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“My movement was that of a drunk person. And that’s why I got fired” –Patient DC
Amyotrophic Lateral SclerosisTyler Gibson, William Tyor MD, Christina Fournier MD, George Wilmot, MD
Neuroscience and Behavioral Biology, Atlanta Veterans Memorial Hospital
Current Treatment
References
Patient DK- 53 year old, Caucasian male
Neurological Exam
Differential Diagnosis
HPI•Symptoms started 2008
• CC: “tripping over nothing”
•Left leg weakness --> difficulty standing
•NCVs & EMG testing (2009)
• Diagnosed with ALS
•Motorized wheelchair (2009)
•Since last visit (last 6 months)
• Worsening of upper extremity weakness
• Patient DK and his family• For sharing his experience with ALS, and allowing me to sit in on his appointment
• Christina Fournier, MD• For allowing me to observe her in clinic and explaining key terms
•George Wilmot, MD• For his feedback and guidance on my presentation
• William Tyor, MD• For his guidance as my mentor
• The VA Memorial Hospital staff• For taking time to familiarize us with the clinic setting and being so accepting
• Linton Hopkins, MD; Paul Lennard, PhD; Jaffar Khan, MD• For their constant feedback, and allowing me to be a part of this unique program that has given me a rare opportunity to observe physician-patient relationships, and learn the importance of listening to patients’ words.
Amyotrophic Lateral Sclerosis (ALS) is a degenerative motor neuron disease with evidence of both upper and lower motor neuron abnormalities, causing progressive motor dysfunction.
Medication:•Riluzole• Only FDA approved drug for ALS• Slows progression on average 10%• (A) - decreases Glutamate release• (B) - noncompetitive binding for NMDA
receptor• (C) – blocks voltage-gated Na+ channel• Patient DK could not tolerate
Systematic:•Mobility devices• Power-chair dependent (2009)
Acknowledgements
Bruijn L, et al. "Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1". Science 281 (1998): 1851–4.
Doble, A. "The pharmacology and mechanism of action of riluzole." Neurology 47.6 Suppl 4 (1996): 233S-241S
Jackson, Carlayne E., and Wilson W. Bryan. "Amyotrophic lateral sclerosis." Seminars in neurology. Vol. 18. No. 01. © 1998 by Thieme Medical Publishers, Inc., 2008.
Rothstein, Jeffrey D. "Current hypotheses for the underlying biology of amyotrophic lateral sclerosis." Annals of neurology 65.S1 (2009): S3-S9.
Rowland, Lewis P., and Neil A. Shneider. "Amyotrophic lateral sclerosis." New England Journal of Medicine 344.22 (2001): 1688-1700.
Yan, Jun, et al. "Combined immunosuppressive agents or CD4 antibodies prolong survival of human neural stem cell grafts and improve disease outcomes in amyotrophic lateral sclerosis transgenic mice." Stem Cells 24.8 (2006): 1976-1985.
• Transitional Study (Yan, Jun, et al., 2006)• SOD1 transgenic mice – later onset, slower progression, lived longer
• Phase I trial (NCT01348451)• Ended February 2013• 5 injections, 10,000 cells/injection• No disease acceleration, one patient improved
• Phase II trial (NCT01730716)• Approved by FDA in April 2013• Emory & University of Michigan• Cervical or Cervical + Lumbar spinal injections• Five different doses of 40 injections, up to 400,000 cells/injection
Future Directions
Mental Status•Awake and Alert•Frustrated due to progression
Cranial Nerves•Intact Bulbar function• No aphasia or dysarthria
•No facial, tongue, or eye weakness•Absent jaw jerk•Neck Extension & Flexion (4/5)
Motor•Other extremities ≤(2/5)• Hamstring and Quadriceps
(3/5)•Bilateral atrophy in hands & feet•Normal tone•L Fasciculations
Sensory•Normal
Reflexes•Brisk
Involvement of: Upper Motor Neuron Lower Motor Neuron
Symptoms: Muscle Spasticity, Hyperreflexia, Hoffmann or Babinski signs, Clonus
Muscle weakness with atrophy, Cramps, Fasciculation, Decreased tendon reflex
Possible Diagnosis: Multiple Sclerosis, Primary lateral sclerosis, Kennedy’s disease
Multifocal motor neuropathy, Polyneuropathy, Spinal muscular atrophy
In order to diagnose ALS there must be signs of upper and lower motor neuron damage, not attributed to other causes
PMHx•Cardiac arrest (2006)•Hypertension•Hyperlipidemia•Gastroesophageal reflux•Chronic pain syndrome•Depression
SHx•Married•Unemployed, No insurance•1½ pack of cigs per day for 20 years
Rx•Atorvastatin calcium•Omeprazole•Promethazine•Pregabalin (Lyrica)•Bupropion HCL•Tizanidine•Albuterol •Oxycodone & Morphine
Diagnostic Studies: Patient DK
Neurological Exam:• Brisk Reflexes• Muscular weakness with atrophy• Fasiculation
Diagnostic Studies (2009):• Electromyography – Abnormal• Typical of motor neuron disease
• Nerve Conduction Study -Abnormal• Decreased lower extremity amplitude
• MRI imaging – Normal
Upper Motor NeuronUpper Motor Neuron
Lower Motor NeuronLower Motor Neuron
Progressive Upper and Lower motor neuron degeneration were
present diagnosis of ALS
http://www.neurology.org/content/47/6_Suppl_4/233S/F8.large.jpg
Pathophysiology• Unknown etiology• 90% cases are sporadic• 10% cases are familiar 25% from superoxide dismutase 1 (SOD1) mutation
Molecular pathways remain unknown
Jaiswal et al. B
MC
Neuroscience 2009 10:64
doi:10.1186/1471-2202-10-64
Theory of Glutamate Excitotoxicity• Most widespread theory
SOD1• Enzyme to protect from superoxide (produced from mitochondria)• Mutation Buildup of free radicles Apoptosis
• Are currently 110 mutations of SOD1 linked with ALS
• Neuropathic pain: Lyrica• Muscle relaxant: Tizanidine• Shortness of breath: Albuterol
Mitochondrial dysfunction has also been reported due to increased intracellular Ca2+
Human Spinal Cord Derived Neural Stem Cell Transplantation
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