“My movement was that of a drunk person. And that’s why I got fired” –Patient DC
Amyotrophic Lateral Sclerosis
Tyler Gibson, William Tyor MD, Christina Fournier MD, George Wilmot, MD
Neuroscience and Behavioral Biology, Atlanta Veterans Memorial Hospital
Patient DK
- 53 year old, Caucasian male
HPI
•Symptoms started 2008
• CC: “tripping over nothing”
•Left leg weakness --> difficulty standing
•NCVs & EMG testing (2009)
• Diagnosed with ALS
PMHx
• Cardiac arrest (2006)
• Hypertension
• Hyperlipidemia
• Gastroesophageal reflux
• Chronic pain syndrome
• Depression
Diagnostic Studies: Patient DK
Neurological Exam:
Future Directions
Human Spinal Cord Derived Neural Stem Cell Transplantation
Upper Motor Neuron
• Brisk Reflexes
• Muscular weakness with atrophy
• Fasiculation
Diagnostic Studies (2009):
Lower Motor Neuron
• Electromyography – Abnormal
• Typical of motor neuron disease
•Motorized wheelchair (2009)
•Since last visit (last 6 months)
• Worsening of upper extremity weakness
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
Progressive Upper and Lower
motor neuron degeneration were
present  diagnosis of ALS
• MRI imaging – Normal
Pathophysiology
• Transitional Study (Yan, Jun, et al., 2006)
• SOD1 transgenic mice – later onset, slower progression, lived longer
Motor
•Other extremities ≤(2/5)
• Hamstring and Quadriceps (3/5)
•Bilateral atrophy in hands & feet
•Normal tone
•L Fasciculations
• Phase I trial (NCT01348451)
• Ended February 2013
• 5 injections, 10,000 cells/injection
• No disease acceleration, one patient improved
Molecular pathways remain unknown
• Phase II trial (NCT01730716)
Theory of Glutamate Excitotoxicity
• Most widespread theory
Repeated glutamate NMDA
receptor activation
Opening of Ca2+
voltage-gated channels
• Approved by FDA in April 2013
• Emory & University of Michigan
Increased intracellular Ca2+
• Cervical or Cervical + Lumbar spinal injections
• Five different doses of 40 injections, up to 400,000 cells/injection
Apoptosis
http://origin-ars.els-cdn.com/content/image/1-s2.0-S1474442209702029-gr3.jpg
Sensory
•Normal
Jaiswal et al. BMC Neuroscience 2009 10:64
doi:10.1186/1471-2202-10-64
Cranial Nerves
• Intact Bulbar function
• No aphasia or dysarthria
• No facial, tongue, or eye weakness
• Absent jaw jerk
• Neck Extension & Flexion (4/5)
• Decreased lower extremity amplitude
• Unknown etiology
• 90% cases are sporadic
• 10% cases are familiar  25% from superoxide dismutase 1 (SOD1) mutation
Neurological Exam
Mental Status
• Awake and Alert
• Frustrated due to progression
• Nerve Conduction Study -Abnormal
Mitochondrial dysfunction
has also been reported due
to increased intracellular Ca2+
Reflexes
•Brisk
Acknowledgements
• 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
Differential Diagnosis
Amyotrophic Lateral Sclerosis (ALS) is a degenerative motor neuron
disease with evidence of both upper and lower motor neuron abnormalities,
causing progressive motor dysfunction.
Involvement of:
Symptoms:
Possible Diagnosis:
Upper Motor Neuron
Lower Motor Neuron
Muscle Spasticity,
Hyperreflexia,
Hoffmann or Babinski
signs,
Clonus
Muscle weakness with
atrophy, Cramps,
Fasciculation,
Decreased tendon reflex
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
SOD1
• Enzyme to protect from superoxide (produced from mitochondria)
• Mutation  Buildup of free radicles  Apoptosis
• Are currently 110 mutations of SOD1 linked with ALS
•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
Current Treatment
• 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.
Medication:
•Riluzole
References
• 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
http://www.nutragenetics.net/products.php
http://www.neurology.org/content/47/6_Suppl_4/233S/F8.large.jpg
Systematic:
•Mobility devices
• Power-chair dependent (2009)
• Neuropathic pain: Lyrica
• Muscle relaxant: Tizanidine
• Shortness of breath: Albuterol
 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.