Amyotrophic Lateral Sclerosis

Epidemiology

Incidence: 1.5 to 2.7 per 100,000 in Europe and North America
Prevalence: 0.32 per 100,000
Gender: More common in men by ratio of 1.5 to 1
Age of onset: 50 to 65 years old (median 64 years)
1. Onset age <30 years in 5% of cases
2. Familial-Type ALS cases typically have onset, on average, 10 years earlier than sporadic type

Pathophysiology

Progressive degeneration of both Upper Motor Neurons and Lower Motor Neurons
Affects bulbar level and anterior horn cells of the spinal cord
Postulated mechanisms of motor Neuron injury
1. Superoxide dismutase 1 (SOD1) gene mutation affecting this antioxidant enzyme is one better known cause
  1. SOD1 defect has been used in animal models to study other mechanisms of ALS related axonal injury
2. Failed Proteostasis
  1. Misfolded, defective genes accumulate and aggregate within the cell with disorded degradation
3. Extracellular glutamate excess
  1. Over-stimulation of glutamate receptors results in excitotoxic Neuron degeneration
4. Mitochondrial dysfunction
  1. Decreased ATP production
  2. Altered Calcium Homeostasis (decreased cytoplasm buffering function and increased Neuron damage risk)
  3. Decreased axonal transport of mitochondria to regions of higher energy need
5. Other mechanisms
  1. Disordered RNA metabolism
  2. Impaired axonal transport of organelles, RNA, Proteins, lipids
  3. Free radical exposure

Background

First described by French Neurologist Jean-Martin Charcot in 1869
U.S. baseball player Lou Gehrig was diagnosed in 1939, leading to increased general population awareness of the disease

Causes

Idiopathic or sporadic ALS (90 to 95% of cases)
Familial-Type ALS ( 5-10% of cases)
1. Autosomal Dominant inheritance (at least 19 genetic defects have been identified, including SOD1)
2. Hexanucleotide repeat expansion in C9orf72 gene accounts for 30 to 50% of familal ALS (and 7% of sporadic cases)

Risk Factors

Blood relative with Familal-Type ALS
Tobacco Abuse (esp. when started at younger age)
Recurrent Head Trauma History
1. Study of italian football players (soccer) found ALS Odds Ratio 3.2
2. Chio (2005) Brain 128(Pt 3): 472-6 [PubMed]
Chemical Exposures
1. Pesticide and herbicide exposure (>4 years)
2. Formaldehyde exposure (prolonged)
3. Lead Poisoning
4. B-Mathylamino-L-Alanine (BMAA) exposure
  1. Neurotoxin found in the cycad seeds (species Cycas micornesica)
  2. Possible cause of higher Incidence (50 to 100 fold higher) in Japan, Guam and southwest New Guinea
Dietary factors
1. High glutamate intake (high Protein diet, tomatoes, mushrooms, milk, cheese)
2. High fat diet
3. In contrast, Omega 3 Fatty Acids and Fiber supplementation may be protective against development of ALS

Types
Presentations

Limb-Onset ALS (70% of cases)
1. Presents with combination of Upper Motor Neuron and Lower Motor Neuron Deficits
2. Later onset of bulbar symptoms
Bulbar -Onset ALS (25% of cases)
1. Presents with speech and Swallowing difficulty
2. Later onset of extremity weakness
3. More moon in women over age 65 years
4. Life Expectancy 2 to 4 years
Trunk Presentations with respiratory Muscle Weakness (5%)
1. Associated with nocturnal hypoventilation (Daytime Somnolence, morning Headache)
Other Motor Neuron Diseases (often progress to ALS)
1. Progressive Spinal Muscular Atrophy
2. Pseudobulbar Palsy
3. Progressive Bulbar Palsy
  1. Starts with speech and Swallowing difficulty (related to LMN deficits of CN 9, CN 10, CN 12)
  2. Better prognosis with disease duration >4 years, and segmental Muscle involvement
4. Primary Lateral Sclerosis (PLS)
  1. Pure Upper Motor Neuron involvement
  2. Progresses to ALS within 3 to 4 years in 77% of cases
  3. Considered sporadic adult onset PLS if persists >4 years
    1. Median survival >20 years (contrast with 3 to 5 years in ALS)
5. Progressive Muscular Atrophy (PMA)
  1. Pure Lower Motor Neuron Deficits (LMN deficits)
  2. Progresses to UMN deficits (and ultimately ALS) in 30% of patients by 18 months after symptom onset

Symptoms

No sensory deficits
Motor symptoms
1. Muscle aches and Muscle cramps (often precedes Muscle Weakness)
  1. Worse with cold exposure
2. Muscle Twitches (Muscle fibrillations)
3. Motor Weakness (generalized, asymmetric)
  1. Often starts in distal upper limbs and progresses proximally, then inferiorly (towards feet)
  2. However weakness may begin distally or proximally and affect both upper and lower limbs at start
Bulbar symptoms (typically presents in advanced, later stages; earlier presentation in bulbar-onset ALS)
1. Dysarthria (early bulbar symptom)
  1. Slow, labored, disordered speech (spastic Dysarthria)
  2. Nasal speech may occur later (associated with flaccid Dysarthria, Soft Palate weakness)
2. Dysphagia (later bulbar symptom)
  1. Gag Reflex is typically preserved (but Soft Palate is weak)
3. Drooling (Sialorrhea)
  1. Difficulty Swallowing Saliva
  2. Lower facial Muscle Weakness (UMN deficit)
Repiratory symptoms (late onset in most cases)
1. Dyspnea or Orthopnea
2. Nocturnal hypoventilation
Pseudobulbar symptoms
1. Emotional lability
2. Excessive Yawning
Other symptoms
1. Fatigue
2. Decreased Exercise capacity
3. Depressed mood

Signs

Muscle Fasciculations and fibrillations (esp. upper limbs)
Muscle atrophy (e.g. hands, Forearms, Shoulders, thighs, feet)
Hyperreflexia
Increased Muscle tone
Spasticity (esp. lower limbs)
1. Supinator Catch
2. Patellar Catch
3. Clonus
Oropharynx
1. See bulbar symptoms as above
2. Tongue Fasciculations, weakness, atrophy

Differential Diagnosis

See Muscle Weakness Causes
See Acute Motor Weakness Causes
See Asymmetric Peripheral Neuropathy
See Oropharyngeal Dysphagia
Hereditary neurologic syndromes
1. Spinobulbar muscular atrophy (Kennedy Disease)
2. Hereditary spastic paraparesis
3. Acid Maltase Deficiency
4. Facioscapulohumeral Muscular Dystrophy
5. Adenomyeloneuropathy
6. Huntington Disease
7. Hexosaminidase Deficiency
Metabolic Disorders
1. Iron Poisoning
2. Mercury Poisoning
3. Lathyrism
4. Organophosphate Poisoning
Autoimmune and Inflammatory Conditions
1. Multifocal motor Neuropathy
2. Post-Polio Syndrome
3. Chronic Inflammatory Demyelinating Polyneuropathy
4. Myasthenia Gravis
5. Inclusion Body Myositis
6. Polymyositis
7. Multiple Sclerosis
Structural Spine Disorders
1. Cervical Spondylotic Myelopathy
Neurodegenerative Disorders
1. Corticobasal Degeneration
2. Multiple System Atrophy
3. Progressive Supranuclear Palsy
4. Parkinsonism

Labs

See Muscle Weakness for lab and diagnostic evaluation

Diagnosis

Diagnosis is frequently delayed 13 to 18 months from onset of symptoms
Key ALS clinical features
1. Combined, progressive UMN deficits and LMN deficits involving both Brainstem and multiple spinal cord levels
2. ALS is primarily a clinical diagnosis with diagnostic testing to confirm ALS and exclude other causes
Electromyogram (EMG)
1. Muscle fibrillation on mechanical stimulation
2. Increased duration and amplitude of Action Potentials

Management

Riluzole
1. Dosing: 50 mg orally twice daily
2. Anti-glutamate properties
3. Only modest effect at best (extended life 3 months)
  1. Best effect if used early
  2. Indicated in ALS <5 years, without Tracheostomy and with Forced Vital Capacity (FVC) > 60%
4. Very expensive ($700/month)
Treat at ALS center
1. Physical Therapy
2. Occupational Therapy
3. Speech Therapy
4. Dietitian
5. Neurologist
6. Social Worker
7. Nursing Care Manager
Symptomatic treatment
1. Progressive Pseudobulbar palsy
2. Spontaneous laugh (Tricyclic Antidepressants)
3. Musculoskeletal pain (often due to Muscle cramping and spasm)
  1. Develops in 70% of ALS patients
Screen and treat comorbid conditions
1. Follow Forced Vital Capacity (FVC)
  1. Noninvasive Ventilation is indicated for falling FVC (typically at <50 to 60% of predicted)
  2. Patient may report Dyspnea, Daytime Somnolence, morning Headaches
2. Major Depression is more common in ALS
3. Nutrition
  1. Dysphagia progressively results in Malnutrition, weight loss, aspiration
  2. Percutaneous endoscopic Gastrostomy (PEG Tube) is typically needed after weight loss >10%
4. Supplements with limited evidence of ALS prevention (no clear evidence of benefit for treatment)
  1. Pu-erh Tea Extract
    1. May help prevent rapid ALS related deterioration
  2. Vitamin E
    1. Shown effective in rats but not proven in humans
Other management to avoid
1. Immunosuppressants are not effective or indicated
2. Vitamin A has not been shown beneficial
3. Dietary Creatine has not been shown beneficial

Course

Median survival 3 to 5 years from symptom onset
Majority of patients (>50%) die within 1-3 years of diagnosis
Only 10-20% survive >5 to 10 years beyond symptom onset

Complications

Uniformly fatal
1. Typically cause of death is related to respiratory complications
Respiratory Failure
1. ALS progresses to assisted ventilation in nearly all cases (typically via Tracheostomy)
Totally Locked-In State (TLS)
1. Paralysis of all voluntary Muscles
2. ALS typically progresses to TLS in those sustained on Mechanical Ventilation
3. Oculomotor function may be preserved in some cases
Frontotemporal Dementia
1. May occur in up to 10 to 15% of ALS patients

References