In a middle‑aged adult presenting with limb weakness, muscle wasting, fasciculations, spasticity and dysarthria, how should I work up for amyotrophic lateral sclerosis and what are the first‑line disease‑modifying and supportive management options?

Workup and Management of Amyotrophic Lateral Sclerosis

Immediately refer the patient to a multidisciplinary ALS clinic, as this care model extends survival by approximately 142 days and improves quality of life more than any other intervention, including pharmacologic therapy. 1

Diagnostic Workup

Clinical Diagnosis

The diagnosis of ALS requires demonstrating both upper and lower motor neuron signs in the same body region: 2, 3

Upper motor neuron signs:

• Hypertonicity and hyperreflexia 2
• Spasticity in affected limbs 2
• Pathologic reflexes (Babinski, Hoffman) 2

Lower motor neuron signs:

• Muscle fasciculations (visible twitching) 2
• Progressive muscle weakness and atrophy 2
• Hyporeflexia in advanced disease 4

Bulbar involvement (present in ~80% of bulbar-onset cases):

• Dysarthria (speech difficulty) 2, 3
• Dysphagia (swallowing difficulty) 2, 3
• Sialorrhea (drooling from impaired saliva swallowing) 2
• Nasal regurgitation from soft palate weakness 2

Imaging Studies

MRI brain and spine without contrast is the primary imaging modality to exclude ALS mimics and support the diagnosis: 5, 2

• Look for abnormal T2/FLAIR hyperintensity along the corticospinal tracts (reflects axonal degeneration and gliosis) 2
• Assess for "snake eyes" appearance in the anterior horns of the spinal cord (indicates lower motor neuron disease) 5, 2
• Rule out structural lesions, vascular disease, inflammatory conditions, or cervical myelopathy that can mimic ALS 5

Electrodiagnostic Testing

Electromyography (EMG) and nerve conduction studies are essential to confirm lower motor neuron involvement and exclude mimics, though specific diagnostic criteria are not detailed in the provided guidelines. 6, 7

Baseline Assessments at Diagnosis

Respiratory function: 1

• Forced vital capacity (FVC) or slow vital capacity (SVC)
• Maximum expiratory pressure (MEP)
• Awake capnography to measure PaCO₂

Nutritional status: 2

• Body mass index (BMI) and weight (malnutrition increases mortality risk >4-fold) 2
• Bioelectrical impedance analysis (BIA) for body composition and phase angle 2
• Videofluoroscopic swallowing study at diagnosis to detect silent aspiration, as dysphagia can occur without symptoms 2

Cognitive screening: 1, 2

• Screen for cognitive impairment (present in ~40% of patients), as this reduces NIV compliance and affects treatment decisions 1, 2

Disease-Modifying Therapy

Riluzole

Riluzole is the only FDA-approved disease-modifying drug for ALS, though its benefit is modest: 6, 8

• Extends survival by 3-6 months on average 6
• Functions as a glutamate antagonist and sodium channel blocker 8

Edaravone

While not detailed in the provided guidelines, edaravone is another approved disease-modifying therapy based on general medical knowledge.

Supportive Management (First-Line Interventions)

Respiratory Support (Highest Priority)

Non-invasive ventilation (NIV) provides the greatest survival and quality-of-life benefit of any ALS treatment, exceeding riluzole. 1

Initiate NIV when any of the following criteria are met: 1

• FVC <80% of predicted with respiratory symptoms (dyspnea, orthopnea, morning headaches, daytime hypersomnolence)
• FVC <50% of predicted regardless of symptoms
• Awake PaCO₂ >45 mmHg

NIV implementation: 1

• Use bilevel positive airway pressure (BPAP) with backup respiratory rate for optimal patient-ventilator synchrony 1
• Do not withhold NIV trial based solely on bulbar symptoms, though bulbar dysfunction is the primary limitation to effectiveness 1
• Screen for cognitive impairment before recommending NIV, as cognitive dysfunction reduces compliance 1, 2

Monitoring schedule: 1

• Pulmonary function testing (FVC/SVC, MEP) every 6 months minimum
• Screen for sleep disturbances at each visit
• Assess awake CO₂ tension at least annually

Airway clearance: 1

• Implement mechanical insufflation-exsufflation (MI-E) devices when peak cough flow falls below effective levels
• Use lung volume recruitment (breath stacking) techniques for reduced lung function

Nutritional Support

Dysphagia management: 2

• Implement structured dysphagia screening every 3 months using the Eating Assessment Tool-10 (EAT-10; 86% sensitivity, 76% specificity) 2
• Modify food texture to prevent aspiration and improve intake 2
• Teach chin-tuck posture to protect airways during swallowing 2
• Consider head rotation for hypertonicity or incomplete upper esophageal sphincter closure 2

Nutritional optimization: 2

• Target weight gain if BMI <25 kg/m²; weight stabilization if BMI 25-35 kg/m² 2
• Estimate energy needs at 30 kcal/kg body weight when indirect calorimetry unavailable 2
• Advise multiple small meals throughout the day for patients with fatigue 2
• Provide high-calorie meal enrichment and nutritional supplementation as needed 2

Gastrostomy timing: 2

• Place percutaneous endoscopic gastrostomy (PEG) before severe respiratory compromise (ideally before FVC drops significantly) 2
• Perform PEG before >10% weight loss, as placement after this threshold increases mortality risk 4-fold (RR 4.18; 95% CI 2.72-6.42) 2

Symptom Management

Spasticity: 5

• Oral antispasticity agents (baclofen, tizanidine) for generalized spasticity, though sedation may be dose-limiting 5
• Targeted botulinum toxin injections for focal spasticity interfering with function 5

Sialorrhea: 2

• Anti-muscarinic therapy (glycopyrrolate, scopolamine patches) 2
• Botulinum toxin A injections into salivary glands 2

Constipation: 2

• Add dietary fiber for constipation from abdominal muscle weakness 2

Palliative Care Integration

Initiate palliative care at diagnosis, not at end-of-life: 2, 3

• Early referral establishes relationships before communication becomes limited 2
• Focus on patient autonomy, dignity, and quality of life throughout disease course 2

Advance care planning: 1, 2

• Begin discussions at diagnosis regarding preferences for long-term mechanical ventilation via tracheostomy (chosen by only 4-9% of patients) 2
• Address feeding tube preferences 1
• Discuss end-of-life care preferences 1
• Repeat these conversations as disease progresses 1

Caregiver support: 2

• Implement structured support including counseling, support groups, and crisis management from diagnosis 2
• Recognize that caregiver burden is substantial and worsens with patient behavioral deficits 2

Critical Monitoring Parameters

Every 6 months: 1

• Pulmonary function testing (FVC, MEP)

Every 3 months: 2

• Dysphagia screening with EAT-10

Every visit: 1, 2

• Weight and BMI 2
• Sleep disturbance screening 1
• Cognitive and behavioral assessment 2

Annually: 1

• Awake capnography for CO₂ measurement

Prognostic Information

Mean survival is 3-5 years from symptom onset, with only 5-10% of patients surviving >10 years. 2, 3

Key prognostic factors: 2

• Each 5% weight loss increases mortality risk by 34% 2
• Each 1-point BMI decrease increases mortality risk by 24% 2
• Each 1-degree decrease in phase angle (BIA) increases mortality risk by 68% 2
• Malnutrition at diagnosis increases death risk >4-fold 2

Common Pitfalls to Avoid

• Late referral to multidisciplinary ALS clinic is the most harmful error, as this care model provides the greatest survival benefit 1, 2
• Delaying NIV initiation until severe respiratory failure develops, missing the window for optimal benefit 1
• Withholding NIV based solely on bulbar symptoms, as NIV should still be trialed 1
• Late gastrostomy placement after >10% weight loss or severe respiratory compromise, which markedly increases mortality 2
• Delaying videofluoroscopy until symptomatic dysphagia develops, missing silent aspiration 2
• Late palliative care referral, which negatively impacts quality of life for patients and caregivers 2