What investigations should be done in a patient with suspected or diagnosed Amyotrophic Lateral Sclerosis (ALS)?

Investigations for Amyotrophic Lateral Sclerosis (ALS)

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

Essential Electrophysiological Studies

• EMG and nerve conduction velocity (NCV) studies are mandatory as they detect lower motor neuron degeneration and distinguish ALS from other conditions 1, 2, 3
• These studies should demonstrate evidence of acute and chronic denervation in multiple regions (bulbar, cervical, thoracic, lumbosacral) 3, 4

Neuroimaging

Brain MRI without IV contrast is the primary imaging modality to exclude structural lesions, tumors, and inflammatory conditions that mimic ALS 1, 2, 5

• Look for abnormal T2/FLAIR hyperintensity in the corticospinal tracts, particularly in the posterior limb of the internal capsule and cerebral peduncles 2, 5
• T2*-weighted or susceptibility-weighted imaging may show abnormal hypointensity in the precentral gyrus, which can be highly sensitive and specific for ALS 2

Spine MRI without IV contrast should be obtained when clinical presentation suggests possible structural, infectious, or neoplastic etiologies 1, 2

• May reveal abnormal T2/STIR signal in the anterior horns ("snake eyes" appearance), though this finding is neither sensitive nor specific and often appears late in disease 2, 5

Laboratory Tests to Exclude ALS Mimics

The following blood tests are essential to rule out treatable conditions that can present with motor neuron-like symptoms:

• Complete blood count (CBC) to evaluate for infectious or inflammatory conditions 1, 2
• Comprehensive metabolic panel including glucose, electrolytes, kidney function, and liver enzymes 1, 2
• Thyroid function tests (TSH, free T4) to exclude thyroid disorders causing weakness 1, 2
• Vitamin B12, folate, and vitamin E levels to identify deficiencies causing neurological symptoms 1, 2
• Serum protein electrophoresis to rule out paraproteinemic neuropathies 1, 2
• Anti-ganglioside antibodies (GM1, GD1a, GD1b) to exclude immune-mediated motor neuropathies like multifocal motor neuropathy 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 be performed when the diagnosis is uncertain or to exclude inflammatory/infectious mimics 1, 2

• Order cell count, protein, glucose, IgG index, oligoclonal bands, and cytology 1, 2
• CSF protein may be normal or mildly elevated in ALS, but marked pleocytosis (>50 cells/μL) suggests an alternative diagnosis 2

Genetic Testing

Genetic testing for ALS-associated genes should be considered, particularly when:

• There is a family history of ALS or frontotemporal dementia 1, 2
• The patient presents at a younger age (<50 years) 6
• Key genes to test include C9orf72 (most common), SOD1, FUS, and TARDBP 1, 2, 6

Dysphagia Assessment (Essential for Baseline and Monitoring)

All ALS patients require dysphagia screening at diagnosis and every 3 months thereafter as part of comprehensive evaluation 7, 1

• EAT-10 questionnaire has 86% sensitivity and 76% specificity for identifying unsafe swallowing 7, 1
• Volume-Viscosity Swallow Test (V-VST) demonstrates 92% sensitivity and 80% specificity for detecting dysphagia 7, 1
• Videofluoroscopy is recommended for instrumental assessment when dysphagia symptoms are present 7
• Clinical assessment should evaluate lip closure, saliva pooling, tongue strength and mobility, palatal movement, cough quality, and phonation 7

Common Pitfalls to Avoid

• Do not rely solely on clinical examination—up to 10% of patients initially diagnosed with ALS have a mimic disorder 8
• Do not skip the comprehensive laboratory panel—several treatable conditions (vitamin B12 deficiency, thyroid disorders, immune-mediated neuropathies) can present identically to ALS 1, 2, 3
• Do not delay genetic testing in familial cases—approximately 10% of ALS is familial, and genetic counseling is important for family members 6
• Do not overlook early dysphagia—swallowing abnormalities can occur even without bulbar symptoms, and early detection prevents aspiration pneumonia 7, 1

Diagnostic Timeline

• The diagnosis remains clinical, requiring progressive upper and lower motor neuron signs with exclusion of mimics 1, 3, 8
• Mean time from symptom onset to diagnosis is often 12-18 months, but earlier diagnosis improves access to multidisciplinary care and clinical trials 6, 9