dr ezgi tiryaki, hennepin neuron diseasesblogs.bellvitgehospital.cat/aulaela/wp-content/... ·...

ALS and Other MotorNeuron Diseases

Ezgi Tiryaki, MD; Holli A. Horak, MD, FAAN

ABSTRACTPurpose of Review: This review describes the most common motor neuron disease,ALS. It discusses the diagnosis and evaluation of ALS and the current understanding of itspathophysiology, including new genetic underpinnings of the disease. This article alsocovers other motor neuron diseases, reviews how to distinguish them from ALS, anddiscusses their pathophysiology.Recent Findings: In this article, the spectrumof cognitive involvement inALS, newconceptsabout protein synthesis pathology in the etiologyofALS, andnewgenetic associationswill becovered. This concept has changed over the past 3 to 4 years with the discovery of newgenes and genetic processes that may trigger the disease. As of 2014, two-thirds of familialALS and 10% of sporadic ALS can be explained by genetics. TAR DNA binding protein43 kDa (TDP-43), for instance, has been shown to cause frontotemporal dementia as wellas some cases of familial ALS, and is associated with frontotemporal dysfunction in ALS.Summary: The anterior horn cells control all voluntary movement: motor activity, res-piratory, speech, and swallowing functions are dependent upon signals from the anteriorhorn cells. Diseases that damage the anterior horn cells, therefore, have a profoundimpact. Symptoms of anterior horn cell loss (weakness, falling, choking) lead patients toseek medical attention. Neurologists are the most likely practitioners to recognize anddiagnose damage or loss of anterior horn cells. ALS, the prototypical motor neurondisease, demonstrates the impact of this class of disorders. ALS and other motor neurondiseases can represent diagnostic challenges. Neurologists are often called upon to serveas a ‘‘medical home’’ for these patients: coordinating care, arranging for durable medicalequipment, and leading discussions about end-of-life care with patients and caregivers. Itis important for neurologists to be able to identify motor neuron diseases and to evaluateand treat patients affected by them.

Continuum (Minneap Minn) 2014;20(5):1185–1207.

INTRODUCTIONThe term motor neuron disease refers tovarious disease entities that result inprogressive degeneration of motor neu-rons. The term motor neuron disease isalso sometimes used interchangeablywithamyotrophic lateral sclerosis (ALS), whichis themost commondisease in this category.

Motor neuron diseases can be hered-itary or acquired and vary in underlyingpathology and clinical presentation. ALScan affect both the lower motor neuronand the upper motor neuron, but most

motor neuron diseases affect only thelower motor neuron.

The lower motor neurons are locatedin the spinal cord anterior horn and inthe brainstem (motor nuclei of cranialnerves) and innervate the skeletal mus-cles. Since lower motor neurons of thespinal cord reside in the anterior horn,these diseases are also sometimes re-ferred to as anterior horn cell diseases.The upper motor neurons are located inthe motor cortex and give rise to thecorticospinal and corticobulbar tracts.

Address correspondence toDr Ezgi Tiryaki, HennepinCounty Medical Center,Department of Neurology, 701Park Avenue P5-200,Minneapolis, MN 55415,[email protected].

Relationship Disclosure:

Dr Tiryaki’s institutionreceives support from TheALS Association. Dr Horak’sinstitution receives a grantfrom the Centers for DiseaseControl and Prevention.

Unlabeled Use ofProducts/InvestigationalUse Disclosure:Drs Tiryaki and Horak discussthe unlabeled use of variousdrugs for the symptomaticmanagement of ALS.

* 2014, American Academyof Neurology.

1185Continuum (Minneap Minn) 2014;20(5):1185–1207 www.ContinuumJournal.com

Review Article

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

mailto:[email protected]

See Table 1-1 for a list of the mostcommon motor neuron diseases, whichare discussed in this article. Of these,ALS is more common than all theothers, so an adult presenting with

motor neuron symptoms is most likelyto have ALS.

The clinical hallmark of motor neu-ron disease is lower motor neurondysfunction: atrophy, weakness, andfasciculations of affected motor units.A motor unit is one motor neuron, itsaxon, the neuromuscular junction, andall the individual muscle fibers it in-nervates (Figure 1-11).

As the motor neuron undergoesapoptosis, the motor nerve axon de-generates, and the neuromuscularjunction is destroyed. Muscle fibersinnervated by that axon will be dener-vated and, subsequently, atrophy.

Electrically, the individual fiber willshow fibrillations and positive waves, amarker of the instability of the dener-vated muscle membrane. When con-tracting as a group, the fibers of anaffected motor unit will fasciculate,which can be seen clinically and electri-cally on EMG. Initially, with an acquiredmotor neuron disease, adjacent motornerve axons will reinnervate the muscle

KEY POINT

h Amotor unit is one motorneuron, its axon, and allthe individual musclefibers it innervates.

TABLE 1-1 Motor NeuronDiseases

b ALS

b Multifocal motor neuropathy

b Spinal muscular atrophy

b Spinal bulbar muscularatrophy/Kennedy disease

b Monomelic amyotrophy

b Poliomyelitis

b West Nile virus

b Paraneoplastic motorneuron diseasea

ALS = amyotrophic lateral sclerosis.a For more information on paraneoplasticmotor neuron disease, please see the article‘‘Paraneoplastic Neuropathies’’ by SrikanthMuppidi, MD, and Steven Vernino, MD,PhD, FAAN, in this issue of Continuum.

FIGURE 1-1 Motor unit. A motor unit consists of the anteriorhorn cell or lower motor neuron and all theskeletal muscle fibers it innervates. The number of

muscle fibers in a motor unit may vary depending on the muscle.Depicted are two motor neurons that each innervate four fibers.

Reprinted with permission from Saladin K, McGraw-Hill.1 B 2009McGraw-Hill Education.

1186 www.ContinuumJournal.com October 2014

ALS and Other Motor Neuron Diseases


fibers (causing a reinnervation patternon EMG). However, as these motorneurons die too, eventually there arenot enough motor neurons left forreinnervation and the predominatingprocess that occurs is denervation.

Motor neurons of cranial nerve nucleiare variably affected, depending uponthe disease and phenotype. Cranialnerves XI and XII are most oftenaffected, especially with ALS and spinalbulbar muscular atrophy/Kennedy dis-ease. Cranial nerves III, IV, and VI(extraocular muscle nuclei) are affectedlate, or never, in these diseases.

DIAGNOSISMotor neuron diseases are diagnosedclinically. Supportive testing, such asnerve conduction studies and EMG canconfirm active denervation, which in-dicates loss of the motor neuron. Forspecific differential diagnoses, genetictesting or infectious disease titers canconfirm the underlying pathology. Thesetests will be discussed in detail for eachpertinent disease. Imaging does not playa role in the diagnosis of motor neurondisease, other than to exclude mimics.

Electrical Studies in MotorNeuron DiseaseNerve conduction studies and EMG canbe very useful in the diagnosis of motorneuron disease. Electrodiagnostic stud-ies reflect that sensory function is pre-served while motor function is affected.Specifically, in the setting of advancedmotor axon loss, nerve conductionstudies may show low compoundmuscle action potential amplitudes withnormal sensory nerve amplitudes. Thismay not apply to spinal bulbar muscularatrophy/Kennedy disease, which oftenhas some sensory involvement on nerveconduction studies.

EMG in motor neuron disease willeventually show both active denervationand reinnervation in affected myotomes.

A patternof (1) low-amplitude compoundmuscle action potentials with preservedsensory responses on nerve conductionstudies; (2) denervation changes (fibrilla-tions, positive waves); and (3) andreinnervation changes (reduced numbersof large-amplitude, long-duration, poly-phasic motor unit potentials) will bedocumented by the electromyographer.If a polyradicular pattern of denervation/reinnervation is seen (ie, more than oneor two radicular levels), then the electro-myographer must consider a motorneuron disease as the etiology of thepattern. EMG performed for suspectedALS must include at least three regions ofthe neuraxis to confirm a widespreadpattern of denervation/reinnervation be-yond regional damage fromradiculopathies.

CLINICAL DISEASESALSALS is the most common acquiredmotor neuron disease. ALS affects morethan the motor neurons and is oftenassociated with cognitive abnormalities(frontotemporal dysfunction) and pseu-dobulbar affect.

About 5000 people in the UnitedStates are diagnosed with ALS each year.The incidence worldwide is estimated tobe 4 to 8 per 100,000 individuals. Themean age of onset is 56 years inindividuals without a known family his-tory and 46 years in individuals withfamilial ALS. The male to female ratio is1.6 to 1. Average disease duration fromonset of symptoms is about 3 years, butit can vary significantly. Patients usuallydie of respiratory failure.2

The primary feature of ALS is motorneuron dysfunction, which typically be-gins in one limb or one region of thespinal cord, but may also begin in cranialnerve nuclei, which is termed ‘‘bulbar’’onset (‘‘bulb’’ being an antiquated termfor the brainstem). Limb onset occurs in80% and bulbar onset in 20% of cases.Patients will often report gradual onset of

KEY POINT

h EMG performed forsuspected ALS mustinclude at least threeregions of theneuraxis to confirm awidespread patternbeyond regionaldamage fromradiculopathies.



weakness and may or may not recognizethe muscle wasting and fasciculations(Case 1-1). It is not uncommon for thefasciculations to go unrecognized by thepatient and only be noticed by a familymember or physician.

ThepatientwithALSmay thendevelopeither spread of the weakness to theopposite limb or to another region ofthe brain or spinal cord; progression andspread of symptoms are hallmarks of ALS.The patient may also develop uppermotor neuron signs and symptoms (eg,spasticity, weakness, hyperreflexia) in thatlimb or in another limb. Patients will oftenreport the spasticity and weakness asstiffness but rarely as pain. Muscle crampscan occur in ALS and can be quiteuncomfortable and, at times, painful.

Some patients have a predominantlyupper motor neuron presentation ofweakness and spasticity, while others havelower motor neuron predominant symp-toms (Figure 1-2). Some patients have acombination of both in the same limb.No two patients will have the same pre-sentation, although certain patterns areseen more often than others (Table 1-2).

Bulbar-onset ALS has a combinationof upper motor neuron/lower motor

neuron presentation that starts in bulbarmuscles (pharyngeal, oral, and occasion-ally respiratory). These patients tend tohave a shorter life span because of thecritical nature of bulbar muscle functionin eating, swallowing, and breathing.Primary lateral sclerosis is an uppermotor neuronYonly disease that has aslow progression and manifests withexclusive upper motor neuron symptoms.Primary muscular atrophy is a lowermotor neuronYonly disease and may haveeither a rapid progression or slow pro-gression. A predominantly lower motorneuron form of ALS that starts in theupper extremities is called the brachialdiplegia variant. It is more common inmen, and patients will have severe arm/hand paralysis early with relatively pre-served leg and bulbar function for a while.

Cognitive and behavioral abnormali-ties, in the form of frontotemporaldysfunction, occur in up to 50% ofpatients with ALS.3 The cognitive andbehavioral abnormalities may be presentat the onset of the disease but may notbe recognized initially and may require adedicated neuropsychological assess-ment. Patients are often unaware ofany cognitive and behavioral changes,

KEY POINTS

h It is not uncommon forfasciculations to gounrecognized by thepatient and only benoticed by a familymember or physician.

h Progression and spreadof symptoms arehallmarks of ALS.

h ALS is often describedas painless, but musclecramps can be quiteuncomfortable and, attimes, painful.

Case 1-1A 64-year-old right-handed man presented to the neurology clinic with a chief concern of not being ableto lift things. He had seen his primary care physician and an orthopedist for this problem. The patientstated that his symptoms had been present for 3 months, but his wife reported symptoms for at least6 months.

On examination, with the patient in a gown, there was atrophy in the right arm. Fasciculations werenoted in the right biceps brachii and left deltoid. The patient was not aware of these fasciculations.The patient had reduced strength in right arm muscles and subtle weakness in the left arm muscles.There was no sensory loss. Reflexes were brisk in both arms, and the patient had a prominent jaw jerk.

On EMG, the right deltoid, right biceps, and right first dorsal interosseous had increased insertionalactivity with fibrillations. In the right biceps, frequent fasciculations were recorded.

Comment. This case demonstrates several features of ALS. One, there is often an insidious onset, anda family member may notice symptoms before the patient. Second, patients will often be referred toother specialists due to the weakness. Next, patients with neuromuscular problems should always beexamined while they are wearing a gown; proximal muscle atrophy and fasciculations may not benoticed otherwise. Finally, EMG findings are often patchy, especially early in the disease; several musclesmay need to be examined for denervation and reinnervation changes.




and family members may mistake thesechanges for argumentativeness, fear, orstubbornness. The frontotemporal dys-function may be significant enough toreach the more strict criteria offrontotemporal dementia in about 15%of patients. Frontotemporal dementiadiagnosis requires neuropsychologicalassessment for diagnosis; patients withfrontotemporal dementia have moresignificant and progressive dysfunctionwith semantic loss, behavioral disorders,and executive dysfunction abnormali-ties. Symptoms of frontotemporal dys-

function typically manifest as deficits inexecutive processes: difficulty with de-cisions, trouble prioritizing concerns,and inability to weigh consequences.Rarely are there memory abnormalities.Frontotemporal dysfunction has impor-tant clinical and financial implications forpatients and their caregivers.

Pseudobulbar affect may be present ina portion of patients with ALS.Pseudobulbar affect is a condition ofdysregulation of motor output of emotion.Patients will report excessive crying orlaughing and the inability to control their

TABLE 1-2 Common Clinical Patterns of Amyotrophic Lateral Sclerosis

PatternUpper Motor NeuronInvolvement Only

Lower Motor NeuronInvolvement Only

Upper and Lower MotorNeuron Involvement

Limb onset Primary lateral sclerosis Progressive muscular atrophy Classic ALS

Bulbar onset Pseudobulbar palsy Progressive bulbar palsy Classic ALS

ALS = amyotrophic lateral sclerosis.

FIGURE 1-2 Upper motor neuron and lower motor neuron signs that are seen in addition to weakness.



responses to emotions. Pseudobulbaraffect is not to be confused with depres-sion, which is a change in the patient’smood state. Many neurodegenerativeconditions are associated with pseudo-bulbar affect; it is not unique to ALS.

Genetics and pathophysiology ofALS. ALS has traditionally been thoughtof as a sporadic disease. Even after thesuperoxide dismutase 1 (SOD1) genemutation discovery, only about 10% ofpatients could definitively point to afamily history of the disease. This con-cept has changed over the past 3 to 4years with the discovery of new genesand genetic processes that may triggerthe disease. As of 2014, two-thirds offamilial ALS and 10% of sporadic ALS canbe explained by genetics. Familial ALScan have great variability in age of onsetand disease duration. This suggests thatdisease-modifying factors play a role. Thedistinction between familial and sporadic

ALS based on family history may beartificial as new genes are discovered.

In 1993, SOD1 was the first gene tobe discovered for ALS.4 It accounts for20% of familial ALS. This gene defect has apredisposition for leading to cell death ofthe motor neuron, likely by protein accu-mulating inmotor neurons and astrocytes,causing a toxic gain of function. Familieswith SOD1 mutations have strong autoso-mal dominant penetrance, an earlier ageof onset, and death or respiratory failurewithin 1 to 2 years of onset.

A major feature of ALS is the accumula-tionof aproteinnamed transactive response(TAR) DNA binding protein 43 kDa(TDP-43).5 This protein plays multiple rolesin RNA processing.6 The gene for thisprotein is known as TARDBP, andmutations of TARDBP account for 5%of familial ALS. TARDBP-related ALS isclinically not distinguishable from ALSdue to other causes.

KEY POINTS

h Many neurodegenerativeconditions are associatedwith pseudobulbaraffect, which is notunique to ALS.

h The distinction of familialand sporadic ALS basedon family history maybecome obsolete overtime as new genes arediscovered.

FIGURE 1-3 Neuropathology of ALS. A, Atrophic anterior horns and demyelinatedcorticospinal tracts (arrow); B, transactive response DNA binding protein 43 kDa(TDP-43) cytoplasmic inclusions (arrows) in dentate granules of hippocampus;

C, ubiquitin-positive (arrow), and D, TDP-43-positive inclusions (arrow) in spinal cord motorneurons; and E, diffuse cytoplasmic TDP-43 deposition (arrow) in spinal cord motor neurons.


Reprinted with permission from Giordana MT, et al, Neurol Sci.3 B 2010 Springer-Verlag. link.springer.com/article/10.1007%2Fs10072-010-0439-6.




http://link.springer.com/article/10.1007%2Fs10072-010-0439-6


TDP-43 aggregates can even be foundin ALS patients without the mutatedform of the gene, suggesting that thisprotein may play a role in sporadic ALS(Figure 1-3). TDP-43 pathology has alsobeen linked to frontotemporal dementia(Figure 1-4). This, in addition to theclinical overlap of cognitive and behavioralchanges, raises the question of whetherALS and frontotemporal dementia aredifferent manifestations of a spectrum ofTDP-43 deposition. A certain proportionof several other neurodegenerative dis-eases (eg, Alzheimer disease, hippocam-pal sclerosis, Pick disease, Parkinsondisease, and Huntington disease) showTDP-43 immunoreactive histopathol-

ogy, giving rise to the term TDP-43proteinopathies (Case 1-2).6

Fused in sarcoma (FUS) is a proteinwith two RNA binding domains and aterminal nuclear localization signal. Nor-mally a nuclear protein, it accumulates inthe cytoplasm in ALS associated withFUS mutations.7 This similarity to TDP-43suggests the possibility of a commonmechanism of disease.8 FUS also appearsto interact with histones and play a role inthe repair of DNA damage. This role maybe important for the integrity of the motorneuron. FUS mutations account for about5% of familial ALS.

A hexanucleotide repeat expansion(GGGGCC) in the noncoding region

FIGURE 1-4 Neuropathology of frontotemporal dementia/ALS. A, Atrophy of the frontal lobes(arrow); B, transactive response DNA binding protein 43 kDa (TDP-43) cytoplasmicinclusions (arrows) in dentate granules of hippocampus; C, spongiosis involving

layer I and II of the frontal cortex (arrow); and D, ubiquitinated inclusions (arrows) in spinal cordmotor neurons.


Reprinted with permission from Giordana MT, et al, Neurol Sci.3 B 2010 Springer-Verlag. link.springer.com/article/10.1007%2Fs10072-010-0439-6.





of chromosome 9 open reading frame 72(C9orf72) can cause ALS and fronto-temporal dementia and may accountfor the largest proportion of inheritedALS (Figure 1-59).10,11 When copiesreach as few as 30, this expansion appearsto be capable of producing disease.

No protein aggregate is associated withthis mutation, and much is still beingdiscovered about this gene and proteinproduct (Figure 1-6).

Other genes that have been associ-ated with familial ALS each account fora small proportion of cases. It isestimated that 60% of individualswith familial ALS have an identifiedgenetic mutation. Given the rapiddiscovery of new mutations, pleasesee alsod.iop.kcl.ac.uk/ for an up-to-date resource.12

The genetics of ALS are of researchinterest because of the potential tohelp uncover the mechanism of celldeath in ALS. Neuronal cytoplasmicprotein aggregation and defective RNAmetabolism appear to be commonpathogenic mechanisms involved inALS and possibly in other neurodegen-erative disorders. Even though theresearch potential is significant, theclinical utility of genetic testing cur-rently is limited. (Case 1-3).

Diagnosis of ALS. ALS remains aclinical diagnosis. Focal onset of weak-ness with muscle wasting and briskreflexes that progresses and spreads

Case 1-2A 69-year-old woman presented for a follow-up appointment regarding her ALS, diagnosed 6 monthspreviously. She had lower motor neuron and upper motor neuron symptoms in three limbs. At thisappointment, her daughter reported that the patient had fallen four times in 1 month and would notuse her walker despite repeated reminders to do so. Further, the daughter had tried to discuss a livingwill and end-of-life issues, but the patient never was interested, often stating, ‘‘oh, that.’’ The patientwas very impatient during the appointment, often standing up and asking to leave. When asked abouther disease, the patient denied any symptoms, stating she could ‘‘walk all day.’’ She did not demonstratecapacity to make decisions because she could not verbally explain her condition. On examination, thepatient did not exhibit depression, hermoodwas good, andwhen asked about her safety, she laughed andstated, ‘‘I can still get around.’’

Comment. This case illustrates the difficulties associated with frontotemporal dysfunction. The patienthad difficulty understanding the seriousness of her symptoms and difficulty planning into the future.This had both immediate and long-term safety consequences. A patient without insight may continueto attempt physical activities when they lack the strength to safely do so, such as driving, climbing ladders,or walking unaided. A patient without insight or planning cannot adequately convey his or her wishesregarding end-of-life issues. Patients who do not have an advocate are at risk for both overuse and underuseof medical procedures. Family members need to be educated about frontotemporal dysfunction, and, ifthey have medical power of attorney, to be surrogate decision makers for the patient.

FIGURE 1-5 Genetics of familial ALS.

C9orf72 = chromosome 9 open reading frame;SOD1 = superoxide dismutase 1, soluble;TARDBP = transactive response DNA bindingprotein; FUS = fused in sarcoma RNA binding




over time prompts the consideration ofALS as the underlying cause. Despitebest efforts, up to 10% of ALS patientsare initially misdiagnosed.13,14

In 1994, the El Escorial criteria werepublished, summarizing a consensusstatement of the World Federation ofNeurology to facilitate accurate diagno-sis of ALS.15 The diagnosis by theEl Escorial criteria requires the pres-ence of upper motor neuron and lowermotor neuron degeneration within thesame region. There must be diseaseprogression within a region withspread to other regions of the body(Table 1-316). In addition, laboratory,electrophysiologic, or neuroimag-

ing studies must exclude other condi-tions that may explain the signs oflower motor neuron and upper motorneuron degeneration.

When applying the criteria, the bodyis divided into four regions (bulbar,cervical, thoracic, lumbosacral) withoutconsideration for right or left side. Eachregion is evaluated for either uppermotor neuron or lower motor neuronfindings. Preserved reflexes may indi-cate hyperreflexia in wasted muscles. Alist of upper motor neuron and lowermotor neuron signs in these variousregions is provided in Table 1-4.

The El Escorial criteria have four levelsof diagnostic certainty (definite, probable,

KEY POINTS

h Neuronal cytoplasmicprotein aggregationand defective RNAmetabolism appear tobe common pathogenicmechanisms involved inALS and possibly in otherneurodegenerativedisorders.

h Focal onset of weaknesswith muscle wastingand brisk reflexes thatprogresses and spreadsover time prompts theconsideration of ALS asthe underlying cause.

h The diagnosis of ALS issuspected by thepresence of uppermotor neuron andlower motor neurondegeneration within thesame region.

h Preserved reflexes mayindicate hyperreflexia inwasted muscles.

FIGURE 1-6 Pathophysiology of motor neuron degeneration.

RNA = ribonucleic acid.

Case 1-3A 50-year-old woman came in for a second opinion with regard to her diagnosis of ALS. She hadextensive lower motor neuron and upper motor neuron features in four regions of the brainstem andspinal cord. She wanted genetic testing performed. She reported that her sister died of ALS 5 yearsago, and her mother died at an early age with cognitive abnormalities and choking.

Comment. This patient may have familial ALS. She presented at a young age and had at leastone immediate family member who was diagnosed with the disease. Before testing is performed ina patient with a similar history, the patient should, ideally, meet with a genetic counselor to discussthe ethical and emotional issues surrounding the uncovering of a genetic trait. Once the patient isable to give full, informed consent, testing may be considered. For this patient, with a family memberwith possible frontotemporal dysfunction, testing for C9orf72 or TARDBP was reasonable. An FUSmutation is less likely due to its rarity, and SOD1 mutations are not associated with dementia.Genetic testing is changing: Whole genome sequencing will look for notable deviations in theentire genome (array of genes) rather than the sequential, step-by-step method currently being used.This may allow patients to be evaluated quickly for a broad array of genetic traits.



possible, and suspected) (Table 1-517).The certainty of the diagnosis dependson the number of regions that areinvolved. The diagnosis of definite ALSrequires upper motor neuron andlower motor neuron involvement ofthree out of four regions. Probable ALSshows involvement of two regions. Asingle region with a combination ofupper motor neuron and lower motor

neuron findings is considered possibleALS. If only upper motor neuron orlower motor neuron findings are pres-ent, only a suspicion for ALS is raised.

The revised El Escorial criteriaintroduced the category of laboratory-supported probable ALS in which theinvolvement of two regions is demon-strated by EMG findings rather thanclinically.16 The revised El Escorial

KEY POINT

h According to El Escorialcriteria, upper motorneuron and lowermotor neuroninvolvement in threeregions constitutesdefinite ALS.

TABLE 1-3 Summary of Revised El Escorial Criteriaa

b PresenceSigns of lower motor neuron degeneration by clinical, electrophysiologic, orneuropathologic examination

Signs of upper motor neuron degeneration by clinical examination

And

Progressive spread of signs within a region or to other regions

b AbsenceElectrophysiologic evidenceof other disease processes thatmight explain the signsof lower motor neuron and/or upper motor neuron degeneration

Neuroimaging evidence of other disease processes that might explain theobserved clinical and electrophysiologic signs

a Data from Brooks BR, et al, Amyotroph Lateral Scler Other Motor Neuron Disord.16

informahealthcare.com/doi/abs/10.1080/146608200300079536?journalCode=aml.

TABLE 1-4 Clinical Findings in Motor Neuron Disease by Region of Involvement

Motor Neuron Signs Bulbar Cervical Thoracic Lumbosacral

Lower motor neuron signs(eg, reduced tone, muscleatrophy, fasciculations,reduced muscle stretchreflexes)

Tonguefasciculationsand atrophy

Wasting of intrinsichand muscles(in particular, firstdorsal interosseousmuscle), thenarand hypothenar

Fasciculationsin back andabdominalarea

WastingFoot drop

Upper motor neuron signs(eg, spasticity, clonus, briskand spreading muscle stretchreflexes, pathologicreflexes)

Slowness oftonguemovementBrisk jaw jerk

Exaggeratedgag andyawning

Pseudobulbaraffect

Prominent snout,glabellar, andpalmomental reflex

Hoffman reflexGrasp reflex

Brisk pectoralisreflex

Loss ofsuperficialabdominalreflexes

IncreasedtoneBabinskisign

Ankle clonusCrossedadductors




http://informahealthcare.com/doi/abs/10.1080/146608200300079536?journalCode=aml

criteria are considered a gold standardand allow for a very accurate diagnosisof ALS with nearly 100% specificity.However, the sensitivity may be as lowas 57% at the time of diagnosis18

because patients often present withonly lower motor neuron or uppermotor neuron features or present withsymptoms only in one region at onset.

In 2008, the Awaji criteria wereintroduced to facilitate more accurateearly diagnosis and earlier entry into

clinical trials.19 According to thesecriteria, the presence of fasciculations ina muscle with chronic reinnervationchanges is sufficient evidence for lowermotor neuron involvement, in particularin bulbar muscles (Table 1-620). TheAwaji criteria have been shown to in-crease diagnostic sensitivity from 62.2%to 81.1% without changing specificity.20

Testing for ALS and its mimics. Nearlyevery patient with ALS asks: ‘‘Is thereanything else it could be?’’ While ALS is a

TABLE 1-5 Diagnostic Certainty Based on Revised El Escorial Criteriaa,b,c

Level of Certainty Degree of Involvement

Suspected ALS UMN signs only in one or more regions, or

LMN signs only in one or more regions

Possible ALS UMN and LMN signs in one region, or

UMN signs in at least two regions, or

UMN and LMN signs in two regions without

UMN signs rostral to the LMN signs

Probable ALS UMN and LMN signs in two regions with someUMN signs rostral to the LMN signs

Laboratory-supported probable ALS UMN signs in one or more regions with LMNinvolvement by EMG in at least two regions

Definite ALS UMN and LMN signs in three regions

Laboratory-supported familial ALS UMN and LMN signs in one region andconfirmatory genetic testing

ALS = amyotrophic lateral sclerosis; UMN = upper motor neuron; LMN = lower motor neuron; EMG = electromyography.a Data from Caravalho M, et al, Clin Neurophysiol.17 www.clinph-journal.com/article/S1388-2457(07)00643-8/abstract.b Cervical and lumbar region requires involvement of two muscles innervated by different nerve roots.c Bulbar and thoracic region requires involvement of only one muscle per region.

TABLE 1-6 Criteria for Detection of Neurogenic Changes on Needle Electromyographya

Revised El Escorial Criteria Awaji Criteria

Evidence of lower motor neuron loss Rapid firing of a reduced numberof motor units

Same

Evidence of reinnervation Large amplitude, long duration,polyphasic motor unit potentials

Same

Evidence for ongoing denervation Fibrillations and positive waves Fibrillations and positive wavesor fasciculations in the presenceof chronic neurogenic changes

a Data from Costa J, Arch Neurol.18



http://www.clinph-journal.com/article/S1388-2457(07)00643-8/abstract

clinical diagnosis, testing is helpful toexclude mimics and assess for othercauses of motor neuron involvement.

Nerve conduction studies and EMGcan exclude mimics such as poly-radiculopathy, multifocal motor neuro-pathy, and mononeuritis multiplex.

MRI of the brain and spinal cord arehelpful to exclude alternative explana-tions of symptoms. Cervical stenosiswith cervical myelopathy can producelower motor neuron symptoms at thelevel of cord compression and uppermotor neuron symptoms below thelevel. Any patient with this presentation(lower motor neuron symptoms inregions above regions with uppermotor neuron symptoms) should haveneuroimaging to exclude a compressivecervical myelopathy. Any patient withbulbar involvement, by definition, hassymptoms above the cervical leveland is, therefore, not likely to have acervical myelopathy.

Conventional neuroimaging techniquesdo not demonstrate gross structural ner-vous system changes in ALS.21 Advancedimaging techniques, such as diffusiontensor imaging and proton magneticresonance spectroscopy, show promise,but are not currently of clinical utility.

Other mimics of ALS are exceedinglyrare. Table 1-7 lists laboratory tests usedto exclude conditions mimicking ALS.Unfortunately, in a patient with a classicpresentation, it is more likely to be ALSthan a mimic.

The El Escorial criteria help in rulingout mimics. If there are atypical fea-tures or lack of symptom progressionthat spreads into other anatomic re-gions, then reassessment of the diag-nosis is recommended (Figure 1-722).

Management of ALS. Patients withALS go through various emotional andclinical stages (Table 1-823). Patients mustcome to terms with the diagnosis, copewith functional decline and disability, and

KEY POINTS

h Any patient with bulbarinvolvement, bydefinition, hassymptoms above thecervical level and is,therefore, not likely tohave a cervicalmyelopathy.

h The El Escorial criteriahelp in ruling outmimics of ALS. If thereare atypical features orlack of symptom pro-gression that spreadsinto other anatomic re-gions, thenreassessment of thediagnosis isrecommended.

TABLE 1-7 Laboratory Testing for Motor Neuron Disease

Clinical Presentation Disease Testing

Upper motor neuronpredominant

Tropical spasticparaparesis

Human T-cell lymphotropicvirus 1 serology

Copper or vitamin B12

deficiency myelopathyCopper and zinc,vitamin B12 levels

Lower motor neuronpredominant

Multifocal motorneuropathy

GM1 antibodies

Spinal muscularatrophy

Genetic testing, musclebiopsy

West Nile virus Serology (serum, CSF)

Polio Serology (serum, CSF),stool antigen

Hypothyroidism Thyroid-stimulating hormone,free T4

Hyperparathyroidism Ionized calcium, intactparathyroid hormone

Lyme disease Serology (serum, CSF)

Paraneoplastic Antibody panel (serum, CSF)

CSF = cerebrospinal fluid.




make end-of-life plans, including forhospice care and death. These phasesof the disease require a close collabora-tion between the patient, his or hercaregivers, the physician, and the ALScare team, if present. The patient andcaregivers may go through these phasesdifferently and have differing needs.Cognitive impairment may decreaseacceptance of care interventions andimpair decision making.

The complexity and progressive natureof ALS often necessitates multidisciplinarycare, which leads to better outcomes andless utilization of emergency care.Prolonged survival and improved qualityof life are important benefits of such team-based ALS treatment.24Y26

Neurologists have the important taskof making the diagnosis and deliveringthe news. While ALS is not curable, everysymptom requires treatment, and neurol-ogists play a key role in symptommanagement. Respiratory and nutritionalmanagement are important for quality oflife and can alter the disease course.Disease-specific advanced directives thatfocus on the expected problems in ALSare available27 and should be regularlyrevisited and revised. Neurologists alsoplay a crucial role in sharing informationabout ongoing research and carrying outclinical trials. All ALS patients should beencouraged to participate in the NationalALS Registry at wwwn.cdc.gov/als/.

Disease-modifying drug treat-ment. The only US Food and DrugAdministrationYapproved drug for thetreatment of ALS is riluzole, which blocksthe release of glutamate and has beenavailable to patients since 1996. The drugshould be discussed with patients andmay be offered early in the course;benefits are not clear in advanced stagesof the disease.28,29 A survival advantageof 2 to 3 months has been shown.30Y32

Riluzole is generally well tolerated, butgastrointestinal side effects or fatiguemay require discontinuation. Monitoring

of liver function tests 1 month afterinitiation and at 3-month intervalsthereafter is recommended; treat-ment should be discontinued if the

FIGURE 1-7 Algorithm of diagnosis of ALS.

ALS = amyotrophic lateral sclerosis; LMN = lowermotor neuron; EMG = electromyography;UMN = upper motor neuron.

Adapted with permission from Bromberg M, Neurologist.22

B 1999 Lippincott Williams & Wilkins. journals. lww.com/theneurologist/toc/1999/03000.



http://neuromuscular.wustl.edu

http://lww.com/theneurologist/toc/1999/03000

http://lww.com/theneurologist/toc/1999/03000

alanine aminotransferase level is fivetimes the upper limit of normal. Arare complication is hypersensitivitypneumonitis.33 Despite many at-tempts at identifying additional drugs,and an exponential increase in clinicalresearch studies, no further agentshave risen to the level of significancethus far.

Symptomatic treatment. The symp-toms of ALS relate to the decline instrength of muscles of the limbs,

swallowing, speaking, and breathing. Inaddition, pseudobulbar affect and cog-nitive changes are common. Table 1-9provides a summary of interventionsthat can be used to treat the symptomsof ALS. The following interventionshave been shown to have benefit: carein a multidisciplinary setting, the use ofriluzole, noninvasive ventilation, treat-ment of pseudobulbar affect withdextromethorphan/quinidine, and nu-tritional support. Other interventions

KEY POINTS

h Cognitive impairmentmay decreaseacceptance of careinterventions andimpair decision-making.

h All ALS patients shouldbe encouraged toparticipate in theNational ALS Registryat wwwn.cdc.gov/als/.

TABLE 1-8 Staging of Amyotrophic Lateral Sclerosisa

Stage Clinical Involvement

Stage 1 Symptom onset (involvement of first region)

Stage 2A Diagnosis

Stage 2B Involvement of a second region

Stage 3 Involvement of a third region

Stage 4A Need for gastrostomy

Stage 4B Need for respiratory support (noninvasive ventilation)a Adapted with permission from Roche JC, et al, Brain,23 with a proposed staging system based onclinical progression. B 2012 The Author. brain.oxfordjournals.org/content/135/3/847.full.

TABLE 1-9 Summary of Interventions in Amyotrophic Lateral Sclerosis

SymptomNonpharmacologicIntervention Pharmacologic Interventiona Practice Tips

Air hunger Meditation,mindfulness-basedbreathing exercises

Lorazepam 1Y3 mg 3 times/d

Morphine sulfate tablets orelixir (20 mg/mL) 5Y10 mgevery 8 hours as neededor morphine subcutaneouspump at 1Y5 mg/hour

Consider using a fanKeep room temperature low

Elevate head of bed

Anxiety Psychologicalsupport, counseling

Selective serotonin reuptakeinhibitors (SSRIs) (see SSRI dosinglisted in depression section)

Lorazepam 0.5Y1 mg 3 times/das needed

Cramps andfasciculations

Positioning, stretching,massage, pool therapy

Magnesium oxide 400Y600 mg/d

Vitamin E 400 IU 2Y3 times/d

Carbamazepine 200 mg 2 times/d

Phenytoin 100 mg 3Y4 times/d

Quinine sulfate is no longerapproved for leg cramps in theUnited States; othermedicationsare under investigation(mexiletine and levetiracetam)

Continued on next page





http://brain.oxfordjournals.org/content/135/3/847.full

TABLE 1-9 Summary of Interventions in Amyotrophic Lateral Sclerosis (Continued)


Constipation Review fluid andfiber intake

Begin with:Polyethylene glycol 8.5Y17 g/dor every other day as needed

Sennosides 15 mg, start 1 tab2 times/d and increase to 3Y4 tabs2 times/d as needed

Bulk fiber laxative 1Y2 Tbsp/d as needed(take with 8Y10 oz of water)

Progress to:Bisacodyl suppository 10 mg/d perrectum as needed (if good stoolconsistency but unable to have a bowelmovement)

Magnesium citrate1.745 g/30 mL, 150Y300 mL/d

Adjust tube feedingformula if applicable

Depression Psychologicalsupport, counseling

SSRIsSertraline 50Y200 mg/dParoxetine immediate release

tablets 10Y50 mg/dParoxetine controlled release

tablets 12.5Y62.5 mg/dCitalopram 20Y40 mg/dEscitalopram 10Y20 mg/dFluoxetine 10Y80 mg/d

Serotonin norepinephrinereuptake inhibitorVenlafaxine extended release

tablets 37.5Y225 mg/d

Norepinephrine dopaminereuptake inhibitorBupropion hydrochloridesustained release tablets300Y400 mg/d in 2 divided doses

Bupropion hydrochloride extendedrelease tablets 300Y450 mg/d

Norepinephrine serotonin modulatorMirtazapine 15Y45 mg/d at bedtime

Select appropriateantidepressant dependingon side effect profile

Dry mouthand thicksecretions/phlegm

Assisted coughinsufflator-exsufflatorand chest walloscillation, reducedintake of dairy

Guaifenesin tablets, capsules,oral solution 200Y400 mgevery 4 hours as needed

Guaifenesin extended releasecapsules 600Y1200 mg every12 hours with maximum of 2400 mg/d

Carbocisteineb 750 mg 3 times/d andreduce to 750 mg 2 times/d whensatisfactory response is obtained

Review fluid intakeConsider humidifier






Early satiety Metoclopramide 5Y10 mg 30 minbefore meals and at bedtime

Encourage frequent,smaller meals

Excessiveyawning

Baclofen 10Y20 mg 3Y4 times/d

Fatigue Energy conservationtechniques

Amantadine 100 mg 2 times/d

Methylphenidate 5Y10 mg 2 times/d

Amphetamine and dextroamphetaminecombination tablet 5Y10 mg every4Y5 hours

Pyridostigmine 60 mg 3 times/d

Carefully screen fornocturnal hypoventilation

Insomnia Sleep hygiene Amitriptyline 10Y75 mg at bedtime

Trazodone 50 mg at bedtime

Chloral hydrate 500 mg at bedtime

Diphenhydramine 25Y50 mg at bedtime

Lorazepam 0.5Y2.5 mg at bedtime

Carefully screen forrespiratory failure and painRule out advanced ordelayed sleep phasesyndromes

Jaw quiveringor clenching

Stretching Clonazepam 0.5 mg 3 times/d as needed

Lorazepam 0.5 mg 3Y4 times/d as needed

Diazepam 2.5Y5 mg 3 times/d as needed

Botulinum toxin injection

Laryngospasm Lorazepam (if frequent) 0.5Y2 mg2Y3 times/d as needed

Proton pump inhibitorOmeprazole 40 mg/d

Educate on self-limitingnature and identify triggersTeach breathing outagainst the vocal folds

Nasalcongestion/postnasal drip

Pseudoephedrine 30Y60 mg 3 times/d

Diphenhydramine 25Y50 mg 2 times/d

Budesonide nasal spray 2 sprays 2 times/d

Ipratropium bromide nasal spray 0.03Y0.06%solution, 2 sprays in each nostril 3 times/d

Rule out allergies

Pain Positioning, stretching,pool therapy, massage,acupuncture, meditation

Acetaminophen 325Y650 mg 4 times/d

Nonsteroidal anti-inflammatory drugs

Morphine sulfate 5Y10 mg 2 times/d

Other narcotics

Initiate bowel regimenwith use of narcotics

Pseudobulbaraffect

Dextromethorphan 20 mg/quinidine10 mg 2 times/d

SSRIParoxetine 40 mg/d (or other SSRI asdocumented in depression section)

c

Consider using SSRI ifpatient has concomitantdepression; consider usingamitriptyline if patienthas concomitant sialorrheaor insomnia





are based on expert opinion and havefew data to support their use. Refer tothe AAN guidelines regarding best evi-dence for management.34Y36 Please alsorefer to the February 2009 article ‘‘ALSUpdate: Signs of Progress, Reasons forHope’’ in the issue onMyasthenic Disorders and ALS for a fulloverviewofALS symptomaticmanagement.

Multifocal Motor NeuropathyMultifocal motor neuropathy (MMN) isarguably one of the most importantentities to exclude when diagnosing apatient with symptoms consistent withALS. MMN is a lower motor neurondisease that affects one limb before

progressing to other limbs. Patients havesevere focal weakness, atrophy, andfasciculations. Weakness in MMN is outof proportion to the degree of atrophy.However, an important exclusion fact isthat patients with MMN do not haveupper motor neuron symptoms. MMN isa demyelinating disease of the motornerve, in which there is a focal conduc-tion block of the motor axon. Thisdisease is excluded by nerve conductionstudies in which motor nerves arecarefully assessed for demyelination andproximal conduction block.37 Laboratorytesting for GM-1 antibodies are helpful,but the sensitivity of this antibody is nothigh (30% of patients with MMN). For



Sialorrhea Home suctiondevice

Atropine sulfate ophthalmicdrops (1Y2 drops sublingual every4Y6 hours) or tablets (1Y2 mg orallyevery 6 hours)

Glycopyrrolate 0.1Y0.2 mg 3 times/d

Scopolamine transdermal patch1Y2 patches every 72 hours

Amitriptyline 10Y150 mg at bedtime

Hyoscyamine 0.125Y0.25 mg every 4 hours


Radiotherapy per radiationoncology assessment

Spasticity Stretching, positioning,pool therapy, massage

Baclofen 40Y80 mg/d in 3Y4 divided doses

Tizanidine 6Y24 mg/d in 3 divided doses

BenzodiazepinesDiazepam 2Y10 mg 3Y4 times/dClonazepam 1Y2 mg 2Y3 times/d

Dantrolene 100 mg 2Y3 times/d (carefullymonitor liver enzymes if also on riluzole)


Urinaryurgency andfrequency

Toileting schedule Oxybutynin extended release tablets5Y10 mg/d up to 30 mg/d

Rule out urinary tractinfection

a All medications are taken orally unless otherwise indicated.b Medication not available in the United States.c Tricyclic antidepressants and SSRIs can be used off-label to manage pseudobulbar affect; dextromethorphan/quinidine is the only US Foodand Drug AdministrationYapproved treatment.

KEY POINTh Weakness in multifocal

motor neuropathy isout of proportion tothe degree of atrophy.



further discussion of multifocal motorneuropathy, refer to the article ‘‘Ac-quired Immune Demyelinating Neurop-athies’’ by Mazen M. Dimachkie, MD,FAAN, FANA, and David S. Saperstein,MD, in this issue of .

OTHERMOTORNEURONDISEASESSpinal Muscular AtrophySpinal muscular atrophy (SMA) is a geneticdisease in which there is autosomalrecessive loss of the SMN1 gene onchromosome 5q13.2. In the UnitedStates, the carrier frequency is 1/50.2,38

The classic phenotypes of SMA aretype I (Werdnig-Hoffman disease),type II, and type III (Kugelberg-Welanderdisease). Type IV is known as adult-onsetSMA. The shorthand description of thisdisease is: ‘‘Type I, never sit; type II,never walk; type III, never run.’’ Al-though ignoring the full spectrum ofpatient presentations, this may be auseful way to categorize disease severity.Type IV patients have variable presenta-tions and may even be able to playsports into their teenage years beforeweakness manifests and limits function.

Type I patients typically manifestimmediately after birth or in the

neonatal period. Infants will haverespiratory distress and poor feeding;however, they are noted to be alertwith intact extraocular movements. Inthe past, EMG or muscle biopsy was theinitial workup; currently, the appropri-ate first step is genetic testing for theSMN1 gene deletion. Given the pro-found loss of motor neurons withsevere paralysis, these patients tend tohave early mortality.

The muscle biopsy of SMA is worthrecognizing because it is the classicexample of grouped atrophy. There isdropout of axons before birth and theremaining motor axons then innervateadjacent muscle fibers, causing fiber-type grouping (Figure 1-839).

Table 1-1040 presents the spectrumof phenotypic manifestations in spinalmuscular atrophy. Type II patients sitbut never walk and the disease man-ifests within the first 18 months of life.Again, when the disease is suspected,genetic testing is the appropriate firststep. These patients will be wheelchairdependent. The majority of patientslive into young adulthood, but respi-ratory complications of restrictive lungdisease are a major cause of earlymorbidity and mortality. Restrictivelung disease is due to a combinationof diaphragmatic and accessorymuscle weakness and scoliosis (whichlimits lung capacity).

Type III patients walk; their weak-ness is typically proximal more thandistal, and hip and shoulder girdles areprominently affected. Rising from achair may be very difficult. Type IVpatients do not present until adulthood.

The SMN1 protein product is impor-tant in the formation of spliceosomes.Spliceosomes are important agents inthe processing of pre-mRNA into mRNA.

Homozygous recessive gene deletionsare lethal to motor neurons.41 It isuncertain why the motor neuron is sospecifically vulnerable to this gene defect,

FIGURE 1-8 Spinal muscular atrophy muscle biopsy withgrouped atrophy.

Reprinted with permission from Pestronk A. WashingtonUniversity.39 neuromuscular.wustl.edu.





because this gene and protein productare ubiquitous in all cells. The phenotypeis predicated by the presence of asecond gene, SMN2, also located onchromosome 5. More copies of SMN2modify the clinical presentation of SMA.Humans have variable numbers ofSMN2 genes: some patients have noSMN2 genes, some have as many asfour. SMN2 makes a less robust proteinproduct, but it is enough to havea favorable impact on motor neuronsurvival and function.

SMN is a candidate for gene therapy:alternative gene splicing can removethe most commonly affected region in

the SMN1 gene (exon 7), which leadsto a less robust, but functional, proteinproduct. This is being evaluated to tryto aid patients with SMA.

Spinal Bulbar Muscular Atrophy(Kennedy Disease)Spinal bulbar muscular atrophy, orKennedy disease, is an adult-onset he-reditary X-linked motor neuron disease.Males are always affected, while femalecarriers can manifest with less severesymptoms. Spinal bulbar muscular atro-phy manifests in the fourth to seventhdecades for most patients. The diseaseis caused by an unstable trinucleotide

TABLE 1-10 Spectrum of Phenotypic Manifestations in Proximal Spinal Muscular Atrophya

Spinal MuscularAtrophy (SMA)Type

TypicalAge of Onset

Typical LifeSpan Also Called

Clinical Characteristicsand MaximumMilestones Achieved

0 Prenatal G6 months SMA-arthrogryposismultiplex congenitatype

Congenital hypotonia,weakness, respiratory failure,and proximal joint contracturesUnable to breathe unsupported

I Birth to 6 months About 32%survivalprobability92 years

Werdnig-Hoffmanndisease

Infantile onset of generalizedhypotonia, weakness, impairedbulbar function, and respiratoryinsufficiencyUnable to sit unsupported

II 6 to 12 months About 70%survival toadulthood

SMA, Dubowitz type Onset of limb weakness asinfants or toddlersProgressive weakness, respiratoryinsufficiency, scoliosis, and jointcontractures in childhoodAble to sit independently

IIIa After 12 months Normal Kugelberg-Welanderdisease

Onset of proximal muscleweakness in childhood

IIIb After 3 years Able to walk independently,although 50% of patientswith type IIIa lose independentambulation by 12 years of age

IV Adulthood Normal Onset of proximal leg weaknessin adulthoodAble to walk independently

a Reprinted with permission from Jones HR, et al, eds, Elsevier.40 B 2013 Elsevier.



CAG repeat on the X chromosome inthe androgen-receptor gene. Patientswith repeat numbers greater than 40are affected. The affected proteinproduct, the androgen receptor, canlead to degeneration of motor neurons.In addition, there are endocrinologicchanges due to androgen insensitivitythat manifest as enlargement of malebreasts (gynecomastia), low spermcount, impotence, or infertility.

In spinal bulbar muscular atrophy,bulbar onset is most common; perioraland tongue fasciculations are typical initialsymptoms. Male patients then developproximal weakness, fasciculations, andatrophy in proximal muscle groups.Many patients eventually use wheelchairsdue to hip girdle weakness (Case 1-4).42

In spinal bulbar muscular atrophy,the endocrine system is affected andpatients are more likely to developdiabetes mellitus.

The evaluation of a patient withsuspected spinal bulbar muscular atro-phy includes laboratory, EMG, andgenetic testing. The creatine kinase(CK) will be elevated, occasionally sig-

nificantly. Nerve conduction studies willshow both motor and sensory nerveconduction abnormalities (despite min-imal sensory findings on patient exam-ination). EMG will show acute andchronic denervation. Genetic testing isdone to evaluate for a CAG expansionon the X chromosome; this is confir-matory. Despite our understanding ofthe genetic basis for spinal bulbarmuscular atrophy, there are no knowntreatments at this time. Testosteronehas been tried without success.42

Spinal bulbar muscular atrophy hasmany features in common with ALS.However, the temporal progression ofspinal bulbar muscular atrophy is overmany years and with a lesser degree ofdisability. There may be a family historyof an X-linked lower motor neuronillness. Clinically, in spinal bulbar mus-cular atrophy, tongue and perioralfasciculations occur early and are prom-inent, but the dysphagia is proportion-ally less severe. Gynecomastia is onlyseen in spinal bulbar muscular atrophy,and not ALS. Genetic testing for thetrinucleotide repeat is conclusive.

KEY POINT

h Spinal bulbar muscularatrophy patients haveprominent tongue andperioral fasciculations.

Case 1-4A 55-year-old man presented for a neurologic consultation for an evaluation of difficulty swallowing.For several years, he had noticed choking on liquids and now noticed choking on solid foods.During the history, he reported that he fell occasionally. Examination showed tongue atrophywith fasciculations and mild perioral facial weakness. Motor examination showed mild (4+/5)weakness in his proximal hip flexors and ankle dorsiflexors bilaterally. Reflexes were decreased diffusely.Fasciculations were noted in proximal muscles of the shoulder and hip girdle. Gynecomastia wasnoted on chest wall examination. EMG showed rare fasciculations with insertional activity andlargeYduration polyphasic motor units with decreased recruitment (a chronic neurogenic pattern).

A more detailed family history was obtained. The patient recalled that his mother’s brother haddifficulty with gait and eventually used a wheelchair for mobility. With this information, genetictesting was performed for the CAG repeat expansion on the X chromosome associated with theandrogen-receptor gene.

Comment. This case illustrates the difficulties in distinguishing motor neuron diseases. Many of thispatient’s clinical characteristics (eg, age, choking, falling, fasciculations) were suggestive of ALS. However,the patient reported several years of symptoms, which is atypical for ALS. His EMG showed only milddenervation and reinnervation. Spinal bulbar muscular atrophy (Kennedy disease) is rare, but shouldbe considered in any male patient who reports years of lower motor neuron symptoms.




Monomelic Amyotrophy(Benign Focal Amyotrophy)Monomelic amyotrophy is, as thename implies, a focal loss of motorneurons that does not spread to otherregions. This syndrome has othernames, including benign focalamyotrophy, juvenile segmental muscu-lar atrophy, and Hirayama disease.

This disease is rare and most ofteninvolves a unilateral cervical spine region,but it may occur bilaterally. Typically, theonset is in the teenage years: patientsmay notice several years of slow progres-sion and then stability. Males are moreoften affected.

Nerve conduction studies and EMGwill reveal a lower motor neuron picturein the affected upper limbs only. Otherlimbs should be normal for this diagno-sis. Some authors have implicated focalintermittent compression of the spinalcord during late adolescent growth asthe etiology.43Y45

There are no specific tests formonomelic amyotrophy; therefore, ini-tially, this disease may be difficult todistinguish from early ALS. Flexion/extension MRI may show anterior corddisplacement and atrophy in the cervi-cal region. Over time, monomelicamyotrophy will not progress and noupper motor neuron features manifest.The presence of conduction blockshould initiate an evaluation for MMNrather than monomelic amyotrophy.

PoliomyelitisPoliomyelitis is infection of the spinalcord (myelitis) by the polio virus. Thepolio virus is in the genus Enterovirusand is an RNA virus transmitted by oral-fecal contamination.46 This virus hasstrong, trophic predilection for the spinalcord, specifically the anterior horn cells.In the prevaccine era, polio virus wasendemic worldwide, and infectionsspiked in the summer months. Mostcases were asymptomatic or mild, but a

significant percentage of affected pa-tients, often children, developed acuteflaccid paralysis due to myelitis. Thepolio vaccine was developed in 1955,leading to the end of this illness in theUnited States.

The myelitis and subsequent anteriorhorn cell death could be regional (unilat-eral or bilateral limbs), or extensive,involving even the upper cervical cordand respiratory functioning. After theinitial infection and paralysis, thosepatients who survived experienced aslow improvement in strength, due toreinnervation of motor units fromremaining motor neurons. However, overtheir lifetime, these patients may experi-ence a slow, subacute return of weakness,likely due to premature aging of theremaining motor neurons. This has oftenbeen called the ‘‘post-polio syndrome.’’47

West Nile VirusWest Nile virus is an infectious virus of theFlavivirus family, transmitted by a mosqui-to vector. Most patients infected with thisvirus have a self-limited viral illness withfever, chills, and respiratory symptoms.46

However, the virus does exhibitneurotrophic properties with a predilec-tion for the motor neuron.48 A smallpercentage of those infected with WestNile virus (5% or so) will have involve-ment of the motor neurons.48 Thesepatients develop an acute, regional, flaccidparalysis; occasionally, there is concurrentsensory involvement. The virus may alsoinfect the cerebrum, causing an enceph-alopathy. EMG will not demonstratedenervation changes for 3 to 4 weeks.

Treatment is supportive: intensive careunit monitoring, fluids, and fever manage-ment are performed, but will not stop thedestruction of the motor neurons if theyare infected. Formore information, refer tothe article ‘‘Infectious Neuropathies’’ byMichael K. Hehir II, MD, and Eric L.Logigian, MD, FAAN, in this issue of

.

KEY POINT

h There are no specifictests for monomelicamyotrophy; therefore,initially, this diseasemay be difficult todistinguish from focalALS. Over timemonomelic amyotrophywill not progress andno upper motor neuronfeatures manifest.



CONCLUSIONMotor neuron diseases are a heteroge-neous group of disorders which includehereditary, idiopathic, or acquiredcauses. Damage to the lower motorneuron produces weakness, hypotonia,muscle atrophy, and fasciculations.

Treatment is dependent upon theetiology, but motor neurons cannot berepaired and management is often sup-portive. ALS, the most common motorneuron disease, is best approached withmultidisciplinary care: treating specificsymptoms and focusing on quality of life.

REFERENCES1. Saladin K. Anatomy & physiology: the unity of

form and function. Dubuque, IA: McGraw-Hill,2010.

2. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK1450/. Accessed June 3, 2014.

3. Giordana MT, Ferrero P, Grifoni S, et al.Dementia and cognitive impairment inamyotrophic lateral sclerosis: a review.Neurol Sci 2011;32(1):9Y16.

4. Rosen DR, Siddique T, Patterson D, et al.Mutations in Cu/Zn superoxide dismutase geneare associated with familial amyotrophiclateral sclerosis. Nature 1993;362(6415):59Y62.

5. Neumann M, Sampathu DM, Kwong LK, et al.Ubiquitinated TDP-43 in frontotemporal lobardegeneration and amyotrophic lateralsclerosis. Science 2006;314(5796):130Y133.

6. Warraich ST, Yang S, Nicholson GA, Blair IP.TDP-43: a DNA and RNA binding protein withroles in neurodegenerative diseases. Int JBiochem Cell Biol 2010;42(10):1606Y1609.

7. Kwiatkowski TJ Jr, Bosco DA, Leclerc AL,et al. Mutations in the FUS/TLS gene onchromosome 16 cause familial amyotrophiclateral sclerosis. Science 2009;323(5918):1205Y1208.

8. Vance C, Rogelj B, Hortobagyi T, et al.Mutations in FUS, an RNA processing protein,cause familial amyotrophic lateral sclerosistype 6. Science 2009;323(5918):1208Y1211.

9. Genetics Home Reference. ghr.nlm.nih.gov/condition/amyotrophic-lateral-sclerosis.Accessed June 3, 2014.

10. Renton AE, Majounie E, Waite A, et al. Ahexanucleotide repeat expansion in C9ORF72is the cause of chromosome 9p21-linkedALS-FTD. Neuron 2011;72(2):257Y268.

11. DeJesus-Hernandez M, Mackenzie IR, Boeve BF,et al. Expanded GGGGCC hexanucleotiderepeat in noncoding region of C9ORF72 causeschromosome 9p-linked FTD and ALS. Neuron2011;72(2):245Y256.

12. ALSoD. ALS Online Genetics Database.alsod.iop.kcl.ac.uk. Accessed June 3, 2014.

13. Ludolph AC, Knirsch U. Problems and pitfallsin the diagnosis of ALS. J Neurol Sci 1999;165(suppl 1):S14YS20.

14. Chio A. Risk factors in the early diagnosis ofALS: European epidemiological studies.Amyotroph Lateral Scler Other MotorNeuron Disord 2000;1(suppl 1):S13YS18.

15. Brooks BR. El Escorial World Federation ofNeurology criteria for the diagnosis ofamyotrophic lateral sclerosis. Subcommittee onMotor Neuron Diseases/Amyotrophic LateralSclerosis of the World Federation of NeurologyResearch Group on Neuromuscular Diseasesand the El Escorial ‘‘Clinical limits ofamyotrophic lateral sclerosis’’ workshopcontributors. J Neurol Sci 1994;124(suppl):96Y107.

16. Brooks BR, Miller RG, Swash M, et al. El Escorialrevisited: revised criteria for the diagnosis ofamyotrophic lateral sclerosis. AmyotrophLateral Scler Other Motor Neuron Disord2000;1(5):293Y299.

17. Caravalho M, Dengler R, Eisen A, et al.Electrodiagnostic criteria for diagnosis of ALS.Clin Neurophysiol 2008;119(3):497Y503.

18. Makki AA, Benatar M. The electromyographicdiagnosis of amyotrophic lateral sclerosis: doesthe evidence support the El Escorial criteria?Muscle Nerve 2007;35(5):614Y619.

19. Carvalho MD, Swash M. Awaji diagnosticalgorithm increases sensitivity of El Escorialcriteria for ALS diagnosis. Amyotroph LateralScler 2009;10(1):53Y57.

20. Costa J, Swash M, de Carvalho M. Awajicriteria for the diagnosis of amyotrophiclateral sclerosis: a systematic review. ArchNeurol 2012;69(11):1410Y1416.

21. Foerster BR, Welsh RC, Feldman EL. 25 yearsof neuroimaging in amyotrophic lateralsclerosis. Nat Rev Neurol 2013;9(9):513Y524.

22. Bromberg M. Accelerating the diagnosis ofamyotrophic lateral sclerosis. Neurologist1999;5(2):63Y74.

23. Roche JC, Rojas-Garcia R, Scott KM, et al. Aproposed staging system for amyotrophiclateral sclerosis. Brain 2012;135(pt 3):847Y852.




http://www.ncbi.nlm.nih.gov/books/NBK1450/

http://www.ncbi.nlm.nih.gov/books/NBK1450/

http://ghr.nlm.nih.gov/condition/amyotrophic-lateral-sclerosis

http://ghr.nlm.nih.gov/condition/amyotrophic-lateral-sclerosis

http://alsod.iop.kcl.ac.uk

24. Traynor BJ, Alexander M, Corr B, et al. Effectof a multidisciplinary amyotrophic lateralsclerosis (ALS) clinic on ALS survival: apopulation based study, 1996Y2000.J Neurol Neurosurg Psychiatry 2003;74(9):1258Y1261.

25. Chio A, Bottacchi E, Buffa C, et al. Positiveeffects of tertiary centres for amyotrophiclateral sclerosis on outcome and use ofhospital facilities. J Neurol NeurosurgPsychiatry 2006;77(8):948Y950.

26. Van den Berg JP, Kalmijn S, Lindeman E, et al.Multidisciplinary ALS care improves quality oflife in patients with ALS. Neurology 2005;65(8):1264Y1267.

27. Benditt JO, Smith TS, Tonelli MR. Empoweringthe individual with ALS at the end-of-life:disease-specific advance care planning. MuscleNerve 2001;24(12):1706Y1709.

28. Traynor BJ, Alexander M, Corr B, et al. Anoutcome study of riluzole in amyotrophiclateral sclerosisVa population-based study inIreland, 1996Y2000. J Neurol 2003;250(4):473Y479.

29. Zoccolella S, Beghi E, Palagano G, et al.Riluzole and amyotrophic lateral sclerosissurvival: a population-based study in southernItaly. Eur J Neurol 2007;14(3):262Y268.

30. Miller RG, Mitchell JD, Moore DH. Riluzolefor amyotrophic lateral sclerosis (ALS)/motorneuron disease (MND). Cochrane DatabaseSyst Rev 2012;3:CD001447.

31. Bensimon G, Lacomblez L, Meininger V. Acontrolled trial of riluzole in amyotrophiclateral sclerosis. ALS/Riluzole Study Group.N Engl J Med 1994;330(9):585Y591.

32. Lacomblez L, Bensimon G, Leigh PN, et al.Dose-ranging study of riluzole inamyotrophic lateral sclerosis. AmyotrophicLateral Sclerosis/Riluzole Study Group II.Lancet 1996;347(9013):1425Y1431.

33. Cassiman D, Thomeer M, Verbeken E, et al.Hypersensitivity pneumonitis possibly causedby riluzole therapy in ALS. Neurology2003;61(8):1150Y1151.

34. Miller RG, Rosenberg JA, Gelinas DF, et al.Practice parameter: the care of the patientwith amyotrophic lateral sclerosis (anevidence-based review): report of theQuality Standards Subcommittee of theAmerican Academy of Neurology: ALSPractice Parameters Task Force. Neurology1999;52(7):1311Y1323.

35. Miller RG, Jackson CE, Kasarskis EJ, et al.Practice parameter update: the care of thepatient with amyotrophic lateral sclerosis:

multidisciplinary care, symptom management,and cognitive/behavioral impairment (anevidence-based review): report of the QualityStandards Subcommittee of the AmericanAcademy of Neurology. Neurology 2009;73(15):1227Y1233.

36. Miller RG, Jackson CE, Kasarskis EJ, et al.Practice parameter update: the care of thepatient with amyotrophic lateral sclerosis:drug, nutritional, and respiratorytherapies (an evidence-based review):report of the Quality Standards Subcommitteeof the American Academy of Neurology.Neurology 2009;73(15):1218Y1226.

37. Dimachkie MM, Barohn RJ, Katz J.Multifocal motor neuropathy, multifocalacquired demyelinating sensory and motorneuropathy, and other chronic acquireddemyelinating polyneuropathy variants.Neurol Clin 2013;31(2):533Y555.

38. Prior TW. Professional Practice and GuidelinesCommittee. Carrier screening for spinalmuscularatrophy. Genet Med 2008;10(11):840Y842.

39. PestronkA.Washington University NeuromuscularDisease Center. neuromuscular.wustl.edu.Accessed July 3, 2014.

40. Jones HR, Burns TM, Aminoff MJ, Pomeroy SL,eds. The Netter collection of medicalillustrations, nervous system: spinal cord andperipheral nervous system. 2nd ed.Philadelphia, PA: Elsevier, 2013.

41. Markowitz JA, Singh P, Darras BT. Spinalmuscular atrophy: a clinical and researchupdate. Pediatr Neurol 2012;46(1):1Y12.

42. Finsterer J. Perspectives of Kennedy’s disease.J Neurol Sci 2010;298(1Y2):1Y10.

43. Hirayama K. Juvenile muscular atrophy ofdistal upper extremity (Hirayama disease):focal cervical ischemic poliomyelopathy.Neuropathology 2000;20(suppl):S91YS94.

44. PradhanS. Bilaterally symmetric formofHirayamadisease. Neurology 2009;72(24):2083Y2089.

45. Foster E, et al. Mechanisms of upper limbamyotrophy in spinal disorders. J ClinNeurosci 2014;21(7):1209Y1214.

46. Cho TA, Vaitkevicius H. Infectious myelopathies.Continuum (Minneap Minn) 2012;18(6 InfectiousDisease):1351Y1373.

47. Gonzalez H, Olsson T, Borg K. Management ofpostpolio syndrome. Lancet Neurol 2010;9(6):634Y642.

48. Steiner I, Kennedy PG. West Nile virusintroduction into the New World. Neurology2013;81(16):1441Y1442.




dr ezgi tiryaki, hennepin neuron diseasesblogs.bellvitgehospital.cat/aulaela/wp-content/... ·...

Documents