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

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

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

DISCLOSURES  Speakers bureau / trainer for Allergan pharmaceuticals  MSU 4

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

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

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

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

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

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

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

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

BoNT immunoresistance 24

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

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

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

BoNT  All available formulations contain  Human albumin 28

CERVICAL DYSTONIA 29

CERVICAL DYSTONIA 30 ANTEROCOLLISTORTICOLLIS LATEROCOLLIS RETROCOLLIS

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

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

Blepharospasm  1711 patients in studies = FDA approval 38

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

Hemifacial spasm 41

Hemifacial spasm 42

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Bleph / hemifacial 44

BoNT-upper limb spasticity  Function  Hygiene  Comfort 45

46  3 studies with total of 305 patients = FDA approval  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

Upper limb spasticity 47

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Chronic daily headache – chronic migraine 49

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

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, Parkinson’s disease or multiple sclerosis …. 51

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

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

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

BoNT- Hyperhydrosis  50 units in sites  Minor’s 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

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

BoNT- sialorrhea 75

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

BoNT- sialorrhea 77

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: % with urinary retention  Requiring intermittent catheterization  Avg 63 days 80

Overactive bladder 81

-Writer’s cramp = -focal hand dystonia = -focal limb dystonia = -task specific dystonia 82

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Adductor spastic dysphonia - Laryngeal or Vocal cord dystonia 84

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

Adductor spastic dystonia Laryngeal or Vocal cord dystonia 86

others  Tremors  Low back pain  Tics  Foot dystonia ( eg Parkinson’s disease) 87

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Questions and comments 89

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