Prof. of Neurology, Cairo University Vice President of the Egyptian Society of Neurology, Secretary General of Pan Arab union of Neurological

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2 Prof. of Neurology, Cairo University Vice President of the Egyptian Society of Neurology, Secretary General of Pan Arab union of Neurological Societies

3 The Egyptian Society of Neurology, Psychiatry and Neurosurgery (ESNPN)

4 Neurological Applications of BTX-A

5 Origin A B C1 D E F? G Botulinum Toxins

6 Botulism 1. Food Born 2.. Infant Bowel Infection 3. Wound Infection

7 Structure

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9 FIRST SPECULATION ON THERAPEUTIC USE OF BTX In 1822, a German physician called Justinus Kerner was the 1st to give the idea of using Botulinum toxin in doses restricting its action to the sympathetic nervous system, to improve conditions he believed to originate from hyper excitation of this system such as st vitus dance, now known as Huntington's chorea.

10 Botulinum toxin type A: research The concept of using minute dosage of botulinum toxin to modify neuromuscular function focally in man has evolved by Alan Scott of the Smith Kettewell eye Research Foundation in San Francisco, CA 1960 s

11 Botulinum toxin type A: research In the late 1970 s Dr Scott formed his company, Oculinum Inc., where he continued research on botulinum toxin type A. In 1978 the FDA granted Dr Scott permission to study the use of toxin to treat strabismus in human volunteers s

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13 Scott s first report of the technique in the treatment of strabismus in human appeared in Treatment began in the United Kingdom in 1982.

14 Clostridium botulinum unique molecular structures Non-toxic Associating Proteins Stabilize and protect the pure neurotoxin protein from degradation Influence the diffusion characteristics of the molecule Non-toxic, nonhemagglutinin (NTNH) Hemagglutinin (HA) 150 kda neurotoxin protein

15 Mechanism Of action

16 1. Binding BOTOX initially binds onto a distinct acceptor on the external membrane of cholinergic nerve terminals Light chain BOTOX Heavy chain ACh Synaptic vesicle The binding site is located on the heavy chain, which is highly selective for cholinergic nerve terminals Disulphide bond End-plate region

17 2. Internalisation Once bound to the nerve terminal, BOTOX is internalised by a process called endocytosis, to form a toxin-receptor vesicle inside the cell BOTOX ACh Synaptic vesicle The light chain of the molecule is then released into the centre of the cell (cytoplasm)

18 3. Blocking When inside the nerve terminal BOTOX cleaves SNAP-25 Heavy chain Light chai n SNARE complex does not form properly As the SNARE complex cannot form properly, exocytosis of cholinergic vesicles is prevented resulting in chemodenervation SNAP-25 Syntaxin VAMP Synaptic vesicle does not fuse with membrane, and ACh is not released

19 BTX-B BTX-D BTX-F BTX-G BTX-C1 BTX-A BTX-E BTX-C1

20 Serotypes and their targets The seven distinct neurotoxin serotypes have different: Biochemical structures Molecular weights Potencies SNARE protein targets Sero-type A B C1 D E F G Target protein SNAP-25 VAMP SNAP-25/Syntaxin VAMP SNAP-25 VAMP VAMP

21 Re-establishment of neuromuscular transmission BOTOX prevents affected terminals from stimulating muscle contraction, however, the synthesis and storage of ACh or the conduction of electrical signals along the nerve fibre is unaffected Collateral axonal sprout Evidence indicates that chemodenervation by BOTOX results in growth of the end-plate region, and the emergence of axonal sprouts. These sprouts may then begin to release ACh

22 Re-establishment of neuromuscular transmission (2) This development of a new neuromuscular junction means that muscle activity resumes usually after about three months Eventually, the original junction resumes activity, and sprouts regress Repeated injections are thus required to maintain therapeutic effects Functioning neuromuscular junction

23 Botulinum Toxin Mechanism Current Hypothesis depaiva et al., 1999

24 BOTOX duration of action The clinical effects are seen 2 to 4 days after initial injection Reasonable response after 2 weeks Studies indicate that it takes around 3 to 6 months for re-establishment of transmission, and thus re-emergence of symptoms

25 BOTOX duration of action Long-term treatment has been shown to be safe, and can be repeated as needed Number of months

26 Commercial available Botulinum Toxin Products BOTOX Allergan Dysport Ipsen Myobloc/ Neurobloc Elan Serotype A A B Complex MW 900kDA ~900kDA 700kDA* Package (units) ,500/5,000/ 10,000 Neurotoxin Protein per Vial(ng) ~ /50/100 Form Vacuum Dried Lyphollized Solution PH ~7 ~7 5.6 First Year of Approval

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30 Dilutions of injection in case of Botox (each vial contains 100 units of Botulinum toxin type A) Saline added to vial 4 ml Final Dilution 2.5 u / 0.1 ml 2 ml 5.0 u / 0.1 ml 1 ml 10.0 u / 0.1ml Depending on: indication, size of muscles, treating physician preference.

31 Botulinum Toxin Type A use in medicine Belpharospasm Torticollis Hemifacial spasm Spasmodic dysphonia Writer s cramp Adult Spasticity Juvenile Spasticity Hyperhidrosis and glabellar lines

32 Botulinum Toxin Type A use in medicine Multiple Dystonias Tremors Tics Hypersalivation Headaches Tennis elbow Postoperative pain Detrusor-sphincter dessynergia Spastic bladder Achalasia Anal fissure Facial lines Bruxism

33 Blepharospasm (essential) A localised movement disorder that affects the muscles controlling the eyes (orbicularis oculi) Results in closure of the eyes

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35 Neuromuscular disorder characterised by frequent involuntary contractions of the muscles on one side of the face Hemifacial spasm

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37 A deviation in direction of one or both eyes that is uncontrollable by the patient, usually due to overexertion of a muscle or muscle group Results in eyes that are crossed or otherwise out of alignment Strabismus

38 Cervical Dystonia

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41 Writer s Cramp

42 Laryngeal Dysphonia

43 Juvenile cerebral palsy A wide range of physical disabilities, caused by damage to the brain during its development Characterised by disorders of movement and posture

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46 Adult Spasticity

47 Common Patterns Of Adult Spasticity: UPPER LIMB Adducted or internally rotated shoulder Flexion of the elbow Pronation of the forearm Wrist flexion Finger flexion with thumb in palm

48 Adult Spasticity: Upper Limb Deformities Adducted/ internally rotated shoulder Wrist-flexion

49 Adult Spasticity: Upper Limb Deformities Clenched fist Thumb-in-palm-deformity

50 Commen Patterns Of Adult Spasticity: LOWER LIMB Hip flexion Adducted thighs Knee flexion, knee extension Ankle plantar flexion Striatal toe Equinovarus foot

51 Adult Spasticity: Lower Limb Deformities Equinovarus Striatal toe

52 Adult Spasticity: Lower Limb Deformities Knee-extension Thigh-adduction

53 ASSESSMENT OF SPASTICITY Modified Ashworth Scale 0 No increase in muscle tone 1 Slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the range of motion when the affected part(s) is moved into flexion or extension. 1+ Slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the range of motion. 2 More marked increase in muscle tone through most of the range of motion, but the affected part(s) is easily moved. 3 Considerable increase in muscle tone; passive movement is difficult. 4 Affected part(s) is rigid in flexion or extension

54 Sapsticity in Adult : Treatment Goals Improved mobility. Decreased pain. Decreased spasms. Increased range of motion. Improved orthotics fit. Improved positioning. Improved hygiene.

55 BOTOX in Adult Spasticity: PATIENT SELECTION Particularly good candidates should : Experience moderate to severe muscle tone limiting their ability to benefit from physiotherapy. Likely to experience a clear functional benefit from a localized reduction in Spasticity (e.g.: improvement in movement, positioning, hygienic care, or pain). Be at risk of developing fixed deformities. Experience intolerable side-effects from systemic antispasmodic medications.

56 Examples of suggested injection sites

57 Upper Limb injection sites

58 Pectoralis Major

59 Biceps Brachii

60 Brachialis

61 Brachioradialis

62 Flexor Carpi Radialis

63 Flexor Carpi Ulnaris

64 Flexor Digitorum Profundus

65 Flexor Digitorum Superficialis

66 Lower Limb injection sites

67 Adductor Longus

68 Semi tendenosus

69 Semi Membrenosus

70 Gatsrocnemius

71 Tibialis Posterior

72 Soleus

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74 BOTOX IN ADULT SPASTICITY: TREATMENT GOALS ACHEIVEMENT Improved wound healing after BOTOX

75 BOTOX IN ADULT SPASTICITY: TREATMENT GOALS ACHEIVEMENT Before BOTOX After BOTOX

76 BOTOX IN ADULT SPASTICITY: TREATMENT GOALS ACHEIVEMENT Before BOTOX After BOTOX

77 Botulinum Toxin Type A Egyptian History

78 First introduction to Egypt We were very close to Europe in using BTX-A in medicine First experience was on 1989 with Prof. James Toole

79 First introduction to Egypt-Cont. First injection in clinic with Dr. Marian Sominetta Moro ( France) in 1992

80 First introduction to Egypt-Cont. First one presented BTX-A in Egypt Dr. James A Temlett ( South Africa) in Neurology Department- Cairo University

81 First introduction to Egypt-Cont. First Egyptian trial on 12 cases Hemifacial spasm and Blepharospasm. Meeting of ESNPN in Hurghada on April 1994

82 Building Experience We start with Movement Disorders like Hemifacial spasm, Blepharospasms and Cervical Dystonia. Adult Spasticity, JCP Recently writer s cramp, oromandibular Collaborate with PT for patient best outcomes of the treatment

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85 Advantages Effective in high percent of cases. Easily injectable (out patient procedure) Repeated easily, patient awake. Minimal side effects and if they happen they are : - Site specific (not systemic like oral medications). - Transient (unlike surgery). No anaphylactic reactions have been recorded. Could be combined with other measures.

86 Difficulties!!!

87 Cost? Benefit is transient Right dose Re-injection is mandatory (though could be in a modified smaller dose depending on degree of recurrence of symptoms) Injection tools guidance is sometimes a must Good patient selection

88 The problem of non response

89 Non- Response to Botulinum Toxin therapy Primary non-responder: no response to first injection of toxin. Secondary non-responder: a relative or complete loss of efficacy at subsequent injections.

90 Reasons of Non-response Causes in the toxin: - expired - Badly stored. - Inappropriate reconstitution.

91 Causes in the treating physician: Dose may be too low. Wrongly injected muscles (injection technique). Bad selection of patients e.g. : In cases of spasticity: the presence of contractures, joint deformities, weakness or atrophy present with no functional benefit.

92 Causes in patient himself: Presence of neutralizing antibodies: confirmed by in-vivo mouse neutralizing assay.

93 Recommendations to avoid antibodies Formation Wait as long as possible between injections (at least 3 months). Avoid boosters. Use smallest clinically effective dose. Use the lowest protein load product? Use another strain e.g. type B. (different serotype).

94 BOTOX IN ADULT-ONSET SPASTICITY: DOSE RECOMMENDATIONS Total maximum dose per visit = units BOTOX Total maximum dose per limb = units Botox Maximum dose per injection site = 50 units BOTOX Reinjection intervals 3 months

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98 Before Botox After Botox

99 Before Botox After Botox

100 Before Botox After Botox

101 What is better for patient future

102 Objective Patient Passport Increase identification of spasticity patients by providing education, motivation and information for patients and their families Education about spasticity and treatments Motivation to request spasticity assessment and treatment Information provided to patients and their families about how to access specialist spasticity services Ideally given to patients 2 weeks after stroke Place of distribution: [stroke unit/rehabilitation unit/neurology ward/geriatric ward/other medical ward/community.

103 Patient Passport Page 1 Passport developed by an independent multi-disciplinary working group of experts in the area of spasticity management and rehabilitation Developed via collaboration during and after the Stroke Rehabilitation Advisory Board 27 November 2006, London, UK Multidisciplinary meeting of Injectors, Referrers and Patient Groups

104 Spasticity Patient Passport Page 2 : Information about the patient and aims of Passport Name of the patient, information about their stroke and explains aims of the Passport and why it should be kept by patient Page 3 : Health Care Team Contact Details Space to add contact details for the specialist Spasticity service Should be filled in before it is given to the patient so that the patient knows who to contact if Spasticity develops Page 4 : What is Spasticity? Provides explanation of disease Page 5 : Spasticity checklist and what to do next Provides patient (and their family) with checklist of Spasticity symptoms. If Spasticity is suspected, patient should request access to specialist Spasticity services Page 6 : Questions you should ask your family practitioner Questions to confirm Spasticity symptoms

105 Patient Passport Page 7 and 8 Year planner Encourages the patient to retain the passport

106 Thank you