Provide a concise summary of amyotrophic lateral sclerosis (ALS), including epidemiology, clinical presentation, diagnostic criteria, management, and prognosis.

Amyotrophic Lateral Sclerosis (ALS): Clinical Summary

Definition and Epidemiology

ALS is a relentlessly progressive neurodegenerative disease characterized by degeneration of both upper and lower motor neurons, leading to progressive muscle weakness, paralysis, and typically death within 3-5 years of symptom onset. 1

• ALS represents approximately 85% of all motor neuron disease cases 1
• Annual incidence is 1-2 per 100,000 people 2
• In Germany, 6000-8000 people are affected, with 1200-1600 newly diagnosed patients annually 3
• Only 5-10% of patients survive longer than 10 years 1, 4
• 10-15% of cases are familial (autosomal dominant inheritance), while 90% are sporadic 2, 5

Pathophysiology

• Progressive degeneration occurs in both upper motor neurons (corticospinal tracts) and lower motor neurons (anterior horn cells) 1
• Molecular hallmark is protein aggregation in motor neuron cytoplasm, most commonly TDP-43 deposits 3
• Common causal genes in familial cases include C9orf72 (30-50% of familial ALS, 7% of sporadic), SOD1, FUS, and TARDBP 3, 5
• Cellular mechanisms include mitochondrial dysfunction, glutamate excitotoxicity, oxidative stress, inflammation, and apoptosis 1, 6

Clinical Presentation

Motor Features

• Upper motor neuron signs: hypertonicity, hyperreflexia, spasticity 1
• Lower motor neuron signs: muscle fasciculations, progressive weakness, muscle atrophy 1, 3
• Disease typically begins focally in one limb (asymmetric onset) then spreads to other body regions 4, 5
• Nearly all patients eventually develop bulbar involvement affecting speech and swallowing, regardless of initial onset site 4

Bulbar Symptoms

• Approximately 80% of bulbar-onset patients develop dysarthria and dysphagia 1
• Dysphagia eventually develops in 42.9% of upper limb onset cases and 71.4% of lower limb onset cases 4
• Sialorrhea occurs due to impaired swallowing of saliva 1
• Nasal regurgitation results from soft palate weakness 1

Extra-Motor Manifestations

• Up to 50% of patients develop behavioral changes, executive dysfunction, or language problems 5
• 10-15% meet clinical criteria for frontotemporal dementia (FTD) 5
• Cognitive impairment affects up to 40% of patients and significantly impacts treatment decisions and compliance 1

Diagnostic Approach

Clinical Diagnosis

• Diagnosis requires progressive upper and lower motor neuron signs in the same body region 2, 7
• Median time from symptom onset to diagnosis is 14 months 7
• ALS presents with relentlessly progressive symptoms, not waxing and waning patterns 2
• Acute pain is not an initial symptom of ALS 2

Diagnostic Testing

• MRI brain and spine (without contrast): Look for abnormal T2/FLAIR signal in corticospinal tracts and "snake eyes" appearance in anterior horns 1
• Electromyography (EMG): Confirms lower motor neuron involvement and helps establish diagnosis 2, 6
• Videofluoroscopy: Detects early dysphagia signs and should be performed at diagnosis in all patients 8
• Additional tests exclude ALS-mimicking conditions 1

Key Diagnostic Findings on Imaging

• Abnormal T2/FLAIR signal anywhere within corticospinal tracts (reflects axonal degeneration, gliosis, and secondary demyelination) 1
• Abnormal T2 signal in anterior horns with "snake eyes" appearance (reflects lower motor neuron disease) 1

Management

Disease-Modifying Therapy

• Riluzole is the only FDA-approved disease-modifying medication, modestly extending survival by 3-6 months 6, 7

Nutritional Management

Nutritional status is a critical prognostic factor for survival in ALS patients. 8

Assessment and Monitoring

• Assess BMI and weight at diagnosis and throughout follow-up 8, 1
• Target weight gain if BMI <25 kg/m², weight stabilization if BMI 25-35 kg/m² 1
• Each 5% weight loss increases death risk by 34% 8
• Each 1-point BMI loss increases death risk by 24% 8
• Use bioelectrical impedance analysis (BIA) to assess body composition (validated against DEXA) 8

Energy Requirements

• Estimate 30 kcal/kg body weight when indirect calorimetry unavailable, adjusted for physical activity and body composition 8
• Harris-Benedict equation is not valid for individual ALS patients (limits of agreement -677 to +591 kcal/day) 8

Dysphagia Management

• Modify food texture to ease oral and pharyngeal transport while preventing aspiration 1
• Chin-tuck posture prevents laryngeal penetration in majority of cases 1
• Head rotation indicated for hypertonicity or incomplete upper esophageal sphincter release 1
• Throat clearing every 3-4 swallows prevents post-swallowing aspiration 1
• Advise multiple small meals daily for patients with fatigue 1
• Add dietary fiber for constipation from abdominal weakness 1

Enteral Nutrition

• Gastrostomy placement should occur before severe respiratory compromise 8
• Weight loss >10% at PEG placement increases mortality (RR 4.18,95% CI 2.72-6.42) 8
• Mean feeding duration is 11-18 months 1

Respiratory Management

• Monitor slow vital capacity (SVC) and peak cough flow (PCF) regularly 3
• Non-invasive ventilation (NIV) improves quality of life and survival 1
• Assess cognitive function before recommending NIV, as compliance is reduced in cognitively impaired patients 1
• Only 4-9% of patients choose invasive mechanical ventilation 1
• Respiratory failure from respiratory muscle weakness is the most common cause of death 1

Symptomatic Management

• Anti-muscarinic therapy or botulinum toxin A for sialorrhea 1
• Regular screening for dysphagia at diagnosis and during follow-up 4
• Assistive devices for mobility and communication 3

Palliative Care

Palliative care should be integrated from the time of diagnosis, with emphasis on patient autonomy, dignity, and quality of life. 1

• Early referral to palliative services establishes relationships before communication becomes limited 1
• Initiate advance care planning discussions at diagnosis, including preferences for ventilatory support, feeding tubes, and end-of-life care 1
• 78% of European centers consider advance directives useful, though only 30% of patients complete them 1
• Implement structured caregiver support including counseling and support groups 1
• Late referral to palliative services is the most common harmful error 1

Multidisciplinary Care

• Multidisciplinary care improves both survival and quality of life 1
• Care in specialized ALS centers ensures optimal treatment regarding symptomatic medication, assistive devices, nutrition support, and ventilation therapy 3
• Neurologist serves as care coordinator in diagnostic phase 1

Prognosis

• Mean survival is 3-5 years after symptom onset 1, 4, 5
• Survival range extends from months to decades for approximately 5% of patients 6
• Malnutrition at diagnosis increases death risk 4.25-fold 8
• Each 1-degree decrease in phase angle increases death risk by 68% 8
• Higher fat mass during disease significantly increases survival (10% risk reduction per 2.5 kg FM gain) 8
• Disease progression is highly variable and measured by ALS Functional Rating Scale-Revised (ALSFRS-R) 3

Critical Pitfalls to Avoid

• Delaying videofluoroscopy assessment—aspiration can occur without clinical signs or subjective complaints 8, 1
• Using Harris-Benedict equation for individual energy estimation—leads to under- or overfeeding in majority of patients 8
• Late gastrostomy placement after significant weight loss or respiratory decline 8
• Late referral to palliative services—negatively impacts quality of life for patients and caregivers 1
• Failing to screen for cognitive impairment—affects treatment decisions, NIV compliance, and prognosis 1
• Neglecting caregiver support—caregiver burden is substantial and worsens with patient behavioral deficits 1