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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

http://origin-ars.els-cdn.com/content/image/1-s2.0-S1474442209702029-gr3.jpg