What are the diagnostic steps for Amyotrophic Lateral Sclerosis (ALS)?

Diagnosing Amyotrophic Lateral Sclerosis (ALS)

The diagnosis of ALS requires demonstrating both upper and lower motor neuron degeneration with progressive symptom spread, confirmed through electromyography (EMG) and nerve conduction studies, while systematically excluding ALS-mimicking conditions through neuroimaging and targeted laboratory testing. 1, 2

Core Diagnostic Requirements

The fundamental diagnostic approach centers on three pillars 1:

• Evidence of upper motor neuron signs: Spasticity, hyperreflexia, extensor plantar responses 3
• Evidence of lower motor neuron signs: Muscle weakness, atrophy, fasciculations 3
• Progressive spread of symptoms: Documented clinical progression over time 1

Clinical Presentation Patterns

Spinal (Limb) Onset (~67% of cases)

• Focal muscle weakness and wasting starting distally or proximally in upper or lower limbs 3
• Progressive spasticity develops in weakened limbs, affecting manual dexterity and gait 3
• Mean age of onset approximately 60 years with slight male predominance (1.5:1) 3

Bulbar Onset (~33% of cases)

• Dysarthria and dysphagia for solids or liquids as initial symptoms 3
• Approximately 80% develop these symptoms 1
• Limb symptoms typically emerge within 1-2 years 3

Essential Electrophysiological Testing

EMG and nerve conduction velocity (NCV) studies are the cornerstone diagnostic tests and must be performed in all suspected cases 1, 2, 4:

• EMG findings: Fibrillation potentials, positive sharp waves, fasciculation potentials at rest, incomplete interference pattern with abnormal motor unit potentials 4
• NCV studies: Evaluate axonal degeneration and help distinguish ALS from other conditions 2, 4
• These tests detect lower motor neuron degeneration and confirm neurogenic changes 1, 4

Neuroimaging Protocol

Brain MRI (without IV contrast)

MRI of the brain is usually appropriate for initial imaging to exclude mimicking conditions 1, 2:

• Abnormal T2/FLAIR signal in corticospinal tracts, particularly posterior limb of internal capsule and cerebral peduncles 2
• T2*/susceptibility-weighted imaging may show hypointensity in precentral gyrus (highly sensitive and specific) 2

Spine MRI (without IV contrast)

• May be appropriate in select cases to exclude structural, infectious, or neoplastic etiologies 1, 2
• Can show abnormal T2/STIR signal in anterior horns ("snake eyes" appearance), though not specific and appears later in disease 2

Comprehensive Laboratory Exclusion Panel

A systematic laboratory workup is mandatory to exclude treatable ALS-mimicking conditions 1, 2:

Basic Metabolic and Hematologic

• Complete blood count for infectious/inflammatory conditions 1, 2
• Blood chemistry profile (glucose, electrolytes, kidney and liver function) 1, 2
• Thyroid function tests 1, 2

Nutritional Deficiencies

• Vitamin B12, folate, and vitamin E levels 1, 2

Immunologic Testing

• Serum protein electrophoresis (paraproteinemic neuropathies) 1, 2
• Anti-ganglioside antibodies (GM1, GD1a, GD1b) for immune-mediated motor neuropathies 1, 2
• Paraneoplastic antibody panel 1, 2
• Anti-acetylcholine receptor and anti-MuSK antibodies (myasthenia gravis) 1, 2

Cerebrospinal Fluid Analysis

CSF examination should include 1, 2:

• Cell count, protein, glucose, IgG index, oligoclonal bands, cytology 1, 2
• Critical caveat: Marked pleocytosis (>50 cells/μL) suggests alternative diagnosis 2
• CSF protein may be normal or mildly elevated in ALS 2
• Emerging biomarker: Elevated neurofilament levels support ALS diagnosis (Class II evidence) 5

Genetic Testing Considerations

Genetic testing for ALS-associated genes should be considered, especially with family history 1, 2:

• C9orf72, SOD1, FUS, TARDBP genes 1, 2
• 5-10% of cases are familial; 20% of familial cases have SOD1 mutations 3
• 2% of apparently sporadic patients have SOD1 mutations 3

Key Diagnostic Pitfalls to Avoid

Common ALS-Mimicking Conditions to Exclude

• Cervical spondylotic myelopathy 3
• Multifocal motor neuropathy 3
• Kennedy's disease 3
• Myasthenia gravis 1, 2

Timing Considerations

The average diagnostic delay is 10-16 months from symptom onset 6, and approximately 20% motor neuron loss has already occurred by symptom onset 5. This underscores the urgency of expediting the diagnostic process once ALS is suspected 5.

Diagnostic Criteria Application

Use the Gold Coast Criteria (newer, simpler criteria) along with clinical findings 5:

• Signs of upper and lower motor neuron damage not explained by other disease processes are suggestive of ALS 3
• Progressive nature must be documented 1
• Electrophysiological confirmation of lower motor neuron involvement is essential 4

Swallowing Assessment at Diagnosis

Screening for dysphagia should be performed at diagnosis as part of comprehensive evaluation 7:

• EAT-10 questionnaire (sensitivity 86%, specificity 76% for aspiration) 7, 1
• Volume-Viscosity Swallow Test (sensitivity 92%, specificity 80%) 7, 1
• Videofluoroscopy is recommended at diagnosis to detect early dysphagia signs 7, 1