What tests are needed to exclude treatable causes when suspecting Amyotrophic Lateral Sclerosis (ALS)?

Diagnostic Testing for Suspected Amyotrophic Lateral Sclerosis (ALS)

When suspecting ALS, comprehensive testing is required to exclude treatable mimics, as ALS is primarily diagnosed by ruling out other conditions that can present with similar symptoms.

Primary Diagnostic Tests

• Electromyography (EMG) and nerve conduction velocity (NCV) studies are the cornerstone tests for diagnosing ALS, as they can detect lower motor neuron degeneration and help distinguish ALS from other conditions 1
• MRI of the brain without IV contrast is usually appropriate for initial imaging to exclude other conditions with similar clinical presentations 1
• MRI of the spine without IV contrast may be appropriate in certain cases to exclude structural, infectious, or neoplastic etiologies that can mimic motor neuron disease 1

Laboratory Tests to Exclude Treatable Mimics

• Complete blood count (CBC) to evaluate for infectious or inflammatory conditions 1, 2
• Blood chemistry profile including glucose, electrolytes, kidney function, and liver enzymes to exclude metabolic causes 1, 3
• Thyroid function tests to rule out thyroid disorders that can cause weakness 1, 4
• Vitamin B12, folate, and vitamin E levels to exclude deficiencies that can cause neurological symptoms 1, 4
• Serum protein electrophoresis to rule out paraproteinemic neuropathies 1, 4
• Anti-ganglioside antibodies (GM1, GD1a, GD1b) to exclude immune-mediated motor neuropathies 1, 5
• Lyme disease serology as Lyme-induced polyradiculopathy can mimic ALS 5
• Paraneoplastic antibody panel to exclude paraneoplastic syndromes 1, 4
• Anti-acetylcholine receptor and anti-MuSK antibodies to rule out myasthenia gravis 1, 4
• Creatine kinase (CK) to help differentiate from muscular dystrophies (typically elevated in muscular dystrophies) 6, 4

Cerebrospinal Fluid (CSF) Examination

• CSF analysis including cell count, protein, glucose, IgG index, oligoclonal bands, and cytology to exclude infectious, inflammatory, or neoplastic causes 1
• CSF protein may be normal or mildly elevated in ALS, but marked pleocytosis (>50 cells/μl) suggests alternative diagnoses 1

Genetic Testing

• Genetic testing for ALS-associated genes (e.g., C9orf72, SOD1, FUS, TARDBP) should be considered, especially in cases with family history 6, 4
• C9orf72 hexanucleotide repeat expansion testing is particularly important as it accounts for 30-50% of familial ALS and 7% of sporadic ALS 4

Additional Considerations

• Muscle biopsy may be considered in atypical cases to exclude myopathies or inflammatory muscle diseases 6, 4
• Neuropsychological testing should be considered as up to 50% of ALS patients have cognitive or behavioral changes 4

Common Pitfalls to Avoid

• Relying solely on imaging: MRI findings in ALS can be normal early in the disease course or show nonspecific changes 1
• Missing treatable mimics: Conditions like Lyme disease, multifocal motor neuropathy, and cervical myelopathy can mimic ALS but are potentially treatable 5
• Overlooking cognitive assessment: The overlap between ALS and frontotemporal dementia is significant and can affect management 4
• Delaying diagnosis: While thorough testing is necessary, excessive testing can delay diagnosis and treatment initiation 2, 4

Imaging Findings in ALS

• The most common MRI brain findings include abnormal T2/FLAIR signal in the corticospinal tracts, particularly in the posterior limb of the internal capsule and cerebral peduncles 1
• T2*-weighted or susceptibility-weighted imaging may show abnormal hypointensity in the precentral gyrus and gray matter, which can be highly sensitive and specific for ALS 1
• Spine MRI may show abnormal T2/STIR signal in the anterior horns ("snake eyes" appearance), though this finding is not specific for ALS and may only appear later in the disease course 1