What is the recommended diagnostic work‑up and treatment for a patient with suspected amyotrophic lateral sclerosis (ALS)?

Diagnostic Work-Up and Treatment for Suspected ALS

For suspected ALS, establish the diagnosis through clinical demonstration of both upper and lower motor neuron signs with progressive spread, combined with EMG/NCV studies and comprehensive laboratory testing to exclude treatable mimics, followed by multidisciplinary symptomatic management including nutritional support, respiratory monitoring, and early palliative care referral. 1, 2

Diagnostic Approach

Clinical Evaluation

The diagnosis hinges on identifying both upper motor neuron signs (spasticity, hyperreflexia, pathological reflexes) and lower motor neuron signs (weakness, atrophy, fasciculations) with progressive symptom spread across body regions. 1, 2 Approximately 80% of bulbar-onset patients present with dysarthria and dysphagia as initial symptoms. 1, 2

Essential Electrophysiological Studies

• EMG and nerve conduction velocity studies are mandatory as the cornerstone diagnostic tests to detect lower motor neuron degeneration and distinguish ALS from treatable motor neuropathies. 1, 2, 3
• These studies help exclude conditions like multifocal motor neuropathy with conduction block, which can mimic ALS but are treatable. 3

Neuroimaging

• Brain MRI without IV contrast is the primary imaging modality to exclude structural lesions, tumors, inflammatory conditions, and other ALS mimics. 1, 2, 3
• Look for abnormal T2/FLAIR signal in corticospinal tracts, particularly in the posterior limb of internal capsule and cerebral peduncles. 3
• T2*-weighted or susceptibility-weighted imaging may show abnormal hypointensity in the precentral gyrus with high sensitivity and specificity for ALS. 3
• Spine MRI without IV contrast may be appropriate to exclude structural, infectious, or neoplastic etiologies, particularly when symptoms suggest spinal pathology. 1, 3

Comprehensive Laboratory Panel

This is critical because up to 10% of patients initially diagnosed with ALS have a treatable mimic disorder. 2 The mandatory laboratory evaluation includes:

• Complete blood count to evaluate for infectious or inflammatory conditions 1, 3
• Comprehensive metabolic panel including glucose, electrolytes, kidney and liver function 1, 3
• Thyroid function tests to exclude thyroid-related weakness 1, 3
• Vitamin B12, folate, and vitamin E levels to exclude deficiencies causing neurological symptoms 1, 3
• Serum protein electrophoresis to rule out paraproteinemic neuropathies 1, 3
• Anti-ganglioside antibodies (GM1, GD1a, GD1b) to exclude immune-mediated motor neuropathies 1, 3
• Paraneoplastic antibody panel to exclude paraneoplastic syndromes 1, 3
• Anti-acetylcholine receptor and anti-MuSK antibodies to rule out myasthenia gravis 1, 3

Cerebrospinal Fluid Analysis

• Perform CSF analysis including cell count, protein, glucose, IgG index, oligoclonal bands, and cytology to exclude infectious, inflammatory, or neoplastic causes. 1, 3
• CSF protein may be normal or mildly elevated in ALS, but marked pleocytosis (>50 cells/μl) suggests an alternative diagnosis. 3

Genetic Testing

• Consider genetic testing for ALS-associated genes (C9orf72, SOD1, FUS, TARDBP), especially with family history of ALS or frontotemporal dementia. 1, 2, 3
• Genetic factors may be involved even without obvious family history and may be underestimated. 4

Dysphagia Assessment

Initial and Follow-Up Screening

Screen for dysphagia at diagnosis and every 3 months thereafter as part of comprehensive evaluation, since dysphagia occurs in 6.2-85.7% of ALS patients and is present in 48.1-85.7% of bulbar-onset cases. 5, 1, 2

Screening Tools

• EAT-10 questionnaire demonstrates high discriminatory ability to identify patients who aspirate (sensitivity 86%, specificity 76%, negative predictive value 95%). 5, 1
• Volume-Viscosity Swallow Test (V-VST) shows high sensitivity (92%) and specificity (80%) for detecting dysphagia compared to videofluoroscopy. 5, 1
• Use the ALS Functional Rating Scale-Revised (ALSFRS-R) to track overall disease progression including swallowing function. 5

Clinical Assessment Components

Evaluate lip closure, saliva pooling, tongue strength/mobility/tone, chewing capacity, palatal movement response to tactile stimulation, cough quality and strength, and phoniatric function. 5

Instrumental Assessment

• Videofluoroscopy is recommended at diagnosis for clinical evaluation of dysphagia to detect early swallowing abnormalities, identify silent aspirations, and evaluate compensatory postures. 5, 1, 2
• Fiberoptic endoscopic evaluation of swallowing (FEES) is an efficient bedside alternative that can identify impaired chewing, tongue muscle deficit, and velopharyngeal closure issues. 5

Treatment and Management

Nutritional Support

Nutritional support is essential for patients with dysphagia and weight loss, as malnutrition is present in 0-21% at diagnosis and 7.5-53% during follow-up depending on criteria used. 5, 1 Aspiration pneumonia occurs in approximately 13-15% of patients. 5

Respiratory Management

Respiratory support is critical since respiratory failure from respiratory muscle weakness is the most common cause of death. 1, 2 Monitor slow vital capacity (SVC) and peak cough flow (PCF) regularly to guide timing of ventilatory interventions. 4

Palliative Care

Early referral to palliative services is recommended to establish relationships with staff and address end-of-life issues before communication becomes limited. 1, 2 This is particularly important given mean survival of 3-5 years after symptom onset, with only 5-10% surviving beyond 10 years. 1, 2

Monitoring Schedule

• Conduct comprehensive evaluations every 3 months to assess dysphagia progression, nutritional status (BMI), respiratory function, and overall disease progression using ALSFRS-R. 5, 1, 2
• More frequent monitoring may be needed based on rate of clinical progression. 5

Critical Pitfalls to Avoid

Do not delay comprehensive laboratory testing – up to 10% of suspected ALS cases are treatable mimics. 2 Do not wait for severe dysphagia before initiating swallowing evaluations – early abnormalities can be detected even without bulbar symptoms. 5 Do not postpone palliative care discussions – early referral improves quality of life and allows for meaningful communication before disease progression limits this capacity. 1, 2