Neurology Book


Amyotrophic Lateral Sclerosis

Aka: Amyotrophic Lateral Sclerosis, ALS, Lou Gehrig's Disease, Bulbar Motor Neuron Disease
  1. Epidemiology
    1. Incidence: 1.5 to 2.7 per 100,000 in Europe and North America
    2. Prevalence: 0.32 per 100,000
    3. Gender: More common in men by ratio of 1.5 to 1
    4. 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
  2. Pathophysiology
    1. Progressive degeneration of both Upper Motor Neurons and Lower Motor Neurons
    2. Affects bulbar level and anterior horn cells of the spinal cord
    3. 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
  3. Background
    1. First described by French Neurologist Jean-Martin Charcot in 1869
    2. U.S. baseball player Lou Gehrig was diagnosed in 1939, leading to increased general population awareness of the disease
  4. Causes
    1. Idiopathic or sporadic ALS (90 to 95% of cases)
    2. 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)
  5. Risk Factors
    1. Blood relative with Familal-Type ALS
    2. Tobacco Abuse (esp. when started at younger age)
    3. 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]
    4. 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
    5. 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
  6. Types: Presentations
    1. 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
    2. 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
    3. Trunk Presentations with respiratory Muscle Weakness (5%)
      1. Associated with nocturnal hypoventilation (Daytime Somnolence, morning Headache)
    4. 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
  7. Symptoms
    1. No sensory deficits
    2. 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
    3. 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 SwallowingSaliva
        2. Lower facial Muscle Weakness (UMN deficit)
    4. Repiratory symptoms (late onset in most cases)
      1. Dyspnea or Orthopnea
      2. Nocturnal hypoventilation
    5. Pseudobulbar symptoms
      1. Emotional lability
      2. Excessive Yawning
    6. Other symptoms
      1. Fatigue
      2. Decreased Exercise capacity
      3. Depressed mood
  8. Signs
    1. Muscle Fasciculations and fibrillations (esp. upper limbs)
    2. Muscle atrophy (e.g. hands, Forearms, Shoulders, thighs, feet)
    3. Hyperreflexia
    4. Increased Muscle tone
    5. Spasticity (esp. lower limbs)
      1. Supinator Catch
      2. Patellar Catch
      3. Clonus
    6. Oropharynx
      1. See bulbar symptoms as above
      2. Tongue Fasciculations, weakness, atrophy
  9. Differential Diagnosis
    1. See Muscle Weakness Causes
    2. See Acute Motor Weakness Causes
    3. See Asymmetric Peripheral Neuropathy
    4. See Oropharyngeal Dysphagia
    5. 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
    6. Metabolic Disorders
      1. Iron Poisoning
      2. Mercury Poisoning
      3. Lathyrism
      4. Organophosphate Poisoning
    7. 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
    8. Structural Spine Disorders
      1. Cervical Spondylotic Myelopathy
    9. Neurodegenerative Disorders
      1. Corticobasal Degeneration
      2. Multiple System Atrophy
      3. Progressive Supranuclear Palsy
      4. Parkinsonism
  10. Labs
    1. See Muscle Weakness for lab and diagnostic evaluation
  11. Diagnosis
    1. Diagnosis is frequently delayed 13 to 18 months from onset of symptoms
    2. 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
    3. Electromyogram (EMG)
      1. Muscle fibrillation on mechanical stimulation
      2. Increased duration and amplitude of Action Potentials
  12. Management
    1. 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)
    2. Treat at ALS center
      1. Physical Therapy
      2. Occupational Therapy
      3. Speech Therapy
      4. Dietitian
      5. Neurologist
      6. Social Worker
      7. Nursing Care Manager
    3. 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
    4. 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
    5. 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
  13. Course
    1. Median survival 3 to 5 years from symptom onset
    2. Majority of patients (>50%) die within 1-3 years of diagnosis
    3. Only 10-20% survive >5 to 10 years beyond symptom onset
  14. Complications
    1. Uniformly fatal
      1. Typically cause of death is related to respiratory complications
    2. Respiratory Failure
      1. ALS progresses to assisted ventilation in nearly all cases (typically via Tracheostomy)
    3. 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
    4. Frontotemporal Dementia
      1. May occur in up to 10 to 15% of ALS patients
  15. References
    1. Masrori (2020) Eur J Neurol 27(10):1918-29 +PMID: 32526057 [PubMed]
    2. Zarei (2015) Surg Neurol Int 6:171 +PMID: 26629397 [PubMed]

Amyotrophic Lateral Sclerosis (C0002736)

Definition (MEDLINEPLUS)

Amyotrophic lateral sclerosis (ALS) is a nervous system disease that attacks nerve cells called neurons in your brain and spinal cord. These neurons transmit messages from your brain and spinal cord to your voluntary muscles - the ones you can control, like in your arms and legs. At first, this causes mild muscle problems. Some people notice

  • Trouble walking or running
  • Trouble writing
  • Speech problems

Eventually, you lose your strength and cannot move. When muscles in your chest fail, you cannot breathe. A breathing machine can help, but most people with ALS die from respiratory failure.

The disease usually strikes between age 40 and 60. More men than women get it. No one knows what causes ALS. It can run in families, but usually it strikes at random. There is no cure. Medicines can relieve symptoms and, sometimes, prolong survival.

NIH: National Institute of Neurological Disorders and Stroke

Definition (NCI) An autosomal dominant inherited form of amyloidosis.
Definition (MSH) A degenerative disorder affecting upper MOTOR NEURONS in the brain and lower motor neurons in the brain stem and SPINAL CORD. Disease onset is usually after the age of 50 and the process is usually fatal within 3 to 6 years. Clinical manifestations include progressive weakness, atrophy, FASCICULATION, hyperreflexia, DYSARTHRIA, dysphagia, and eventual paralysis of respiratory function. Pathologic features include the replacement of motor neurons with fibrous ASTROCYTES and atrophy of anterior SPINAL NERVE ROOTS and corticospinal tracts. (From Adams et al., Principles of Neurology, 6th ed, pp1089-94)
Definition (CSP) progressive degeneration of the neurons that give rise to the corticospinal tract and of the motor cells of the brain stem and spinal cord, resulting in a deficit of upper and lower motor neurons.
Concepts Disease or Syndrome (T047)
MSH D000690
ICD9 335.20
ICD10 G12.21
SnomedCT 86044005
English Gehrig Disease, Gehrig's Disease, Gehrigs Disease, Lou Gehrig Disease, Lou Gehrig's Disease, ALS, Sclerosis, Amyotrophic Lateral, ALS - Amyotroph lat sclerosis, Amyotrophic Lateral Sclerosis/Progressive Muscular Atrophy, Amyotrophic Lateral Sclerosis, LOU GEHRIGS DIS, GEHRIGS DIS, LOU GEHRIG DIS, MOTOR NEURON DIS AMYOTROPHIC LATERAL SCLEROSIS, amyotrophic lateral sclerosis, amyotrophic lateral sclerosis (diagnosis), ALS (amyotrophic lateral sclerosis), ALS (Amyotrophic Lateral Sclerosis), Motor Neuron Disease, Amyotrophic Lateral Sclerosis, Amyotrophic sclerosis, Lou-Gehrigs Disease, Disease, Lou-Gehrigs, Amyotrophic Lateral Sclerosis [Disease/Finding], amyotrophic laterals sclerosis, lou gehrig disease, lou gehrigs disease, lou gehrig's disease, Lou Gehrig's disease (ALS), Amytrophic lateral sclerosis, Charcot Disease, Amyotrophic lateral sclerosis, Bulbar motor neuron disease, Lou Gehrig's disease, ALS - Amyotrophic lateral sclerosis, Amyotrophic lateral sclerosis (disorder), creeping; palsy, lateral sclerosis; amyotrophy, palsy; creeping, sclerosis; spinal, lateral (amyotrophic), amyotrophy; lateral sclerosis, spinal; sclerosis, lateral (amyotrophic), Motor neuron disease, bulbar
Spanish ALS, enfermedad bulbar de la neurona motora, enfermedad de Lou Gehrig, esclerosis lateral amiotrófica (trastorno), esclerosis lateral amiotrófica, Esclerosis lateral amiotrófica, Enfermedad de la Neurona Motora de la Esclerosis Amiotrófica Lateral, Enfermedad de Lou Gehrig, Esclerosis Amiotrófica Lateral
Japanese ALS, キンイシュクセイソクサクコウカショウ, ALS, Gehrig病, 筋萎縮性側索硬化症, Lou Gehrig病, 側索硬化症-筋萎縮性, 筋萎縮側索硬化, 筋萎縮側索硬化症, 筋萎縮性側索硬化
Swedish Amyotrofisk lateralskleros
Czech amyotrofická laterální skleróza, Amyotrofická laterální skleróza, ALS, Charcotova choroba, Charcotova nemoc, Lou Gehrigova nemoc
Finnish Amyotrofinen lateraaliskleroosi
Italian Morbo di Lou Gehrig, SLA, Malattia del neurone motore, Sclerosi laterale amiotrofica
Polish Stwardnienie boczne zanikowe, Choroba Lou Gehringa
Hungarian Amyotrophiás lateral sclerosis, ALS
Norwegian ALS, Amyotrofisk lateralsklerose, Amyotrofisk lateral sklerose
French Maladie de Gehrig, Sclérose latérale amyotrophique, Maladie de Charcot, Maladie de Lou Gehrig, SLA (Sclérose Latérale Amyotrophique)
Dutch amyotrofie; laterale sclerose, creeping; palsy, laterale sclerose; amyotrofie, palsy; creeping, sclerose; spinaal, lateraal (amyotrofisch), spinaal; sclerose, lateraal (amyotrofisch), amyotrofe laterale sclerose, ALS, Amyotrofische laterale sclerose (ALS), Lou-Gehrig-ziekte, Motoneuronziekte, Sclerose, amyotrofische laterale, Sclerose, laterale, amyotrofische (ALS)
Portuguese Esclerose lateral amiotrófica, Doença de Lou Gehrig, Doença do Neurônio Motor em Esclerose Lateral Amiotrófica, Esclerose Amiotrófica Lateral
German amyotrophische Lateralsklerose, ALS, Amyotrophische Lateralsklerose, Gehrig-Krankheit, Myatrophische Lateralsklerose, Lateralsklerose, amyotrophische, Lateralsklerose, myatrophische, Loe-Gehrig-Krankheit, Motoreuronerkrankung, amyotrophe Lateralsklerose, Charcot-Syndrom II
Derived from the NIH UMLS (Unified Medical Language System)

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