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SPORADIC ALS

Sporadic ALS: Common forms   Clinical features   Diagnostic criteria   Differential diagnosis   Discussion of diagnosis   Epidemiology   Laboratory features   Pathology   Prognosis   Susceptibility loci   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     ALS-PD1     ALS-PD2

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
    FIG4	6q21	Mutations
    CHRNA3 , CHRNA4 CHRNB4	15q25, 20q13, 15q24	Mutations33
    UNC13A	19p13.3	Intron 21 link 34
    	9p21.2	Linkage

    • Habitus: Lifelong slim (2.2x higher)
    • History of
      • Varsity athletics: 1.7x higher
      • Smoking²¹
        • More with: Increased smoking
        • Current smoking in females: 1.7x higher
        • Less with increased time after quitting
    • ? 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
    • SMN1
      • Increased frequency (2x) of 1 or 3 gene copies in ALS
    • FIG4 ³²
      • ALS Mutations
        • Heterozygous
        • Missense or Termination
      • Frequency: 1% to 2% of ALS patients
      • ALS type
        • Family history: Familial or Sporadic
        • Clinical pattern: ALS or PLS; Brisk tendon reflexes
      • Also see: CMT 4J
• 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
    • Lipids: Cholesterol, LDL & Triglycerides mildly reduced with FVC < 70%
  • 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
      • Amyotrophic lateral sclerosis-Parkinsonism/Dementia complex 1 (ALS-PD1)
• 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"