What is the appropriate workup to diagnose amyotrophic lateral sclerosis in an adult presenting with progressive motor weakness?

How to Test for ALS

The diagnosis of ALS requires mandatory electromyography (EMG) and nerve conduction studies to detect lower motor neuron degeneration, combined with brain MRI to exclude mimics, and a comprehensive laboratory panel to rule out treatable conditions—because up to 10% of patients initially diagnosed with ALS actually have a mimic disorder. 1, 2

Essential Electrophysiological Testing (First-Line Mandatory)

EMG and nerve conduction velocity (NCV) studies are the cornerstone of ALS diagnosis and must be performed in all suspected cases. 1, 3

• Nerve conduction studies should include at least four sensory and four motor nerves in both an arm and leg, with stimulation at three sites in three different nerves to detect conduction blocks that distinguish treatable motor neuropathies from ALS 3
• Needle EMG must examine at least two limbs (arm and leg with at least five muscles each), thoracic paraspinal muscles, and bulbar muscles to demonstrate widespread non-myotomal denervation with both acute and chronic changes 3
• Look for characteristic findings of fibrillations, fasciculations, and widespread denervation that extends beyond single myotomal distributions 3, 4
• Motor evoked potentials after transcranial magnetic stimulation are the test of choice to identify upper motor neuron impairment 4

Neuroimaging to Exclude Structural Mimics

Brain MRI without IV contrast is the primary imaging modality and must be obtained to exclude tumors, structural lesions, and inflammatory conditions. 1, 5

• Order T2/FLAIR sequences to look for abnormal hyperintensity in the corticospinal tracts, particularly in the posterior limb of the internal capsule and cerebral peduncles 1, 5
• Include T2-weighted or susceptibility-weighted imaging (SWI) to detect abnormal hypointensity in the precentral gyrus*, which can be highly sensitive and specific for ALS 1, 5
• Consider cervical and thoracic spine MRI without contrast if there is concern for cervical myelopathy or syrinx, looking for the "snake eyes" appearance on T2/STIR images in the anterior horns 5

Comprehensive Laboratory Panel (Mandatory to Exclude Mimics)

A complete laboratory workup is mandatory because treatable mimic disorders are present in up to 10% of initially diagnosed ALS cases. 2

Basic Screening Tests

• Complete blood count (CBC) to evaluate for infectious or inflammatory conditions 1
• Comprehensive metabolic panel including glucose, electrolytes, kidney function, and liver enzymes 1
• Thyroid function tests (TSH, free T4) to exclude thyroid disorders causing weakness 1

Nutritional and Metabolic Testing

• Vitamin B12, folate, and vitamin E levels to identify deficiencies causing neurological symptoms 1

Immunological Testing

• Serum protein electrophoresis to rule out paraproteinemic neuropathies 1
• Anti-ganglioside antibodies (GM1, GD1a, GD1b) to exclude multifocal motor neuropathy, which is treatable 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 be performed to exclude inflammatory and infectious mimics. 1, 2

• Order cell count, protein, glucose, IgG index, oligoclonal bands, and cytology 1

Genetic Testing

Genetic testing for ALS-associated genes should be performed, particularly when there is a family history of ALS or frontotemporal dementia. 1, 2

• Test for key genes including C9orf72, SOD1, FUS, and TARDBP 1, 6
• Approximately 10% of ALS is familial, and genetic counseling is important for family members 1, 6
• Genetic factors may be involved even without a clear family history and may be underestimated 6

Dysphagia Assessment at Diagnosis

Dysphagia screening should be performed at diagnosis and every 3 months thereafter, as swallowing abnormalities can occur even without bulbar symptoms. 1, 2

• Use the EAT-10 questionnaire, which has 86% sensitivity and 76% specificity for identifying unsafe swallowing 1, 7
• Perform the Volume-Viscosity Swallow Test (V-VST), which demonstrates 92% sensitivity and 80% specificity for detecting dysphagia 1, 7
• Videofluoroscopy should be performed at diagnosis when dysphagia symptoms are present to detect early signs of swallowing abnormalities, identify silent aspirations, and evaluate compensatory postures 7, 1, 2

Clinical Diagnostic Criteria

The diagnosis requires demonstrating both upper motor neuron signs (hypertonicity, hyperreflexia, spasticity) and lower motor neuron signs (fasciculations, weakness, muscle atrophy) with progressive spread of symptoms. 2, 5, 8

• The revised El Escorial criteria require lower motor neuron signs, upper motor neuron signs, progressive spread within or to other regions, and absence of evidence of other disease processes 5
• Clinical examination typically reveals progressive weakness starting in distal limbs, though weakness may manifest in any body segment (bulbar, cervical, thoracic, or lumbosacral) 8
• Approximately 80% of bulbar-onset patients develop dysarthria and dysphagia as presenting symptoms 2

Critical Pitfalls to Avoid

• Never rely solely on clinical examination without electrophysiological confirmation, as up to 10% of patients initially diagnosed with ALS have a mimic disorder 1, 2
• Do not skip the comprehensive laboratory panel, as several treatable conditions (multifocal motor neuropathy, myasthenia gravis, thyroid disorders, vitamin deficiencies) can present identically to ALS 1, 2
• Do not delay genetic testing in familial cases or when there is associated frontotemporal dementia, as this has implications for family counseling 1, 6
• Do not overlook early dysphagia assessment, as swallowing abnormalities can occur before bulbar symptoms develop, and early detection prevents aspiration pneumonia 1, 2
• When sensory symptoms are present, consider alternative diagnoses, as ALS does not affect sensory pathways 5