What is the diagnostic workup to exclude other conditions mimicking Amyotrophic Lateral Sclerosis (ALS) in a patient presenting with symptoms suggestive of ALS?

Diagnostic Workup to Exclude ALS Mimics

The workup to exclude conditions mimicking ALS requires electromyography with nerve conduction studies as the cornerstone test, combined with brain and spine MRI, comprehensive laboratory testing for treatable mimics, and CSF analysis to rule out inflammatory, infectious, and neoplastic conditions. 1, 2

Essential Electrophysiological Testing

• EMG and nerve conduction velocity (NCV) studies are mandatory as the primary diagnostic tools to detect lower motor neuron degeneration and distinguish ALS from other conditions 1, 2
• These studies help differentiate ALS from compressive neuropathies, multifocal motor neuropathy, and other peripheral nerve disorders 3

Neuroimaging Protocol

Brain MRI

• Brain MRI without IV contrast is the primary imaging modality to exclude structural lesions, tumors, multiple sclerosis, and inflammatory conditions that mimic ALS 1, 2
• The protocol should include T1/T2, FLAIR, and T2*-weighted or susceptibility-weighted sequences 1
• Look for abnormal T2/FLAIR hyperintensity in the corticospinal tracts (posterior limb of internal capsule, cerebral peduncles) which supports ALS diagnosis 1, 2
• T2*-weighted imaging may show abnormal hypointensity in the precentral gyrus, which can be highly sensitive and specific for ALS 1, 2

Spine MRI

• Spine MRI without IV contrast should be obtained to exclude structural, infectious, or neoplastic etiologies such as cervical myelopathy, spinal cord tumors, or syringomyelia 1, 2
• May show "snake eyes" appearance (abnormal T2/STIR signal in anterior horns), though this is not specific for ALS 1

Comprehensive Laboratory Panel

The following blood tests are essential to exclude treatable ALS mimics: 2

Metabolic and Hematologic Tests

• Complete blood count (CBC) to evaluate for infectious or inflammatory conditions 1, 2
• Comprehensive metabolic panel including glucose, electrolytes, kidney function, and liver enzymes to exclude metabolic causes 1, 2
• Thyroid function tests (TSH, free T4) to rule out thyroid disorders causing weakness 1, 2

Nutritional Deficiencies

• Vitamin B12, folate, and vitamin E levels to exclude deficiencies causing neurological symptoms 1, 2

Immune-Mediated Conditions

• Serum protein electrophoresis to rule out paraproteinemic neuropathies (such as POEMS syndrome or monoclonal gammopathy) 1, 2
• Anti-ganglioside antibodies (GM1, GD1a, GD1b) to exclude multifocal motor neuropathy with conduction block, which is treatable with immunotherapy 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 is recommended to exclude inflammatory, infectious, or neoplastic causes 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 alternative diagnoses such as Lyme disease, HIV-associated myelopathy, or lymphomatous meningitis 1

Genetic Testing

• Genetic testing for ALS-associated genes should be considered, particularly when there is family history of ALS or frontotemporal dementia 1, 2
• Test for key genes including C9orf72, SOD1, FUS, and TARDBP 2, 4
• Approximately 10% of ALS cases are familial, making genetic counseling important for family members 2

Critical Pitfalls to Avoid

• Do not rely solely on clinical examination: Up to 10% of patients initially diagnosed with ALS have a mimic disorder 2, 5
• Do not skip the comprehensive laboratory panel: Several treatable conditions (multifocal motor neuropathy, myasthenia gravis, Kennedy's disease, thyroid disorders) can present identically to ALS 2, 6
• Watch for red flags suggesting alternative diagnoses: Pure sensory symptoms, acute onset, prominent pain, bowel/bladder dysfunction early in disease, or failure to progress over 6-12 months should prompt reconsideration of the diagnosis 5, 6
• Beware of compressive neuropathies: Hand surgeons report that 11% have performed nerve decompression surgeries on patients later diagnosed with ALS 3
• Key warning signs include: Weakness without sensory symptoms, profound weakness in multiple nerve distributions, progressively bilateral symptoms, presence of bulbar symptoms (tongue fasciculations, speech/swallowing difficulties), and failure to improve after surgery 3

Important ALS Mimics to Exclude

The workup specifically targets these treatable or distinct conditions: multifocal motor neuropathy with conduction block, myasthenia gravis, Kennedy's disease (X-linked bulbospinal muscular atrophy), cervical spondylotic myelopathy, spinal cord tumors, primary lateral sclerosis, progressive muscular atrophy, inclusion body myositis, POEMS syndrome, paraneoplastic syndromes, and thyroid disorders 5, 6, 7