1. www.wemove.org Spasticity Slide Library Version 2.3 - All Contents Copyright © WE MOVE 2001 Spasticity Management Chemodenervation Part 5 of 6

2. Chemodenervation Injectable therapy Results in local muscle weakening Temporary and titratable Agents include: –Botulinum toxin –Phenol –Ethyl alcohol www.wemove.org

3. Botulinum Toxin Produced by the bacterium, Clostridium botulinum Seven serotypes (A-G); only “A” and “B” approved for clinical use Trade names of BTX-A: –BOTOX ® (Allergan) –DYSPORT ® (Ipsen, Ltd.) Conversion ratio: 1 Unit BOTOX~3-5 Units Dysport Trade name of BTX-B, from Elan: –Myobloc TM in USA –NeuroBloc ® in Europe www.wemove.org

4. Spasticity Slide Library Version 2.3 - All Contents Copyright © WE MOVE 2001 Botulinum Toxin Mechanism of Action

5. Botulinum Toxin Type A

6. Botulinum Toxin Type B

7. Binding and Internalization

8. Acetylcholine Vesicle Fusion Complex

9. Botulinum Toxin Cleavage Targets

10. The Reinnervation Process

11. BTX: Clinical Effects in Spasticity Injected directly into overactive muscle Focal, temporary chemodenervation Onset usually within 24-72 hours, maximum effect at approximately 2 weeks Clinical benefit usually >12 weeks; may be extended with adjunctive therapy Preliminary BTX-B results in spasticity indicate clinical efficacy; autonomic side effects in some patients www.wemove.org

12. BTX-A: Safety and Adverse Effects No anaphylactic reactions have been reported Adverse effects an extension of pharmacology: dose-dependent weakness Little spread beyond injected area Not indicated during pregnancy or lactation www.wemove.org

13. BOTOX ® Current FDA-Approved Indications “For the treatment of cervical dystonia in adults to decrease the severity of abnormal head position and neck pain associated with cervical dystonia.” 2000 “For treatment of strabismus and blepharospasm associated with dystonia, including benign essential blepharospasm or VII nerve disorders in patients 12 years of age and above.” December, 1989 Considered “accepted as safe and effective” for spasmodic dysphonia, hemifacial spasm NIH Consensus Statement, 1990; Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology, 1990 www.wemove.org

14. Myobloc ® Current FDA-Approved Indications “For the symptomatic treatment of patients with cervical dystonia to reduce the severity of abnormal head position and neck pain associated with cervical dystonia.” 2000 www.wemove.org

15. Clinical Trials of BTX-A in Adult-Onset Spasticity >10 randomized, double-blind trials of BTX-A for spasticity in adults MS, SCI, TBI, stroke; upper and lower limbs Typical results: –reduced Ashworth score; increased range of motion –maximum tone reduction seen 2-6 weeks post-injection –passive functional gains, e.g., increased ease of care, hygiene –more difficult to demonstrate active functional gains www.wemove.org

16. Clinical Trials of BTX-A in Cerebral Palsy >6 randomized, double-blind trials of BTX-A for spasticity in CP Ambulatory and non-ambulatory; children and adults Typical results: improved gait, ease of care, deferred surgery Pre-operative injection reduced pain following orthopedic surgery Barwood, 2000 www.wemove.org

17. BTX for Spasticity: Patient Selection Spasticity interferes with function, comfort, or care Focal tone reduction will not decrease current level of function No fixed contracture (may be difficult to distinguish from severe spasticity) www.wemove.org

18. BTX: Muscle Identification Knowledge of anatomy and primary clinical patterns essential Anatomic landmarks often appropriate for targeting superficial muscles Electromyography often required to access deeper muscles or for more complex patterns www.wemove.org

19. EMG and Electrical Stimulation Used to confirm needle location before injection May increase efficacy, reduce necessary dose Reduce spread to non-target muscles ES may be more appropriate for patients with little voluntary control, or severe spasticity with diffuse muscle contraction –target intensity 0.25-0.5 mA www.wemove.org

20. BTX-A: Preparation and Dilution BOTOX ® vial contains 100 Units BTX-A –Keep frozen until use –Dilute with normal saline (0.9%, no preservative) to desired concentration just prior to use –Typical dilution 2.5-10 U BOTOX ® /0.1 mL Dysport ® vial contains 500 Units BTX-A –Dilute with normal saline (0.9%, no preservative) to desired concentration just prior to use –Dysport ® is reconstituted with 1mL saline per vial www.wemove.org

21. BTX-A: Preparation and Dilution, cont’d Myobloc TM /NeuroBloc ® vials contain 2,500 Units, 5,000 Units or 10,000 Units No freezing or reconstitution required www.wemove.org

22. Supplies and Equipment 1.0 ml syringes (tuberculin type) Needles: Teflon coated, 26-30 gauge, 1/2 inch (1.5 cm) EMG machine with Teflon-coated monopolar injection needles www.wemove.org

23. BOTOX ® Dosing Guidelines: Adults Maximum volume per site: 0.5 - 1.0 mL, except in select situations Total maximum dose per visit: 400 - 600 Units, except in select situations Reinjection ≥ 3 months, except in select situations www.wemove.org

24. Sample BOTOX ® Dosages in Adults: Upper Extremity Muscle Biceps Pectoralis Complex Flexor carpi radialis Flexor carpi ulnaris Units*/Muscle 75-200 75-150 25-100 20-70 Sites/muscle 2-4 2 When injecting regional muscles in combination, reduce per muscle dose * BOTOX Units www.wemove.org

25. Sample BOTOX ® Dosages in Adults: Lower Extremity Muscle Thigh adductors Medial hamstrings Quadriceps mechanism Gastrocnemius medial/lateral Posterior tibialis Anterior tibialis Units*/Muscle 75-300 50-200 50-250 50-150 Sites/muscle 6/leg 3 6 4 2 2-3 * BOTOX Units www.wemove.org

26. BOTOX ® Dosing in Children Total maximum dose per visit: lesser of 400 U* or 12 U/kg Maximum per large muscle: 3-6 U/kg Maximum per small muscle: 1-2 U/kg Maximum per site: 50 U Reinjection ≥ 3 months *BOTOX Units www.wemove.org

27. Follow-up and Reinjection PT assessment pre-injection and 1-2 weeks post-injection Clinical benefit usually >12 weeks (variable) Decision to re-treat requires evaluation of entire clinical picture including: –response in relation to goals; excess weakness, other emergent disability –medication changes, caregiver feedback www.wemove.org

28. Non-Response to BTX-A Therapy Primary non-responder: no response to initial injection Secondary non-responder: a relative or complete loss of efficacy at subsequent visit For primary and secondary non-responders: –dose may be too low –injection technique (muscles injected) may require modification –change in pattern of muscle involvement during treatment –inappropriate reconstitution or storage of toxin –neutralizing antibodies present Test for non-response: Frontalis test, sternocleidomastoid test, antibody assays (limited sensitivity, specificity) www.wemove.org

29. BTX-A Antibody Formation Estimated that 3-11% of all focal dystonia patients have neutralizing antibodies These patients received more frequent injections, “booster” injections, and higher doses/treatment –Recommendations: wait as long as possible between injections (at least 3 months); avoid boosters; use smallest clinically effective dose Test for neutralizing antibodies: mouse assay www.wemove.org

30. Phenol/Alcohol Injection Phenol 4-6%, ethyl alcohol 35-60% Motor nerve block or motor point block –motor point most common for alcohol “intramuscular alcohol wash” –protein denaturation Nonselective tissue destruction at higher concentrations –Wallerian degeneration, muscle necrosis, microcirculation damage Regrowth of axons after variable time period www.wemove.org

31. Motor Nerve vs. Motor Point Block Motor nerve block –perineural injection –low volume –complete blockade –complete reduction of tone Motor point block –intramuscular injection –more difficult –small motor branches targeted –multiple small dose injections; larger volume –graded response –highly variable duration of response www.wemove.org

32. Phenol/Alcohol: Clinical Effects Spasticity reduction Highly variable duration Phenol results (similar for alcohol) –10 days to 2 years (avg. 10 months; Khalili, 1984) –9-22 months (avg. 13 months; Petrillo, 1980) –1-36 months (Easton, 1979) Repeat injections may affect duration www.wemove.org

33. Phenol/Alcohol: Adverse Effects Pain –common; 2%-32% –mixed nerve most likely source –onset often several days after injection –often burning paresthesia, exacerbated by touch –duration usually several weeks; may be chronic Edema –more common in lower extremities –usually resolves in 1-2 weeks Tissue-destructive effects, esp. at higher concentrations www.wemove.org

34. Phenol/Alcohol: Clinical Trials Numerous open trials (primarily phenol) have demonstrated efficacy –upper and lower limbs –children and adults –motor nerve and motor point No placebo-controlled trials www.wemove.org

35. Phenol/Alcohol: Dilution and Dosing Phenol –Typical concentration 4-6% w/v in sterile aqueous solution; glycerin improves solubility –Typical volume for motor nerve block: 0.1-3.0 mL –Typical volume for motor point block: 1.0-10.0 mL Alcohol –Typical concentration 35-60%, volume highly variable www.wemove.org

36. Phenol/Alcohol: Targeting and Injection Teflon-coated needle Electrical stimulation, current 0.25-0.5 mA Needle EMG for motor point block –innervation band –characteristic endplate noise –painful Fluoroscopy, ultrasound, CT guidance for deep or difficult muscles Open nerve blocks are possible; require anesthesia www.wemove.org

37. Phenol Plus BTX-A Phenol for large proximal muscles, especially with relatively pure motor innervation BTX-A for smaller distal muscles Can help prevent overexposure to BTX-A, remaining below ceiling dose www.wemove.org

38. Phenol vs. BTX-A Randomized, double-blind trial, 20 patients with plantar flexor spasticity 100 U BOTOX ® to each of the soleus, tibialis posterior, and medial and lateral heads of the gastrocnemius (400 U total) VS. 3 mL 5% phenol to the tibial nerve, isolated by electrical stimulation Kirazli Y, Yagiz On A, Kismali B, Aksit R. Comparison of phenol block and botulinus toxin type A in the treatment of spastic foot after stroke: A randomized, double-blind trial. Am J Phys Med Rehabil 77:510-515 (1998) www.wemove.org

39. Phenol vs. BTX-A, cont’d Dorsiflexion: improvement with both treatments –BTX-A significantly better at weeks 2 and 4, but not at week 8 –Return to baseline by 12 weeks Eversion: improved following BTX-A, but not phenol Brace tolerance, ROM: improved in most patients in both groups Ambulation: improved by BTX-A for the duration of the study. With phenol treatment, early dysesthesias, plus common peroneal nerve paralysis in two obese patients, limited the ambulation scores in the phenol group Kirazli et al. 1998 www.wemove.org