, jitteriness, and respiratory difficulties prior to becoming comatose. The mechanism causing hypoglycemia should be elicited. Possible mechanisms include hyperinsulinism, endocrine deficiencies, and inborn errors of metabolism. Treatment consists of correcting hypoglycemia and eliminating its causes. More about it...40, 110

POLYCYTHEMIA

Polycythemia may produce coma. Neonatal polycythemia is defined as central venous hematocrit greater than 65%. Polycythemic neonates look plethoric and have signs of respiratory distress and congestive heart

failure. Treatment consists of partial exchange transfusion.


Apnea


The dorsal and ventral respiratory groups have many afferent

connections. The most important afferent fibers are from a sensor in the lower medulla that monitors cerebrospinal fluid pH. The cerebrospinal fluid pH depends on blood pCO2 and reflects the acid-base balance status. The dorsal and ventral respiratory groups react to the signals from this sensor by modifying their discharge frequency and intensity. The discharge frequency and intensity of the dorsal and ventral respiratory groups dictate the respiratory rate and tidal volume. The dorsal and ventral respiratory groups also receive and integrate information regarding lung volume, airflow through the upper airway, and arterial oxygenation through the fifth and the tenth cranial nerve connections. In addition, fibers from structures in the pons and from higher central nervous system locations connect with the dorsal and ventral respiratory groups and help modulate breathing during all behavioral stages and sustain breathing during active sleep. During active sleep, respiration becomes less dependent on cerebrospinal fluid pH than while awake or during quiet sleep. Two important pontine centers are: (1) the apneustic center, which provides inspiratory drive to the medullary respiratory centers, and (2) the pneumotaxic center, which suppresses the apneustic center. The apneustic

center helps the transition from inspiration to expiration.

In addition to understanding the normal neuroanatomy of breathing, the evaluation of a neonate with apnea requires some understanding of polysomnography.

POLYSOMNOGRAPHY

Polysomnography with pH probe is a laboratory investigation often used in the evaluation of apnea. The polysomnogram monitors brain, cardiac, and respiratory functions; oxygen and CO2 concentrations; body movements; and esophageal pH. The polysomnogram is useful because it detects apnea; allows classification of the apnea as central, obstructive, or mixed; determines the behavioral stage during which apnea occurred; establishes the cardiac and electroencephalographic consequences of the apnea; and occasionally reveals the cause of apnea. The polysomnogram also allows detection and quantification of periodic breathing.

Apnea is an abnormal respiratory pause. A respiratory pause refers to a cessation in nasal and oral airflow that lasts longer than 3 seconds. A respiratory pause is abnormal if: (1) it is associated with pathological respiratory, cardiovascular, and neurological consequences; (2) it is of a


Apnea

type not normally seen in the neonatal period; (3) it occurs with a frequency above that of normal neonates; (4) it is trigger by electroencephalographic seizures or gastroesophageal reflux; or (5) it lasts more than 20 seconds in a premature infant or 15 seconds in a fullterm

neonate.



Microcephaly


The diagnosis of congenital toxoplasmosis is established by specific serum IgM-enzyme-linked immunosorbent assay. Neonates with congenital toxoplasmosis should be treated. The treatment of choice is pyrimethamine and sulfadiazine. Treatment should be continued for 1 year. Neonates with chorioretinitis or cerebrospinal fluid protein above 100 mg/dL should probably receive corticosteroids.

Rubella Congenital rubella syndrome is not a frequent cause of congenital

microcephaly. Microcephaly usually develops during infancy. Congenital rubella presents with cardiac disease (peripheral pulmonary stenosis, patent ductus arteriosus, and myocardial necrosis); ocular abnormalities (cataracts, salt and pepper chorioretinitis, and microphthalmia); and deafness. Congenital rubella syndrome is most likely to occur in neonates infected in the first trimester of pregnancy. Seizures and irritability may also be present. Cerebrospinal fluid pleocytosis is present in most patients. The diagnosis is established by specific serum IgM-enzyme-linked

immunosorbent assay.



Arm


Electromyography in patients with peripheral nerve lesions does not

show denervation potentials in muscles of similar myotomes innervated through a different nerve. The distribution of arm weakness due to a peripheral nerve lesion is usually very different than that produced by an upper motor neuron lesion. The differentiation between an upper motor neuron lesion and peripheral nerve injury can usually be made on clinical grounds. Electromyography and nerve conduction velocities are abnormal in peripheral nerve lesions.

Radial Nerve Radial nerve damage produces wrist drop (Figure 223.1). Extension

of the fingers is impaired. Elbow flexion with the forearm in midposition, between supination and pronation, will be affected with lesions above the elbow. Lesions below the elbow do not affect elbow flexion because the branch for the brachioradialis muscle leaves the radial nerve above the elbow. Finger flexion is normal once the wrist is placed in a neutral position.

Radial nerve lesions do not involve the deltoid and biceps muscles, nor do they involve muscles innervated by the same spinal segment as the radial nerve (C6-C8) but through a different peripheral nerve. Median and

ulnar nerve lesions do not produce wrist drop.

Figure 223.1.— Left wrist drop and finger extension weakness in a patient with a radial nerve injury. Weakness was noted after an intravenous board was removed. It resolved with physical therapy.




The structures that influence the alpha motor neuron from “above” are

in the brain, cerebellum, brainstem, and spinal cord. The structures can be divided in two systems: the pyramidal system and the extrapyramidal system. The term pyramidal system is reserved for neurons housed in the cerebral cortex that make direct contact with the alpha motor neuron and whose axons travel through the pyramids in the medulla (Figure 94.1). The term upper motor neuron is used for the pyramidal system neurons and neurons housed in the cerebral cortex that make direct contact with the alpha motor neurons in the brainstem above the pyramids.

Figure 94.1.— Schematic representation of the upper motor neuron (represented in blue). Arrows indicate direction of normal signal conduction; 1: neuron in motor cortex; 2: alpha motor neuron.

The term extrapyramidal system refers to all the neurons in the brain that influence the motor-sensory unit without making contact with the alpha motor neuron and neurons in the cerebellum, brainstem, and spinal cord that influence the motor-sensory unit with or without making direct

contact with the alpha motor neuron.

The upper motor neurons and the extrapyramidal system are often referred to as the upper motor neuron system (Figure 94.2).



Figure 94.2.— Schematic representation of the upper motor neuron system and the motor-sensory unit. Arrows indicate direction of normal signal conduction. 1: motor cortex; 2: basal ganglia; 3: cerebellum; 4: red nucleus; 5: reticular formation; 6: lateral vestibular nucleus.





Cephalohematomas are subperiosteal hemorrhages. Blood accumulates

between the periosteum and the external surface of the bone. The mass feels hard and, unlike caput succedaneum and subgaleal hemorrhages, it does not cross the sutures. A raised hard rim is often felt at the edges of the mass. Cephalohematomas may be associated with skull fractures. Cephalohematomas require no treatment. Linear and depressed skull

fractures usually involve the parietal bones. Linear skull fractures can not be diagnosed clinically. A skull radiograph is necessary. Depressed skull fractures manifest clinically as a depression in the contour of the skull. Linear bone fractures in the neonatal period require no treatment unless they are complicated by an internal injury. Treatment of depressed fractures consists of elevation of the depressed bone by using a breast pump attached to an obstetrical vacuum or by a neurosurgical procedure if the breast pump procedure fails. Retinal bleeding occurs in a large number of normal births and, unless extensive, should not be considered a

suggestive sign of brain injury.



Apnea


A failure of any of these conditions to occur can lead to apnea. The nervous system breathing apparatus generates and coordinates the contractions of the diaphragm, upper airway respiratory muscles, and intercostal muscles. Pivotal to the function of the nervous system breathing apparatus are the dorsal and ventral respiratory groups. The dorsal and ventral respiratory groups are in the medulla. The neurons of the dorsal respiratory group are intermingled with the neurons of the tractus solitarius. The neurons of the ventral respiratory group are intermingled with the neurons of the nucleus ambiguus and retroambigualis (Figure 15.1).

Figure 15.1.— Neurological structures involved in normal breathing. A: midbrain; B: pons; C: medulla; D: cervical spine; 1: chemoreceptor; 2: dorsal respiratory group at the nucleus of the tractus solitarius; 3: ventral respiratory group at the nucleus ambiguus and nucleus retroambigualis; 4: upper airway motor neurons; 5: upper airway motor muscles; 6: phrenic center; 7: diaphragm; 8: intercostal muscles' anterior horn cells; 9: intercostal muscles. Not represented are the pontine respiratory center and the fibers that travel from higher cortical centers to


Apnea

the dorsal and ventral respiratory groups.

The dorsal and ventral respiratory groups have efferent and afferent

connections. The efferent connections of the respiratory groups are with the phrenic center, alpha motor neurons of the intercostal muscles, and the cranial nerve motor neurons of the upper airway muscles. The dorsal and ventral respiratory groups generate discharges that lead to the contractions of upper airway muscles and the intercostal muscle 100 milliseconds before the onset of diaphragmatic contractions. The upper airway muscle and intercostal muscle contractions prevent the narrowing of the upper airway and the collapse of the chest wall that would otherwise occur due to the negative intrathoracic pressure generated by the diaphragmatic contraction.





The MRI of the brain establishes the diagnosis of Joubert syndrome.

The superior cerebellar peduncles are prominent and have horizontal courses. These characteristics of the superior peduncles, in association with a deep interpeduncular fossa, produce the molar tooth sign on axial view. Sagittal images of the fourth ventricles reveal the batwing sign due to the convex appearance of the upper fourth ventricular wall.

Hydrocephalus may also occur but is rare. Cervicomedullary

abnormalities are often present. Patients with Joubert syndrome may

have retinal dystrophy and cystic kidneys. Joubert syndrome must be differentiated from romboencephaloclasis.

Romboencephaloclasis Romboencephaloclasis is characterized by absence or hypoplasia of the

cerebellar vermis and fusion of the cerebellar hemispheres. Rhomboencephaloclasis is associated with other central nervous system malformations. The most frequent associated anomalies are fusion of the cerebellar dentate nuclei, superior cerebellar peduncles, and thalami.

Magnetic resonance imaging is diagnostic.



Clinical Paroxysmal Events


Most electroencephalographic seizures are unilateral and have a restricted electrical field. Seizures with bilateral electroencephalographic

onset are rare (Figure3.1).

Figure 3.1.— An electroencephalographic seizure. Generalized high voltage sharp waves followed by a period of depression and a sequence of rhythmic discharges with a well-defined onset, body, offset, and electrical field; that do not look like artefact or physiologic.

The term electroclinical seizure refers to a clinical paroxysmal event that is associated with an electroencephalographic seizure. The term convulsion refers to an electroclinical seizure characterized by increased motor activity. The term clinically silent electroencephalographic seizure refers to a scalp-recorded electroencephalographic seizure that occurs during the course of normal neonatal activity. In neonates, clinically silent electroencephalographic seizures probably occur more frequently than

electroclinical seizures. Clinically silent electroencephalographic seizures and electroclinical seizures have similar single photon emission computed tomography findings in neonates with hemimegalencephaly, which suggests that they may have similar consequences and should be

treated the same way (Figure 3.2).


Clinical Paroxysmal Events

A B

Figure 3.2.— [A] Ictal single photon emission computed tomography in a neonate during an electroclinical seizure. [B] Ictal single photon emission computed tomography in a neonate during a clinically silent electroencephalographic seizure. The bright signal represents an area of increased isotope uptake.





DIFFERENTIAL DIAGNOSIS OF LEG MONOPARESIS

Leg monoparesis usually presents in neonates as an inability to lift up the foot or the whole leg against gravity. The first step to determine the cause of leg monoplegia is to establish the anatomical location of the lesion (Figure 233.1 A-H).

Figure 233.1.— Schematic representation of the cortical component of the somatic motor system and sites of possible injuries causing leg monoparesis. The colored rectangles indicate the location of weakness produced by damage to the different components of the somatic motor system. V: ventricles; T: thalamus; UQ: upper quadrant; LQ: lower quadrant; BP: brachial plexus; LSP: lumbosacral plexus. A: brain and midbrain; B: upper pons; C: lower pons and medulla; D: upper spinal cord above the brachial center; E: lower spinal cord below the brachial center but the above the lumbosacral plexus; F: lumbosacral motor center; G: lumbosacral plexus; H: lower extremity peripheral nerves.




MUSCLE LESION

Muscle agenesis of the depressor angularis oris is the most common muscle lesions in neonates. More about... 184

Agensis of the pectoralis muscle may produce an asymmetrical Moro reflex.

The muscles may also be affected by tumors such as rhabdomyosarcoma or reactive hyperplasia.

STERNOCLEIDOMASTOID TUMOR OF INFANCY

Sternocleidomastoid tumor is characterized by a hard, immobile, fusiform swelling in the sternocleidomastoid muscle that is usually not present at birth but develops between 7 to 14 days of life. The mass increases in size for 2 to 4 weeks, remains stable for about 1 month (Figure 267.1[A]), and then decreases in size until it disappears completely by 5 to 8 months. Magnetic resonance imaging shows a significant mass (Figure 267.1[B]) that may enhance with contrast. The possibility of a malignant tumor should be considered but this possibility is very rare. Torticollis may be noted while the mass is present and often when the mass has disappeared. Craniofacial asymmetry may occur. Hip dislocation occurs in patients with more than 30 degrees of limitation in passive rotation of the neck. Treatment consists of passive exercise to stretch the sternocleidomastoid muscle and placing the infant in a position that encourages the face to move towards the side opposite to the facial deviation. Surgery is indicated in a small number of patients between 6

months and 2 years depending on the severity of the residual torticollis.

A B



Figure 267.1.— [A] Sternocleidomastoid tumor of infancy. [B] MRI of the neck demonstrates a large mass in the left sternocleidomastoid muscle.





Subdural Hematoma Over the Convexity Subdural hematomas are due to rupture of the superficial cortical veins

that bridge through the dura mater. Patients with subdural hematomas over the convexity present with focal seizures, hemiparesis, and gaze preference. These findings may be followed by the development of a unilateral third cranial nerve deficit (ptosis and poorly reactive pupil) if herniation occurs. The diagnosis is established by CT or MRI of the brain. Treatment, if necessary, is surgical either by subdural taps or direct surgical intervention. Subdural hematoma should be drained if seizures persist despite administration of phenobarbital, if the subdural collection is large, or if there is evidence of midline shift or impending transtentorial

herniation. More about... 250, 286

Subarachnoid Hemorrhage

Subarachnoid hemorrhage may be primary or secondary. Primary subarachnoid hemorrhage results from bleeding directly into the subarachnoid space due to structural vascular accidents (rupture of an aneurysm and an arteriovenous malformation), a coagulopathy, or an unknown cause.



Macrocephaly


SUBDURAL SPACE

Subdural hematomas may produce macrocephaly during the neonatal period. Progressive increases in head circumference may be noted during the third week of life. Subdural hematomas present with irritability or hyperalertness, or with signs of focal cerebral disturbances such as seizures, hemiparesis, or gaze preference. The causes of subdural hematomas are trauma and coagulation disorders. Subdural hematoma is diagnosed by CT of the brain. More about... 53, 250

SUBARACHNOID SPACE

Patients with benign enlargement of the subarachnoid space are usually not born macrocephalic; however, some patients with this condition may have excessive head growth during the neonatal period. The presence of bilateral enlarged frontal subarachnoid spaces (>5.7 mm), widening of the Sylvian fissure (>7.6 mm) and other sulci, and normal or minimally enlarged ventricles establishes the diagnosis. The anterior fontanelle is large and soft to palpation. Family members, most often the father, may

also have a large head.





Methylmalonic acidemia has amino and organic acid profiles similar to

propionic acidemia, but also has very high levels of methylmalonic acid and higher lactic acid levels than propionic acidemia due to inhibition of pyruvate carboxylase. Some patients with methylmalonic acidemia also show homocystinuria, hypomethioninemia, and cystothioninuria.

Propionic and methylmalonic acidemias may produce pancytopenia. The diagnosis of propionic and methylmalonic acidemias are established by finding decreased activity of propionyl-CoA carboxylase in leukocytes or cultured skin fibroblasts and decreased activity of methylmalonyl-CoA mutase in liver and cultured fibroblasts. A neutral pH does not exclude propionic and methylmalonic acidemias since the lactic acid elevation that occurs with these organic acidemias is usually in the 3 to 6 mmol/L range and a neutral pH is maintained until levels of lactic acids are at least 5 mmol/L.

Treatment of propionic and methylmalonic acidemias consists of metabolic support, elimination of protein intake, removal of ammonia, and carnitine supplementation. In addition, neonates with propionic acidemia should be given biotin and those with methylmalonic acidemia should be given vitamin B12. Propionyl-CoA carboxylase deficiency also occurs in

multiple carboxylase deficiency.

Sulfite oxidase deficiency

Sulfite oxidase deficiency may occur as an isolated enzyme defect or in association with xanthine dehydrogenase deficiency in molybdenum cofactor deficiency. Sulfite oxidase deficiency is tentatively diagnosed by an elevated sulfite level in the urine and blood, and decreased uric acid in the blood. Neonates with molybdenum cofactor deficiency may have mild facial dysmorphism (large head, upturned nose, telecanthus, cleft palate,

and broad nasal bridge), enophthalmus, and lens dislocation. In addition to the elevated sulfite and low uric acid levels, the metabolic profile

consists of hypoglycemia, lactic acidosis, and hyperammonemia. Sulfite oxidase activity in the liver cells is absent. Sulfite oxidase deficiency can

be diagnosed in cultured fibroblasts.




HORIZONTAL SUSPENSION RESPONSE

Horizontal suspension response is elicited by placing the neonate face down and lifting the neonate by the trunk. A hypotonic neonate bends ventrally and the head and limbs drop straight down like a rag doll (Figure 90.1 [A]). A normal neonate straightens the torso, briefly lifts the head up, and flexes the elbows, hips, knees, and ankles (Figure 90.1 [B]).

A B

Figure 90.1.— [A] Hypotonic horizontal suspension response. [B] Normal horizontal suspension response.

DIFFERENTIAL DIAGNOSIS OF HYPOTONIA

Generalized hypotonia must be differentiated from decreased generalized movements due to pain. Neonates with generalized hypotonia and neonates with decreased movement due to pain have the same posture, yet during arm traction and during vertical and horizontal suspensions the typical hypotonic responses are not present in neonates with decreased generalized movement due to pain. Neonates with decreased generalized movement due to pain become stiff and cry during any of these maneuvers.





VERTICAL SUSPENSION RESPONSE

Vertical suspension response is elicited by holding the neonate with both hands under the axillas and lifting the neonate up. A hypotonic neonate shows poor shoulder support, the head drops, and the lower extremities remain extended and limp (Figure 89.1 [A]). A normal neonate shows good shoulder and head support and flexion at the hips, knees, and ankles (Figure 89.1 [B]).

A B

Figure 89.1.— [A] Hypotonic vertical suspension response. [B] Normal vertical suspension response.





The study of choice to diagnose a germinal matrix bleed is a brain ultrasound. On the coronal view, the germinal matrix hemorrhage appears as an area of increased echogenicity just below the frontal horn of the lateral ventricles (Figure 252.1). Germinal matrix bleeds require no treatment.

Figure 252.1.— Germinal matrix hemorrhages (GMH) appear as an area of increased echogenicity just below the frontal horn. L: left; D: days; PVHI: periventricular hemorrhagic infarction; B: bilateral.

The evolution of germinal matrix hemorrhages varies. Ganglionic germinal matrix bleeds may resolve or progress (Table 252.2) to intraventricular hemorrhages, periventricular infarctions, or parenchymal hemorrhage.

Resolution of ganglionic germinal matrix hemorrhages

Germinal matrix bleeds may resolve, leading to disappearance of the ultrasonographic abnormality in the area of the bleed or the appearance of a cyst in the same area. Most cysts ultimately disappear.



Progression of ganglionic germinal matrix bleed to intraventricular hemorrhage

Intraventricular hemorrhage is probably the most frequent complication of germinal matrix bleeding (Figure 250.2). It occurs when blood from the germinal matrix tears the ependymal layer and spills into the ventricles. Intraventricular hemorrhage may resolve, produce an acute hemorrhagic hydrocephalus, or lead to post-hemorrhagic hydrocephalus.

Figure 252.2.— Progression of germinal matrix hemorrhage.

Resolution of intraventricular hemorrhage

Intraventricular hemorrhages resolve in a significant number of premature neonates. When the amount of intraventricular bleeding is small, the blood clears and no hydrocephalus develops. The diagnosis of a resolved intraventricular bleed should be delayed for at least 2 months and neonates with even small intraventricular bleeds should be followed for at least 3 months because of the possibility of developing post-hemorrhagic hydrocephalus. Acute hemorrhagic hydrocephalus

Acute hemorrhagic hydrocephalus is usually associated with a sudden clinical deterioration. The usual presentation is that of a previously healthy premature neonate who suddenly develops blood pressure and heart rate instability, and a bulging fontanelle. Acute hydrocephalus results from obstruction of the cerebrospinal fluid pathway at the aqueduct of Sylvius or foramina of Monro. There is no treatment for acute hydrocephalus other than support.



Figure 252.3.— Ultrasound studies demonstarting progression of germinal matrix hemorrhage to intraparenchymal hemorrhage and the development of acute hydrocephalus. GMH: germinal matrix hemorrhage; D: days; IPH: intraparenchymal hemorrhage.





Paramount to determining the anatomical diagnosis is the distinction between upper motor neuron system and motor-sensory unit dysfunction. This distinction can often be made based on the evaluation of the dynamic tone. Dynamic tone refers to the response of the striated muscles to being stretched by a brief high-intensity force. The dynamic tone is evaluated by determining: (1) the resistance the limbs offer to the examiner’s effort to quickly extend them, and their speed of recoil after such a maneuver; (2) the characteristics of the Moro and stretch muscle reflexes; and (3) the presence of clonus.

The limbs of neonates with increased dynamic tone offer increased resistance to the examiner’s effort to quickly extend them, and have a quick recoil once the limb is released. Moro reflex is exaggerated, muscle stretch reflexes are increased, radiating stretch reflexes (cross adductor response) are evident, and clonus may be present in the limbs and jaw of neonates with hypotonia and increased dynamic tone. Neonates with hypotonia and increased dynamic tone do not give the appearance of weakness because of the forceful displacement of the limbs during these maneuvers. Neonates with hypotonia and increased dynamic tone often have cortical thumbs.

The site of pathology in neonates with hypotonia and increased dynamic tone is the upper motor neuron: either in the brain, brainstem, rostral spinal cord, or a combination of these sites. The distinction among brain, brainstem, or spinal cord hypotonia can often be made based on associated neurological findings such as seizures, weakness of facial muscles, increased facial dynamic tone, parasympathetic pupil abnormalities, lack of bowel movements, and anal sphincter weakness (Figure 98.1).



Figure 98.1.— Schematic representation of the possible sites of neuromuscular damage in neonates with generalized hypotonia and increased dynamic tone. The symbols in the rectangular box depict the presence (in green background) and the absence (in red background) of important neurological findings. These findings help to localize the site of damage in hypotonic neonates. (1) brain; (2) brainstem; and (3) rostral spinal cord.

The limbs of neonates with decreased dynamic tone offer little resistance to the examiner’s effort to quickly extend them and they have poor recoil. Moro and muscle stretch reflexes are diminished in neonates with hypotonia and decreased dynamic tone. Clonus is not present. Neonates with decreased dynamic tone are weak. Cortical thumbs are not present.



Apnea


Transtentorial Herniations

Transtentorial herniations are rare in neonates because the sutures and

fontanels are open. Two types of transtentorial herniations occur in the neonatal period: uncal and central. Uncal herniation acts as an extraaxial posterior fossa mass lesion. In uncal herniation, the uncus of the temporal lobe goes through the tentorial incisure and pushes the brainstem, displacing it to the side and compressing it. The initial clinical sign of uncal herniation is a dilated pupil followed by outward and downward deviation of the eye. These findings occur because of common oculomotor nerve compression. Signs of common oculomotor nerve compression are followed by bilateral brainstem signs because the uncus compresses the brainstem on the side of the herniation and the edge of the tentorium cerebelli compresses the brainstem on the opposite side. Evidence of progressive rostrocaudal brainstem damage appears as uncal herniation progresses. Uncal herniation occurs with supratentorial lesions, particularly with those that produce hemorrhage and swelling of the temporal lobe. Uncal herniation has been reported to occur with meningitis

in the neonatal period.

Central herniation behaves as a midline posterior fossa lesion. In central herniation, the diencephalon is displaced across the tentorial incisure.





TUBEROUS SCLEROSIS

Tuberous sclerosis in the neonatal period has three presentations: (1) hypopigmented spots; (2) cardiac rhabdomyomas; and (3) seizures.

The most frequent presentation is multiple hypopigmented spots on the trunk and limbs. The hypopigmented spots are flat and the edges irregular but sharply delineated. Their shape resembles an ash leaf or an arrow head. The hypopigmented spots may be difficult to see in neonates with light-skin (Figure 299.1 [A]). A Wood’s lamp examination (Figure 299.1 [B]) may “bring them out.”

A B C

Figure 299.1.— Tuberous sclerosis. [A] Skin examination under normal light; [B] skin examination under Wood's light; [C] typical location of intracranial calcifications (close to the foramina of Monro).

The diagnosis of tuberous sclerosis can be made if seizures occur in a neonate with one typical hypopigmented spot. In the absence of neonatal seizures, the question of how many typical depigmented spots are needed to diagnose tuberous sclerosis has not been determined. The best approach to a patient with one typical or few atypical depigmented spots but without seizures is to perform ultrasonography of the brain, heart, and kidneys. A brain CT should also be done. The presence of a typical tuberous sclerosis lesion in any of these organs establishes the diagnosis.



The second most frequent presentation is a heart murmur secondary to cardiac rhabdomyomas. Cardiac rhabdomyomas are readily discovered by ultrasound.

The third most frequent presentation is seizures due to cortical tubers. Hydrocephalus due to subependymal hamartomas may also occur.



Arm


Ulnar Nerve Ulnar nerve damage results in difficulty flexing the wrist and a striking

inability to flex the metacarpal phalangeal joint of the fourth and fifth

fingers. Long-standing ulnar nerve damage produces a partial claw hand because the damage is restricted to the lumbricoids of the small and ring fingers while sparing those of the middle and index fingers. The lumbricoids of the second and third fingers are innervated by the median nerve. Neonates with Klumpke palsy have a complete claw hand due to weakness of all the lumbricoid muscles. Ulnar nerve lesions are very rare in neonates.





The anatomical location of the lesion is established by determining if

the weakness is spastic or flaccid. Spastic weakness is characterized by increased muscle stretch reflexes, sustained ankle clonus, and excessive resistance and recoil of the leg when the leg is suddenly pulled by the foot and let go. Clonus is often present. Spastic weakness occurs with upper motor neuron lesions (Figure 234.1 A-E). Flaccid weakness is characterized by decreased or absent muscle stretch reflexes, no resistance of the leg when suddenly pulled by the foot, and no recoil when let go. Flaccid weakness occurs with upper or lower motor neuron lesions (Figure 234.1 F-H).

Figure 234.1.— Schematic representation of the cortical component of the somatic motor system and sites of possible injuries causing leg monoparesis. The colored rectangles indicate the location of weakness produced by damage to the different components of the somatic motor system. V: ventricles; T: thalamus; UQ: upper quadrant; LQ: lower



quadrant; BP: brachial plexus; LSP: lumbosacral plexus. A: brain and midbrain; B: upper pons; C: lower pons and medulla; D: upper spinal cord above the brachial center; E: lower spinal cord below the brachial center but the above the lumbosacral plexus; F: lumbosacral motor center; G: lumbosacral plexus; H: lower extremity peripheral nerves.

SPASTIC LEG MONOPARESIS

Spastic leg weakness may occur after several weeks with lesions that involve the central component of the lumbosacral somatic motor system in the brain, brainstem, or spinal cord (Figure 234.1 A-E). Brain lesions in the mesial aspect of the precentral gyrus, or in the fibers from the neurons in this area before they reach the internal capsule, may produce contralateral spastic leg monoparesis. Brain lesions that extend beyond the mesial aspect of the precentral gyrus, or the fibers from this region, are more likely to produce contralateral hemiparesis. Spastic leg monoplegia due to a lesion close to or in the cortex may be associated with seizures. Lesions in the lumbosacral motor system that occur between the internal capsule and the lower medulla rarely produce leg monoparesis, because a lesion in this area, unless extremely small and strategically located, will involve the arm fibers and produce hemiparesis. Unilateral spinal cord lesions between the lower medulla and first thoracic segment (Figure 234.1 D) usually do not produce leg monoplegia (they usually produce hemiparesis unless small and strategically located because the leg and the arm fibers travel very close together). A unilateral lesion below the second thoracic spinal segment and above the lumbosacral center (Figure 234.1 E) may produce spastic leg monoparesis but spastic diplegia occurs more frequently because most lesions in this area are tumors. Tumors usually produce mass effect and push the enlarged spinal cord against all sides of the bony spinal canal.





Bilateral lumbosacral somatic motor center lesions (Figure 239.1 D)

may produce paraparesis. The neurological deficit depends on the level of the lesion. Neonates with a lesion at or below S2 have bilateral toe flexion weakness and bladder and rectal sphincter dysfunction. Neonates with lesions at L5 and below have, in addition to the previous deficits, weakness of knee flexion, ankle dorsiflexion, and plantar flexion, and decreased ankle jerk reflex. Neonates with lesions at L3 and below have, in addition to the previous deficits, weakness of hip adduction and knee extension, and decreased knee jerk reflex.

Figure 239.1.— Possible sites of anatomical injury producing paraparesis. A: parasagittal region; B: bilateral periventricular regions; C: spinal cord below T1; D: lumbosacral center; V: ventricles; T: thalamus; UQ: upper quadrant; FN: facial nerve; LQ: lower quadrant; BP: brachial plexus; LSP: lumbosacral plexus. The colored rectangles indicate the location of weakness produced by damage to the different components of the somatic motor system.


Arm


Upper-Middle Trunk Syndrome

Upper-middle trunk syndrome is characterized by a posture similar to the upper trunk syndrome but, in addition, there is weakness of extensors of the elbow, wrist, and fingers. Neonates with upper-middle trunk lesions do not have the typical flexion of the wrist that occurs with Duchenne-Erb palsy. Upper-middle trunk syndrome indicates involvement of the fibers of the C5-C7 spinal segment. The damage may occur at the roots (Figure 219.1; VR), spinal nerves (Figure 219.1; SN), ventral ramus (Figure 219.1; VRa), or trunks (Figure 219.1; ST and MT).

Figure 219.1.— Schematic representation of the brachial plexus. The structures that constitute the brachial plexus include the ventral ramus (VRa), trunks (T), divisions (D), cords (C), and branches (B). C: cervical spinal segment; T: thoracic spinal segment; SC: spinal cord; DRa: dorsal ramus; ST: superior trunk; MT: middle trunk; LT: lower trunk; A: anterior; P: posterior; LC: lateral cord; MC: middle cord; PC: posterior cord; LB: lateral branch; MB: medial branch; IB: internal branch; AB: anterior branch; PB: posterior branch.


Facial Weakness


The orbicularis oculi muscle is innervated by the temporal branch. It has bilateral cortical innervation. The buccinator is innervated by the buccal branch. It has contralateral cortical innervation. The depressor angularis oris muscle is innervated by two branches: the buccal branch and the mandibular branch. The depressor angularis oris muscle has contralateral cortical innervation. The mandibular branch also innervates the depressor labii inferioris muscle and the mentoris muscle. These muscles have contralateral cortical innervation (Figure 177.1).

Figure 177.1.— Anatomical localizations of injuries in the facial motor system. T: thalamus; AC: internal auditory canal; FC: facial canal; SMO: styloidmastoid orifice; BB: buccal branch; MB: mandibular branch; TB: temporal branch; OOM: orbicularis oculi muscle; RM: risorius muscle; DAOM: depressor angularis oris muscle; BM: buccinator muscle; MM:


Facial Weakness

mentoris muscle. Light blue line indicates components of the facial nerve that have ipsilateral (hence bilateral) cortical innervation; dark blue line indicates components of the facial nerve that have contralateral innervation. A: cerebral lesion above the thalamus; B: cerebral lesion below the thalamus and above the pons; C: pontine lesion; D: facial nerve lesion; E: mandibular branch lesion; F: depressor angularis oris muscle.

Facial motor system lesions may involve the facial motor pathway above the facial motor nucleus (upper motor facial asymmetry) or involve the facial motor nucleus and the structures below it (lower motor facial

symmetry).



Macrocephaly


Vein of Galen Aneurysm Neonates with aneurysm of the vein of Galen may be macrocephalic at birth.

Nevertheless, the most common neonatal presentations of vein of Galen aneurysm in the neonatal period are cardiac failure (Figure 289.1[A]), cerebral infarction, or cerebral bleed. The cause of cardiac failure is multifactorial. High cardiac output due to decreased cerebrovascular resistance, increased venous return, and cardiac ischemia due to decreased diastolic pressure contribute to the production of cardiac failure. Macrocephaly can be caused by the large size of the vein of Galen aneurysm, but most often it is caused by an obstruction of the aqueduct of Sylvius. A cranial bruit is often present in neonates with vein of Galen aneurysm.

Vein of Galen aneurysm is a malformation due to abnormal connections between intracranial vessels (usually thalamoperforators, choroidal, and anterior cerebral arteries), and a vein in the region of the vein of Galen (may not be the vein of Galen but a persistent fetal structure, the midline prosencephalic vein). Vein of Galen aneurysm is diagnosed by contrast-enhanced CT, MRI, or angiogram of the brain (Figure 289.1[B and C]).

A B C

Figure 289.1.— Vein of Galen aneurysm. [A] Congestive heart failure (large heart). [B] MRI demonstrating a vein of Galen aneurysm. [C] Arteriogram demonstrating collateral circulation to the aneurysm.

Cranial ultrasound will demonstrate a large echolucent area in the region of the vein of

Galen. Embolization is the treatment of choice.


Macrocephaly

A B C

Figure 289.2.— Vein of Galen aneurysm (ultrasonographic appearance). [A] Midline sagittal view demonstrating a large echolucent area. [B] Coronal view demonstrating a vein of Galen aneurysm. [C] Ultrasonography demonstrating high flow in the area of the vein of Galen aneurysm.





Progression of ganglionic germinal matrix bleed to intraparenchymal hemorrhages

Intraparenchymal bleed in premature neonates with germinal matrix bleed are due to extension of the periventricular hemorrhagic infarction beyond the periventricular area.

Prognosis of ganglionic germinal matrix hemorrhages

The prognosis of germinal matrix hemorrhage depends on its evolution. Germinal matrix hemorrhage without any progression has a good prognosis. The prognosis of germinal matrix hemorrhages that progress to intraventricular hemorrhages depends on its subsequent evolution. Intraventricular hemorrhages that resolve have a better prognosis that those that progress to acute or posthemorrhagic hydrocephalus, and so on.

A grading system to prognosticate the likely outcome of neonates with germinal matrix hemorrhages based ultrasonographic findings is sometimes used. This system classifies germinal matrix bleeding as grades I to IV. Grade I intraventricular hemorrhages are restricted to the germinal matrix; grade II intraventricular hemorrhages consist of blood in the germinal matrix and in the ventricles; grade III intraventricular hemorrhages consist of blood in the germinal matrix and ventricles, and ventricular dilatation; and grade IV hemorrhages consist of blood in the germinal matrix hemorrhage extending to the parenchyma. The incidence of neurological sequela is about 10% for grade I and II intraventricular hemorrhages, about 50% for grade III intraventricular hemorrhages, and about 90% for grade

IV intraventricular hemorrhages. Premature neonates with germinal matrix hemorrhages do not require any specific laboratory investigations to look for an etiology for the bleed.

PARENCHYMAL HEMORRHAGES IN FULLTERM NEONATES

The site of an intra-axial hematoma in the fullterm neonate differs from that of the premature neonate. Intraaxial hematomas in the fullterm neonate may occur in the periventricular area, centrum semiovale, thalamus, or ventricles.

Periventricular hemorrhagic infarctions are rare in fullterm neonates



since they result from germinal matrix hemmorrhages and germinal matrix hemorrhages are rare in fullterm neonates. The cause of periventricular hemorrhagic infarction is usually not found. Coagulation studies are usually not done in these patients.

Centrum semiovale and thalamic hemorrhages usually occur in neonates with clotting disorders. The most common cause of clotting disorders in neonates is thrombocytopenia. Neonates with platelet count below 20,000 per cubic millimeter are at high risk for bleeding. Sepsis is probably the most common cause of thrombocytopenia in the neonatal period. Maternal immune thrombocytopenic purpura, systemic lupus erythematous, and exposure to thiazide or digoxin are also associated with low platelets. Bleeding diathesis may also occur with factors VII, VIII, or IX, or vitamin K deficiencies. Centrum semiovale hemorrhages may also occur with vascular malformations, aneurysms, cerebral tumors, and meningitis.

Figure 256.1.— CT of the brain demonstrating centrum semiovale hematoma. Cerebral edema and displacement of the lateral ventricles.

Patients on extracorporeal membrane oxygenation are at risk for

intraparenchymal bleeding because of the use of heparin. Coarctation of the aorta may contribute to the production of intraparenchymal bleeding. The cause of intraperenchymal hemorrhage is often not found.

Intraventricular hemorrhages in fullterm neonates usually arise from the choroid plexus. Coagulation defects are usually not found in these patients, hence coagulation studies are not often done.

Treatment of intra-axial bleeding is usually supportive. Correction of the bleeding diathesis is necessary. Neurosurgical treatment is seldom possible in patients with parenchymal bleeding.



CEREBELLAR, BRAINSTEM, AND SPINAL CORD HEMORRHAGES

Cerebellar, brainstem, and spinal cord hemorrhages are very rare in the neonatal period. Cerebellar hemorrhages may occur as a result of arteriovenous malformation rupture, venous infarction, cerebellar contusion, or due to extension of an intraventricular or subarachnoid

hemorrhage. Cerebellar hemorrhages are more common in premature infants than in fullterm infants. The possibility of bleeding diathesis, posterior fossa skull fracture and von Hippel-Lindau disease should be considered in neonates with cerebellar hematomas. von Hippel-Lindau disease is characterized by retinal angiomas; cerebellar and spinal cord spinal cord hemangioblastomas; renal cell carcinomas; pheochromocytomas; angiomas of the liver and kidney; and cysts of the pancreas, kidney, liver and epididymis. von Hippel-Lindau is a an autosomal dominat disorder due to a defective tumor supressor gene at

chromosome 3p25-26. Most neonates with cerebellar hematomas require observation only (Figure 256.2). Surgical treatment is restricted to large surface cerebellar hematomas with mass effect.

A B

Figure 256.3.— Cerebellar hematoma. [A] T1-coronal view demonstrates a large circular lesion with peripherally increased signal in the right cerebellar hemisphere. [B] T2-coronal view demonstrates a large circular lesion devoid of signal.




The diagnosis of Zellweger syndrome is established by fibroblast

culture and liver biopsy. They do not show peroxisomes when stained for peroxisomal enzymes. Electromicroscopy of the same tissue shows that the peroxisomal membranes are present. They are called “ghost peroxisomes”

because the membrane is present but the enzymes are not. Genetic defects at 7q11.23 and 1p22-p21 are associated with Zellweger syndrome. Most patients with Zellweger syndrome die during the first year of life.

Survivors are mentally retarded. Zellweger syndrome has an autosomal recessive inheritance.

Walker-Warburg Syndrome The acronym HARD +/- E has being used for this disorder. This

acronym stands for the first letter of the major features of this condition: hydrocephalus, agyria (cerebral and cerebellar), retinal dysplasia, and occasionally encephalocele. In addition to retinal dysplasia, other ocular abnormalities include microphthalmia (Figure 161.1 [A]), vitreous abnormalities, retinal detachment, glaucoma, cataracts, and corneal opacities. Neonates with Walker-Warburg syndrome are hypotonic and usually have seizures. Arthrogryposis is usually distal. The brain abnormalities in Walker-Warburg syndrome are probably due to a defect in the external basal lamina of the brain. The external basal lamina of the brain is the boundary that stops the neuronal migrational process. Failure of the external basal lamina to develop causes the neurons to cross over sulci and into the meninges creating a flat brain and engulfing the meninges. Walker-Warburg syndrome is familial. The familial incidence is most likely due to an autosomal recessive inheritance, but the possibility of a persistent intrauterine viral infection affecting several members in one family has been considered. Walker-Warburg syndrome is diagnosed by MRI. The MRI shows smooth cerebral and cerebellar surfaces, large lateral ventricles in relation to cerebral mass, and absence of cerebellar vermis (Figure 161.1 [B,C]).

A B C



Figure 161.1.— Walker-Warburg syndrome. [A] T2-axial weighted image demonstrates microphthalmia; [B] T1-axial weighted image demonstrates lissencephaly with large lateral ventricles; and [C] T1-axial weighted image demonstrates agenesis of the cerebellar vermis (cerebellar hemispheres in apposition without an intervening vermis).



Apnea


PHRENIC-DIAPHRAGMATIC AND UPPER AIRWAY MOTOR UNITS

Diseases that affect the motor unit may affect the phrenic-diaphragmatic motor unit, upper airway motor unit, or both. The degree of involvement of both units may be the same or one unit may be more involved than the other.

Phrenic-diaphragmatic motor unit diseases produce central apnea by lack of effective diaphragmatic contraction. Upper airway motor unit diseases produce obstructive apnea because the normal contraction of the upper airway muscles that prevent the narrowing of the upper airway (which occurs as the result of the negative pressure created by diaphragmatic contraction) does not occur. Diseases that affect both the phrenic-diaphragmatic and upper airway motor units may present with central, obstructive, or mixed apnea. Apnea due to phrenic-diaphragmatic or upper airway motor unit diseases occur more frequently during active sleep. During active sleep there is a physiologic generalized hypotonia due to hyperpolarization of the anterior horn motor neurons that affects primarily the intercostal muscles. Diseases of the phrenic-diaphragmatic and cranial upper airway motor units may involve the motor neuron, nerves, myoneural junction, or muscles.

The only motor neuron disease that may present with apnea in the neonatal period is Werdnig-Hoffman disease. Most neonates with Werdnig-Hoffmann disease do not have apnea because the disease tends to spare the phrenic center even when severe generalized hypotonia is present. When apnea occurs, it is usually central, but obstructive and mixed apnea may occur. The diagnosis of Werdnig-Hoffman disease is confirmed by DNA testing.





Monoparesis may occur with central and peripheral nervous system lesions. Hemiparesis due to a single lesion occurs exclusively with central nervous involvement. Peripheral lesions involving the brachial plexus and the lumbar plexus on the same side can produce hemiparesis but they are very rare. Decreased limb movements of both upper extremities (upper extremity diparesis) usually results from bilateral brachial plexus lesions. Bilateral lower extremity weakness usually implies a lesion in the thoracic spine, conus, or cauda equina. Quadriparesis usually results from cervical spine lesions, although diseases of the anterior horn motor neurons (Werdnig-Hoffmann disease) may produce similar findings.

The presence of monoparesis, hemiparesis, upper extremity diparesis, or paraparesis, although the most valuable finding for anatomical localization in the nervous system, must be corroborated with other neurological and general findings in order to achieve a precise and reliable anatomical diagnosis.





DIFFERENTIAL DIAGNOSIS OF ARTHROGRYPOSIS MULTIPLEX CONGENITA

Arthrogryposis multiplex congenita involving both upper extremities may resemble bilateral brachial plexus palsy. The characteristics of arthrogryposis multiplex congenita that distinguish it from brachial plexus palsy are: (1) the presence of skin pits at the wrists and (2) the permanent nature of the arm position (Figure 167.1). In patients with brachial plexus palsy there is no skin pits and the abnormal position is only present when the neonate attempts to move the arm

Figure 167.1.— Typical arm position and wrist pit characteristic of arthrogryposis multiplex congenita.

DIFFERENTIAL DIAGNOSIS OF A NEONATE WITH ARTHROGRYPOSIS MULTIPLEX CONGENITA

Neonates with proximal arthrogryposis are likely to have amyoplasia congenita. Neonates with distal arthrogryposis present a complex diagnostic problem. Most neonates with distal arthrogryposis can only be diagnosed by recognizing a constellation of signs leading to the diagnosis of a syndrome. Few neonates with distal arthrogryposis have specific laboratory findings. Zellweger syndrome courses with increased very-long-chain fatty acids in plasma. Smith-Lemli-Opitz syndrome courses with high levels of the cholesterol precursor 7-dehydrocholesterol and low cholesterol levels. Trisomies are associated to chromosomal abnormalities.



Walker-Warburg syndrome is associated with characteristic magnetic resonance imaging abnormalities. Spinal muscular atrophy is diagnosed by DNA testing. Spinal cord abnormalities may be detected by MRI of the spine. Congenital hypomyelinating neuropathy is diagnosed by nerve conduction studies. Schwartz-Jampel syndrome courses with electromyographic myotonia and bone dysplasia. Sodium-channel myotonia and myotonic dystrophy may course with electromyographic evidence of myotonia.

TREATMENT OF ARTHROGRYPOSIS MULTIPLEX

Treatment of arthrogryposis in the neonatal period consists of serial casting.



Facial Weakness


REFERENCES

Alfonso I, Palomino JA, DeQuesada G, et al. Congenital varicella syndrome. Am J Dis Child. 1984;138:603-604. Bajandas FJ, Lanning BJ. The pupil. Neuro-opthalmology Review Manual. 3rd ed. Thorofare, NJ: Slack Inc; 1988:113-124. Dodge PR, Ganstrop I, Byers RK, et al. Myotonic dystrophy in infancy and childhood. Pediatrics. 1965;35:3-19. Duus P. Topical Diagnosis in Neurology. 2nd ed. New York, NY: Thieme Med Pubs; 1989:70-159. Harrison DH. Treatment of infants with facial palsy. Arch Dis Child. 1994;71:277-280. Haymaker W. Bing’s Local Diagnosis in Neurological Diseases. 15th ed. St Louis, Mo: Mosby Co; 1969:217-233. Hepner WR. Some observations on facial paresis in the newborn infant: etiology and incidence. Pediatrics. 1951;8:494-497. McHugh HE. Facial paralysis in birth injury and skull fractures. Arch Otolaryng. 1963;78:57-69. McHugh HE, Sowden KA, Levitt MN. Facial paralysis and muscle agenesis in the newborn. Arch Otolaryngol. 1969;89:131-143. McLellan MS, Parrino CS. Bell’s palsy at 1 month 4 days of age. Am J Dis Child. 1969;117:727-729. Monrad-Krohn GH. On the dissociation of voluntary and emotional innervation in facial paresis of central origin. Brain. 1924;47:22-35. Monrad-Krohn GH. On facial dissociation. Acta Psychiatr Neurol Scand. 1939;14:557-566. Nelson KB, Eng GD. Congenital hypoplasia of the depressor anguli oris muscle: differentiation from congenital facial palsy. J Pediatr. 1972;81:16-20.





Neonates with bone fracture may show evidence of trauma. The most common signs of trauma are cephalohematoma, cutaneous bruises, and abnormally shaped limbs. Bone fractures may be displaced or nondisplaced. Displaced bone fractures are easily diagnosed by observation and conventional radiography (Figure 195.1).

Figure 195.1.— Displaced left humeral fracture.

Nondisplaced fractures may be difficult to detect. The first sign of nondisplaced bone fracture on conventional radiograph is new periosteal formation. Evidence of new periosteal formation on conventional radiograph does not appear until 10 days after a fracture (Figure 195.2). Gallium scan may show evidence of bone fractures before the signs of

periosteal formation become evident on conventional radiographs. Bone fracture is usually limited to one limb. Fractures in more than one limb may produce an unusual pattern of decreased movements. The presence of unexplained single or multiple fractures in a neonate should suggest the possibility of child abuse. Bone survey and ophthalmologic examination are mandatory in these cases.

A B



Figure 195.2.— [A] Normal radiograph of the forearm. [B] New periosteal ulnar bone in a radiograph taken 10 days after [A].





DIFFERENTIAL DIAGNOSIS OF PAROXYSMAL MOTOR EVENTS

The initial clinical assessment of the neonate is pivotal in the differential diagnosis of paroxysmal motor events.

A neonate with paroxysmal motor events with the clinical characteristics of benign neonatal sleep myoclonus, arousals, or behavioral movements do not need laboratory tests, EEG or brain imaging if they have a normal neurological examination and an an unremarkable history.

A neonate with jitteriness, a normal neurological examination, and an unremarkable history requires a serum glucose and calcium determinations. If the blood sugar and calcium levels are normal, no further evaluation is needed unless drug withdrawal is suspected. If drug withdrawal is suspected urine toxicology is required. If urine toxicology is also normal, the diagnosis of benign jitteriness can be made.

Neonate should be admitted and evaluated if they have: (1) paroxysmal motor events without the clinical characteristics of benign neonatal sleep myoclonus, arousal, behavioral movements, or jitteriness; (2) an abnormal neurological examination; or (3) symptoms and signs that place them at risk for seizures . The evaluation includes serum glucose and calcium levels, EEG, and MRI of the brain. The EEG should include provocative maneuvers such as noise, tactile stimulation, and rocking. The provocative maneuvers may trigger the paroxysmal motor event and demonstrate the presence or absence of concomitant electroencephalographic seizures. If an EEG can not be performed, 4-channel continuous EEG monitoring can be initiated by the nursing personnel. Four-channel continuous EEG monitoring is a valuable tool to determine the nature of paroxysmal motor events and correlates well with continuous video-EEG telemetry (Figure

11.1) If the events do not occur during the EEG or their nature is not clearly determined by 4-channels EEG monitoring, continuous video-EEG telemetry should be performed.



Figure 11.1.— An electroencephalographic seizure captured by 4-channel EEG monitoring. Sequence of rhythmic discharges.

REFERENCES

Alfonso I, Papazian O, Martinez RD, et al. Selection of neonates with clinical paroxysmal events not requiring antiepileptic drugs. Ann Neurol. 1991;30:462-463. Alfonso I, Papazian O, Aicardi J, et al. A simple maneuver to provoke benign neonatal sleep myoclonus. Pediatrics. 1995;96:1161-1163. Alfonso I, Harvey S, Acuña A, et al. Interictal and ictal SPECT in a neonate with hemimegalencephaly. Clin Nucl Med. 1997;22:323-324. Alfonso I, Papazian O, Litt R, et al. Single photon emission computed tomographic evaluation of brainstem release phenomenon and seizures in neonates. J Child Neurol. 2000;15:56-58. Alfonso I, Alvarez LA, Gilman J, et al. Intravenous valproic dosing in neonates. J Child Neurol 2000;15: 827-829. Alfonso I, Jayakar P, Yelin K, et al. Four-channel EEG monitoring in the evaluation of paroxysmal motor events in neonates. J Child Neurol. 2001;16:625-628. Daoust-Roy J, Seshia SS. Benign neonatal sleep myoclonus: a differential diagnosis of neonatal seizures. Am J Dis Child. 1992;146:1236-1241. DiFazio MP, Davis RG. Utility of early single photon emission computed tomography (SPECT) in gelastic epilepsy associated with hypothalamic hamartoma. J Child Neurol. 2000;15:416-417.



Gal P, Oles S, Gilman J, et al. Valproic acid efficacy, toxicity, and pharmacokinetics in neonates with intractable seizures. Neurology. 1988;341:467-471. Lombroso CT. Neonatal EEG polygraphy in normal and abnormal newborns. In: Niedermeyer E, Lopes Da Silva F, eds. Electroencephalography: Basic Principles, Clinical Application, and Related Fields. Baltimore, Md: Williams and Wilkins; 1993:803-875. Mizrahi EM, Kellaway P. Clinical significance of brainstem release phenomena in the newborn. Neurology. 1985;35(suppl 1):199. O’Brien MJ, Lems YL, Prechtl HFR. Transient flattening in the EEG of newborns: a benign variation. EEG Clin Neurophysiol. 1987;67:16-26. Parker S, Zuckerman B, Bauchner H, et al. Jitteriness in fullterm neonates: prevalence and correlates. Pediatrics. 1990;85:17-26.



Apnea


REFERENCES

Brazy JE, Kinney HC, Oakes WF. Central nervous system structural lesions causing apnea at birth. J Pediatr. 1987;111:163-175. Daily WJR, Klaus M, Meyer HBP. Apnea in premature infants: monitoring, incidence, heart rate changes, and an effect of environmental temperature. Pediatrics. 1969;43:510-518. Deonna T, Arczynska W, Torrado A. Congenital failure of automatic ventilation (Ondine’s curse). Pediatrics. 1974;84:710-714. Fenichel GM, Olsen BJ, Fitzpatrick JE. Heart rate changes in convulsive and nonconvulsive apnea. Ann Neurol. 1980;7:577-582. Feske SK, Carrazana EJ, Kupsky WJ, et al. Uncal herniation secondary to bacterial meningitis in a newborn. Pediatr Neurol. 1992;8:142-144. George CFE, Kryger MH, Dement J, et al, eds. Neuromuscular disorders. In: Principles and Practice of Sleep Medicine. 2nd ed. Philadelphia, Penn: WB Saunders; 1994:776-781. Gibson E. Apnea. In: Spitzer AR, ed. Intensive Care of the Fetus and Neonate. St Louis, Mo: Mosby; 1996:470-481. Guilleminault C, Ariagno RL, Korobkin R, et al. Mixed and obstructive apnea and near-miss for sudden infant death syndrome: comparison of near miss and normal control infants by age. Pediatrics. 1979;64:882-891. Guilleminault C, McQuinty J, Ariagno RL, et al. Congenital alveolar hypoventilation syndrome in six infants. Pediatrics. 1982;70:684-694. Guilleminault C. Sleep Apnea in the Full-term Infant in Sleep and its Disorders in Children. New York, NY: Raven Press; 1987:195-211. Guilleminault C, Stoohs R, Skrobal A, et al. Upper airway resistance in infants at risk for sudden infant death syndrome. Pediatrics. 1993;122:881-886. Hansen T, Corbet A. Control of breathing. In: Taeusch HW, Ballard RA, Avery ME, eds. Schaffer and Avery’s Diseases of the Newborn. 6th ed. Philadelphia, Penn: WB Saunders; 1991:470-474. Henderson-Smart DJ, Pettigrew AG, Campbell DJ. Clinical apnea and brainstem function in preterm infants. N Engl J Med. 1983;308:353-357.





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Carter BS, Haverkamp AD, Merenstein GB. The definition of acute perinatal asphyxia. Clin Perinatol. 1993:287-304. Davies PA, Rudd PT. Neonatal Meningitis. London: Mac Keith Press; 1994. de Louvois J, Blackbourn J, Hurley R, et al. Infantile meningitis in England and Whales: a two year study. Arch Dis Child. 1991;66:603-607. De Vivo DC, Di Mauro S. Disorders of pyruvate metabolism, the citric acid cycle, and the respiratory chain. In: Fernandes J, Saudubray JM, Tada K, eds. Inborn Metabolic Diseases. Diagnosis and Treatment. Berlin: Springer-Verlag; 1990:127-157. Evans OS. Metabolic acidosis. In: Swaiman KD, ed. Pediatric Neurology. St Louis, Mo: Mosby; 1989:975-986. Fenichel GM. Neonatal Neurology. New York, NY: Churchill Livingstone; 1990. Lombeck I. Genetic defects of the metabolism of magnesium, zinc, manganese, molybdenum, and selenium. In: Fernandes J, Saudubray JM, Tada K, eds. Inborn Metabolic Diseases. Diagnosis and Treatment. Berlin: Springer-Verlag; 1990:493-505. Lombroso CT. Neonatal EEG polygraphy in normal and abnormal newborns. In: Niedermeyer E, Lopes Da Silva F, eds. Elecroencephalography, Basic Principles, Clinical Applications, and Related Fields. Baltimore, Md: Williams & Wilkins; 1993:803-875. Lyon G, Adams RD, Kolodny EH. Neurology of Hereditary Metabolic Diseases in Children. New York, NY: McGraw Hill; 1996. Maestri NE, Clissold D, Brusilow SW. Neonatal onset ornithine transcarbamylase deficiency: a retrospective analysis. J Pediatr. 1999;134:268-272. Mizrahi EM, Tharp BR. A characteristic EEG pattern in neonatal herpes simplex meningitis. Neurology. 1982;32:1215-1220. Ogier H, Charpentier C, Saudubray J-M. Organic acidemia. In: Fernandes J, Saudubray JM, Tada K, eds. Inborn Metabolic Diseases. Diagnosis and Treatment. Berlin: Springer-Verlag; 1990:271-299. Odièvre M. Disorder of fructose metabolism. In: Fernandes J, Saudubray JM, Tada K, eds. Inborn Metabolic Diseases. Diagnosis and Treatment. Berlin: Springer-Verlag; 1990:107-112. Ozand PT, Gascon FF. Organic acidurias: a review. Part 1. J Child Neurol. 1991a;6:196-219. Ozand PT, Gascon FF. Organic acidurias: a review. Part 2. J Child Neurol. 1991b;6:288-303.



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Holm VA, Cassidy SB, Butler MG, et al. Prader-Willi syndrome: consensus diagnostic criteria. Pediatrics. 1993;91:398-402. Hsich GE, Robertson RL, Irons M, et al. Cerebral infarction in Menkes disease. Pediatr Neurol. 2000;23:425-428. Jones KL. Smith’s Recognizable Patterns of Human Malformation. Philadelphia: Penn: WB Saunders; 1997. Lyon G. Congenital malformation of the brain. In: Levene MI, Lilford RJ, eds. Fetal and Neonatal Neurology and Neurosurgery. Edinburgh: Churchill Livingstone; 1995:193-214. Maria BL, Boltshauser E, Palmer SC, et al. Clinical features and revised diagnostic criteria in Joubert syndrome. J Child Neurol. 1999;14:583-590. McLone DG, Knepper PA. The cause of Chiari II malformation: a unified theory. Pediatr Neurosci. 1989;15:1-12. Miller SP, Riley P, Shevell MI. The neonatal presentation of Prader-Willi syndrome revisited. J Pediatr. 1999;134:226-228. Negishi H, Lee Y, Itoh K, et al. Nonsurgical management of epidural hematomas in neonates. Pediatr Neurol. 1989;5:253-256.





Hageman AT, Gabreels FJ, Liem KD, et al. Congenital myotonic dystrophy: report on 13 cases and a review of the literature. J Neurol Sci. 1993;115:95-101. Hakamada S, Kumagai T, Hara K. Congenital hypomyelination neuropathy in a newborn. Neuropediatrics. 1983;14:182-183. Hart ZH, Chang CH, Di Mauro S, et al. Muscle carnitine deficiency and fatal cardiomyopathy. Neurology. 1978;28:147-151. Heckmatt JZ, Sewry CA, Hodes D, et al. Congenital centronuclear (myotubular) myopathy. A clinical, pathological and genetic study in eight children. Brain. 1985;108:941-964. Hogan GR, Gutmann I, Schmidt R, et al. Pompe’s disease. Neurology. 1969;19:894-900. Jones HR Jr, Bulton CF, Harper CM Jr. Pediatric Clinical Electromyography. Philadelphia, Penn: Lippincott-Raven; 1996. Lipsitz PJ, English IC. Hypermagnesemia in the newborn infant. Pediatrics. 1967;40:856-862. McMenamin JB, Becker LE, Murphy EG. Congenital muscular dystrophy: a clinicopathologic report of 24 cases. J Pediatr. 1982;100:692-697. Munsat TL, Piper D, Cancilla P. Inflammatory myopathy with facioscapulohumeral distribution. Neurology. 1972;22:335-347. Namba T, Brown SB, Grob D. Neonatal myasthenia gravis: report of two cases and review of the literature. Pediatrics. 1970;45:488-504. Ouvrier RA. Giant axonal neuropathy. A review. Brain Dev. 1989;11:207-214. Papazian O. Transient neonatal myasthenia gravis. J Child Neurol. 1992;7:135-141. Pickett J, Berg B, Chaplin E, et al. Syndrome of botulism in infancy: clinical and electrophysiologic study. N Engl J Med. 1976;295:770-772. Ptacek LJ, Johnson KJ, Griggs RC. Mechanisms of disease: genetics and physiology of the myotonic muscle disorders. N Engl J Med. 1993;328:482-489.



Facial Weakness


Facial Nerve Lesions Facial nerve lesions usually occur at the facial canal or after the facial

nerve exits through the stylomastoid foramen but before it divides into its

terminal branches (Figure 182.1 [D]). A distribution of weakness in neonates with facial nerve lesions includes the corner of the mouth, nasolabial fold, lower eyelid, upper eyelid, and forehead equally and ipsilaterally to the injury.

Figure 182.1.— Anatomical localizations of injuries in the facial motor system. T: thalamus; AC: internal auditory canal; FC: facial canal; SMO: styloidmastoid orifice; BB: buccal branch; MB: mandibular branch; TB: temporal branch; OOM: orbicularis oculi muscle; RM: risorius muscle; DAOM: depressor angularis oris muscle; BM: buccinator muscle; MM:


Facial Weakness

mentoris muscle. Light blue line indicates components of the facial nerve that have ipsilateral (hence bilateral) cortical innervation; dark blue line indicates components of the facial nerve that has contralateral innervation. A: cerebral lesion above the thalamus; B: cerebral lesion below the thalamus and above the pons; C: pontine lesion; D: facial nerve; E: mandibular branch lesion; F: depressor angularis oris muscle.

Facial nerve lesions may be due to trauma, malformation, or parotid

gland tumor.

Facial nerve trauma

Facial nerve trauma (Figure 182.2) usually occurs immediately after the styloidmastoid orifice. Obstetrical trauma often involves the brachial plexus. Neonates with facial and brachial plexus injuries present with hemifacial weakness, ipsilateral or contralateral arm weakness, and Horner syndrome.

A B

Figure 182.2— Traumatic facial nerve injury. [A] At rest, no asymmetry is noted. [B] During crying the facial asymmetry becomes obvious.





Werdnig-Hoffmann Disease Werdnig-Hoffmann disease or spinal muscular atrophy type I is an

autosomal recessive disorder caused by premature death of the alpha motor neurons. A history of decreased and weak fetal movements in the last trimester is often present. Neonates with Werdnig-Hoffmann disease may have different presentations: (1) hypotonia from birth, (2) an acute onset of hypotonia and weakness after an apparently normal period, or (3) acute

onset of respiratory failure. Hypotonia from birth is the most common presentation.

Werdnig-Hoffmann disease usually presents with hypotonia and decreased dynamic tone. Hypotonia and decreased dynamic tone affects the axial musculature more than the appendicular musculature, the proximal muscles more than the distal muscles, the lower extremities more than the upper extremities, the lower cranial nerve muscles more than the upper cranial nerve muscles, and, in most cases, the intercostal muscles more than the diaphragm.

The tongue of a neonate with Werdnig-Hoffmann disease may be weak, thin, and have clinical fasciculations. Fine rhythmic tremor of the finger may be present (polyminimyoclonus). Neonates with Werdnig-Hoffmann disease look alert. They do not have ptosis, ophthalmoplegia, or sphincter or sensory disturbances. Serum creatine phosphokinase, sensory nerve conduction, and motor nerve conduction in the neonatal period are normal.





The serum and urine amino acid profiles of MSUD are characterized by the accumulation of the branched-chain ketoacids produced by the block in the pathways of leucine (Figure 73.1 A), isoleucine, and valine (Figure 73.2 A), and the accumulation of alloisoleucine. Alloisoleucine is a by-product of isoleucine that only occurs when there is an excess of

isoleucine. Alloisoleucine is found in all neonates with MSUD.

Treatment of MSUD consists of metabolic support with emphasis on avoiding protein catabolism, hyperaminoacidemia, and acidosis. The total amount of fluid should be from 120 to 150 mL/kg to provide a total caloric intake of 150 to 170 kcal/kg per day, with 35% as carbohydrates, 50% as fat, and 15% as protein. The total protein, or at least 2.5 g/kg per day, should be given by oral or gavage feeding of infant formula that is free of branched-chain amino acids (BCAA). If orogastric feeding is not possible, and since there is no BCAA-free intravenous formula, the total protein intake should be limited to 1 g/kg per day. Thiamine 10 mg/kg per day should be used. Hemodialysis or peritoneal dialysis are seldom

necessary. Response to therapy is gauged by blood leucine levels. The prognosis of MSUD is guarded, although early intervention may lead to a better prognosis.

Dihydrolipoyl dehydrogenase deficiency

The metabolic profile of dihydrolipoyl dehydrogenase deficiency includes laboratory findings similar to MSUD (Figure 73.1 B).




The metabolic abnormality of dihydrolipoyl dehydrogenase also includes lactic acidosis due to pyruvate dehydrogenase and high concentration of alpha-ketoglutarate due to citric acid cycle dysfunction

(Figure 73.2 B).



Figure 73.2.— Metabolic pathways involved in branched-chain amino acid disorders. A: maple syrup urine disease; B: dihydrolipoyl dehydrogenase deficiency; C: isovaleric acidemia; D: glutaric acidemia type II; E: multiple carboxylase deficiency; F: HMG-CoA lyase deficiency.

Treatment of dihydrolipoyl dehydrogenase deficiency consists of metabolic support with emphasis on avoiding protein catabolism, hyperaminoacidemia, and acidosis. It is guided by the same principles as the treatment of MSUD. The prognosis of dihydrolipoyl dehydrogenase deficiency is poor.





The term motor-sensory unit (Figure 93.1) refers to the lower motor neuron, the muscle fibers it innervates, and the muscle sensory apparatus. The muscle sensory apparatus consists of the gamma motor neurons and their axons, the intrafusal muscle fibers, and the sensory fibers that carry information from the intrafusal muscle fibers to the alpha motor neurons.

Figure 93.1.— Schematic representation of the motor-sensory unit. Arrows indicate direction of normal signal conduction. AMN: alpha motor neuron; GMN: gamma motor neuron; DGC: dorsal ganglion cell; EFMF: extrafusal motor fiber (muscle fiber); IFMF: intrafusal motor fiber (muscle spindle).

The function of the gamma motor neuron is to contract the intrafusal fiber when the length of the muscle has been reduced by a contraction of the muscle. In addition to its muscular component, the intrafusal fiber has receptors that signal the tension inside the muscle. The function of the motor-sensory apparatus is to keep the muscle tone fixed at different muscle lengths.

The alpha motor neuron is influenced by structures “below it” and “above it.” The structures that influence the alpha motor neuron from “below” are the muscle sensory apparatus and the Renshaw cells (Figure 93.2). The Renshaw cells are neurons that are in close proximity to the alpha motor neuron.



Figure 93.2.— Schematic representation of the alpha motor neuron and its relation to the Renshaw cell. Arrows indicate direction of normal signal conduction. AMN: alpha motor neuron; RC: Renshaw cell.

The Renshaw cells receive excitatory signals from the alpha motor neuron by a collateral axon of the alpha motor neuron and send inhibitory signals back to the alpha motor neuron.





Neonates with hypotonia and decreased dynamic tone of the upper

extremities and increased dynamic tone of the lower extremities are likely to have a lesion at the C5 to T1 spinal cord segments (Figure 100.1). Damage at the C5 to T1 spinal cord segments causes: (1) a lower motor lesion in the arm due to injury to anterior horn motor neurons that supply the brachial plexus, and (2) an upper motor lesion of the legs due to injury of the pyramidal tract en route to the lumbosacral anterior horn motor neurons.

Figure 100.1.— Schematic representation of the possible sites of neuromuscular damage in neonates with generalized hypotonia and decreased upper extremity dynamic tone and increased lower extremity dynamic tone.

The pathological processes that affect the body of the alpha motor neuron are: dysgenetic, destructive, or degenerative. The pathological processes that involve the nerve may affect the myelin (dysmyelinating or



demyelinating processes) or the axon. The myoneural junction may be affected at the presynaptic region by toxins and dysgenesis or at the postsynaptic region by toxins, immunological disorders, or dysgenesis. The pathological processes that affect the muscle are dystrophies, metabolic disorders, and dysgenesis. Once the pathological diagnosis is determined within the motor-sensory unit, an etiological diagnosis should be established by analyzing other clinical and laboratory findings and using a process of elimination.

Systemic Illness

Generalized hypotonia due to systemic illness occurs acutely and usually improves as the systemic illness improves. Nevertheless, occasionally the improvement in postural tone lags behind the general improvement and in these cases the possibility of a neuromuscular disorder is often raised. Usually a few days of observation is all it takes to differentiate generalized hypotonia due to systemic illness from generalized hypotonia due to a neuromuscular disorder. The dynamic tone of a neonate with hypotonia due to systemic illness is normal or decreased. Frequent causes of hypotonia due to systemic illness are sepsis and hypoglycemia.





A very characteristic feature of diastrophic dysplasia is the presence of

soft cystic masses in the auricle during the neonatal period (Figure 155.1 [A]). Atlantoaxial instability may occur in these patients. These masses often become hypertrophic cartilage in early infancy. Radiographs of the distal limbs may show bone abnormalities (Figure 155.1 [B]). Diastrophic dysplasia is an autosomal recessive disorder. The gene maps to the distal

long arm of chromosome 5.

A B

Figure 155.1.— Diastrophic dysplasia. [A] Cystic auricular mass; [B] short, bent, and thick tubular bones.

Distal Arthrogryposis Syndrome

Neonates with distal arthrogryposis syndrome are usually fullterm and of average weight. They appear healthy. The face is usually not dysmorphic, although cases with cleft palate, cleft lip, small tongue, trismus, ptosis, and mild epicanthal folds have been described. The arthrogryposis involves the hands and, to a lesser extent, the feet. The cause of distal arthrogryposis syndrome is not known. A collagen abnormality leading to abnormal tendons has been considered. Arthrogryposis improves with time. Patients with distal arthrogryposis syndrome usually have normal intelligence. Distal arthrogryposis syndrome is an autosomal dominant condition with variable expression. The gene for distal arthrogryposis is in the pericentromeric region of



chromosome 9.





The presentations of cerebral arterial infarcts vary according to the vessels involved. Arterial infarcts in neonates have three presentations: (1) arterial border zone infarct, (2) single artery infarct, and (3) multi-artery

infarct.

Brain arterial border zone infarct

The presentation of arterial border zone infarcts varies in premature neonates and in fullterm neonates.

Brain arterial border zone infarct in premature neonates

Arterial border zone infarcts in premature neonates usually involves the end zones of irrigation of the long penetrating arteries and the oligodendroglia.

The most common sites of involvement are the periventricular region adjacent to: (1) the lateral aspect of the trigone of the lateral ventricles, (2) the foramina of Monro, (3) the frontal horns of the lateral ventricles, and (4) the occipital horns of the lateral ventricles. Involvement of the centrum semiovale may occur in severe cases.

The selective involvement of oligodendrocytes in the periventricular region in premature neonates is due to the vulnerability of immature oligodendroglia to free radicals (mature oligodendroglia are capable of neutralizing free radicals), and to the irrigation field of the long penetrating arteries. The irrigation field of the long penetrating arteries is such that the border zone of irrigation is in the periventricular region (Figure 246.1).

Figure 246.1.— Schematic representation of the major steps in free radical metabolism. Beneficial management of free radicals in the presence of sufficient enzyme activity. Superoxide dysmutase (SOD)



converts superoxide anions (02) in the presence of hydrogen (H+) to hydrogen peroxide (H202). Hydrogen peroxide in the presence of cytoplasmic glutathione peroxidase (GLUT. PERO.) and peroxomal

catalase (CATALASE) becomes water and oxygen.

Oligodenroglia damage is related to the production of free radicals during ischemic-reperfusion injury, the immaturity of the enzyme system involved in the detoxifications of free radicals, and the excess of iron store in immature oligodendroglia cells (Figure 246.2).

Figure 246.2.— Schematic representation of abnormal free radical metabolism. BAD: poor management of free radicals occurs because of decreased superoxide dysmutase (SOD) activity. Decreased superoxide dysmutase activity leads to an increase in superoxide anion (02-). WORSE: very poor management of free radicals occurs because of decreased glutathione peroxidase (GLUT. PERO.) and catalase activities (CATALASE), and increased iron content in the cytoplasm. Hydrogen peroxide in the presence of iron (Fe++) produces hydroxyl radicals by the

Fenton reaction (FR).



Apnea


Obstructive apnea is produced by structural or functional narrowing of the upper airway (Figure 20.1 A-H) or by ineffective diaphragmatic contractions that fail to create negative intrapulmonary pressure (Figure 20.1 J). Structural narrowing may occur because of a mass in, or a deformation of, the upper airways. Functional narrowing results from weak upper airway muscle contractions or lack of coordination between the diaphragmatic and upper airway muscle contractions. Functional narrowing occurs with nervous system lesions (Figure 20.1 A-E). Ineffective diaphragmatic contractions occur with loss of adhesion between the visceral and the chest wall pleura or with alveolar collapse.

Figure 20.1.— Sites of possible lesions producing obstructive apnea. A: fibers that connect the neurons of the respiratory groups to the upper motor neurons of the airway muscles; B: motor neurons of the upper airway muscles; C: cranial nerves; D: myoneural junction of upper airway muscles; E: upper airway muscles; F: soft palate; G: larynx; H: vocal cords; I: tongue region; J: interpleural space.


Apnea


The polysomnographic characteristics of central apnea are: (1) absence

of nasal and oral airflow, and (2) absence of chest and abdominal movements (Figure 19.1).

Figure 19.1.— Central apnea (cessation of airflow at the nose and mouth, and absence of thoracic and abdominal movements). Sleep stage: quiet sleep (tracé alternant and regular respiration), bradycardia and desaturation.

Central apnea is due to failure of the diaphragm to generate negative intrathoracic pressure. Lesions at multiple levels in the ventilatory system can lead to central apnea (Figure 19.2 A-G).


Apnea

Figure 19.2— Sites of possible lesions producing central apnea. A: chemoreceptor; B: respiratory groups; C: cervico-medullary junction; D: anterior horn cells of the phrenic nerve; E: phrenic nerve; F: myoneural junction; G: diaphragm.

The polysomnographic characteristics of obstructive apnea are absence of nasal and oral airflow in the presence of thoracic or abdominal movements (Figure 19.3). Paradoxical chest/abdominal movement is a frequent polysomnographic finding during obstructive apnea. Normally the chest circumference increases during inspiration and decreases during expiration, and the abdominal circumference decreases during inspiration and increases during expiration. In obstructive apnea the opposite occurs. This situation is referred to as paradoxical breathing.


Apnea

Figure 19.3.— Obstructive apnea (cessation of nasal airflow despite thoracic and abdominal respiratory movements). EEG shows low-voltage irregular activity. The apnea is followed by tachycardia and desaturation.



Arm


The suprascapular nerve (Figure 206.1; SPS) arises from the upper

trunk and innervates the infraspinatus (Figure 206.1; IS) and supraspinatus muscles (Figure 206.1; SS). The lateral pectoral nerve (Figure 206.1; PL) arises from the upper trunk and the anterior division of the middle trunk. The medial pectoral nerve (Figure 206.1; PM) arises from the lower trunk. Both pectoral nerves innervate the pectoral muscles (Figure 206.1; P). The subscapular nerve (Figure 206.1; SBS) arises from the posterior cord to innervate the subscapular (Figure 206.1; SBS) and teres major (Figure 206.1; TM) muscles. The thoracodorsal nerve (Figure 206.1; TD) arises from the posterior cord to innervate the latissimus dorsi muscle (Figure 206.1; LD). The primary function of the muscles innervated by the intermediate nerves are movement and stability of the shoulder girdle.

The brachial plexus has 5 distal nerves. The external branch of the lateral cord remains isolated and gives rise to the musculocutaneous nerve (Figure 206.1; MC). The medial branches of the lateral and medial cords join and form the median nerve (Figure 206.1; M). The internal branch of the medial cord gives rise to the ulnar nerve (Figure 206.1; U). The anterior branch of the posterior cord gives rise to the radial nerve (Figure 206.1; R) and the posterior branch of the posterior cord gives rise to the axillary nerve (Figure 206.1; A).


Arm

Figure 206.1.— Schematic representation of the brachial plexus nerves and muscles. (PS): paraspinal muscles; (R): rhomboid muscle; DS: dorsoscapular nerve; LT: long thoracic nerve: (SA): serratus anterior muscle; (SS): supraspinatus muscle; (IS): infraspinatus muscle; SPS: suprascapular nerve; PL: pectoralis lateralis nerves; (P): pectoralis muscle; PM: pectoralis medialis nerve; (TM): teres major muscle; (SBS): subscapularis muscle; SBS: subscapularis nerve; TD: thoracodorsal nerve; (LD): latissimus dorsi muscle; MC: musculocutaneous nerve; (Bi): biceps muscle; (Br): brachialis muscle; M: median nerve; U: ulnar nerve; A: axillary nerve; (TMi): teres minor muscle; (D): deltoid muscle; R: radial nerve.



Arm


The brachial plexus is formed by the intermingling of the fibers from the ventral rami of C5 to C8 and T1 in the majority of individuals (Figure 204.1). Some individuals have a large C4 contribution to the brachial plexus and a small T1 contribution, while others have a large T2 contribution and a small contribution from C5.

In most individuals, the ventral rami of C5 and C6 join and become the superior trunk (Figure 204.1). The ventral ramus of C7 remains isolated and becomes the middle trunk. The ventral rami of C8 and T1 join and become the lower trunk. Each trunk then splits into an anterior and a posterior division. The anterior divisions of the superior and middle trunks join to form the lateral cord. The anterior division of the inferior trunk remains isolated and becomes the medial cord. The three posterior divisions join to form the posterior cord (Figure 204.1). Each cord divides into two branches. The lateral cord divides into a lateral and a medial branch. The medial cord divides into a medial and an internal branch. The posterior cord divides into an anterior and a posterior branch. It is from these branches that the distal nerves arise.


Arm

Figure 204.1.— Schematic representation of the brachial plexus. The structures that constitute the brachial plexus include the ventral ramus (VRa), trunks (T), divisions (D), cords (C), and branches (B). C: cervical spinal segment; T: thoracic spinal segment; SC: spinal cord; SF: sympathetic fibers to the eye; DRa: dorsal ramus; ST: superior trunk; MT: middle trunk; LT: lower trunk; A: anterior; P: posterior; LC: lateral cord; MC: middle cord; PC: posterior cord; LB: lateral branch; MB: medial branch; IB: internal branch; AB: anterior branch; PB: posterior branch; MC: musculocutaneous nerve; M: median nerve; U: ulnar nerve; A: axillary nerve; R: radial nerve.



Arm


Flaccid Arm Monoplegia Due to an Upper Motor Neuron Lesion Flaccid arm weakness due to an upper motor neuron lesion occurs

immediately after the insult (Figure 213.1).

A B

Figure 213.1.— Flaccid right arm weakness. [A] Patient had a seizure and then developed right arm weakness. The patient had a neurological evaluation 10 hours after the seizure. Stretch muscle reflexes and Moro reflex were decreased. [B] MRI revealed a left posterior limb internal capsule stroke.

The site of anatomical involvement may be the brain, brainstem, cerebellum, or upper cervical spine (Figure 213.2 A-D). Neonates with flaccid arm weakness have an asymmetrical Moro reflex due to lack of movement of the affected arm during the maneuver and decreased muscle stretch reflexes.


Arm

Figure 213.2.— Sites of possible nervous system injury that can produce arm monoparesis: A: brain to midbrain; B: upper pons; C: lower pons and medulla; D: rostral spinal cord; E: brachial center; F: brachial plexus; G: peripheral nerves; V: ventricles; T: thalamus; UQ: upper quadrant; FN: facial nerve; LQ: lower quadrant; BP: brachial plexus; LSP: lumbosacral plexus. The colored rectangles indicate the location of weakness produced by damage to the different components of the somatic motor system.

Localization of an upper motor neuron lesion to the brain, brainstem, or spinal cord may be difficult. The distribution of the arm weakness is not helpful. Acute upper motor neuron lesions produce weakness that involves the shoulder, arm, forearm, and hand equally, regardless of the location of the lesion within the upper motor neuron. Several other neurological findings may help localize the lesion within the upper motor neuron. Flaccid facial weakness may be present with lesions of the pons, midbrain, and brain. Facial weakness due to a lesion in the brain and midbrain is ipsilateral to the arm weakness. Facial weakness due to a lesion at the pons is contralateral to the arm weakness. Facial weakness will not be present with lesions localized to the cerebellum, medulla, or the cervical spine, unless a second anatomical site is involved by the same pathological process. Flaccid arm weakness due to an upper motor neuron lesion may be associated with gaze preference and convulsions. Gaze preference occurs with brain involvement at the cortex because of the close proximity of the cortical area that controls rapid eye movements and arm movements.


Arm

Gaze preference with eye deviation away from the weak arm usually occurs, but irritative lesions causing seizures may produce eye deviation toward the weak arm associated with nystagmoid movements. Convulsions involving the paralyzed arm with secondary generalization may occur.

The distinction between upper and lower motor neuron flaccid arm monoplegia may be difficult because the neurological manifestations are similar. The distinction relies on finding signs of central nervous system involvement suggesting an upper motor neuron lesion, or the typical arm posture characteristic of lower motor neuron lesion. Our approach in cases when the anatomical diagnosis can not be made by clinical evaluation is to obtain a brain MRI. We look for the possibility of an upper motor neuron lesion first because the causes of upper motor neuron lesions may require immediate intervention. If brain MRI is normal, we do an EMG of the affected arm and and MRI of the brachial plexus.





Muscle imbalance at the shoulder may lead to internal rotation contracture of the shoulder and to posterior dislocation of the head of the humerus (Figure 261.1). Posterior dislocation of the head of the humerus requires articuloplasty and release of the muscle contracture that led to it. Lengthening of the subscapularis muscle tendon usually achieves shoulder muscle balance without causing an unstable shoulder. Flexion contracture of the elbow, and supination or pronation deformities of the forearm may

also occur and require surgical management.

A B

Figure 261.1.— Posterior subluxation of the humerus. [A] Special “Y” scapular view. [B] MRI showing posterior incongruency between the articular faces.

The possibility of surgical reconstruction of the plexus or neurolysis of the neuroma should be considered in patients who do not recover. The neuroma results from scarring and aberrant axonal growth at the site of injury (Figure 261.2).



Figure 261.2.— Neuroma of the brachial plexus.



Apnea


Signs of central herniation are characterized by findings of progressive

rostrocaudal brainstem damage. Signs of midbrain dysfunction initially occur. They include downward deviation of both eyes resulting from compression of the superior colliculi, pupillary abnormality as a result of involvement of the Edinger-Westphal nucleus or its fibers, and extraocular muscle abnormalities as a result of asymmetrical common oculomotor nucleus involvement or involvement of the medial longitudinal fascicle. Signs of midbrain dysfunction are followed by signs of pontine dysfunction. Signs of pontine dysfunction are disconjugate eye movements due to medial longitudinal fascicular involvement and asymmetrical facial grimacing due to involvement of the facial nerve fibers. Signs of pontine dysfunction are followed by signs of medullary dysfunction. Signs of medullary dysfunction are swallowing difficulties and apnea.

The diagnosis of transtentorial herniation is established by brain imaging studies. These studies reveal supratentorial pathology, peribrainstem cisterns obliteration, or direct evidence of brainstem compression (Figure 24.1). The treatment for apnea due to herniation is mechanical respiration. The patient should be placed on a ventilator to maintain a Pa CO2 of 25 to 30 mm Hg. Mannitol 250 mg/kg may be given intravenously. Treatment of the primary disorder should be addressed.

Figure 24.1.— Diffuse brain swelling and obliteration of the ambient cistern.




Neonates suspected of having a degenerative disease but without

family history or clinical signs suggestive of a particular degenerative disease should have their urine tested for sialic acid, glycoproteins, mucopolysaccharides, and N-acetylaspartate and arylsulfatase activity. Blood should be tested for very-long-chain fatty acids, N-acetylaspartate, copper, and ceruloplasmins, and an MRI of the brain should be performed. Enzyme studies in leukocytes and fibroblasts, and biopsies of nerve, muscle, skin, or liver should be done when a specific disease is suspected. There is no specific treatment for any of these disorders. The diagnosis of a degenerative disorder should be followed by genetic counseling.

CEREBELLUM

Cerebellar lesions produce hypotonia with decreased or normal dynamic tone (Figure 115.1). Hypotonia and decreased or normal dynamic tone occur because damaged cerebellar neurons alter the alpha motor neurons indirectly by their influence on brain and brainstem structures.

Figure 115.1— Salient features of cerebellar hypotonia. Arrow indicates the site of dysfunction (cerebellum). US: brain ultrasound; CT:



computerized tomography; MRI: magnetic resonance imaging.





Trauma

Cervical spinal cord injury should be considered in every traumatic delivery, breech delivery, or if a snap is heard during delivery. The study of choice to diagnose cervical spinal cord injury is MRI. Spinal film should not be used to screen for the possibility of spinal cord injury. Spinal films are usually normal even when spinal cord injury is present on MRI. Radiographic evidence of vertebral fractures or dislocations and separation of vertebral epiphysis indicate a high possibility of spinal cord injury and should be followed by MRI (Figure 125.1). Evidence of cord compression or epidural, subdural, or intramedullary bleeding may be present on MRI. Although mental status should be normal in patients with cervical spinal cord injury, it seldom is. Most patients are lethargic (at least during the first hour after delivery) due to concomitant head trauma at the time of the spinal cord injury. When traumatic spinal cord injury is suspected in a neonate, the head should be immobilized.

Traumatic spinal cord injuries should be treated with 3 mg/kg of methylprednisolone and an infusion of 5.4 mg/kg per hour for the next 23

hours. Surgical intervention should be carried out in the presence of extramedullary lesions or bone displacement. Supportive therapy includes mechanical respiratory support, maintenance of body temperature, and prevention of urinary tract infections. Physical and occupational therapy should be started when the patient is stable.

Figure 125.1.— T1-weighted sagittal image demonstrates narrowing of the cervico-medullary junction.




Intracanalicular lesions may show evidence of cord injury and pseudomeningocele (Figure 263.1). Paraspinal, rhomboid, and serratus anterior muscle weakness and Horner syndrome may be present. Sensory conduction is normal. Extracanalicular pretruncal lesions may present with paraspinal, rhomboid, and serratus anterior weakness. Horner syndrome may be present. Sensory nerve conduction is abnormal since the site of injury is after the dorsal ganglion. Truncal lesions have normal paraspinal, rhomboid, and serratus anterior function; no Horner syndrome; and abnormal sensory nerve conduction.

Neonates with good initial recovery that later slow down in the rate of improvement or deteriorate are candidates for neurolysis. Neurolysis consists of releasing the scar tissue across the neuroma. When the patient is older, tendon transplantation may improve specific movement.

Figure 263.1.— MRI of the cervical spine demonstrating bilateral root avulsion and pseudomeningocele.



Facial Weakness


At the level of the spinal cord, the central sympathetic tract makes

contact with neurons at the lateral horns of the spinal cord at the C8 and T1 segments. These neurons constitute the second group of neurons. The area where these neurons are located is called the Budge ciliospinal center (Figure 187.1 [2]). Fibers from these neurons leave the spinal cord with the appropriate anterior roots and travel with the spinal nerve briefly. They exit the spinal nerve and form a bundle of fibers that give rise to the cervico-thoracic sympathetic trunk. The oculosympathetic fibers climb in this trunk adjacent to the carotid artery to make contact with neurons in the superior cervical ganglion (Figure 187.1 [3]). The neurons in this ganglion constitute the third group of neurons. Fibers from neurons in the superior cervical ganglion travel with the internal carotid through the cavernous sinus, enter the orbits, and innervate the muscles of Müller and the pupillary dilator muscle (Figure 187.1).

Figure 187.1.— Oculosympathetic pathway. MM: muscle of Müller; CS: cavernous sinus; ECA: external carotid artery; ICA: internal carotid artery; CCA: common carotid artery; BP: brachial plexus; T1: thoracic 1 spinal segment; C8: cervical 8 spinal segment; BCSC: Budge ciliospinal


Facial Weakness

center; CST: central sympathetic tract; A: common site of injury.

Oculosympathetic system dysfunctions manifest during wakefulness.

The affected eye can not open as wide as the normal eye (Figure 187.2). A lesion in the oculosympathetic system may occur anywhere in its trajectory.

A B

Figure 187.2.— Oculosympathetic lesion. [A] No facial asymmetry while crying. [B] Facial asymmetry is restricted to the upper quadrant and it is only present during quiet awake.

Oculosympathetic pathway damage produces Horner syndrome. The manifestations of Horner syndrome are ptosis, miosis, and anhydrosis. Brainstem lesions involve the central sympathetic tract and produce anhydrosis involving the face and body. The pathology of brainstem lesion is usually not found. Lesions in the brachial plexus (Figure 187.1 [A]) are more common than brainstem lesions. They involve the cervico-thoracic sympathetic trunk. These lesions occur either at C8, T1, or T2 ventral roots or spinal nerves. Anhydrosis only involves the face. Horner syndrome due to brachial plexus injury is usually due to trauma but may also occur with congenital chickenpox or involvement of the brachial plexus or

cervicothoracic spine. Horner syndrome may also occur with congenital neuroblastomas. The cause of Horner syndrome is often not found. Neonates with Horner syndrome without an obvious cause should have an MRI of the brain and neck, and blood studies searching for the possibility of excessive catecholamine secretion.


Facial Weakness


In addition to asymmetry of the upper half of the face, a lesion of the oculomotor nerve at the subarachnoid space produces ptosis, mydriasis, and displacement of the ocular axis to the lower lateral corner of the eye

(Figure 190.1). An MRI of the brain and orbits should be obtained in neonates with signs of common oculomotor system dysfunction. Treatment is dictated by the MRI results. Usually no cause is found and no etiological treatment is possible. Ophthalmologic evaluation should be done.

A B

Figure 190.1.— Common oculomotor lesion. [A] No asymmetry during crying. [B] Asymmetry present during quiet awake, involving only the upper half of the face. Left eye deviates down and out.

Damage to the levator palpebrae muscle may occur. The cause is

unknown in most cases. It may be seen as the only manifestation of

myotonic dystrophy and in patients with Turner syndrome (Figure

190.2).


Facial Weakness

Figure 190.2.— Neonate with Turner syndrome and right ptosis.





Congenital Myotonic Dystrophy

Myotonic dystrophy is transmitted as an autosomal dominant trait. Nevertheless, only if the mother has the disease will a neonate show signs of it (Figure 143.1).

Figure 143.1.— Neonate with myotonic dystrophy. Generalized hypotonia with myopathic facies.

Neonates with congenital myotonic dystrophy are usually hypotonic at birth or become hypotonic shortly after birth. The patient presents with generalized hypotonia with decreased dynamic tone, weakness, facial diplegia, and feeding difficulty (masticatory and pharyngeal muscle weakness). Constipation may be present. Clinical myotonia is seldom present in the neonatal period. Weakness in the neonatal period is more proximal than distal. Arthrogryposis is often present. A history of polyhydramnios is common. Chest radiograph shows slender ribs. Slender ribs indicate prenatal onset of weakness of the intercostal muscles.





A distinction between epidural and subdural hematoma may not be possible by CT or MRI of the brain in some cases. The choice of treatment in hypotonic neonates with an epidural or a subdural hematoma is

determined by the clinical manifestations and CT or MRI findings. Hypotonic neonates that are stable or improving should be observed. Neonates with evidence of mental status deterioration, focal cranial nerve findings, or evidence of midline shift or herniation on CT or MRI of the brain should be managed surgically. Patients with epidural or subdural hematomas and associated cephalohematomas should be managed by drainage of the cephalohematoma through a burr hole. If this maneuver fails or a cephalohematoma is not present, direct intracranial drainage should be performed.

Subarachnoid hemorrhage refers to blood between the arachnoid and the piamater. The blood surrounds the brain parenchyma and also follows the piamater into the sulci and fissures. Subarachnoid hemorrhage is usually an incidental finding in neonates with hypotonia. Parenchymal (Figure 109.1 [B]) and intraventricular (Figure 109.1 [C]) hemorrhages are occasionally found in hypotonic neonates. Magnetic resonance imaging of neonates with brain trauma should include the cervicomedullary junction because of the possibility of rostral cervical spine trauma.

A B C

Figure 109.1.— [A] Epidural bleeding, small intraparenchymal bleed on the opposite frontal hemisphere and subarachnoid bleed. [B]



Intraventricular hemorrhage around the ventricles, intraparenchymal blood, and cerebromalacia in the right occipital lobes. [C] Intraventricular blood in the occipital horns of the lateral ventricles.





Neonates with cerebellar hypotonia usually have no other neurological

manifestations nor any clinical signs that suggest that the cerebellum is the affected organ, except for occasionally demonstrating an unusual respiratory pattern. Evidence of an abnormal cerebellum in a brain imaging study is often the first indication of cerebellar pathology. The structures of the cerebellum are easily identifiable by MRI. Magnetic resonance imaging of the brain is better than CT scan for evaluating the posterior fossa. Magnetic resonance imaging provides good anatomical information and allows cerebrospinal fluid flow evaluation. The anatomy of the posterior fossa can be schematically represented by four parenchymal structures and two cerebrospinal fluid spaces. The parenchymal structures are: (1) brainstem, (2) cerebellar vermis, (3) right cerebellar hemisphere, and (4) left cerebellar hemisphere. The cerebrospinal fluid spaces are: (1) the fourth ventricle, and (2) the cisterna magna (Figure 116.1). Cerebrospinal fluid flows from the third ventricle through the aqueduct of Sylvius into the fourth ventricle and from the fourth ventricle to the cisterna magna through the laterally placed foramina of Luschka and the midline foramen of Magendie.

Figure 116.1.— Structures of the posterior fossa. The cerebellum is the largest structure of the posterior fossa. The cerebellum has two components: the cerebellar hemispheres and the vermis. Ventral to the cerebellum is the fourth ventricle and the brainstem (midbrain, pons, and medulla). Dorsal to the cerebellum is the cisterna magna.




Bone, joint, or soft tissue infections may be difficult to detect in neonates. Bone infections, like bone fractures, tend to occur in a single bone and produce decreased movements in one limb. Decreased movements of both upper extremities has been described with cervical

vertebral body infection. Decreased movements of all four extremities may occur in neonates with congenital syphilis. This entity, denominated

pseudoparalysis of Parrot, was once very common. Joint infections are rare in neonates. Soft tissue infection produces induration and color changes in the skin overlying the infection. Bone, joint, and soft tissue infections are diagnosed best by gallium scan (Figure 196.1). Sedimentation rate may be elevated in neonates with localized infections.

Figure 196.1.— Bone scan demonstrating an increased uptake of the right distal head of the humerus.



Arm


The distinction between upper trunk lesions (Figure 217.1 B) and more proximal lesions at C5 and C6 roots or spinal nerves (Figure 217.1 A) is made by physical examination and electrophysiologic studies. A neonate with an upper trunk lesion (217.1 B) has abnormal sensory conduction from C5 and C6 dermatomes but normal strength and electromyographic findings in the rhomboid, serratus anterious, and paraspinal muscles

.

Figure 217.1.— Schematic representation of the brachial plexus and its nerves and muscles. Site of injury. A: C5 root and C6 spinal nerve; B: upper trunk; (PS): paraspinal muscles; (R): rhomboid muscle; DS: dorsoscapular nerve; LT: long thoracic nerve; (SA): serratus anterior muscle; (SS): supraspinal muscle; (IS): infraspinal muscle; SPS: suprascapular nerve; PL: pectoral lateralis nerve; (P): pectoralis muscle; PM: pectoralis medialis nerve; SF: sympathetic fibers to the eyes; (M of M): muscle of Müller; (DP): dilator pupillary muscle; (TM): teres major muscle; (SBS): subscapularis muscle; SBS: subscapularis nerves; TD: thoracodorsal nerve; (LD): latissimus dorsi muscle; MC:


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musculocutaneous nerve; (Bi): biceps muscle; (Br): brachialis muscle; M: median nerve; U: ulnar nerve; A: axillary nerve; (TMi): teres minor muscle; (D): deltoid muscle; R: radial nerve.





There are many neuromuscular disorders that produce generalized hypotonia. The approach to determining the etiology of neuromuscular hypotonia consists of establishing the site of dysfunction in the neuromuscular system (anatomical diagnosis), determining the most likely pathological process that affects the neuromuscular system at that particular location (pathological diagnosis), and finally determining the most likely etiology (etiological diagnosis), taking into account the suspected anatomical and pathological diagnoses.

The possible sites of dysfunction in the neuromuscular system can be schematically represented with a simplified model of the upper motor neuron system and the motor-sensory unit.

SIMPLIFIED MODEL OF THE UPPER MOTOR NEURON SYSTEM

The upper motor neuron system is housed in the central nervous system. The relevant regions of the central nervous system in the understanding of generalized hypotonia are the brain, brainstem, cerebellum, rostral spinal cord, and brachial plexus (C5-T1) of the spinal cord (Figure 95.1)

Figure 95.1.— Schematic representation of the relevant regions of the central nervous system in the understanding of generalized hypotonia. C5-



T1: brachial plexus region of the spinal cord.



Facial Weakness


FACIAL ASYMMETRY DUE TO WEAKNESS

Unilateral or asymmetrical weakness of the mimetic facial muscles, levator palpebrae muscle, and the muscles of Müller can produce facial asymmetry. Mimetic facial muscle weakness is most noticeable when the patient is trying to close his eyes, grimace, or smile. Levator palpebrae muscle weakness and muscle of Müller weakness are most noticeable when the neonate is trying to open his eyes. The mimetic facial muscles are innervated by the facial motor system; the levator palpebrae muscles are innervated by the common oculomotor system; and the muscles of Müller are innervated by the sympathetic ocular system.

FACIAL ASYMMETRY THAT IS WORSE DURING GRIMACING

The facial motor system can produce facial asymmetry that may involve the upper, lower, or both quadrants. The asymmetry is only present or is most noticeable when the neonate grimaces. The muscles used by a neonate when grimacing are those that close the eyes and those that spread the angles of the lips apart and turn the corners of the lower lip down. The muscles used to close the eyelids are the orbicularis oculi muscles. The primary muscles used to spread the angles of the lips apart are the buccinator muscles. The muscles used to turn the corners of the lower lip down are the depressor angularis oris muscles. These muscles are innervated by the facial motor system.



Facial Weakness


The facial nerve motor nucleus is in the mid-lower pons. The axons

from this nucleus go backwards encircling the abducent nucleus and then forward to exit through the lateral surface of the pons (Figure 176.1). Once out of the pons, they travel in the subarachnoid space until they enter the internal auditory canal. They travel in the auditory canal for a short distance and then bend backward and downward into the facial canal.

Figure 176.1.— Schematic representation of the intrapontine trajectory of the facial nerve. N: nucleus; CN: cranial nerve.

The facial nerve travels in the facial canal and exits through the stylomastoid foramen (Figure 176.2). Shortly after exiting through the stylomastoid foramen, the facial nerve divides into five branches to innervate the mimetic facial muscles: temporal, zygomatic, buccal, mandibular, and cervical.


Facial Weakness

Figure 176.2.— Facial motor system. T: thalamus; AC: internal auditory canal; FC: facial canal; SMO: stylomastoid orifice; BB: buccal branch; MB: mandibular branch; TB: temporal branch; OOM: orbicularis oculi muscle; RM: risorius muscle; DAOM: depressor angularis oris muscle; BM: buccinator muscle; MM: mentoris muscle. Light blue line indicates components of the facial nerve that have ipsilateral (hence bilateral) cortical innervation; dark blue line indicates components of the facial nerve that have contralateral innervation.



Arm


Arm monoplegia due to a lesion in the brain may involve the cortex, the centrum semiovale, or the internal capsule. The clinical presentations of cortical and centrum semiovale lesions vary depending on their size. Large lesions produce complete arm palsy. Small lesions in the cortex or centrum semiovale produce weakness that affects one region of the arm more than another (segmental) because the arm motor system occupies a large area at this level. The clinical presentation of a lesion in the internal capsule is characterized by weakness of the whole arm. Internal capsule lesions produce complete weakness because the upper motor neuron fibers of the arm at the level of the internal capsule form a compact fascicle that occupies a relatively small area and even small lesions in this area involve the whole fascicle, thus causing weakness of the whole extremity. Cortical, centrum semiovale, and internal capsule lesions produce contralateral weakness.

Arm monoparesis due to a lesion of the upper motor neuron at the level of the midbrain, pons and upper medulla produce contralateral weakness that usually involves the whole extremity. Lower medulla, and rostal

spinal cord produces total ipsilateral upper extremity weakness.

The presence and characteristics of facial involvement can also help localize the lesion in neonates with spastic arm weakness. Lesions of the upper arm motor neuron system in the brain, midbrain, and pons (Figure 209.1 A and B) are often associated with facial weakness. Lesions below the pons (Figure 209.1 C-G) are not associated with facial weakness unless there is a second lesion involving the facial nerve. This is often the case in neonates who have suffered obstetrical trauma.


Arm




Arm


Fascicular Syndrome

A fascicular lesion of the brachial plexus may present with signs restricted to one muscle or to a few muscles. The clinical manifestations of fascicular brachial plexus lesions may be indistinguishable from those of peripheral nerve branch lesions. The diagnosis of a fascicular brachial plexus lesion is established by the combination of weakness in a muscle innervated by a distal or intermediate nerve of the brachial plexus and (1) clinical or electrophysiological abnormality in a muscle innervated from the same spinal segment but through a proximal brachial plexus nerve; or (2) a Horner syndrome (Figure 222.1). The combination of weakness of a muscle innervated by distal brachial plexus nerves and Horner syndrome imply C8 and/or T1 ventral root or spinal nerve damage.

A B

Figure 222.1.— [A] Inability to extend the distal phalange of the right thumb. [B] Right-sided Horner syndrome. This patient had a brachial nerve lesion confirmed by EMG findings of proximal brachial plexus nerve involvement.

Peripheral Nerve Injury Peripheral nerve lesions always produce segmental flaccid monoparesis.

Segmental limb weakness due to peripheral nerve injury may occur with lesions that damage a nerve, a major branch, or just a few fascicles within a nerve or a branch. Injury to the whole nerve or a major branch produces characteristic clinical findings that differentiate these injuries from

brachial plexus injury and other peripheral nerve injuries. Involvement of a secondary branch or a fascicle within a nerve or a branch produces a pattern of weakness that can seldom be clinically differentiated from a


Arm

fascicular brachial plexus lesion.



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The distribution and characteristics of the facial weakness provide

clues to localize the lesion within the arm upper motor neuron system. Brain and midbrain lesions (Figure 210.1 A and B) usually involve the lower quadrant of the face on the same side as the affected arm. Pontine lesions usually produce hemifacial weakness on the side opposite from the affected arm. A lesion in the lower pons or below it (Figure 210.1 C-G)

does not involve the face.


Brain lesions can be differentiated from midbrain lesions by observing


Arm

the face while the neonate is at rest and when crying. At rest, brain and midbrain lesions produce similar facial findings: lower quadrant facial weakness which manifests by a more superficial nasolabial fold and drop of the corner of the mouth on the weak side. During crying, brain and midbrain lesions produce different facial findings. Neonates with facial weakness due to a brain lesion develop an exaggerated contraction on the affected side while crying, displacing the corner of the mouth downward (Figure 210.2). Neonates with midbrain lesions do not have this reaction, and when they cry the unopposed contraction of the normal side causes the mouth to deviate toward the healthy side. This seemingly paradoxical response that occurs in neonates with brain lesions is reminiscent of the voluntary-emotional dissociation that occurs in an adult with facial

weakness due to a brain lesion above the thalamus.

A B

Figure 210.2.— Spastic facial weakness due to a lesion located above the midbrain. [A] At rest, the nasolabial fold on the right is less pronounced than on the left. [B] When crying, the mouth deviates toward the right side.



Arm


The distinction between upper and lower motor neuron flaccid arm

monoplegia in the first 2 weeks of life is made based on historical information and the presence of associated neurological findings. Magnetic resonance imaging of the brain and brachial plexus and electromyographic studies may further aid in localization. Flaccid arm monoparesis may be due to an upper or lower motor neuron injury. Flaccid arm weakness due to upper motor injury may occur with a lesion in the brain, brainstem, cerebellum, or spinal cord (Figure 212.1 A-D). Flaccid arm monoparesis due to a lower motor neuron injury occurs with a lesion at the brachial center or at the roots and spinal nerves of the C5 through T1 spinal segments, brachial plexus, or peripheral nerves (Figure 212.1 E-G).

Figure 212.1.— Sites of possible nervous system injury that can produce arm monoparesis. A: brain to midbrain; B: upper pons; C: lower pons and medulla; D: rostral spinal cord; E: brachial center; F: brachial plexus; G: peripheral nerves; V: ventricles; T: thalamus; UQ: upper quadrant; FN: facial nerve; LQ: lower quadrant; BP: brachial plexus; LSP: lumbosacral plexus. The colored rectangles indicate the location of weakness produced by damage to the different components of the somatic


Arm

motor system.



Facial Weakness


Lesions at the lower third of the precentral gyrus or at the corticopontine tract prior to its decusation may be associated with limb weakness, ocular abnormalities, and signs of head trauma.

Figure 179.1.— Anatomical localizations of injuries in the facial motor system. T: thalamus; AC: internal auditory canal; FC: facial canal; SMO: styloidmastoid orifice; BB: buccal branch; MB: mandibular branch; TB: temporal branch; OOM: orbicularis oculi muscle; RM: risorius muscle; DAOM: depressor angularis oris muscle; BM: buccinator muscle; MM: mentoris muscle. Light blue line indicates components of the facial nerve that have ipsilateral (hence bilateral) cortical innervation; dark blue line indicates components of the facial nerve that have contralateral innervation. A: cerebral lesion above the thalamus; B: cerebral lesion below the thalamus and above the pons; C: pontine lesion; D: facial nerve lesion; E: mandibular branch lesion; F: depressor angularis oris muscle.


Facial Weakness

Upper limb monoplegia or hemiparesis ipsilateral to the affected facial musculature may occur. The limb findings are due to involvement of the corticospinal fibers that travel very near to the corticopontine fibers. They manifest initially as a flaccid paralysis (weakness, hypotonia, and decreased Moro reflex and muscle stretch reflexes) followed after a few days by a spastic paralysis (weakness, hypotonia, and exaggerated Moro and muscle stretch reflexes). Gaze abnormalities are due to involvement of the neurons in the cortical frontal area that control rapid eye movements or their descending fibers. Damage to this system produces conjugate eye deviation away from the side of the facial weakness during the first weeks after the damage. Cephalohematomas and other signs of skull trauma may be present.

The diagnosis of an upper motor neuron facial asymmetry warrants an MRI of the brain. The lesions frequently found are subdural hemorrhages, infarcts, porencephalic cysts, and tumors. Upper motor neuron facial asymmetry also occurs after hemispherectomy (Figure 179.2).

Figure 179.2— Computed tomography of the brain several days after hemispherectomy in the patient shown in Figure 178.1.





Inborn errors of metabolism are tentatively diagnosed based on

laboratory investigations that require 3 to 5 days to obtain results. The diagnoses of these disorders are confirmed by enzymatic studies that require several weeks to obtain results. Hence, the need for empirical treatment often arises.

The possibility of an inborn error of metabolism is very unlikely if there is no ketonuria (excludes propionic and methylmalonic acidemias) and the following laboratory values are in the normal range: (1) blood glucose (excludes carbohydrate and fatty acid abnormalities); (2) ammonia level (excludes a urea cycle defect); (3) lactic acid (excludes pyruvate, citric acid, and mitochondrial respiratory chain abnormalities); and (4) sulfite in blood and urine (excludes sulfite oxidase deficiency and molybdenum cofactor deficiency). A neonate with these findings should be tentatively considered to not have an inborn error of metabolism until more specific tests such as biotinidase level, acyl and total carnitine, pyruvate, serum for organic and amino acids, urine organic acids, and cerebrospinal fluid lactic acid and glycine results are available.

REFERENCES

Bachmann C. Urea cycle disorder. In: Fernandes J, Saudubray JM, Tada K, eds. Inborn Metabolic Diseases. Diagnosis and Treatment. Berlin: Springer-Verlag; 1990:493-505. Baerlocher K. Disorders of gluconeogenesis. In: Fernandes J, Saudubray JM, Tada K, eds. Inborn Metabolic Diseases. Diagnosis and Treatment. Berlin: Springer-Verlag; 1990:113-123. Baumgartner R. Biotin-responsive multiple carboxylase. In: Fernandes J, Saudubray JM, Tada K, eds. Inborn Metabolic Diseases. Diagnosis and Treatment. Berlin: Springer-Verlag; 1990:311-320. Brismar J, Aqueel A, Brismar G, et al. Maple syrup urine disease: finding on CT and MR scan of the brain in 10 infants. Am J Neuroradiol. 1990;11:1219-1228. Brown M, Hays T. Common hematologic disorders in the newborn. In: Pomerance JJ, Richardson CJ, eds. Neonatology for the Clinician. Norwalk, Conn: Appleton & Lange; 1993:379-393. Burlina AB, Bonafe L, Zacchello F. Clinical and Biochemical approach to the neonate with a suspected inborn error of amino acid and organic acid metabolism. Semin Perinatol. 1999;23:162-173.




The lumbosacral plexus is less complex than the brachial plexus (Figure 230.1). The formation of the lumbosacral plexus can be summarized as follows: each ventral ramus splits into 2 divisions, one anterior and one posterior, except the ventral ramus of L4 and S3. The ventral ramus of L4 splits into 4 divisions, 2 anterior and 2 posterior. The ventral ramus of S3 does not divide.

Figure 230.1.— Schematic representation of the divisions of the ventral rami. Each ventral ramus splits into 2 divisions (one anterior [A] and one posterior [P]) except for the ventral ramus of L4 that divides into 4 (2 anterior and 2 posterior divisions), and the ventral ramus of S3 which does not divide.

The anterior divisions of the L2 and L3, and one of the anterior divisions

of the L4, join to form the obturator nerve (Figure 230.2 [A]). The posterior division of the L2 and L3, and one of the posterior divisions of L4 join to form the nerve to the iliopsoas muscle and the femoral nerve (Figure 230.2 [B]).



A B

Figure 230.2.— Schematic representation of the formation of the obturator nerve (ON), iliopsoas nerve (IPN), and femoral nerve (FN).





Renal abnormalities seldom produce clinical manifestations in the

neonatal period. Neonates with tuberous sclerosis should undergo ultrasound of the heart, kidney, and brain. Magnetic resonance imaging of the brain should be performed as soon as the diagnosis of tuberous sclerosis is made. The brain lesions found in patients with tuberous sclerosis are: white matter anomalities, cortical tubers, subependymal nodules, subependymal giant cell astrocytomas, and cysts. All of the lesions of tuberous sclerosis that occur in the neonatal period and early infancy (white matter anomalies, subependymal nodules, and subependymal giant cell astrocytomas) are hyperintense (white) on T1-weighted images and hypointense (black) on T2-weighted images. White matter lesions and subependymal giant cell astrocytomas are more readily detected in neonates and in young infants, whereas cortical tubers may not be. Lesions in the temporal lobe may indicate a high incidence of infantile

spasm. Cortical tubers, unlike most of the lesions that occur in neonates, are hyperintense on T2-weighted images. Brain computed tomography may show periventricular calcification even in the neonatal period (Figure 300.1 [C]).

Antiepileptic drugs may control the seizures. Phenobarbital is the first choice. The possibility of epilepsy surgery should be considered in these patients. Vigabatrim is an effective treatment for infantile spasm in infants with tuberous sclerosis. Vigabatrim has not been used in neonates. Tuberous sclerosis is an autosomal dominant disorder with variable expression and incomplete penetrance. New mutations constitute about 75% of the cases. The gene loci are 9q34 and 16p13. Mutations on

chromosome 11 have also been associated with tuberous sclerosis.

A B C



Figure 300.1.— Tuberous sclerosis. [A] Skin examination under normal light (no appreciable hypopigmented spot); [B] skin examination under Wood's light (hypopigmented spot); [C] typical location of intracranial calcifications (close to the foramina of Monro).





PARAPARESIS

Paraparesis refers to bilateral leg weakness. Paraparesis may occur with brain lesions, spinal cord lesions in the thoracic area, and lumbosacral center lesions (Figure 238.1 A-D). Brain and thoracic spine lesions may produce spastic or flaccid paraparesis. Lumbosacral center lesions produce flaccid weakness. Spastic weakness is characterized by increased muscle stretch reflexes, strong leg recoil to a sudden intense pull (if the leg is allowed to stay stretched for a few seconds prior to releasing the leg, tests passive tone and not active or dynamic tone), and sustained ankle clonus. Flaccid weakness is characterized by decreased or absent muscle stretch reflexes, weak leg recoil to sudden intense pull of the leg, and no ankle clonus.

Brain lesions in the parasagittal region (Figure 238.1 A) or bilateral periventricular lesions (Figure 238.1 B) produce paraparesis. Paraparesis occurs with parasagittal lesions of the mesial regions of the postcentral gyrus. Bilateral periventricular lesions produce paraparesis because the fibers to the leg musculature travel closer to the lateral ventricles than the fibers to the arm and facial musculatures and, therefore, leg fibers are selectively affected with mild dilatation of the lateral ventricles.

Paraparesis may also occur with spinal cord lesions below T1 and above the lumbosacral center due to involvement of the descending corticospinal pathways (Figure 238.1 C). Paraparesis due to spinal injury may be associated with fecal and urinary incontinence and a sweat line may be present.



Figure 238.1.— Possible sites of anatomical injury producing paraparesis: A: parasagittal region; B: bilateral periventricular regions; C: spinal cord below T1; D: lumbosacral center; V: ventricles; T: thalamus; UQ: upper quadrant; LQ: lower quadrant; BP: brachial plexus; LSP: lumbosacral plexus. The colored rectangles indicate the location of weakness produced by damage to the different components of the somatic motor system.





The lumbosacral plexus has proximal and distal nerves (Figure 232.1).

The proximal nerves are: (1) the nerve to the iliopsoas muscle, which is the muscle that flexes the hip (Figure 232.1 [IPN]); (2) the superior gluteus nerve (Figure 232.1 [SGN]), which innervates the muscles that abduct and internally rotate the hip; and (3) the inferior gluteus nerve (Figure 232.1 [IGN]), which innervates the muscle that extends the hip. The distal nerves are: (1) the obturator nerve (Figure 232.1 [ON]), which innervates the muscles that adduct the thighs; (2) the femoral nerve (Figure 232.1 [FN]), which innervates the muscles that extend the knees; and (3) the sciatic nerve (Figure 232.1 [SN]).

The sciatic nerve (Figure 232.1 [SN]), through its medial fascicle, innervates all the hamstring muscles (Figure 232.1 [HSM]) except the short head of the biceps femoralis, which is innervated through the lateral fascicle (Figure 232.1 [B(sh)M]). The function of the hamstrings are to flex the knees. The sciatic nerve also has two terminal branches. They are the tibial (Figure 232.1 [TN]) and the common peroneal nerve (Figure 232.1 [CPN]). The tibial nerve innervates several muscles in the calf, including the posterior tibialis muscle (Figure 232.1 PostTM]), and then divides into the lateral and medial plantar nerves (Figure 232.1 [PlNs]). The tibial nerve innervates the muscles that produce dorsal flexion and invert the feet. The common peroneal nerve divides into the deep (Figure 232.1 [DPN]) and superficial peroneal nerves (Figure 232.1 [SPN]). The common peroneal nerve innervates the muscles that produce plantar

extension and evert the feet.



Figure 232.1.— Schematic representation of the lumbosacral plexus and most important intermedial nerves. IPN: iliopsoas nerve; SGN: superior gluteal nerve; IGN: inferior gluteal nerve; ON: obturator nerve; FN: femoral nerve; LST: lumbosacral trunk; TN: tibial nerve; CPN: common peroneal nerve; AdM: adductor muscle of the thigh; HSM: hamstring muscles; PostTM: posterior tibialis muscle; B(sh)M: short head of the biceps femoralis muscle; PlNs: plantar nerves; DPN: deep peroneal nerve; SPN: superficial peroneal nerve.





UPPER EXTREMITY DIPARESIS

Upper extremity diparesis occurs with bilateral brachial motor center lesions (Figure 240.1 A) or bilateral brachial plexus involvement (Figure 240.1 B). Upper extremity diparesis due to brachial motor center involvement is usually associated with weakness of the lower extremities since most lesions in this area involve the corticospinal tract destined to innervate the lumbosacral somatic motor center. Bilateral brachial plexus injury occurs in a significant number of patients. Although bilateral, the lesion is usually asymmetrical. A bilateral brachial plexus lesion usually involves the roots.

Figure 240.1.— Possible sites of anatomical injury producing upper extremity diparesis. A: brachial center; B: brachial plexus; V: ventricles; T: thalamus; UQ: upper quadrant; FN: facial nerve; LQ: lower quadrant; BP: brachial plexus; LSP: lumbosacral plexus. The colored rectangles indicate the location of weakness produced by damage to the different components of the somatic motor system.


Facial Weakness


Upper Motor Neuron Facial Asymmetry

Upper motor neuron facial asymmetry occurs with lesions at the lower third of the precentral gyrus or at the corticopontine tract prior to its decusation (Figure 178.1 A and B). Upper motor neuron facial lesions produce exclusive or predominantly contralateral lower quadrant weakness. The characteristics of the facial weakness vary with time.

During the first week, facial weakness due to lesions above (Figure 178.1 A) or below (Figure 178.1 B) the thalamus have similar distribution and characteristics.

Figure 178.1.— Anatomical localizations of injuries in the facial motor system. T: thalamus; IAC: internal auditory canal; FC: facial canal; SMO: styloidmastoid orifice; BB: buccal branch; MB: mandibular branch; TB: temporal branch; OOM: orbicularis oculi muscle; RM:


Facial Weakness

risorius muscle; DAOM: depressor angularis oris muscle; BM: buccinator muscle; MM: mentoris muscle. Light blue line indicates components of the facial nerve that have ipsilateral (hence bilateral) cortical innervation; dark blue line indicates components of the facial nerve that has contralateral innervation. A: cerebral lesion above the thalamus; B: cerebral lesion below the thalamus and above the pons; C: pontine lesion; D: facial nerve lesion; E: mandibular branch lesion; F: depressor angularis oris muscle.

During the first week, the facial weakness involves the corner of the mouth, nasolabial fold, and the lower eyelid. The upper eyelid and the forehead are minimally involved or more often not involved. The asymmetry is not noticeable when the neonate sleeps or when the neonate is in a quiet awake state. The asymmetry only becomes apparent when the neonate cries. When crying, the mouth deviates toward the normal side and the eye on the side opposite from the direction the mouth deviates may close properly or may show minimal signs of weakness, such as not burying the eyelashes as deeply as in the other eye.

After the first week, patients with lesions above (Figure 178.1 A) and below (Figure 178.1 B) the thalamus have similar characteristics during quiet awake and during sleep but not during grimacing. At rest or during quiet awake, no asymmetry is noted. During grimacing, neonates with lesions above the thalamus demonstrate an exaggerated contraction of the affected side (as do adults with simiar lesions with emotional smile but not with voluntary smile) that causes the mouth to deviate toward the affected side (Figure 178.1); whereas during grimacing neonates with lesions below

the thalamus demonstrate mouth deviation towards the normal side.

A B

Figure 178.1.— Facial asymmetry due to a central lesion above the thalamus. The asymmetry is not present in quiet awake [A] but appears during crying [B]. The mouth deviates toward the affected side (right). The patient had a left hemispherectomy.


Arm


The brachial plexus gives rise to proximal, intermediate, and distal

nerves. There are two proximal nerves (Figure 205.1). They are the long thoracic nerve (Figure 205.1; LT) and the dorsal scapular nerve (Figure 205.1; DS). They arise from the ventral rami. The long thoracic nerve arises from the union of fibers from the ventral rami of C5-C7. The long thoracic nerve innervates the serratus anterior muscle (Figure 205.1; SA). The dorsal scapular nerve arises from the ventral ramus of C5. The dorsal scapular nerve innervates the rhomboid muscle (Figure 205.1; R). Both muscles are involved in scapular stability.

The brachial plexus has 5 intermediate nerves (Figure 205.1). They are the suprascapular, lateral pectoral, medial pectoral, subscapular, and thoracodorsal nerves.

Figure 205.1.— Schematic representation of the brachial plexus nerves and muscles. (PS): paraspinal muscles; (R): rhomboid muscle; DS: dorsoscapular nerve; LT: long thoracic nerve: (SA): serratus anterior muscle; (SS): supraspinatus muscle; (IS): infraspinatus muscle; SPS:


Arm

suprascapular nerve; PL: pectoralis lateralis nerves; (P): pectoralis muscle; PM: pectoralis medialis nerve; (TM): teres major muscle; (SBS): subscapularis muscle; SBS: subscapularis nerve; TD: thoracodorsal nerve; (LD): latissimus dorsi muscle; MC: musculocutaneous nerve; (Bi): biceps muscle; (Br): brachialis muscle; M: median nerve; U: ulnar nerve; A: axillary nerve; (TMi): teres minor muscle; (D): deltoid muscle; R: radial nerve.





Plexus reconstruction is done between 6 and 9 months of age. Neonates who, at 6 months of age, do not have elbow flexion or have shoulder external rotation and abduction limited to less than 25%, are surgical candidates. Surgical reconstruction procedures include the use of saphenous nerve graft to bypass the neuroma in upper trunk lesions and the use of fibers from adjacent nervous structures to innervate the upper trunk (neurotization).

The decision to perform a saphenous nerve-transfer operation or to perform a neurotization procedure depends on the presence of a surgically accessible proximal stump (Figure 262.1). The proximal stump is not available in intracanalicular or pretruncal lesions. Saphenous nerve-implant bypass can only be performed if the proximal stump is surgically accessible. Intracanalicular or pretruncal lesions involve the roots, spinal nerves, and ventral rami. Neurotization does not require a surgically accessible proximal stump (Figure 262.1). Preoperative clinical, radiographic, and neurophysiologic findings are used to determine which

of these procedures are appropriate in each case.



Figure 262.1.— Schematic representation of a cervical spinal cord segment. [A] Lesions before the trunk require neurotization. [B] Lesions at or after the trunk can be treated by saphenous nerve transfer or [C] neurolysis. SEN. COND: sensory conduction; ABN: abnormal; PARASP: paraspinal; M: muscle; R: rhomboid; SA: serratus anterior; S: syndrome.





The anterior division of L4 that did not join the anterior division of L2 and L3, and the anterior division of L5 join to form the lumbosacral trunk (Figure 231.1 [A-LST]). The lumbosacral trunk joins the anterior divisions of S1 and S2 and the ventral ramus of S3 to form the medial fascicle of the sciatic nerve. The medial fascicle of the sciatic nerve (Figure 231.1 [A-SN]) becomes the tibial nerve (Figure 231.1 [A-TN]). The posterior division of L4 that did not join the posterior divisions of L2 and L3 (Figure 231.1 [B]), and the posterior divisions of the L5 and S1 and S2, join to form the inferior (Figure 231.1 [B-IGN]) and superior gluteal nerves (Figure 231.1 [B-IGN]) and the lateral fascicle of the sciatic nerve (Figure 231.1 [B-SN]). The lateral fascicle of the sciatic nerve becomes the common peroneal nerve (Figure 231.1 [B-CPN]).

A B

Figure 231.1.— Schematic representation of the formation of the medial and the lateral portion of the sciatic nerve (SN). LST: lumbosacral trunk; TN: tibial nerve; CPN: common peroneal nerve; SGN: superior gluteal nerve; IGN: inferior gluteal nerve.



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