approach to hypotonia

R van ToornMB ChB, (Stell) MRCP (Lond), FCP (SA)

Specialist

Department of Paediatrics and Child Health

Faculty of Health Sciences

Stellenbosch University and

Tygerberg Children’s Hospital

Ronald van Toorn obtained his medical

degree from the University of Stellenbosch,

and completed his paediatric specialist

training at both Red Cross Children’s

Hospital in Cape Town and the Royal

College of Paediatricians in London. One

of his interests is in the field of neuromus-

cular medicine. His working experience

includes the neuromuscular clinics attached

to Birmingham Children’s, Red Cross

Children’s, Guy’s and St Thomas’ hospitals.

CLINICAL APPROACH TO THE FLOPPY CHILDThe floppy infant syndrome is a well-recognised entity for paediatricians andneonatologists and refers to an infant with generalised hypotonia presenting at birthor in early life. An organised approach is essential when evaluating a floppy infant,as the causes are numerous.

A detailed history combined with a full systemic and neurological examinationare critical to allow for accurate and precise diagnosis. Diagnosis at an earlystage is without a doubt in the child’s best interest.

HISTORY

The pre-, peri- and postnatal history is important. Enquire about the quality andquantity of fetal movements, breech presentation and the presence of either poly-or oligohydramnios. The incidence of breech presentation is higher in fetuseswith neuromuscular disorders as turning requires adequate fetal mobility.Documentation of birth trauma, birth anoxia, delivery complications, low cordpH and Apgar scores are crucial as hypoxic-ischaemic encephalopathy remainsan important cause of neonatal hypotonia. Neonatal seizures and an encephalo-pathic state offer further proof that the hypotonia is of central origin. The onsetof the hypotonia is also important as it may distinguish between congenital andaquired aetiologies. Enquire about consanguinity and identify other affected fam-ily members in order to reach a definitive diagnosis, using a detailed familypedigree to assist future genetic counselling.

CLINICAL CLUES ON NEUROLOGICAL EXAMINATION

There are two approaches to the diagnostic problem. The first is based on identi-fying the neuro-anatomical site of the lesion or insult. The second is to determinewhether or not the hypotonia is accompanied by weakness. Careful neurologicalexamination should, in most cases, localise the site of the lesion to the uppermotor neuron (UMN) or lower motor neuron (LMN) unit. Useful clues are listed inFig. 1.

Next assess whether the hypotonia is accompanied by weakness. Weakness isuncommon in UMN hypotonia except in the acute stages. Hypotonia with pro-found weakness therefore suggests involvement of the LMN. Assessment of musclepower of infants is generally limited to inspection.

Useful indicators of weakness are: • Ability to cough and clear airway secretions (‘cough test’). Apply pressure to

the trachea and wait for a single cough that clears secretions. If more thanone cough is needed to clear secretions, this is indicative of weakness.2

• Poor swallowing ability as indicated by drooling and oropharyngeal poolingof secretions.

• The character of the cry — infants with consistent respiratory weakness havea weak cry.

• Paradoxical breathing pattern — intercostal muscles paralysed with intactdiaphragm.

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August 2004 Vol.22 No.8 CME 449

• Frog-like posture and quality ofspontaneous movements — poorspontaneous movements and thefrog-like posture are characteristicof LMN conditions.

Further confirmation of the last indica-tor can be obtained by means of infor-mal neurological examination in thetest positions. Excessive head lag willbe evident on ‘pull to sit’. Minimal

support with a sensation of ‘slippingthrough he hands’ during vertical sus-pension testing and inverted U posi-tion on ventral suspension are furtherindicators (Fig. 2.1 and 2.2).3

Floppy strong

Increased tendon reflexesExtensor plantar responseSustained ankle clonusGlobal developmental delayMicrocephaly or suboptimalhead growthObtundation convulsionsAxial weakness a significantfeature

Upper motor neurondisorderCentral hypotonia

Lower motor neurondisorderPeripheral hypotonia

Creatine kinase assayEMGNerve conductionstudies

Genetic studiesKarotypingFISH methylation studiesVLCFA

Triosomy 21Prader-Willi syndromeZellweger syndrome

Hypoxic ischaemicencephalopathyCerabral malformations

Congenitalstructuralmyopathies

Spinal muscuardystrophyCongenital myotonicdystrophyCongenital musculardystrophies

CT/MRI DNA-based mutationanalysis if available

Muscle or nervebiopsy

Floppy weak

Hypo- to areflexiaSelective motor delayNormal head circumferenceand growthPreserved social interactionWeakness of antigravitationallimb musclesLow pitched weak cryTongue fasciculationsParadoxical chest wallmovement

Fig. 1. Clinical clues on neurological examination (EMG = electromyogram: CT= computed tomograph; MRI = magneticresonance imaging; VLCFA = very long-chain fatty acids; FISH = fluorescent in situ hybridisation)

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450 CME August 2004 Vol.22 No.8

A distinct pattern of weakness mayfavour certain aetiologies:• Axial weakness is a significant fea-

ture in central hypotonia.• Generalised weakness with sparing

of the diaphragm, facial muscles,pelvis and sphincters suggests ante-rior horn cell involvement.

• With myasthenic syndromes, thebulbar and oculomotor musclesexhibit a greater degree of involve-ment.

• Progressive proximal symmetricalweakness suggests a dystro-phinopathy. Signs of proximalweakness in the older infantinclude a lordotic posture,Trendelenburg gait and Gowersign.

• A striking distribution of weaknessof the face, upper arms and shoul-ders suggests fascioscapulohumeralmuscular dystrophy.

• Distal muscle groups are predomi-nantly affected with peripheral neu-ropathies. Signs suggesting distalweakness in an older infant wouldinclude weakness of hand grip,foot drop and a high stepping,slapping gait.

THE FLOPPY WEAK INFANT

Table I gives a comprehensiveapproach to the clinical clues andinvestigations for the more commonphenotypes of the weak floppy infant.

Once the lesion has been localised tothe LMN proceed with further neu-roanatomical localisation according tothe compartments of the LMN. Thecompartments and disease associa-tions are listed in Fig. 3.

Examine the tongue for size and fasci-culations. Fasciculations, irregulartwitching movements, generally indi-cate an abnormality of the anteriorhorn cells (Fig. 4). Do not examine thetongue while the infant is crying. Theco-existence of atrophy would stronglyfavour a denervative aetiology. AnECG may be helpful in demonstratingbaseline fasciculations of the inter-costal muscles (Fig 5). Enlargement ofthe tongue may suggest a storage dis-order such as Pompe’s disease.

The presence of a facial diplegia(myopathic facies) suggests either acongenital structural myopathy ormyasthenia gravis. Respiratory andbulbar weakness can accompanyboth conditions. Fluctuation in strengthwould favour myasthenic syndromes(Fig. 6).

Where clinical evaluation suggestscomplex multisystem involvement (i.e.hypotonia plus) inborn errors ofmetabolism should be excluded.Referral to a tertiary centre for meta-bolic investigations would then beindicated.

THE FLOPPY STRONG CHILD

The presence of facial dysmorphismshould alert the doctor to the possibili-ty of an underlying syndrome or genet-

Fig. 2.1. A 12-week-old male infant withexcessive headlag evident on ‘pull-to-sit’.Note the hypotonic posture of the legswith external rotation.

Fig. 2.2. The same infant in horizontalsuspension. Note the inverted U posture.

Fig. 4. Tongue fasciculations in a childwith spinal muscular atrophy. The com-bination of fasciculations with atrophyis strongly indicative of muscle dener-vation.

Fig. 5. ECG of a floppy infant with spinal muscular atrophy demonstrating base-line fasciculations arising from the underlying intercostal muscles.

Fig. 6. Ptosis and external ophthalmo-plegia in a floppy weak child sugges-tive of myasthenia gravis.

THE FLOPPY CHILD


Nerve fibre: neuropathies

(Demyelinating or axonal)Acquired: Guillain-Barré syndromeInfectious: diphtheria, syphilis, coxsackie, HIV Toxic: drugs, heavy metalsNutritional: Vit B1, B6, B12, E, folateEndocrine: Diabetes, uraemiaMetabolic neurodegenerative causesHereditary: Charcot-Marie-Tooth disease

Muscle

Dystrophinopathies (lack of specific muscle protein):Duchenne, Becker’s fascioscapular humeral, limb gir-dle and congenital muscular dystrophies

Congenital myopathies (abnormal muscle structure)

Muscle membrane disorders: congenital myotonias,congenital myotonic dystrophies

Inflammatory myopathies: dermatomyositis,poliomyositis

Metabolic myopathies: lipid glycogen storage dis-eases

Endocrine myopathies: hypothyroidism

Energy depletion within muscle: mitochondrial, free-fatty acid oxidatation and carnitine disorders

Anterior horn cell:

Spinal muscular atrophyPoliomyelitis

Neuromuscular junction

Myasthenia gravisBotulism

Fig. 3. LMN comportments and disease associations.

THE FLOPPY CHILD


Table I. Clincical clues and investigations of the more common phenotypes of the floppy weak infant

Condition Clinical clues Investigations

Spinal cord transection or Haemangioma or tuft of hair in midline MRI spinal corddisease ScoliosisSyringomyelia or other forms Evidence of bladder or bowel dysfunctionof spinal dysraphism Mixed deep tendon reflexes with absent

abdominal and anal reflexesSpinal muscular atrophy Tongue atrophy and fasciculations ECG: Baseline fasciculations

Paradoxical breathing pattern Deletion of the survival motorSevere proximal muscle weakness with neuron (SMN) gene by PCR absent tendon reflexes testing Preserved social interaction

Peripheral neuropathy Weakness predominantly distal Motor nerve conduction In most cases absent deep tendon reflexes studiesPes cavus Sural nerve biopsy

Molecular DNA testing isavailable for specificdemyelinating disorders

Myasthenia gravis Greater involvement of oculomotor and Response to acethylcholine bulbar muscles esterase inhibitorsTrue congenital myasthenia due to receptor Single-fibre EMGdefects is rare Serum antibodies to Exclude transient neonatal form from acethylcholine receptorsmaternal history Electrodiagnostic studies not

universally positive in youngpatients

Infantile botulism Acute onset descending weakness, Isolation of organism from cranial neuropathies, ptosis, stool cultureunreactive pupils, dysphagia, Presence of toxin in the stool constipation

Congenital muscular Hypotonia, weakness and contractures Creatine kinase usuallydystrophy at birth elevated

Associated brain and eye problems Brain MRI for structural and white matter abnormalities Muscle biopsy: merosin stain

Congenital myotonic Polyhydramnios with reduced fetal Molecular DNA testing bydystrophy movements determining number of CTG

Inverted V-appearance of the mouth repeats (normal range 5 - 39Examination of mother’s face shows inability repeats)to bury her eyelashes and grip myotonia EMG of the motherPremature cataract surgery in the mother

Congenital structural Slender stature CK and EMG usually not myopathy Hypotonia with feeding problems at birth helpful

Weakness that is often non-progressive Muscle biopsy is critical for Nemaline myopathy: often associated with definitive diagnosis.feeding problems ECG when nemaline and Central core: most often associated with desmin myopathies aremalignant hyperthermia suspectedMyotubular myopathy: Ptosis and The genetic basis for severalextraocular palsies consistent of the congenital myopathies clinical features has now been determined

Glycogen storage disease Enlarged heart in a very floppy weak Blood smear vacuolatedPompe’s disease newborn lymphocytes

Unexplained cardiac failure Urine oligosaccharidesTongue may appear large Typical ECG and ECHO

changesAcid maltase assay in cultured fibroblastsMuscle biopsy usually not necessary

THE FLOPPY CHILD


ic disorder. Conditions that need to beexcluded include trisomy 21, Prader-Willi and Zellweger syndrome. Atbirth the facial anomalies in Prader-Willi syndrome are often insignificantand the diagnosis is usually onlyestablished after onset of obesity.Useful early markers include the pres-ence of feeding difficulties, smallhands and feet, almond shaped eyes,narrow bifrontal diameter and hypogo-nadism (Fig. 7). Failure to identifyelectrophysiological abnormalities in aneonate with profound hypotoniashould prompt testing for Prader-Willisyndrome. This can be done by aDNA methylation study which willdetect 99% of cases.

Zellweger syndrome presents in thenewborn with typical facial dysmor-phism including high forehead, widepatent fontanelles and sutures, shalloworbital ridges, epicanthus and microg-nathia. Neurological manifestationsare dominated by severe hypotoniawith depressed or absent tendonreflexes, and poor sucking and swal-lowing. Hepatomegaly and liver dys-function are consistent findings.

VALUE AND CHOICE OFDIAGNOSTIC MODALITIES

Special investigations should be guid-ed by clinical findings. Evaluation oftone and power should be delayed inthe systemically unwell nutritionallycompromised child. Infective and bio-chemical parameters should first benormalised before attempts are madeto examine tone and power.Hypokalaemia and hypophospha-taemia in particular will causereversible weakness. Serum albumin,calcium, phosphorus, alkaline phos-phatase and thyroxine levels will pro-vide confirmation of clinical suspicionin malnutrition, ricketts and hypothy-roidism.

SUSPECTED CENTRAL CAUSE

For infants with central hypotonia, ini-tial investigations include karyotypeand neuroimaging (CT or MRI scan). Akaryotype is a must in the dysmorphichypotonic child. This can be combinedwith FISH testing if Prader-Willi syn-drome is suspected. Cranial MRI willidentify patients with structural CNSmalformations, neuronal migrationdefects and those with white matterchanges (congenital muscular dystro-phies in particular). Hypotonia mayalso be prominent in connective tissuediseases such as Ehlers Danlos orMarfan’s syndrome. An excessiverange of joint mobility, unusual jointpostures, the ability to do various con-tortions of the limbs and/or hyperelas-ticity of the skin are important diag-nostic clues. Although metabolic disor-ders are well recognised as the causefor central hypotonia, because of therarity of the conditions, the diagnosticyield is low. Very long-chain fattyacids (VLCFA) testing should be per-formed if a peroxisomal disorder suchas Zellweger is suspected.

SUSPECTED PERIPHERALCAUSE

Major discoveries have been made inthe genetic analysis of the musculardystrophies, spinal muscular atrophiesand hereditary neuropathies. This

means that most neuromuscular condi-tions can now be diagnosed by molec-ular testing. Examples include spinalmuscular atrophy which can now beconfirmed by polymerase chain reac-tion (PCR) testing for a deletion of thesurvivor motor neuron (SMN) geneand congenital myotonic dystrophywhich can be diagnosed by demon-strating an expansion of cytosinethymine guanine (CTG) triplet repeats.

DNA Xp21 deletion testing (PCRassays) can confirm the diagnosis in65% of males with Duchenne musculardystrophy and 80% of males withBecker’s muscular dystrophy. Only inthe remaining cases is muscle biopsystill advocated. Muscle enzymes levels(creatine kinase assay) are rarely help-ful in the floppy infant, with the excep-tion of muscle disorders where crea-tine kinase values are elevated, suchas congenital muscular dystrophiesand in some of the congenital structur-al myopathies.

Electromyography (EMG) should notbe performed in isolation. It does notallow for a definitive diagnosis asthere are virtually no waveforms thatare pathognomonic for specific dis-ease entities. In the floppy child, EMGis indispensable in deciding whetherthere is true weakness due to neuro-muscular disease, or merely hypotonic-ity from causes in other systems orother parts of the nervous system. Theabnormalities detected may then assistin localizing the disease process to theneuron, neuromuscular junction ormuscle. EMG is also useful to confirma clinical suspicion of myotonia in theolder child.

Nerve conduction studies are useful inthe investigation of hereditary motorsensory neuropathies and distinguish-ing axonal from demyelinating disor-ders. Molecular DNA testing can thenbe used for specific demyelinating dis-orders. Commercial testing is not yetavailable for most axonal forms ofhereditary neuropathies.

Muscle biopsy remains the investiga-tion of choice in an infant with a sus-

Fig. 7. A 1-year-old girl with Prader-Willi syndrome. Marked hypotoniaand feeding difficulties were evidentduring the first few months of her life.

THE FLOPPY CHILD


pected congenital structural myopathy,as none of the clinical features aretruly pathognomonic. Even a CK with-in the reference range and normalEMG does not exclude the presence ofa myopathy. Muscle biopsy is alsoindicated in infants with suspectedlimb-girdle muscular dystrophies(LGMD).

The term ‘benign essential hypotonia’or ‘hypotonia with favourable outcome’should be used with caution sincenewer investigative techniques haveresulted in most previously labelledcases being classified into specific disor-ders. There are however many benigncongenital hypotonia cases that remainunclassified, even with detailed exami-nation of the muscles. Patients labelledas ‘hypotonia with favourable outcome’should fulfil all of the following criteria1:

• early hypotonia, usually since birth • active movements of limbs and nor-

mal tendon reflexes • normal or mild motor retardation that

improves later on • normal muscle enzymes, EMG,

motor nerve conduction studies(MNCS) and histology.

PRINCIPLES OFMANAGEMENT

Regular physiotherapy will prevent con-tractures. Occupational therapy isimportant in facilitating activities ofdaily living. Vigorous treatment of respi-ratory infections is indicated. Annual fluvaccination is necessary. Annualorthopaedic review is required to moni-tor for scoliosis and to exclude hip dislo-cation/subluxation. Feeding intervention by nasogastric tubeor gastrostomy will benefit the under-nourished child. Maintenance of idealweight is important, as excessive weightgain will exacerbate existing weakness.Children with neuromuscular disordersdeserve special attention when it comesto anaesthesia. The anaesthetist shouldbe forewarned about the possibility ofan underlying muscle disease even if thechild has very mild or non-existingsymptoms. A family history of muscledisease or mild hyper-CK-aemia may beof importance. Muscle relaxants shouldonly be used if essential because oftheir more profound and prolongedeffect in myopathic children. All childrenwith neuromuscular disease should also beconsidered potentially susceptible tomalignant hypothermia (the strongestcorrelation is with central core disease)and implicating agents should thereforebe avoided.

Ethical considerations such as theappropriateness of cardiopulmonaryresuscitation in the event of cardiacarrest or acute respiratory failure needto be addressed sensitively.

References available on request.

When evaluating a floppy infant,the first goal should be to distin-guish whether the disorder is cen-tral or peripheral in origin.

Hypotonia with weakness suggestsa lower motor neuron lesion, where-as weakness is uncommon in disor-ders affecting the upper motor neu-ron except during the acute stage.

Evaluation of tone and powershould be delayed in the unwell,nutritionally compromised child.

Muscle enzymes are rarely helpfulin the floppy child, with the excep-tion of the congenital muscular dys-trophies and some of the structuralcongenital myopathies.

EMG does not allow a definitivediagnosis but is indispensable indeciding whether there is weaknessdue to neuromuscular disease, ormerely hypotonia from causes inother systems or parts of the nerv-ous system.

The most common of the neuromus-cular disorders, spinal muscularatrophy (SMA), is now diagnosableby molecular genetic analysis(PCR).

Where clinical evaluation suggestscomplex multisystem involvement(i.e. hypotonia plus) inborn errorsof metabolism should be excluded.

Children with neuromuscular disor-ders deserve special attention whenit comes to anaesthesia.

The term ‘benign essential hypoto-nia’ or ‘hypotonia with afavourable outcome’ should be usedwith caution and only after compli-ance with strict diagnostic criteria.

IN A NUTSHELLThe onset of the hypotoniais also important as it maydistinguish between congenital and aquired aetiologies.

There are two approachesto the diagnostic problem.The first is based on identi-fying the neuro-anatomicalsite of the lesion or insult.The second is to determinewhether or not the hypoto-nia is accompanied byweakness.

Children with neuromuscu-lar disorders deserve spe-cial attention when itcomes to anaesthesia.

THE FLOPPY CHILD


approach to hypotonia

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