Differential Diagnosis in Neurology

3.6. Amyotrophic Lateral Sclerosis (ALS)

• General considerations:
  • Incidence varies from 0.2 to 2.4 per 100,000 people in the world excluding the Western Pacific
  • Prevalence rate is between 0.8 and 7.4 people per 100,000
  • Age is the greatest risk factor with peak mortality between 55 to 75 years of age
  • Peak onset is between 65–70 years of age; earlier onset has greater survival time
  • Male to female ratio is 1.5–2.5:1
  • Survival from time of diagnosis
    • 50% die within 3 years
    • 75% die within 5 years
    • 10% live longer than 10 years
  • 85–90% of ALS is sporadic:
    • 10–15% of familial ALS have a mutation in the gene for cu/zn superoxide dismutase (SoD1)
  • Genes for cytoskeletal molecules that may be linked to ALS:
    • Neurofilament-Heavy (NF-H) mutation
      • 1% in sporadic ALS
      • 0.3% of familial ALS
  • Possible involvement of the fast conducting corticospinal pathways to a greater degree than polysynaptic pathways
  • Twenty percent of familial forms are manifestations of mutations of the copper/zinc ( Cu/Zn) superoxide dismutase 1 (SOD1) gene on chromosome 21
• Clinical features:
  • May start as atrophy of intrinsic hard muscles in various patterns:
    • First dorsal interosseous
    • Lateral hand split
    • Medial hand benediction sign. The fourth and fifth fingers are involved first as they are with syringomyelia. In CRPS the fourth and fifth fingers are dystonic.
  • Atrophy and fasciculations in a muscle group with increased reflexes
  • Segmental spread: a group of muscles in one extremity that then demonstrate contralateral weakness and atrophy (mirror patterns)
  • Onset in a bulbar distribution (12% of patients)
  • Painless foot drop; clawhand; wrist drop
  • Prominent fasciculations associated with cramps on exercise of the affected muscle
  • Spasticity, hyperreflexia, Babinski signs, retention of cremasteric and abdominal reflexes
  • Fasciculations and fibrillations in a scalloped atrophic tongue
  • A significant number of patients have dementia; other cognitive deficits noted
  • Poor facility of corticospinal type movements
• Rare Signs
  • Extraocular movement abnormalities are an exception; may be a decrease of vertical saccades
  • Sphincter dysfunction (occurs late in disease in those on ventilators)
  • Sensory loss (there does appear to be some dorsal column dysfunction)
  • Extrapyramidal signs in 5%; impairment of postural reflexes
  • Autonomic involvement
    • Blood pressure, heart rate, GI function
• Associated Features
  • Sleep apnea; morning headache
  • Sialorrhea
  • Silent and asymptomatic aspiration
  • Disturbance of sleep architecture
  • Decline of voice power with speech
  • Cachexia greater than that expected from decreased nutrition
  • Absence of expected bed sores (possible changes in type III procollagen)
  • Pseudobulbar palsy

ALS Variants

Bulbar Presentation

• General considerations:
  • Growing evidence that ALS is a multisystem degeneration
• Clinical features:
  • Most common in post-menopausal women
  • Poor prognosis; in past death occurred in approximately one year
  • Possibly up to 25% of ALS patients present with this onset
  • Spread to the lower cervical upper thoracic myotomes; later to lumbosacral muscles
  • Rarely, it remains bulbar

Primary Lateral Sclerosis

• General considerations:
  • Does not involve the lower motor neuron
• Clinical features:
  • Age of onset is usually between 50 and 55 years
  • Progresses very slowly
  • May start as spastic paraparesis
  • Severe generalized spasticity, bilateral Hoffman and Babinski signs
  • Pseudobulbar palsy
  • Cognitive impairment is common; overt dementia is rare

Progressive Muscular Atrophy

• General considerations:
  • Rarest variant of ALS
  • Occurs in approximately 2.5% of patients
• Clinical features:
  • Slowly progressive with better outcome than in classic disease
  • A pure lower motor neuron disease
  • Differential is between this and lower motor onset of SMA

Flail Arm Syndrome (Bibrachial Diplegia)

• General considerations:
  • Relatively symmetric proximal and distal wasting of the upper extremities
  • Hyperactive reflexes in both upper and lower extremities
  • Corticospinal tract dysfunction with Babinski signs

Mill's (Hemiplegic Variant)

• General considerations:
  • Rare; possibly 5% of patients
• Clinical features:
  • Corticospinal and lower motor neuron involvement of one side

Familial ALS

• General considerations:
  • Approximately 5–10% of ALS patients
  • AD inheritance:
    • 20% of patients have mutations in the Cu/Zn SOD1 gene on chromosome 21; all 5 exons are involved
    • Gain of function deficit
    • Recessively inherited ALS occurs:
      • Apparent single founder for these patients (D90A mutation)
      • Tunisian families with 2q33–35 mutations

Chronic Juvenile ALS

• General considerations:
  • Chronic juvenile ALS
  • Slow progression
  • Onset approximately 12 years of age
• Clinical features:
  • Earlier onset; approximately 12 years of age
  • Less male predominance
  • Initial manifestations occur in the lower extremities
  • Slow progression
• Pathology:
  • No perikaryal or axonal spheroids
  • Greater involvement of Clarke's columns

Guam Parkinsonian ALS Dementia Complex

• General considerations:
  • Endemic areas for this clinical complex are: Western Pacific, Kii peninsula of Japan; West New Guinea
  • No gene has been identified
  • Excitotoxic cell death from B-N-methylamine BMAA, derived from the cycad nut is not causative
  • ALS form of the complex has declined
• Clinical features:
  • Parkinsonism presents primarily as akinetic rigid variety
  • Dystonia is prominent ("Lubag"); particularly of the mouth
  • ALS in combination with Parkinsonian features; patients may have severe dementia

Differential Diagnosis of ALS

Since ALS and its variants may strike all levels of the neuraxis the differential diagnosis is extremely wide. In reality, the diagnosis is restricted, as there are few illnesses that strike the upper and lower motor neurons simultaneously.

The clinician must not miss the illnesses that simulate ALS but are treatable. The most common of these is cervical spondylosis. This is primarily a disease of the motion segments of the spinal segments and occurs in both cervical and lumbar areas concomitantly. It is asymmetrical, biceps jerks are lost, knee jerks are increased ankle reflexes may be asymmetrically decreased. If the ventral roots are severely constricted in the cervical canal fasciculations are noted in the upper extremities. It does not involve the cranial nerves; the neck is in a forward flexed posture and cannot be moved to lateral, anterior and posterior planes. The hands are usually spared, whereas in ALS the first dorsal interosseous is often affected very early. Mentation is normal. The problem arises when the patient has both diseases. Cervical spondylosis does not affect paraspinal muscles. MRI of the cervical spine and back corroborate the diagnosis.

The pure motor autoimmune neuropathies may simulate the lower motor form of ALS. The causative antibodies are GMI, MAG, and Gdlb. Serum protein electrophoresis and immune focused electrophoresis often demonstrates an IgM peak (particularly for MAG). Most importantly EMG identifies a conduction block. Wasting is not nearly as prominent as in progressive muscular atrophy (which is most often proximal).

Hexosaminidase A deficiency is extremely rare and has prominent psychiatric and cerebellar features.

There still is controversy over the link between lymphoma and leukemia with ALS. Clearly, there is a strong association between many malignancies and destruction of various parts of the neuraxis (anti-Hu, anti-Yo, anti-Ri, anti-Ma and anti-anti TA). A careful evaluation of the bone marrow is in order if there is a suspicion of a lymphoproliferative disorder.

Hyperparathyroidism, hyperthyroidism, benign fasciculations, and hyperexcitable syndromes all may produce wide spread fasciculation. A fasciculation must be accompanied by wasting and weakness to be significant. Neurogenic cramps induced by exercise, if in the lower extremity are most often due to disc or spondylitic disease in the lumbar roots particularly S1. This rarely occurs in the upper extremity. Neurogenic cramps of the upper extremity suggest the cramp fasciculation syndrome or motor neuron disease. The differentiation can easily be made by EMG. Acid maltase deficiency may give exercise induced cramps with muscle weakness.

There is some evidence that anterior horn cell disease may occur in anterior horn cells formerly affected by a polio virus infection. The post-polio syndrome is painful and most probably represents accelerated cell death in those anterior horn cells that had compensated for the death of their neighbors.

Monomelic ALS seems to affect all muscles of the affected extremity rather than particular muscles of the hand which occurs in ALS (benediction sign of 4th and 5th finger or the lateral hand). There are frequently EMG findings in unaffected muscles in ALS.

Amyotrophy of extremities occurs with multiple system atrophies. The most severe is spinocerebellar atrophy (SCA3) or Machado–Joseph disease. The amyotrophy is never the dominant component of these syndromes.

Kennedy's disease, a bulbar neuronopathy, is X-linked and distinguished by facial fasciculations, genetics and gynecomastia. The CK is usually high and there are diminished SNAPs.

The late onset spinal muscular atrophies may overlap with ALS. They usually have symmetric proximal weakness and some are distal with pes cavus.