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SPORADIC ALS

Sporadic ALS: Common forms   Clinical features   Diagnostic criteria   Differential diagnosis   Discussion of diagnosis   Epidemiology   Laboratory features   Pathology   Prognosis   Treatment Variants of ALS   Hereditary ALS   Primary lateral sclerosis   Primary muscular atrophy Multisystem disorders   + EOM & Extrapyramidal Δ   Fronto-Temporal dementia   Multiple system atrophy   Polyglucosan body disease   Western Pacific ALS

From NLM Jean Martin Charcot

MRI: FLAIR Motor Neuron Disease (Late) Cerebral Peduncles: Hyperintensity

Sporadic ALS: Common forms

Lou Gehrig & Babe Ruth

• ALS: Epidemiology⁷
  • Frequency statistics
    • Incidence/100,000/year
      • Overall: 0.4 to 2; Male = 2.1; Female 1.8
      • 65 to 74 years: Male = 10.2; Female = 7.4
      • Increases in 1990's in: Females; Patients > 75 years; Southern Europe
    • Prevalence: 3 to 8 per 100,000
    • Risk increases with age up to 74 years
    • Life-long risk of ALS (Living to 70 years) = 1:2000
    • Mortality
      • Causes 1 in 700 deaths
      • Rate: 1.9/100,000/year
    • Geography: World-wide distribution
      • General frequency: Uniform
      • Exception: Variants on Guam (Chamorro) & Kii peninsula of Japan
  • Male:Female
    • Western countries 1.5:1
    • India 3:1
    • Younger onset patients: More male predominance
  • Onset age
    • Mean: 46 to 63 years
      • US & Europe: 56 to 63 years
      • India: 46 years
    • Before 20 years: Only rare cases
    • Genetics
      • MAO-B5 allele²: Higher (60 years) with allele; Lower (52 years) with others
      • Homozygous CNTF gene defect⁸
        • Present in 2% of normals
        • Earlier onset of sporadic & SOD ALS: 48 vs 58 years; Normal disease duration
        • Associated with loss of 15% to 20% of neurons in postnatal mice
      • Associated with variants in SMN2 gene number
      • SOD1: 50 bp deletion in promoter region ³⁰
        • ALS onset age: Increased
        • SOD1 activity: Reduced
        • SP1 binding: Reduced
  • ALS associations: Disease & Gene¹⁰

    ALS: Possible Susceptibility & Modifier Genes26
    Gene	Locus	Variant
    ApoE ε4	19q13	ε4 genotype
    CNTF	11q12	Null allele
    EAAT2	11p13	Low expression
    GluR2	4q32	RNA editing Δ
    NEFH	22q12	KSP deletions
    SMN1	5q12	Copy number
    SMN2	5q12	Copy number
    VEGF	6p12	Promoter SNPs
    Dynactin	2p13	Mutations
    PON1	7q21	Linkage
    FLJ10986	1	Linkage
    ITPR2	12p11	Linkage
    DPP6	7	Linkage
    Progranulin	17q21.3	Mutations

    • Habitus: Lifelong slim (2.2x higher)
    • History of
      • Varsity athletics: 1.7x higher
      • Current smoking in females: 1.7x higher²¹
    • ? Lymphoma with M-protein or CSF protein elevated
    • Chromosomal rearangements¹⁴
      • Frequency: 5.9% vs 0.05 to 0.1% in general population
      • Types: Balanced translocations (3/85); Pericentric inversions (2/85)
    • EAAT2 (glutamate transporter) : RNA processing errors
    • APOE
      • Plasma levels high
        • Correlate with rapid deterioration & shorter survival time
        • Relative risk = 0.647
      • APOE phenotype: No clear correlations
    • Vascular endothelial growth factor (VEGF)¹⁸
      • Low VEGF producing homozygous haplotypes
        • 1.8-fold higher risk of ALS
        • Haplotypes: -2578A/-1,154A/-634G; -2578A/-1,154G/-634G
      • Associated with low circulating VEGF levels
      • Association found for both sporadic & familial ALS
      • Earlier death in SOD mutant mice with impaired VEGF expression
    • Hyperlipidemia²⁵
      • Total cholesterol or LDL high: 2x more frequent in ALS than controls
      • LDL/HDL ratio high: 12 month longer survival in ALS
    • Progranulin (PGRN; GRN)³¹
      • ALS
        • ALS mutations: Missense; 5' regulatory; DNA variants
        • ALS clinical associations of IVS2 + 21G>A or IVS3-47-46insGTCA mutations
          • Younger disease onset
          • Shorter survival
      • Fronto-temporal dementia: Null mutations
• ALS: Clinical features
  • Typical pattern: Upper + Lower motor neuron signs with normal sensation
  • Weakness
    • Patterns of weakness & dysfunction: Common features
      • Limb weakness
        • Early patterns
          • Asymmetric
          • May involve proximal or distal musculature
        • Specific patterns
          • Upper > Lower extremity
            • Higher frequency in patients of African descent
          • Distal lower extremity
            • More common at disease onset in hereditary ALS
      • Bulbar dysfunction²⁸
        • Most commonly associated with upper motor neuron dysfunction
        • Frequency
          • More common in older females: 50% with bulbar presentation
          • Bulbar signs at onset: 20% to 30% of all sporadic ALS cases
        • Features
          • Dysarthria
            • Speech rate: Slow
            • Speech pattern: Slurred; Short phrases; Inappropriate pauses
            • Voice quality: Reduced; Hypernasality; Reduced range of pitch & loudness
          • Dysphagia
            • Aspiration: Fall in O₂ saturation or increased respiratory rate after oral intake
            • Food types: Dry, Tough-textured or Crumbly; Thin liquids
            • Eating time: Increased
            • Saliva: Poor swallowing; Droolong
          • Emotional lability
            • Common association
            • "Pseudobulbar" affect
          • Other bulbar features

            Tongue in ALS: Weak with little wasting At rest & Attempted protrusion

            • Difficulty with voluntary coughing
            • Laryngospasm (20%)
            • Difficulty using external respiratory support
          • Jaw
            • Reflex: Brisk
            • Difficulty closing
          • Tongue
            • Movements: Slow
            • Bulk: Often relatively preserved for degree of dysfunction
      • Respiratory failure
        • May occur in isolation
        • Frequent association: Arm weakness
        • Early stages often asymptomatic
        • Early event: Hypoventilation
          • Occurs first in REM sleep
          • Accessory muscles of respiration become flaccid
        • Symptoms
          • Dyspnea
          • Sleep disorders
          • Morning headache
          • Ineffective cough: Weakness of expiratory muscles
        • Associations: Loss of sense of taste; Weight loss; Depression
        • External respiratory support
          • More effective when bulbar involvement absent
      • Areas of weakness with some specificity for ALS
        • Very proximal denervation
          • Paraspinous
          • Posterior neck
        • Jaw weakness: Closure; Opening
        • Voice
          • Nasal, slurred speech
          • Continuous emission of sound
        • Tongue
          • Weak
          • Movement
            • Slow
            • Reduced amplitude
          • Relatively preserved bulk: Often
          • Associated signs
            • Movement of jaw with tongue
            • Jaw reflex: Hyperactive
        • Isolated respiratory failure
    • Muscle wasting
      • Often present early in disease course
      • Usually associated with Weakness

        Wasting of hands & arms in ALS

    • Progression: Regional (Arms, Legs or Bulbar)
      • Symptoms usually progress first in already affected region
      • Continuous progression once region (bulbar,arms, or legs) involved
      • Other regions involved later
        • Spread usually to adjacent region
        • No predictor of time of involvement
      • Periods of symptomatic stabilization may occur
      • Remissions in symptoms or signs rare
  • Spontaneous motor activity
    • Cramps
      • Common in legs, at night
      • Often resolve spontaneously with disease progression
      • May be severe later in disease: Associated with prominent spasticity
    • Fasciculations
      • ALS rarely presents with fasciculations in the absence of weakness
      • Pathogenesis: ? Greater persistent Na⁺ conductance in motor axons
  • Upper motor neuron
    • Anatomic patterns
      • Bulbar: Causes most tongue & bulbar dysfunction
      • Paraparesis
      • Asymmetry: Common in limbs, especially early in disease
      • Cortical hemiparetic: Occasional
    • Tendon reflexes
      • Hyperactive (100%): In areas with normal strength and weakness
      • More common sign than upgoing toes (30% to 50%)
    • Bulbar involvement associated with emotional lability (75%)
    • May cause disability without associated weakness: Especially in legs
    • Laboratory correlates: Abnormal²⁰
      • MR spectroscopy
      • Transcranial magnetic stimulation
  • Pain: Related to immobility
  • Behavioral
    • Cognitive change: Frontal lobe dysfunction (mild) not uncommon
    • Pseudobulbar affect: Unprovoked laughing & crying; Common with bulbar involvement
    • Dementia: 3% to 5%
  • Rarely involved: Bladder; bowels; Autonomic; Extraocular movements; Sensory
  • Skin: Reduced type IV collagen immunoreactivity
• Diagnostic criteria (by clinical exam, EMG and pathology)
  • Definite ALS: Progressive disease with
    • Upper & lower motor neuron signs in bulbar & 2 spinal regions, or
    • Upper & lower motor neuron signs in 3 spinal regions
  • Probable ALS: Progressive disease with
    • Upper & lower motor neuron signs in 2 regions and
    • Upper motor neuron signs in a region rostral to the lower motor neuron signs
  • External link: Formal diagnostic criteria
• Variant syndromes
  • Primary muscular atrophy (PMA): Lower motor neuron signs only
  • Primary lateral sclerosis (PLS): Upper motor neuron signs only
• Possible differential diagnoses
  • Spondylitic myelopathy or radiculopathy
  • Motor neuron disease variant with only lower or upper motor neuron signs
    • Primary lateral sclerosis (upper motor neuron only)
      • ? Rare association with breast cancer
    • Lower motor neuron disorders, motor neuropathies & motor syndromes
    • Localized pseudobulbar palsy: Older females
  • Polymyositis
  • Benign fasciculations
  • Multiple sclerosis
  • Cerebrovascular disease
    
• Survival²⁹
  • Mean
    • Overall survival: 3 to 4 years
    • Survival after diagnosis: ~2 years
    • Time from initial symptom to diagnosis: ~1 year
  • Longer survival¹⁷
    • Frequency (> 10 years): 4% to 10%
    • Features at onset
      • More frequent than general ALS population
        • Younger age: Mean 43 years; 14 years younger than average
        • Pure upper motor neuron signs
      • No difference from general ALS population: Sex; Site of onset
      • Both UMN & LMN signs at onset: 70%
    • PLS: Longer survival
    • Younger onset: Longer survival
    • Indian²⁷ & African patients: Longer survival; Mean 115 months
    • Drugs: Calcium intake
  • Poorer prognosis for survival
    • Clinical
      • Increasing age
      • Prominent recent weight loss
      • Short time from onset to diagnosis
      • Rapid rate of strength & respiratory loss during 6 months after diagnosis⁹
      • Respiratory failure
      • No gastrostomy
      • Drugs: Aspirin; Acetaminophen
    • Laboratory
      • Pulmonary function: Poor; < 60% of predicted
      • Serum
        • Chloride: Low; ? Relation to poor nutrition
        • Bicarbonate: High
      • EMG
        • Low CMAPs
        • Decrement on RNS
        • SFEMG: Marked jitter; Low fiber density
      • ? Homozygous deletion of SMN2 gene⁵
        • More common in sporadic ALS
        • Survival time: 2 years shorter
  • Death
    • Cause of death: Respiratory failure most common
    • Onset of respiratory failure with reduced consciousness due to hypercapnea
    • Death: Usually peaceful & occurs in sleep
    • Choking unusual
• Laboratory features
  • EMG: Denervation
    • Spontaneous activity: Fibrillations, Positive sharp waves, Fasciculations
    • Motor unit size: Normal or Large
    • Distribution
      • Proximal & Distal
      • In several body regions
      • Thoracic paraspinous: Some specificity for motor neuron diseases
  • Serum
    • CK: Normal to 4x elevated
    • Angiogenin: Mean level 20% elevated, especially spinal ALS²³
    • VEGF: Normal
  • CSF: Usually normal
  • MRI
    • Cortex
      • Reduced T2 signal intensity in motor cortex: Not specific for ALS
      • Reduced N-acetylaspartate by MRI
        • May correlate with spasticity: Reduced finger tap rate
    • Subcortical white matter
      • Corticospinal tract regions: Increased T2 Signal
      • Probably 2° to axonal loss (Wallerian degeneration)
• Pathology
  • Anterior horn cells
    • Shrinkage & Loss of cell bodies
      • Course of cell body loss²²
        • Early: Rapid
        • Late: Slower
      • ? Associated with Apoptosis
      • Sparing: Nucleus of Onufrowicz, or Onuf
        • Parasympathetic neurons in the sacral spinal cord
        • Innervation of bowel & bladder
    • Spheroids (Aggregations of neurofilaments) in proximal axons
    • Bunina bodies (Dense granular inclusions) in cell body cytoplasm
    • Hirano bodies
      • Rod shaped inclusions with ubiquitinated parallel filaments
      • Most prominent in lower motor neurons
    • Hyaline conglomerate inclusions: SOD1 ALS
  • Other spinal cord
    • Pathology
      • Corticospinal tracts: Loss of myelinated axons
      • Posterior columns: Spared except in familial ALS
      • Astroglial proliferation
      • Inflammation: Little or None
      • Inclusions: Ubiquitin & TDP-43 positive²⁴
        • Present in cytoplasm of neurons & glia of sporadic ALS
        • Filamentous or round
        • Also found in: ALS with dementia; non-SOD1 FALS
        • Not present in SOD1 FALS
    • Spinal cord biochemistry¹²
      • Increased levels of
        • Ceramide C16:0, ceramide C24:0, & sphingomyelin
        • Cholesterol esters C16:0 & C18:0
      • Similar changes in presymptomatic SOD/ALS mice & after oxidative stress
  • Other CNS
    • Brainstem: Loss of motor neurons: Sparing of extraocular nuclei
    • Precentral cortex: Loss of Betz & other pyramidal cells
  • Muscle: Early in course
    • Numerous small regions of grouped angular atrophic muscle fibers.
    • Atrophic muscle fibers in one group are often of varied types.
    • Little type grouping except in chronic, slowly progressive cases
• Treatment
  • Symptomatic
    • Respiratory failure¹⁶
      • Nasal-Facial ventilation
        • Most effective with preserved bulbar function
        • Initially nocturnal
        • Starting criteria
          • Related symptoms
          • Sleep oximetry: O₂ saturation < 88%, For five continuous minutes
        • End point: Oximetry without supplemental oxygen 95% or greater
        • Benefits: May improve survival & quality of life
        • Prognosis: Majority of people with ALS who start NPPV do not decide to go on to tracheostomy
      • Tracheostomy: Elective types
        • Percutaneous dilatational tracheostomy
        • Open surgical
      • Safety
        • Training & drills for all caregivers
        • Resuscitation bag for back-up. People
        • Second ventilator system: For patients who require 20- to 24-h ventilation
      • Avoid
        • Supplemental oxygen
        • Continuous positive airway pressure: Increases burden on weak inspiratory muscles;
      • Cough: Mechanical assistance
      • Reduction of dyspnea anxiety: Lorazepam, sublingual 0.5 to 1 mg
      • Treatment of terminal dyspnea
        • Morphine 2.5 to 5 mg q4h
        • Associated anxiety: Lorazepam 1 to 2.5 mg; Midazolam 1 to 2 mg
    • Bulbar dysfunction: Gastrostomy
      • Before gastrostomy: Change diet to easily chewed, high caloric foods
      • Decision for gastrostomy based on clinical, not radiological, assessment
      • Most effective when performed before respiratory compromise
      • Gastrostomy benefits
        • Improves survival
        • Better quality of life
      • Gastrostomy risks
        • Aspiration with over feeding
        • May require intubation or NPPV in patients with vital capacity < 50%
    • Cramps: May resolve spontaneously
      • Quinine sulfate: 200 mg bid
      • Carbamazepine: 200 mg bid
    • Spasticity
      • Baclofen in some patients: 10 to 80 mg; May increase weakness
      • Other: Tizanidin; Memantine; Tetrazepam
      • Rarely dantrolene: Usually increases weakness
    • Pseudobulbar affect
      • Amitriptyline: 10 to 150 mg
      • Neurodex (Anavir): Dextromethorphan (30mg) & Quinidine (30mg) together
      • Other: Fluvoxamine; Lithium; L-DOPA
    • Weakness: Splints, Supports....
    • General: Information & Discussion
      • Provide clear diagnosis & information that disease is progressive in most cases
      • Allow patient to retain some hope
      • Encourage development of support systems
      • Late: Initiate contact with hospice
  • Survival
    • Riluzole
      • May increase survival by an average of 3 months
        • ? More effective¹⁵: Bulbar disease onset; Older age; Earlier in disease course
      • No effect on strength, respiration or quality of life
      • High cost: ~ $10,000 per year
    • Gastrostomy
    • Respiratory support
  • Caregiver support
  • External links: AAN practice guidelines
    • General
    • Riluzole

ALS-like disorders with Fronto-Temporal Dementia¹¹

• Onset age: 4th to 8th decade
• Clinical
  • Fronto-Temporal Dementia (FTD)
    • Dementia
    • Language disorders
    • Personality changes
    • Behavioral disorders
  • Amyotrophic lateral sclerosis syndrome (ALS)
    • Bulbar dysfunction: Dysphagia
    • Limb denervation
    • Upper motor neuron signs in limbs
      • Hyperreflexia
      • Spasticity less prominent in some patients
    • Fasciculations: May occur without signs of ALS
• Course & associations
  • ALS or FTD may present first
    • Time between onset of syndromes may be years
    • Most commonly dementia presents first
  • Association
    • 14% of FTD patients meet criteria for definite ALS
    • 36% of FTD patients meet criteria for posible ALS
• Laboratory
  • EMG: Denervation; Fasciculations
  • CNS Pathology
    • Neuronal loss in frontotemporal lobes
    • Intraneuronal ubiquitin-immunoreactive inclusions
      • Frequency
        • ALS-Dementia: 100%
        • Non-demented ALS patients: 20% to 50%
        • Frontotemporal dementia lacking motor symptoms: Some patients
      • Locations
        • Hippocampal dentate granular cells
        • Neurons in layer II of frontotemporal (extra-motor) cortex
        • Dystrophic cortical neurites
        • Motor neurons
      • Histochemistry
        • Ubiqutin: Staining
        • Tau & α-Synuclein: No staining
    • Cortex: Astrocytosis (Layer V); Loss of Betz cells
    • Loss of pyramidal tract axons: More distally
    • No pathological evidence of other dementing conditions

Western Pacific ALS-like disorders⁶

• Etiology
  • ? Related to environmental toxins in cycad nut (Cycas circinalis): Possibilities include
    • β-Methylamino-L-alanine (BMAA) toxin
      • Consumption of cycad nut containing BMAA toxin
      • Consumption of Guamanian flying fox: Concentrate BMAA to high levels¹⁹
    • Methylazoxymethanol (MAM): Alkylating agent, could produce long latency disease
  • Other environmental associations
    • Deficient calcium & magnesium
  • Tau (MAPT) : May be a modifying gene increasing risk for ALS-PD
  • TRPM 7 mutation: Thr1482Ile
    • Present in some ALS-Guam & PD-Guam patients
• Epidemiology
  • Occurs in high incidence foci
    • Mariana islands & South Guam; Kii peninsula of Japan
    • Frequency in Guam in 1960: Males 179/10⁵; Females 60/10⁵
    • Familial grouping
      • Chammoros
      • No clear Mendelian patterns of inheritance
      • ? Dominant with reduced penetrance
  • Onset mean: 52 years
  • Male:Female = 2:1 to 3:1
  • Recent changes¹³
    • Decreasing incidence: 8 to 10 fold reduction
    • Increasing onset age
    • Less male predominance
• Clinical features
  • Motor neuron disease
    • Upper & Lower motor neuron features: 90%
    • Lower motor neuron syndrome only: 10%
    • Bulbar features common
  • Other CNS
    • Parkinsonism: 15%
    • Dementia: 10%
    • ? Segregates as separate disease: Occurs in other family members
  • Pigmentary retinopathy: 50%
  • Disease duration
    • Mean: 4 years
    • Age at death: 48 to 68 years
  • Positive family history (ALS or PDC): 45%
• Pathology
  • Neurofibrillary tangles
    • Location: Mesial temporal cortex; Basal ganglia; Brainstem
    • Contain Tau protein
  • Granulovacuolar bodies
  • Anterior horn cells
    • Loss (100%)
    • Ubiquitin positive inclusions (50%)

Atypical Motor Neuron Disease with Ophthalmoplegia & Extrapyramidal disorders⁴

• Onset
  • 4th to 7th decade
  • Often bulbar dysfunction: Dysarthria
• Motor
  • Weakness: Bulbar, Arms & Legs
• Upper motor neuron signs
  • Variably present
  • Tendon reflexes: Brisk or Normal
• Ocular
  • Gaze paresis: Especially vertical; Supranuclear
  • Saccades: Abnormal
• Extrapyramidal signs: Variable
  • Rigidity
  • Ballism
  • Tremor
• Progression: Often rapid; Death in 1 to 3.5 years
• Pathology
  • Anterior horn cell loss: With Bunina bodies
  • Brainstem change: Dentate; Collicular nuclei; Periaqueductal gray gliosis
  • Substantia nigra: Neuronal loss
  • Putamina & globus pallidus: Neuronal loss

Amyotrophic Lateral Sclerosis (ALS): Discussion of the Diagnosis¹

• Provide information
  • Information appropriate to what the patient wants & can understand
  • Information appropriate to degree of certainty of ALS diagnosis
  • Avoid imposition of information that the patient does not want
• Respond to the patient's reaction to the information

• Setting
  • Private area
  • Avoid interruptions
  • Relative or friend of patient also present
  • Physician is seated & at level of patient
• Communication style: Direct & empathetic
• Find out what patient knows: "What have you been told is the problem?"
• Provide information gradually: Small pieces of information with increasing seriousness
  • Initial general negative comment: "I'm afraid that the test results not what I was hoping for."
  • Descriptive hierarchy: Do not give very pessimistic message all at once
    • "Your weakness is caused by damage to the telegraph wires (nerves) that tell muscles to contract"
    • "The nerves are being gradually damaged"
    • "The condition is called amyotrophic lateral sclerosis (ALS), Lou Gehrig's disease or motor neuron disease"
    • "Unfortunately, there is no cure, at the moment."
    • "A drug Riluzole may slow the problem down slightly."
    • "Yes, the disease is often eventually fatal, but progression can be slow in some patients"
  • Most patients are more comfortable with a "label" for their condition
• Respond to the patient's reaction to the information
• Ask patients
  • If they have had enough information, or would like more
  • If they have further questions
• Other information
  • Brochure with information about ALS in lay language
  • Organizations that can give additional help
• Contract for further care
  • Short term follow-up appointment
  • Treatment: Dependent on disease stage
    • "A drug Riluzole may slow the problem down slightly."
    • Occupational & Physical therapy
    • Nutrition
    • Respiratory
    • Social work: For patient and caregiver
    • Clinic resources for helping patient cope with ALS
    • Ongoing clinical and research studies in ALS
  • Emphasize availability for future questions

Creatine Protocols: For ALS & Neuromuscular Disorders

• NOTE
  • There is some evidence that this treatment produces a small (3%) short-term improvement in strength in Dystrophinopathies and FSH.³
  • There is evidence that creatine is of NO benefit in ALS
• Prior to initiation of Drug Protocols: Measure strength by quantitative dynamometry
• Drug Protocols
  1. Creatine monohydrate: Dissolved in fluid,with small meal³
     • Adults: 10 grams/day
     • Children: 5 grams/day
  2. Creatine monohydrate
     • Days 1 to 5: 12 grams 3 times a day
     • Days 6 to 30: 2 grams once a day
  3. Creatine and carbohydrate: Phosphagen HP
     • Concentration: 5 grams of creatine in 43 grams of Phosphagen (1 scoop)
     • Days 1 to 5: 7 scoops per day
     • Days 6 to 30: 1 scoop per day
• After 30 days: Measure strength by quantitative dynamometry

Motor Neuron Disease: MRI changes late in course

• Focal signal in corticospinal tract, cerebral peduncle & internal capsule
• MRI changes occur in some but not all ALS patients

Medulla

Pons

Midbrain

Internal capsule

ALS: Early history of concepts

• 1830 Charles Bell: Reports case of middle aged woman with
  • Progressive paralysis of limbs and tongue
  • Preservation of sensation
  • Pathology: Anterior portion of spinal cord showed degeneration
  • Conclusion: ""Anterior column ...of the spinal marrow is for motion, the posterior column is for sensation...""
• 1850 Aran: Describes progressive muscular atrophy (PMA)
  • Thought to be a primary disease of muscle
• 1855 Cruveilhier: Attributes PMA to atopy of anterior horns of spinal cord
• 1870 Fritsch and Hitzig: Identify the cortical motor strip of the brain by electrical stimulation
• 1874 Charcot: Establishes clinical entity of Amyotrophic Lateral Sclerosis (ALS)
  • Based on 20 cases and 5 autopsies
• 1879 Kahler and Pick: Identify atrophy of motor cortex in ALS
• 1883 Dejerinne: Relates Progressive Bulbar Palsy (PBP) to ALS
• 1884 Kahler: PMA, ALS and PBP grouped as "primary degnerations of the motor system"