What is the approach for investigating Amyotrophic Lateral Sclerosis (ALS)?

Investigation for Amyotrophic Lateral Sclerosis (ALS)

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

Electrophysiological Testing (Essential)

EMG and nerve conduction velocity (NCV) studies are mandatory for diagnosing ALS as they detect lower motor neuron degeneration and distinguish ALS from other conditions. 1, 2, 3

• EMG findings that support ALS diagnosis include:

  • Fibrillation potentials and positive sharp waves at rest 4
  • Fasciculation potentials in resting muscle 4
  • Incomplete interference pattern with abnormal motor unit potentials 4
  • Large macro-motor unit potentials indicating collateral nerve sprouting 4

• Motor unit number estimation (MUNE) can measure loss of functioning motor neurons and track disease progression 4

Neuroimaging (To Exclude Mimics)

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, 3

• Common MRI findings in ALS (supportive but not diagnostic):
  • Abnormal T2/FLAIR signal in corticospinal tracts, particularly in the posterior limb of internal capsule and cerebral peduncles 1, 3
  • Abnormal hypointensity in precentral gyrus on T2*-weighted or susceptibility-weighted imaging (highly sensitive and specific) 1

MRI spine without IV contrast may be appropriate to exclude structural, infectious, or neoplastic etiologies that mimic motor neuron disease. 1, 2

• The "snake eyes" appearance (abnormal T2/STIR signal in anterior horns) may appear later in disease but is not specific for ALS 1, 3

Laboratory Testing (To Exclude Treatable Mimics)

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

• Complete blood count (CBC) to evaluate for infectious or inflammatory conditions 1, 2
• Blood chemistry profile including glucose, electrolytes, kidney function, and liver enzymes 1, 2
• Thyroid function tests to rule out thyroid disorders causing weakness 1, 2
• Vitamin B12, folate, and vitamin E levels to exclude nutritional deficiencies 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

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

Genetic Testing

Genetic testing for ALS-associated genes (C9orf72, SOD1, FUS, TARDBP) should be considered, especially when there is family history of ALS or frontotemporal dementia. 1, 2, 3

• Approximately 5-10% of ALS cases are familial 5
• 2% of apparently sporadic patients have SOD1 mutations 5

Dysphagia Evaluation (At Diagnosis and Follow-up)

Screening for dysphagia should be performed at diagnosis and every 3 months during follow-up as part of comprehensive neurological evaluation, even in patients without bulbar symptoms. 6

• Structured questionnaires (EAT-10) have 86% sensitivity and 76% specificity for identifying unsafe swallowing 6, 2
• Volume-Viscosity Swallow Test (V-VST) has 92% sensitivity and 80% specificity for detecting dysphagia 6, 2
• Videofluoroscopy should be performed at diagnosis to detect early signs of dysphagia and silent aspirations 6, 2
• Fiberoptic endoscopic evaluation of swallowing (FEES) is an alternative bedside method 6

Clinical Diagnostic Criteria

The diagnosis requires evidence of both upper and lower motor neuron degeneration with progressive spread of symptoms. 2, 7

• Upper motor neuron signs: Hypertonicity, hyperreflexia, spasticity 3
• Lower motor neuron signs: Muscle fasciculations, weakness, atrophy 3
• Progressive spread through different body regions over time 2, 7

Common Pitfalls to Avoid

• Do not rely solely on clinical examination for upper motor neuron signs in limbs with concurrent muscle wasting, as they may be difficult to appreciate early in disease 8
• Sensory symptoms should prompt consideration of alternative diagnoses, as ALS does not involve sensory pathways 3
• Approximately 10% of patients are initially misdiagnosed, and diagnostic delays are common 9
• Two-thirds of patients present with limb onset (spinal form), while one-third present with bulbar onset (dysarthria, dysphagia) 5