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

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

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

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

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

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

Hemifacial spasm movie Click here

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

Blepharospasm movie (Click here)

Blepharospasm

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

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

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

Baseline Placebo BoNTA* Placebo BoNTA* Placebo Final analysis Placebo Non- Responder (PNR) Placebo Responder (pr) Day Chronic Daily Headache Studies -Common Design Primary analysis *Allergan, Botox®, USA

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

Chronic Daily Headache Studies - Design Silberstein et al, Headache Mathew et al, Headache Silberstein(n=702)Mathew (n=355) (n=355) Concurrent HA Prophylaxis Allowed Randomization to Active Treatment 3:11:1 Injection Paradigm FSFDmFTP Dose 0, 75, 150, 225U 0, 105 – 260U Safety Safe and well-tolerated Safe and well-tolerated Results 1° - HA-Free Days – N.S. 1° - HA-Free Days – N.S. 2° - Responder Rate – N.S. 2° - Responder Rate – N.S. 1° - HA-Free Days – N.S. 1° - HA-Free Days – N.S. 2° - Responder Rate – P<0.05 2° - Responder Rate – P<0.05 %  50%  HA d/m %  50%  HA d/m *Allergan, Botox®, USA

Chronic Daily Headache – Efficacy Measures Mathew et al, Headache Efficacy Measures Outcome Measure Day 180 1o1o1o1o Number of HA-Free Days/month Not significant 2o2o2o2o Responder Rate (% Patients with ≥ 50% decrease HA- days/month) p < 0.05 Additional Number of Headaches/month p < 0.05 Additional Proportion of patients with ≥50% decrease in HA frequency Proportion of patients with ≥50% decrease in HA frequency Number of days of acute HA med use Number of days of acute HA med use Number of intakes of acute meds Number of intakes of acute meds MIDAS MIDAS Headache Specific QOL Headache Specific QOL Not significant *Allergan, Botox®, USA

Chronic Daily Headache – Adverse Events Mathew et al, Headache Treatment-Related Adverse Event BoNTA*Placebop-value Neck Pain 23 (13.3%) 1 (0.5%) <0.001 Arm Pain 7 (4%) 1 (0.5%) Injection Site Hemorrhage 2 (1.2%) 9 (4.9%) Muscular Weakness 38 (22%) 0 (0%) <0.001 Skin Tightness 8 (4.6%) 0 (0%) Blepharoptosis 12 (6.9%) 1 (0.5%) <0.001 <0.001  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

Repeat treatment (up to 3 treatment cycles) with BoNTA* is safe and well-tolerated at doses up to 260U Repeat treatment (up to 3 treatment cycles) with BoNTA* is safe and well-tolerated at doses up to 260U No neutralizing antibodies No neutralizing antibodies No benefit of placebo run-in  pool PNR and PR groups 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: 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 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 Chronic Daily Headache – Safety & Results Mathew et al, Headache *Allergan, Botox®, USA

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

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

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

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

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

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

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

Injection of BTX-A

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

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