What are the steps to diagnose 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, while systematically excluding treatable conditions that mimic ALS through comprehensive laboratory testing and neuroimaging. 1, 2

Clinical Diagnostic Requirements

The diagnosis is fundamentally clinical and requires three key elements 1, 3:

• Upper motor neuron signs: Hypertonicity, hyperreflexia, and spasticity 1
• Lower motor neuron signs: Muscle fasciculations, weakness, and atrophy 1
• Progressive spread: Symptoms must demonstrate progression through different body regions over time 1

Mandatory Electrophysiological Testing

EMG and nerve conduction velocity studies are the cornerstone diagnostic tests and are mandatory for diagnosing ALS. 1, 2, 4

• These tests detect lower motor neuron degeneration and distinguish ALS from other conditions 1, 2
• EMG abnormalities include fibrillation potentials, positive sharp waves, fasciculation potentials at rest, incomplete interference patterns, and abnormal motor unit potentials 4
• Nerve conduction studies help evaluate axonal degeneration 4

Essential Neuroimaging

MRI brain without IV contrast is the initial imaging study of choice to exclude structural lesions, inflammatory conditions, and other diseases that mimic ALS. 1, 2

• Supportive (but not diagnostic) findings include abnormal T2/FLAIR signal in corticospinal tracts, particularly in the posterior limb of internal capsule and cerebral peduncles 1, 2
• Abnormal hypointensity in precentral gyrus on T2*-weighted or susceptibility-weighted imaging is highly sensitive and specific for ALS 1, 2
• MRI spine without IV contrast may be appropriate in certain cases to exclude structural, infectious, or neoplastic etiologies 2

Comprehensive Laboratory Workup to Exclude Mimics

A comprehensive metabolic and immunologic workup is essential to exclude treatable conditions that present with similar symptoms. 1, 2

The following tests are recommended 1, 2:

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

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

• Marked pleocytosis (>50 cells/μL) suggests an alternative diagnosis and should prompt reconsideration of ALS 1, 2
• CSF protein may be normal or mildly elevated in ALS 2

Genetic Testing Considerations

Genetic testing for ALS-associated genes (C9orf72, SOD1, FUS, TARDBP) should be considered, especially in cases with family history 2, 5

• C9orf72 repeat expansions are the most common known genetic cause, seen in approximately 40% of patients with family history and 10% without 5

Dysphagia Screening at Diagnosis

Screening for dysphagia should be performed at diagnosis and every 3 months during follow-up, even in patients without bulbar symptoms. 6, 1

• Structured questionnaires (EAT-10) have 86% sensitivity and 76% specificity for identifying unsafe swallowing 1
• Volume-Viscosity Swallow Test (V-VST) has 92% sensitivity and 80% specificity for detecting dysphagia 1
• Videofluoroscopy should be performed at diagnosis to detect early signs of dysphagia and silent aspirations 1

Nutritional Screening at Diagnosis

Screening for malnutrition (BMI, weight loss) is recommended at diagnosis and during follow-up every 3 months. 6

Common Pitfalls to Avoid

• Diagnosis is by exclusion: No single diagnostic test confirms ALS; the diagnosis requires systematic exclusion of treatable mimics 5, 7, 8
• Diagnostic delay averages 10-16 months: Early referral to ALS specialists is crucial to reduce this delay 9
• Atypical presentations exist: ALS is heterogeneous and may present in multiple ways, requiring a systematic approach 8
• Silent aspiration can occur: Aspiration may be present even without clinical signs or subjective complaints, necessitating objective dysphagia assessment 3