“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.