Botulinum toxin

1. Botulinum toxin EUROPIAN JORNAL OF NEUROLOGY 2006,13 (suppl. 1)

2. Pharmacology of botulinum toxin : difference between type A preparation

3. Pharmacological difference between botulinum toxin types at molecular level • It acts by blocking the docking and fusion of SNARE proteins at neuromuscular junction • The SNARE proteins targeted by different BoNT vary : • BoNTA and BoNTE cleave synapsomal –associated protein SNAP-25 • BoNTB , BoNTD , BoNTF , BoNTG cleave synaptobrevin or vesicle associated membrane protein • BoNTC1 uniqelly cleave both SANP-25 and syntaxin • The duration of action is longest for BoNTA • BoNT has heavy and light chain domains • Heavy chain is binding domain • Light chain act as a catalytic domain

4. Pharmacological difference between botulinum toxin types at molecular level • The receptor type that it acts upon are • Cholinergic endings of neuromuscular junction and the autonomic pre and post –ganglionic synapses • Synapse–rich areas of the hippocampus , cerebellum and Renshaw cells • BoNT is more effective when it is injected in activated muscle • BONT does not cross BBB rather is transported by retrograde axonal transport to the spinal cord and cranial motor nuclei

6. Comparison between Botox and Dysport at the experimental level

7. Comparison between Botox and Dysport at the experimental level

8. Comparison between Botox and Dysport at the experimental level

10. Conclusion • Pharmacological differences between BoNT preparation are influenced by : • Properties intrisic to the drug eg. protein load • Muscle selection eg. Muscle activity pattern ,muscle architecture and fascial planes • Injection technique eg. Volume , dilutions and doses • Botox to Dysport dose conversion ratio of 1 : 2.5 -3 is workable • At therapeutic doses Dysport seems to produce more adverse effects

11. Immunological aspect of Botox ,dysport and Myobloc/neurobloc

12. Treatment parameters as risk factor for botulinum toxin antibody formation • Short inter injection interval • High BoNT dosages at each injection series • Higher cumulative BoNT dosage • Booster injections (with inter injection interval less than 2 weeks ) • Female gender

13. Patient characteristics as risk factor for botulinum toxin antibody formation • The overall reactivity of the patients immune system • Priming of BT antibodies by structurally similar environmental agent • Although formal studies have not been performed in special patient characteristics , Allergies seem to play minor role in BT antibody formation

14. Botulinum toxin preparation as risk factor for botulinum toxin antibody formation

18. Conclusion • Corrected specific biological activities are measure of antigenicity • The lower the corrected specific biological activities the higher the antigenicity and hence antibody induced therapy failure • Testing for neutralizing antibody against BTB revealed BT antibodies in • 9.6 % of patients at 1 year • 18.2% of patients at 18 months • 22.6% of patients after 610 days • It may produce antibody-induced treatment failure in as many as 44% of patients • For BTA preparations the rate of antibody induced therapy failure is in the range of 5%

19. Treatment of cervical dystonia with botulinum toxin

20. Introduction • Cervical dystonia • is due to asymmetric contractions of neck and shoulder muscles • Anterocollis • Retrocllis • Laterocollis • Rotational • Pain is present in up to 60% of patients and is the most disabling feature • A variety of medications have been used to treat CD • Anticholinergic • Baclofen • Benzodiazepins • BoNT is the treatment of choice providing 85% improvement in CD

21. Botulinum toxin treatment for CD - efficacy and safety • Both BoNTA and BoNTB are safe and effective • Technical aspect of BoNT have not been adequately studied • Number of muscles to inject • Optimal dosing • Number of injection sites for specific muscles • Best means of muscle selection and injection • Botullinum toxin injection technique • Anatomy of neck muscles include >26 muscle pairs • CD may be simple with two muscle activation or complex with multidirectional activation • Selecting muscles for injection requires knowledge of the major neck muscles and their primary and secondary actions

22. Botulinum toxin treatment for CD - efficacy and safety • Botulinum toxin doses for CD • Dysport starting dose 500 units • Botox dose range from 100 – 300U • Myobloc /Neurobloc doses range from 2500 to 10 000 • Publish recommendations for the doses of Botox and Dysport are available for individual muscles • SCM 20U of Botox • SCM 100U of Dysport

23. Target muscle selection for CD • The role of EMG has not been defined • Investigators using EMG guidance have reported increased benefit and the potential to use smaller doses • The number of injection sites into cervical muscles range from • one site in smaller muscles • to eight sites in larger muscles

24. Duration of benefitCD • The mean duration of benefit assessed to time of retreatment in randomized double blind study was • 83.9 +/- 13.6 days for Dysport • 80.7+/-14.4 days for Botox • Duration of benefit tend to last longer in patients with moderate symptoms • The greatest degree of improvement was after the first injection

25. Treatment failures in CD • Primary non–responders • 15-30% of CD patients • Anterocollis is the major head posture • Secondary failure • in approximately 10 -15% patients • Due to neutralizing antibody • Common side effects following treatment include • Dysphagia • Dry mouth • Neck weakness

26. Botulinum toxin in blepharospsm and oromandibular dystonia: comparing different toxin preparations

27. Oromandibular Dystonia

28. Oromandibular Dystonia • OMD • FORM OF FOCAL DYSTONIA • INVOLVES MASTICATORY , LOWER FACIAL , LAIBIAL AND LINGUAL MUSCULATURES • Uncommon representing 5% all forms of dystonia • Cranial dystonia • OMD plus blepharospsm • the second most common form of dystonia • Etiology • Idiopathic most patients • Blepharospsm , cervical dystoina , and spasmodic dysphonia are more commonly associated with idiopathic OMD • Tardive dystonia the most common cause of secondary OMD • Neurodegenerative • neuroacanthocytosis

31. Treatment options for OMD • OMD responds poorly to oral medications • Anticholinergics • Tetrbenzine • Baclofen • Clonazepam • Muscle afferent block helpful but needs further evaluation • Lidocaine and alcohol • Pallidial deep brain stimulation • Botullinum toxin the therapy of choice • Jaw opening • Jaw closing • Jaw deviation • Mean total duration of response 16.4+/-7/1 weeks • The best response obtained with jaw closing

32. Injection techniques • Jaw closing • Masseter the initial muscle to be denervated • Botox 50U • Dysport 100U • Medial pterygiod • Approached intra orally or from below • EMG verification needed when approached from below • Botox 20U • Dysport 30U • Temporalis muscle • Three to four injections should be given • Butox 40U • Dysport 100U

33. Injection techniques • Jaw opening dystonia • Lateral pterygoid • Approached intra orally or laterally • EMG recommended in the lateral approach • Botox 20 -40 U • Dysport 60 U • Digastric muscle • Injection should be given on the anterior belly • Mylohyoid • 1 cm from the mandibular tip and lateral to the midline • Botox 20U • Dysport 90U • platysma

34. Injection techniques • Lingual OMD • Exrinsic muscles of the tongue • Genioglossus • Hypoglossus • Styloglossus • Palatoglossus • Tongue trusting is the most common movement in OMD • Posterior fibers of Genioglossus • Botox 10U • Dysport 30U • The treatment of lingual dystonia is often difficult and the success rate is usually low

35. Injection techniques • Pharyngeal OMD • Pharyngeal muscles • Three constrictor muscles • Stylo-, salpingo- ,and palatopharyngie muscles • Patient often complain of choking and swallowing difficulty • Often occurs with spasmodic dysphonia • Constrictor pharynges invariably involved with dysphagia • For Dysport 30U

36. Blepharospasm

37. Clinical features • Focal dystonia with involuntary closure of the eyes • Due to spasm of the orbicularis occuli • Begins 5th to 6th decade of life • Females are affected more • Apraxia of the eye lids • Due to failure to activate levator palpebra muscle • Does not respond well to botulinum toxin • Blepharospasm and apraxia of eye opening may coexist together

38. Etiology • Psychogenic • Idiopathic • Secondary in only 10% • Reflex due to local conditions • Neurodegenerative disorders PD ,HD , WILSON’S ,CJ ,PSP

39. TREATMENT OPTIENS • Conservative treatment • Sun glasses • Benzodiazpines • Anticholinergic • Botulinum toxin injection • Superficially over the orbicularis oculli • The corrugator muscle injected intramuscularly • orbicularis oculli is injected at five sites with total dose of 12.5-20 for Botox • Avoiding injection of the medial 2/3 of the eye lid is important • Effect lasts for up to 12 weeks

41. Botulinum toxin therapy of hemifacial spasm

42. Introduction • Involuntary irregular clonic or tonic movements of the muscles innervated by the 7th nerve on one side • Most often the result of vascular compression of the VII nerve • Typical HFS • Compress the non-facicular portion of facial nerve • Anterior aspect • Caudal aspect • Atypical HFS • Compress the posterior or rostral portion • Initiate at orbicularis oris ,businator • And spread to involve the orbicularis oculli • Prevalent in females and in those 40-79 • Facial weakness can develop • Symptoms tend to persist during sleep • Occurs usually unilaterally • Non vascular causesof HFS :neuroma ,cystic tumor

43. Ddx • Blepharospsm • Facial myokymia • OMD • Facial tic • Masticatory spasm • Post –Bell’s palsy synkinesis • Focal seizure

44. Treatment • Medications • Baclofen • Clonazepam • Carbamazepine • Gabapentin • Phenytoin • Microvascular decompression • 88-97%sucess rate • Doxorubicin • Botulinum toxin

48. Botulinum toxin therapy of laryngeal muscle hyperactivity syndromes : comparing different toxin preparations

49. Introduction • Spasmodic dysphonia is focal dystonia characterized by task specific , action induced spasm of the vocal cord • First described in 1871 by Traube • It can occur independently or as part of Meige’s syndrome or in other disorders like Tardive dyskinesia • There are three types of SD: the adductor type ,the abductor type and the mixed type • The adductor type is characterized by strain-strangled voice quality and intermittent voice stoppage or breaks due to over adduction of the vocal folds • Abductor spasmodic dysphonia is characterized by intermittent breathy breaks ,associated with prolonged abduction folds • Patients with mixed type have features of both • It affect patient in their mid forties and is more common in females

50. Treatment options for ADSD • Surgery • Botulinum toxin • 97%improvment • 35%mild breathiness • Choking in 15% • Muscles injected • Thyroarytenoid muscle • Lateral cricoarytenoid muscle • Injection protocols • Unilateral decrease side effects • Bilateral increase side effect/prolonged duration of benefit • Injection technique • Percutaneous approach ( EMG between cricoid and thyroid cartilage ) • Trans oral approach indirect laryngoscopy • Trans nasal approach • Point touch injection through thyroid cartilage half way b/n notch and lower border