“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 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.,  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 (2001):  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): Transitional Study (Yan, Jun, et al., 2006) SOD1 transgenic mice – later onset, slower progression, lived longer Phase I trial (NCT ) Ended February injections, 10,000 cells/injection No disease acceleration, one patient improved Phase II trial (NCT ) 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 NeuronLower 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 Neuron Lower Motor Neuron Progressive Upper and Lower motor neuron degeneration were present  diagnosis of ALS Repeated glutamate NMDA receptor activation Opening of Ca 2+ voltage-gated channels Increased intracellular Ca 2+ Apoptosis 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. BMC Neuroscience :64 doi: / 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 Ca 2+ Human Spinal Cord Derived Neural Stem Cell Transplantation