What are the diagnostic criteria and treatment options for Amyotrophic Lateral Sclerosis (ALS)?

How to Diagnose ALS

The diagnosis of ALS requires demonstrating both upper and lower motor neuron degeneration through clinical examination combined with electromyography (EMG) and nerve conduction studies (NCS), while systematically excluding other conditions through targeted laboratory testing and neuroimaging. 1, 2

Core Diagnostic Requirements

Clinical criteria demand evidence of:

• Upper motor neuron signs: hypertonicity, hyperreflexia, pathologic reflexes 3
• Lower motor neuron signs: muscle fasciculations, weakness, atrophy 3
• Progressive spread of symptoms over time 2

The diagnosis is fundamentally clinical, but requires systematic exclusion of mimics and confirmation through electrodiagnostic studies. 4

Essential Electrodiagnostic Testing

EMG and NCS are the cornerstone diagnostic tests and must demonstrate lower motor neuron degeneration. 1, 2

• EMG must show fibrillation potentials as evidence of lower motor neuron involvement 5
• These studies help distinguish ALS from other neuromuscular conditions 1
• EMG can detect abnormalities even in clinically unaffected regions 6

Neuroimaging Protocol

MRI of the brain without IV contrast is the initial imaging study to exclude structural lesions, demyelinating disease, and other mimics. 1, 2

Key MRI findings that support (but don't confirm) ALS include:

• Abnormal T2/FLAIR signal in corticospinal tracts, particularly the posterior limb of internal capsule and cerebral peduncles 1, 3
• T2*-weighted or susceptibility-weighted imaging may show hypointensity in the precentral gyrus with high sensitivity and specificity 1

MRI of the spine without IV contrast may be appropriate to exclude structural, infectious, or neoplastic causes that mimic motor neuron disease. 1, 2 The "snake eyes" appearance (abnormal T2/STIR signal in anterior horns) is not specific and appears late in disease. 1

Mandatory Laboratory Exclusion Panel

The following tests must be performed to exclude treatable ALS mimics:

• Complete blood count (CBC) for infectious/inflammatory conditions 1, 2
• Comprehensive metabolic panel including glucose, electrolytes, kidney and liver function 1, 2
• Thyroid function tests to exclude thyroid-related weakness 1, 2
• Vitamin B12, folate, and vitamin E levels to exclude nutritional neuropathies 1, 2
• Serum protein electrophoresis to rule out paraproteinemic neuropathies 1, 2
• Anti-ganglioside antibodies (GM1, GD1a, GD1b) to exclude immune-mediated motor neuropathies 1, 2
• Paraneoplastic antibody panel to exclude paraneoplastic syndromes 1, 2
• Anti-acetylcholine receptor and anti-MuSK antibodies to rule out myasthenia gravis 1, 2

Cerebrospinal Fluid Analysis

CSF examination should include: cell count, protein, glucose, IgG index, oligoclonal bands, and cytology to exclude infectious, inflammatory, or neoplastic causes. 1, 2

Critical caveat: CSF protein may be normal or mildly elevated in ALS, but marked pleocytosis (>50 cells/μL) suggests an alternative diagnosis. 1

Genetic Testing Considerations

Genetic testing for ALS-associated genes (C9orf72, SOD1, FUS, TARDBP) should be considered, especially with family history. 1, 2 This is particularly important as approximately 10% of ALS cases are familial. 4

Emerging Biomarkers

Serum and CSF neurofilament (Nf) levels provide Class II evidence supporting ALS diagnosis and may be elevated even in presymptomatic stages. 7 These biomarkers can help accelerate diagnosis but are not yet universally available or standardized.

Common Diagnostic Pitfalls

Delayed diagnosis remains problematic, with mean time from symptom onset to diagnosis of 9.7-12 months. 5, 7 This occurs because:

• Primary care physicians may not recognize early ALS symptoms 7
• Initial presentations vary widely (limb-onset vs. bulbar-onset) 2
• Multiple conditions mimic ALS, including progressive muscular atrophy (pure lower motor neuron), primary lateral sclerosis (pure upper motor neuron), and adult-onset spinal muscular atrophies 4

Approximately 80% of bulbar-onset ALS patients develop dysarthria and dysphagia, which may initially be misattributed to other causes. 2, 3

Differential Diagnosis Considerations

The broad differential requires systematic exclusion of:

• Other motor neuron diseases with restricted presentations 4
• Structural cervical spine pathology 1
• Multifocal motor neuropathy with conduction block 4
• Myasthenia gravis 1
• Kennedy's disease (X-linked bulbospinal muscular atrophy) 4

Clinical Recognition Algorithm

When evaluating suspected ALS, look for:

1. Progressive weakness affecting multiple limb regions or bulbar muscles 2
2. Mixed upper and lower motor neuron signs in the same region 2, 3
3. Absence of sensory findings (sensory involvement suggests alternative diagnosis) 4
4. Spread of symptoms to additional body regions over weeks to months 2

Up to 40% of ALS patients have cognitive impairment, which may affect diagnostic evaluation and treatment decisions. 3