What are the steps to diagnose amyotrophic lateral sclerosis (ALS)?

Diagnostic Testing for Amyotrophic Lateral Sclerosis (ALS)

The diagnosis of ALS requires electromyography (EMG) and nerve conduction studies as mandatory cornerstone tests, combined with MRI brain imaging to exclude mimics, and a comprehensive laboratory panel to rule out treatable conditions that present similarly. 1, 2

Core Diagnostic Requirements

The diagnosis is fundamentally clinical and requires demonstrating three key elements 2:

• Upper motor neuron signs: Hypertonicity, hyperreflexia, and spasticity 1, 2
• Lower motor neuron signs: Muscle fasciculations, weakness, and atrophy 1, 2
• Progressive spread: Symptoms must show progressive spread through different body regions over time 1, 2

Mandatory Electrophysiological Testing

EMG and nerve conduction velocity studies are absolutely mandatory for diagnosing ALS and serve as the cornerstone diagnostic tests 1, 2. These studies detect lower motor neuron degeneration and distinguish ALS from other conditions 1. The EMG should demonstrate denervation and reinnervation patterns in multiple body regions 3.

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) MRI findings include 1, 2:

• Abnormal T2/FLAIR signal in corticospinal tracts, particularly in the posterior limb of internal capsule and cerebral peduncles 1
• Abnormal hypointensity in precentral gyrus on T2*-weighted or susceptibility-weighted imaging (highly sensitive and specific) 1

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 1
• Blood chemistry profile including glucose, electrolytes, kidney function, and liver enzymes 1
• Thyroid function tests to rule out thyroid disorders causing weakness 1
• Vitamin B12, folate, and vitamin E levels to exclude nutritional deficiencies 1
• Serum protein electrophoresis to rule out paraproteinemic neuropathies 1
• Anti-ganglioside antibodies (GM1, GD1a, GD1b) to exclude immune-mediated motor neuropathies 1
• Paraneoplastic antibody panel to exclude paraneoplastic syndromes 1
• Anti-acetylcholine receptor and anti-MuSK antibodies to rule out myasthenia gravis 1

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.

Genetic Testing

Genetic testing should be considered, as familial ALS is present in 5-10% of all ALS patients 4. Common causal genes include C9orf72, SOD1, FUS, and TARDBP 4. Genetic factors may be involved even without a family history of ALS and may be underestimated 4.

Emerging Biomarkers

Serum and CSF neurofilament light chain (NF-L) levels provide Class II evidence supporting the diagnosis of ALS 5. High neurofilament levels can be detected even in presymptomatic stages, suggesting that the neurodegenerative process is already active before clinical symptoms appear 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, 2. This is critical because dysphagia can occur early and silently 2.

Recommended screening tools 6, 1:

• EAT-10 questionnaire: 86% sensitivity and 76% specificity for identifying unsafe swallowing 1
• Volume-Viscosity Swallow Test (V-VST): 92% sensitivity and 80% specificity for detecting dysphagia 6, 1
• Videofluoroscopy should be performed at diagnosis to detect early signs of dysphagia and silent aspirations 6, 1, 2

Critical Pitfalls to Avoid

Silent aspiration can occur without obvious symptoms, necessitating objective dysphagia assessment rather than relying solely on patient-reported symptoms 2. The neurodegenerative process begins long before symptom onset, with approximately 20% loss of motor neurons already occurring in the "presymptomatic" stage 5. Therefore, early and aggressive diagnostic workup is warranted when ALS is suspected to facilitate earlier treatment initiation 5.