MOTOR NEURON DISEASE

Motor Neuron Disease

Loss of upper and lower motor neuron function The relative degree of upper vs. lower motor neuron loss and the distribution of the loss between bulbar and spinal functions determine the various clinical categories

Classification
Amyotrophic Lateral Sclerosis Progressive Bulbar Palsy Progressive Muscular Atrophy Primary Lateral Sclerosis Multifocal Motor Neuropathy Spinal Muscular Atrophy Kennedys Disease Monomelic Amyotrophy Brachial Amyotrophic Diplegia

Amyotrophic Lateral Sclerosis

General Information
ALS is disease of part of the nervous system that controls voluntary movements Amyotrophic = without muscle nourishment, resulting in loss of nerve signals to muscles Lateral = to the side, referring to location of damage in spinal cord (corticospinal tract) Sclerosis = hardened nature of spinal cord

Statistics
Incidence 0.4-1.76/ 100,000, and increases with each decade of life Usually begins in mid to later life; rare in age <40 Prevalence 4-6/100,000 No significant racial or ethnic pattern M/F 1.2/1 Geographically random, except increased in Kii peninsula, Japan and Guam, where combined with dementia and Parkinsonism

Familial ALS
Between 5 and 10% of ALS cases are familial, the majority autosomal dominant Younger age at presentation, lacks male predominance, has shorter disease duration, and predilection for lower extremity onset Up to 20% of familial ALS patients are associated with mutation in the Cu/Zn SOD1 mutation on chromosome 21 More than 60 different mutations described

Pathology
Loss of neurons in anterior horn of spinal cord and motor nuclei of lower brainstem Pathologic features include cell body shrinkage, pyknosis, ghost cells, neuronophagia, and gliosis Loss of Betz cells in precentral motor cortex Corticospinal tracts depleted of large myelinated fibers, and most readily observed in anterior and lateral columns of spinal cord

ALS
UMN exerts complex control over LMNs that allows smooth, directed movements (e.g. picking up a glass) When UMN is lost, spasticity develops In ALS, death of UMN and LMN results in tight, weak, and atrophic muscles; fasciculations and cramps

ALS Symptoms
Stiffness, weakness, wasting in hand muscles; impaired fine finger movements (e.g. buttoning, turning ignition keys) Cramping, fasciculations (muscle twitches) Exaggerated reflexes (e.g. biceps, knees) Positive Babinskis Spasticity Sensory symptoms (numbness, tingling) rare

ALS Symptoms
Finger abductors, adductors, extensors weak before finger flexors (resulting in clawed hand with hollowing of dorsal interosseus spaces) Weakness spreads to neck, tongue, pharynx, larynx, trunk, Affected parts may feel cold

ALS Symptoms
Leg involvement with foot drop In some, early involvement of thoracic, abdominal, neck muscles Gait disorder Shortness of breath Weight loss

ALS Symptoms
Weakness usually painless Patient may notice atrophy before functional loss Weakness frequently asymmetric Sensory symptoms may be reported in up to 25%, but objective clinical sensory signs uncommon

ALS and Dementia

Historically, ALS was not felt to be associated with cognitive or memory impairment. Recent studies suggest 20-25% of ALS patients have frontotemporal lobe dementia Progressive condition that results in degeneration of the frontal and temporal lobes of the brain

Frontotemproal Dementia
Initial symptoms include changes in personality, language, and behavioral disturbances Difficulties with executive function (e.g., planning a party) Differentiate from Alzheimers Disease, which typically begins with short term memory impairment

Frontotemporal Dementia
Etiology unclear, possibly related to abnormal tau protein metabolism Risk factors include advanced age, family history of dementia, bulbar symptoms, diminished vital capacity Associated with reduced life span Diagnosis assisted by formal neuropsychological testing

ALS Symptoms
Dutch researchers examined 14 studies of cognition in ALS patients without obvious dementia. Findings revealed lower average scores on tests of global cognitive ability, immediate verbal memory, visual memory, executive functioning, (e.g., planning a series of events), verbal fluency and processing speed

ALS Symptoms
Extraocular muscles, bowel/bladder function typically spared

Prognosis
Rate of anterior horn cell deterioration varies from patient to patient 50% die within 3 years, usually from respiratory complications; 90% within 6 years Rare cases survive decades

Evaluation
NCS/EMG integral part of evaluation of ALS patients NCS findings:
Normal SNAPs (sensory nerve action potentials) Low amplitude CMAPs (compound muscle action potentials) when significant axon loss occurs; may accompany modest slowing of NCVs

ALS Evaluation
Median motor distal latencies may be prolonged EMG findings:
Active denervation (fibrillations and positive waves) Fasciculations Chronic denervation (large amplitude, prolonged duration polyphasic MUAPs) MUAPs fire with rapid rate (>10 Hz)

ALS Evaluation
NCS/EMG changes should be found in at least 2 regions (bulbar, cervical, thoracic, lumbosacral) In cervical and lumbosacral regions, at least two muscles from different roots and peripheral nerves must be involved

ALS Evaluation
Exclusion criteria: Marked conduction slowing Conduction block Abnormal sensory responses otherwise unexplained by advanced age or coexisting neuropathy

ALS Evaluation
MRI of spine to exclude structural cause (e.g. spinal stenosis). Serum and urine studies to exclude other metabolic causes (lead toxicity, paraproteinemia) Lumbar puncture usually yields normal CSF CK usually normal or slightly elevated Muscle biopsy occasionally useful

El Escorial Criteria for Diagnosis

Treatments
Rilutek, glutamate inhibitor, extends survival a few months OT, PT may utilize AFOs, walker, manual/power wheelchair, scooter ST electronic speech device; may also assist with swallowing evaluation/treatment Patients eventually require PEG/G-Tube

ALS Treatments
Pulmonary physician to assist with respiratory function May utilize non-invasive BiPAP (Bilevel Positive Airway Pressure one for inhalation, one for exhalation) Invasive - Tracheostomy

Progressive Muscular Atrophy

Pure lower motor neuron syndrome Patients develop distal limb wasting, weakness, fasciculations, cramps; no sensory symptoms/signs Asymmetric weakness Reflexes usually reduced or absent Long clinical course, with slow progression to proximal limb muscles

PMA
Bulbar involvement unusual Upper motor neuron dysfunction usually absent Need to rule out multifocal motor neuropathy (treatable)

Progressive Bulbar Palsy

Variant of ALS Patients present with dysarthria, dysphagia, sialorrhea, aspiration, and pseudobulbar signs Upper motor neuron dysfunction may result in spastic dysarthria with slow oral and tongue movements, and strained voice

Progressive Bulbar Palsy

Dysphagia, often initially more for liquids than solids Hyperactive gag and jaw-jerk reflexes Pseudobulbar affect with inappropriate laughing, crying, and yawning Lower motor neuron dysfunction leads to greater degree of weakness affecting the face, palate, and tongue

Primary Lateral Sclerosis

2-3.7% of ALS patients present with this pure UMN syndrome Age of onset typically 50-55 years May have very slow progression Commonly present with spastic paraparesis, progressing rostrally to eventually cause pseudobulbar palsy

Multifocal Motor Neuropathy

May mimic PMA or ALS Usually affects only motor fibers, sparing sensory fibers Slowly progressive, begins distally Absence of upper motor neuron signs Usually seen in younger patients (<45 years) than ALS, strong male predominance

MMN
Individual motor nerve affected out of proportion to adjacent nerves with same myotomal innervation (e.g., median vs. ulnar) Respiratory and bulbar weakness rare No shortening of life span Weakness out of proportion to atrophy, suggesting demyelination as primary pathology Non-regional spread of weakness (e.g., right arm to left leg) Associatied with AntiGM1 antibodies

MMN
Diagnosis usually by nerve conduction studies, which demonstrate conduction block at nonentrament sites (e.g., ulnar nerve across forearm) Conduction block variably defined as a 20% or greater reduction in the amplitude or area, or both, of the CMAP from proximal to distal stimulation TREATABLE, usually with IVIg 2 g/ kg, given in divided doses over 2-5 days

MMN
Some improvement in up to 80% Significant useful functional benefit in 5060% Despite improvement in strength, IVIg treatment usually does not reduce titers of serum anti-GM1 antibodies

MMN
Cyclophosphamide is the only immunosuppressive treatment reported to produce sustained long-term relief in 5080% of patients with MMN Limited use due to side effects and increased risk of neoplasm

Spinal Muscular Atrophy

Most cases are genetic, autosomal recessive, and linked to chromosome 5 Classification based on age of onset:
SMA I: Werdnig-Hoffman, acute infantile SMA II: intermediate, chronic infantile SMA III: Kugleberg-Welander, chronic juvenile SMA IV: adult onset

SMA
Characteristic clinical presentation is progressive, symmetric proximal weakness and atrophy without UMN signs Werdnig-Hoffman most severe form, death by age 2 Diagnosis suggested by history of impaired motor development or loss of motor skills

SMA
Findings on physical exam include weakness, hypotonia, and absent deep tendon reflexes CK 1-2X normal, but may be 10X normal in type III Positive DNA test for deletion of survival motor neuron gene (SMN)

SMA
EMG findings reveal regular spontaneous motor unit action potentials Fasciculations more common in types II and III than type I Fibrillations and positive waves in all patients Normal sensory nerve action potentials

SMA
Compound nerve action potentials may be low in amplitude, velocities normal Motor unit action potentials large amplitude, prolonged duration, with decreased recruitment Muscle biopsy reveals grouped atrophy of type I and II muscle fibers, as opposed to normal checkerboard pattern

SMA
Prognosis
SMA I: weakness before 6 months, never sit independently, lie expectancy less than 2 years SMA II: onset after 6 months, can sit independently, may survive to 2nd or 3rd decade SMA III: manifest weakness after 18 months, walk independently, survive to 6th decade

SMA
Scoliosis, contractures, and pneumonia are predictable complications Some children with Werdnig-Hoffman do not suck or swallow well, so feeding gastrostomy may be necessary Forced vital capacity decreased in all patients, so respiratory support should be discussed before it is needed

SMA
Development of orthopedic deformities in patients with SMA II and III necessitates team approach SMA I patients rarely survive long enough to develop spinal deformities SMA patients who walked, but never normally, typically lose walking ability by 15 years. Those who developed weakness after walking normally can walk until the 30s or 40s

Kennedys Disease
X-linked recessive disorder caused by a mutation within the androgen receptor gene Typically presents in men in 3rd to 5th decade with gradually progressive weakness Weakness more prominent proximally than distally

Kennedys Disease
Fasciculations frequent in limb muscles DTRs depressed or absent Hand tremors found in up to 80 percent, characteristic of essential tremors; may respond to propranalol Facial fasciculations in more than 90%, best elicited by having patients whistle or blow out of cheeks

Kennedys Disease
Dysarthria and dysphagia rare Sensory loss/symptoms rare, but most patients have absent or low amplitude sensory nerve action potentials (SNAPs) Gynecomastia and impotence in most patients due to androgen insensitivity Diabetes mellitus occurs in small percentage of patients

Kennedys Disease
Diagnosis suggested by clinical presentation and positive family history, confirmed by genetic testing Serum CK usually elevated, sometimes up to 8,000 CMAP amplitudes may be normal or low SNAP amplitudes low or absent

Kennedys Disease
EMG reveals large amplitude, prolonged duration polyphasic MUAPs with decreased recruitment EMG of facial muscles reveal grouped, repetitive motor unit discharges which occur with mild activation of facial muscles Diagnosis confirmed by DNA analysis of the CAG mutation within the first exon of the androgen receptor gene

Kennedys Disease
Slowly progressive, with normal or slightly reduced life expectancy Bulbar weakness late in the disease course

Monomelic Amyotrophy
Etiology unknown Most cases sporadic Most patients 18-22 years Slow onset of unilateral weakness and atrophy of hand muscles Weakness progresses slowly over 1-3 years, then stabilizes

Monomelic Amyotrophy
Atrophy usually limited to hand and forearm muscles (brachioradialis often spared) Postural tremor in 10% DTRs usually normal UMN signs absent Sensation usually preserved

Brachial Amyotrophic Diplegia

Sporadic, adult-onset, chronic progressive severe bilateral proximal arm weakness and atrophy, without lower extremity involvement Pure LMN weakness Differentiate from ALS by slow progression, restriction to proximal arm muscles, and lack of UMN signs

Brachial Amyotrophic Diplegia

Differentiate from monomelic amyotrophy, which usually occurs in younger age group, restriction to hand and forearm muscles, and asymmetric

Reference
Murray B., Mitsumoto H., Russman B., Shapiro B.E. Neuronopathies (Motor Neuron and Dorsal Root Ganglion Disorders). In B. Katirji, H. Kaminski, D. Preston, R. Ruff, B. Shapiro (eds), Neuromuscular Disorders in Clinical Practice. Butterworth-Heinemann, 2002; 417-477.