Botox and Its Role in Parkinson’s Disease Laura Buyan Dent, MD, PhD Associate Professor of Neurology University of Wisconsin School of Medicine and Public Health

Intro Botulinum neurotoxin = Botox=BoNT One of the most poisonous substances known to humans Lethal dose of approximately 1 ng per kilogram body wt Inhaled by a person, 1 g would certainly be lethal 1 g can theoretically kill 1,000,000 persons Discuss the toxin itself History of development specific uses for certain symptoms/problems in PD

Botulism Poisoning that causes a fatal paralytic disease Probably known since humans have stored food Justimius Kerner Poet and Physician 1817-1822 publications correlating toxic agent in improperly prepared and stored sausages----numerous sausage poisonings reported in southwestern Germany Botulism From latin word botulus meaning sausage Sausage poisoning Causes a rapidly progressive profound weakness resulting in death due to paralysis of respiratory muscles

Clostridium Botulinum Emilio Pierre Marie von Ermengerm microbiologist received samples from an outbreak of botulism and identified the microorganism responsible Intoxication, not infection Toxin produced in food by bacteria After digestion, toxin remains active Toxin can be inactivated by heat Now know that clostridium botulinum is found worldwide in soil, dust, marine sediments Types of exposure Improperly preserved food Infant exposure via honey Wound contamination

Clostridium Botulinuum Anaerobic bacteria which produces a neurotoxin Major effect of the neurotoxin is paralysis of muscles

Further Development Bo NT considered for use as a weapon in WW I and II. Military research at Fort Detrick helped to isolate and purify the toxin 1942–1946 Carl Lamanna and Edward Schantz purify the toxin and prepare it in crystalline form 1946 Schantz produces a large amount of this toxin makes it available for clinical research 1972 Schantz moved to Department of Microbiology and Toxicology at University of WI Go Badgers !!!!!!!!!!!!!!!!!!!!!!!

Medical Development 1972 First experimental evidence of BoNT injection causing localized muscle weakness 1980’s injected into humans for treatment of strabismus (“crossed-eye”) 1989 FDA approved for treatment of strabismus, blepharospasm and hemifacial spasm 2017 100 + medical and cosmetic uses

Medical Use Major effect of the neurotoxin is paralysis of muscles

How Does It Work?

Motor System Review Nervous System Muscle Source: The Spinal Cord, Clinical Neuroanatomy, 28e Citation: Waxman SG. Clinical Neuroanatomy, 28e; 2017 Copyright © 2017 McGraw-Hill Education. All rights reserved

Neuromuscular Junction Source: Muscle Tissue, Junqueira's Basic Histology, 14e Citation: Mescher AL. Junqueira's Basic Histology, 14e; 2016, Available at: http://accessmedicine.mhmedical.com/content. Copyright © 2017 McGraw-Hill Education. All rights reserved

BoNT blocks neuromuscular transmission Inhibits release of neurotransmitter (acetylcholine) at the neuromusclular junction Interferes with proteins involved in vesicular release Source: Clostridium, Peptostreptococcus, Bacteroides, and Other Anaerobes, Sherris Medical Microbiology, 6e Citation: Ryan KJ, Ray C. Sherris Medical Microbiology, 6e; 2014 Available at: http://accessmedicine.mhmedical.com/ Copyright © 2017 McGraw-Hill Education. All rights reserved

Formulations and Pharmacology 7 serotypes of BoNT (A,B,C1,D,E,F,G) A & B available for medical use onabotulinumtoxinA(Botox) abobotulinumtoxinA (Dysport) incobotulinumtoxinA(Xeomin) RimabotulinumtoxinB (Myobloc, NeuroBloc) Different formulations may affect different proteins in the pathway of synaptic release of acetylcholine

Medical uses Used to treat a variety of conditions in which there is excessive muscle spasm Also evidence that BoNT affects certain pain receptors directly Can reduce some dysautonomic symptoms due to interfering with contraction of “smooth” muscle which is controlled by the autonomic nervous system

Uses specific to PD

Dystonia Definition = specific type of muscle spasm, often with a twisting component resulting in an unusual posture “On” vs “Off” Painful Risk of contractures Can affect numerous body parts Most common Face Feet Neck trunk

Foot spasms Striatal toes Toe curling

Eye Spasms Blepharospasm Apraxia of eyelid opening Video from Jankovic and Tolosa Parkinson’s Disease & Movement Disorders, 5th ed, 2007

Eye Spasms Blepharospasm Apraxia of eyelid opening Video from Jankovic and Tolosa Parkinson’s Disease & Movement Disorders, 5th ed, 2007

Facial Muscles

Facial Dyskinesia Bruxism= grinding of teeth Facial grimacing usually from levodopa Video from Jankovic and Tolosa Parkinson’s Disease & Movement Disorders, 5th ed, 2007

Facial Dyskinesia Bruxism= grinding of teeth Facial grimacing usually from levodopa Video from Jankovic and Tolosa Parkinson’s Disease & Movement Disorders, 5th ed, 2007

Sialorrhea Drooling Not due to excessive saliva production Occurs due to decrease in automatic swallowing Botox will interfere with the salivary glands releasing saliva

Other Tremor Bent spine / camptocormia Hyperactive bladder Very limited success due to excessive weakness of arms/hands Bent spine / camptocormia Variable success Hyperactive bladder Done by Urology

Side-effects/Safety Unintentional weakness Depends on location of injections Injection site reaction, bruising Development of antibodies Some spread of toxin to distant locations not clinically relevant in with expert use Expensive!!!!!! Manufactured biologically from refined strains of clostridium botulinum Actually very safe. Diffuses only ~ 2 cm from injection site

Clinical visit and practical considerations “art of medicine” Procedure which is done in the office No anesthesia necessary Takes 3-10 days to notices effects Can take days to weeks for side-effects to resolve Effects wear off necessitating repeat treatments Some variability in responses EMG guidance possible

Questions?????