Therapeutic Uses of Botulinum Toxin in Neuro-ophthalmology

1. Therapeutic Uses of Botulinum Toxin in Neuro-ophthalmology Janette I. Lindley, MD FRCSC St. Paul’s Hospital University of British Columbia

2. Overview 1.On label uses: • hemifacial spasm • blepharospasm injection techniques • other: cervical dystonia strabismus wrinkles (glabella)

3. Overview 2. Off label uses: • headache (chronic daily) Phase II Trial Results injection technique • crocodile tears, protective ptosis • other: writer’s cramp, hyperhydrosis, head tremor, focal spasticity, drooling

4. Botulinum Toxin in Neuro-ophthalmology • neurotransmission inhibition (ACH, other) at NMJ • chemical denervation striated muscle peaks @ 2 weeks • Neuronal sprouting heralds return of function @ 3 – 6 mos.

5. Botulinum Toxin • Serotype A (Botox , Dysport) • Serotype B (Myobloc)

6. Hemifacial spasm • Unilateral • Periocular and lower facial +/-platysma stapedius (clicking at hs) • R/O facial nerve compression (MRI)

7. Hemifacial spasm movie Click here

8. Blepharospasm • tonic/ clonic lid closure • may present unilaterally • uncontrollable • functional cause for visual loss • (apraxia of lid opening)

9. Blepharospasm movie (Click here)

10. Blepharospasm

11. Pathological Pain Inhibition • observed (Binder et al) after Rx hyperfunctional facial lines • inhibition of neuromuscular activity and • substance P, glutamate, & calcitonin peptide release • results in analgesic effect

12. Headache Disorders • heterogeneous group of conditions • recent results Phase II trials in chronic daily headache (CDH)/ transformed migraine • randomized, double blind • placebo controlled • 75% completion at 11 mos.

13. CDH or Transformed Migraine • HA15 d/m > 1(3)m • each HA 4 h/d • no primary cause • H/O episodic migraine (>50% pr migr) • 4% of pop ~1.2-1.5 million in Canada • significant disability/resource use

14. BoNTA* BoNTA* BoNTA* BoNTA* BoNTA* Placebo Placebo Placebo Placebo Placebo Placebo BoNTA* Chronic Daily Headache Studies-Common Design Final analysis Primary analysis Placebo Non-Responder (PNR) Baseline Placebo Responder (pr) Placebo -60 -30 0 Day 90 180 270 *Allergan, Botox®, USA

15. Chronic Daily Headache Injection Patterns: Fixed Site-Fixed Dose (FSFD) 75,150,225 UModified Follow-the-Pain (mFTP) 105-260 U. 190 X X X X X X X X Procerus, Corrugator, Frontalis, Temporalis, Masseter (optional), Occipitalis Trapezius, Semispinalis, Splenius capitis

16. Chronic Daily Headache Studies - DesignSilberstein et al, Headache 2005. Mathew et al, Headache 2005. *Allergan, Botox®, USA

17. Chronic Daily Headache – Efficacy MeasuresMathew et al, Headache 2005. *Allergan, Botox®, USA

18. Chronic Daily Headache – Adverse EventsMathew et al, Headache 2005. • No significant difference: Headache, neck rigidity, pain, face pain, dysphagia, hypertonia, hyperesthesia, dizziness, pharyngitis, visual disturbance • Majority of AE's were mild to moderate in severity and transient in nature *Allergan, Botox®, USA

19. Chronic Daily Headache– Safety & Results Mathew et al, Headache 2005. • Repeat treatment (up to 3 treatment cycles) with BoNTA* is safe and well-tolerated at doses up to 260U • No neutralizing antibodies • No benefit of placebo run-in  pool PNR and PR groups • Although the 1° endpoint was not met, significant & clinically meaningful improvements were seen following BoNTA* vs placebo: • Responder rates • Headache frequency • No significant change in proportion of patients with ≥50% Decrease in HA Frequency, Number of Days of Acute HA Med Use, Number of Uses of Acute Meds, MIDAS, Headache Specific QOL *Allergan, Botox®, USA

20. CDH – 1° Outcome MeasureMathew et al, Headache 2005. Number of Headache-Free Days PNR BoNTA* (n=134) PNR PBO (n=145) PR BoNTA* (n=39) PR PBO (n=37) Δ = 1.5 HA-free days at Day 180 Blinded Treatment Days After Placebo Run - In *Allergan, Botox®, USA

21. CDH – 2° Outcome MeasureMathew et al, Headache 2005. Responder Rate % Patients with > 50% Decrease Headache Days *p<0.027 Blinded Treatment * 33 15 Days After Placebo Run - In *Allergan, Botox®, USA

22. Pooled (PNR + pr) 3.4 CDH – Number of HA’s Mathew et al, Headache 2005. Numberof Headaches –Changefrom Baseline *p<0.05 § p=0.001 Blinded Treatment * * * Baseline BoNTA* = 13.5 Placebo = 12.7 * § * * * Days After Placebo Run - In *Allergan, Botox®, USA

23. BoNTA* Placebo CDH – % Decrease HA FrequencyDodick et al, Headache 2005. Subgroup Analysis - No Concomitant Prophylaxis % Decrease in Number of Headaches ≥30% ≥50% *p<0.05 * *p<0.05 * * * * * * Days After Placebo Run - In Days After Placebo Run - In Blinded Treatment *Allergan, Botox®, USA

24. Chronic Daily Headache • mFTP • HA free days - NS •  50%  in HA d/m - S • #HA/mo - S

25. Protective ptosis • 15 – 20 units • into levator ab externo via flipped upper lid

26. Autonomic Nerve Inhibition – Ach Release Blocked • glands • lumen post injection (Swartling) • smooth muscle

27. Injection of BTX-A

28. Conclusions • Onset of effect occurred within 2 – 3 days following injection and lasted for 3 - 4 months. • Side effects are infrequent, mild and transient. • Subjective and objective evidence for reduction in tear production. • Effectiveness needs to be established with a randomised clinical trial.

29. Thanks to: SPH Staff: Cynchia, Maureen, Kathy Residents: Leah, Paul, Briar Allergan: Botox Therapeutic Div G. Davidovic D. Hoppenbrouwer