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Question 1 Which of the following is true regarding botulinum toxin therapy: A) BoNT A and BoNT B are essentially the same and interchangeable B) Only the 3 brands of BoNT A marketed in the USA are equal and interchangeable in dosing C) The only FDA approved medical condition for all 4 BoNTs available in the USA is Cervical Dystonia ***** D) Standard dosing of BoNT is every 6 months 1

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Question 2 Botulinum toxin type A ( in the form of Botox) is FDA approved for which of the following: A) refractory episodic migraine B) chronic daily migraine ****** C) Cluster headache D) all of the above 2

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Botulinum Toxin- Headache and other uses Tim Schoonover DO, FACN Dayton Center for Neurological Disorders 3

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DISCLOSURES Speakers bureau / trainer for Allergan pharmaceuticals MSU 4

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Botulinum toxin ( BoNT) Botulinum neurotoxin (BoNT) is a microbial protein that exists in seven serotypes, designated A through G. Clostridium botulinum Since its introduction 35 years ago, BoNT has become an effective treatment for numerous movement disorders associated with increased muscle tone or muscle overactivity. The ability of BoNT to block acetylcholine release at neuromuscular junctions accounts for its therapeutic action to relieve dystonia, spasticity, and related disorders. 5

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BoNT BoNT is marketed in US as: Botox (Allergan, Inc.) onabotulinumtoxinA Dysport (Ipsen Limited) abobotulinumtoxinA Xeomin (Merz Pharmaceuticals) incobotulinumtoxinA Myobloc (Solstice Neurosciences,Inc.), which is also called Neurobloc in some countries rimabotulinumtoxinB 6

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BoNT Only BoNT-B is marketed as: Myobloc Within BoNT-A brands, there are differences in potency between Botox, Xeomin, and Dysport that require differences in dosages. 7

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History- FDA approved uses 8 Botox 1989 blepharospasm and strabismus 2000 cervical dystonia 2002 cosmetic 2004 axillary hyperhidrosis 2010 chronic migraine 2010 upper limb spasticity 2013 overactive bladder Myobloc 2000 cervical dystonia Dysport 2009 cervical dystonia Xeomin 2010 cervical dystonia 2011 glabellar lines

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BoNT The assay methodology varies between manufacturers, making dose comparison difficult. Within BoNT-A brands, there are differences in potency between Botox, Xeomin, and Dysport that require differences in dosages. It is difficult to extrapolate animal data to potency in humans, given the relative lack of head-to-head studies of different BoNT preparations. 9

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BoNT Given the high range of intra- and inter- patient variability, doses must be established for each BoNT preparation for individual patients. 3 Both basic science and clinical studies indicate that BoNT-A has a longer duration of action than BoNT-B. 4 10

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BoNT The ability of BoNT to block acetylcholine release at neuromuscular junctions accounts for its therapeutic action to relieve dystonia, spasticity, and related disorders. The toxin has additional therapeutic benefits, not necessarily related to neuromuscular transmission: Blockade of acetylcholine release at autonomic nerve endings Blockade of transmitter release at peripheral nerve endings that use mediators other than acetylcholine Substance P In addition to peripheral effects of BoNT, indirect effects on the spinal cord and brain that result from changes in the normal balance of efferent and afferent signals may also occur. Both the direct and indirect actions of the toxin are largely reversible. 11

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13 NOTE: BoNT cannot be detected in serum immediately after injection

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BoNT Binding : The toxin binds to specific receptors on the surface of the presynaptic cell surface. This step takes around half an hour and is mediated by the heavy chain of the toxin. 14

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BoNT Internalization : The plasma membrane of the nerve cell invaginates around the toxin- receptor complex, resulting in the formation of a toxin containing vesicle inside the nerve terminal. 16

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BoNT Translocation : The disulfide bond is cleaved releasing the light chain across the endosomal membrane of the endocytic vesicle into the cytoplasm of the nerve terminal. 18

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BoNT Blocking : The light chain of the toxin impedes on the release of acetylcholine into the synaptic cleft by cleaving a protein required for the docking of acetylcholine vesicles on the inner side of the nerve terminal plasma membrane. The final result of the above mentioned mechanism is blocking the normal flow of neurotransmission, rendering the muscle implied unable to contract. These effects last between 2-6 months and then resolve 20

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The toxin has additional therapeutic benefits, not necessarily related to neuromuscular transmission: Blockade of acetylcholine release at autonomic nerve endings Blockade of transmitter release at peripheral nerve endings that use mediators other than acetylcholine 23

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BoNT immunoresistance 24

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BoNT Resistance results from the development of circulating antibodies that bind to the heavy chain and prevent its association with nerve membranes, thus preventing internalization of the enzymatically active light chain. Auxiliary proteins in the toxin complex could act as adjuvants to stimulate the immune response to the toxin, in keeping with the lower incidence of immunoresistance associated with the decreased proportion of nontoxin protein in clinical preparations. 2 25

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Antibody formation to BoNT A Immunogenicity studies Newest formulation Combined = 2647 patients 7 developed detectable antibodies to BoNT A 0.26% 26 NOTE: BoNT cannot be detected in serum immediately after injection

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BoNT Botulism antidote ( antitoxin) Heptavelent Neutralizes all 7 known types 27

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BoNT All available formulations contain Human albumin 28

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CERVICAL DYSTONIA 29

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CERVICAL DYSTONIA 30 ANTEROCOLLISTORTICOLLIS LATEROCOLLIS RETROCOLLIS

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BoNT-Cervical dystonia Improves head positioning Improves pain Improves spasmodic or tremor component 32

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BoNT-Cervical dystonia-EMG guided injections Sternocleidomastoid Splenius capitis Levator capitis Semispinalis capitis Trapezius Scalene 33

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BoNT cervical dystonia- adverse effects Dysphagia Drying Excessive muscle weakness Bleeding / bruising/ muscle pain Hoarse voice / distal muscle weakness / respiratory 37

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Blepharospasm 1711 patients in studies = FDA approval 38

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40 Adverse effects Blepharospasm - Dry eyes - Reduced eye closure - Bruising - Ptosis - diplopia

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Hemifacial spasm 41

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Hemifacial spasm 42

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Bleph / hemifacial 44

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BoNT-upper limb spasticity Function Hygiene Comfort 45

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46 3 studies with total of 305 patients = FDA approval 90-360 units Botox Stroke, MS, spinal cord BoNT-upper limb spasticity - Biceps brachii -Flexor carpi radialis -Flexor carpi ulnaris -Flexor digitorum profundus -Flexor digitorum - superficialis -Flexor pollicis longus -Adductor pollicis

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Upper limb spasticity 47

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Chronic daily headache chronic migraine 49

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CHRONIC DAILY MIGRAINE ( CDM) what is it? Is a type of chronic daily headache (CDH) 15 or more headache days per month for more than 3 months At least 8 of these headaches are migraine / migrainous 50

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CHRONIC DAILY MIGRAINE why is it important ? 2 % of the adult population (> 3 million) Less than episodic (12%) but More disabling More time missed from work / school More health care visits and cost Similar demographic as episodic migraine More prevalent than epilepsy, Parkinsons disease or multiple sclerosis . 51

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Chronic daily migraine Added to International Classification of Headache Disorders in 2004 American Migraine Prevalence and Prevention Study 74% of Chronic Migraine patients have seen healthcare profession for headaches PCP, neurologists, headache and pain specialists Only 20% received the diagnosis Many with CDM remain unrecognized. 52

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Preventative Medications for CDM OnabotulinumtoxinA (Botox) BoNTA Topiramate ( Topamax) Valproate ( Depakote) Gabapentin ( Neurontin) Amitriptyline ( Elavil ) Tizanidine ( Zanaflex ) Others beta blockers / fluoxetine / etc 53

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Onabotulinumtoxin-A Only FDA approved medication for CDM Likely = inhibits nociceptor mediators ( substance P, glutamate, CGRP) Reduces peripheral sensitization .central sensitization 2 large studies PREEMPT 1 and 2 Over 1200 patients with CDM (with or without medication overuse) Significant reduction in Headache frequency Cumulative hours of headache Nausea / photosensitivity / phonosensitivity disability Adverse effects : neck pain (9%); head ache (9%); muscle weakness (4%) 54

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BoNT-Medication / medical condition interaction Anticholinergic effect Muscle relaxants Motor neuron disease Myasthenia gravis 62

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BoNT A- Realistic expectations Need at least 2 sets of injections By 24 weeks about 47% had > 50% reduction in HA frequency Improvement over several sets May still need oral preventatives 69

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BoNT - Hyperhydrosis 72

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BoNT- Hyperhydrosis 50 units in 10-15 sites Minors iodine starch test Dry underarm paint with iodine soln Sprinkle with starch powder after dry Blue-black coloration in 10 minutes -Inject using color as guide (not direct = tatoo) -Each site ring of effect- about 2 cm diameter -adjust as needed with each visit 73

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BoNT- Hyperhydrosis More than 50% reduction in perspiring in 85 to 95% in studies Adverse effects = placebo 74

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BoNT- sialorrhea 75

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BoNT- sialorrhea Studies included primarily Parkinsons and some ALS patients Substantial reduction in saliva production Type B may be more effective than Type A 76

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BoNT- sialorrhea 77

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cosmetics 78 Procerus and corrugator Orbicularis oculi

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Overactive bladder Urinary urge, frequency, incontinence 1105 pts not adequately treated with oral meds 100 units ( 5 u in 20 sites) AE: 6.5-30 % with urinary retention Requiring intermittent catheterization Avg 63 days 80

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Overactive bladder 81

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-Writers cramp = -focal hand dystonia = -focal limb dystonia = -task specific dystonia 82

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Adductor spastic dysphonia - Laryngeal or Vocal cord dystonia 84

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Adductor spastic dystonia 85 Choked and constrained voice pattern Breaks in vocal flow Studies are not dramatic Clinical experience is however positive

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Adductor spastic dystonia Laryngeal or Vocal cord dystonia 86

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others Tremors Low back pain Tics Foot dystonia ( eg Parkinsons disease) 87

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Questions and comments 89

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