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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 blepharospasm injection techniques other: cervical dystonia strabismus wrinkles (glabella)

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therapeutic uses of botulinum toxin in neuro ophthalmology

Therapeutic Uses of Botulinum Toxin in Neuro-ophthalmology

Janette I. Lindley, MD FRCSC

St. Paul’s Hospital

University of British Columbia

overview
Overview

1.On label uses:

  • hemifacial spasm
  • blepharospasm

injection techniques

  • other: cervical dystonia

strabismus

wrinkles (glabella)

overview3
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

botulinum toxin in neuro ophthalmology
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.
botulinum toxin
Botulinum Toxin
  • Serotype A (Botox , Dysport)
  • Serotype B (Myobloc)
hemifacial spasm
Hemifacial spasm
  • Unilateral
  • Periocular and lower facial +/-platysma stapedius (clicking at hs)
  • R/O facial nerve compression

(MRI)

blepharospasm
Blepharospasm
  • tonic/ clonic lid closure
  • may present unilaterally
  • uncontrollable
  • functional cause for visual loss
  • (apraxia of lid opening)
pathological pain inhibition
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
headache disorders
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.
cdh or transformed migraine
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
chronic daily headache studies common design

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

slide15
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

chronic daily headache studies design silberstein et al headache 2005 mathew et al headache 2005
Chronic Daily Headache Studies - DesignSilberstein et al, Headache 2005. Mathew et al, Headache 2005.

*Allergan, Botox®, USA

chronic daily headache efficacy measures mathew et al headache 2005
Chronic Daily Headache – Efficacy MeasuresMathew et al, Headache 2005.

*Allergan, Botox®, USA

chronic daily headache adverse events mathew et al headache 2005
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

slide19

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

cdh 1 outcome measure mathew et al headache 2005
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

cdh 2 outcome measure mathew et al headache 2005
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

slide22

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

cdh decrease ha frequency dodick et al headache 2005 subgroup analysis no concomitant prophylaxis

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

chronic daily headache
Chronic Daily Headache
  • mFTP
  • HA free days - NS
  •  50%  in HA d/m - S
  • #HA/mo - S
protective ptosis
Protective ptosis
  • 15 – 20 units
  • into levator

ab externo

via flipped upper lid

autonomic nerve inhibition ach release blocked
Autonomic Nerve Inhibition – Ach Release Blocked
  • glands
  • lumen post injection (Swartling)
  • smooth muscle
conclusions
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.
thanks to
Thanks to:

SPH Staff:

Cynchia, Maureen, Kathy

Residents:

Leah, Paul, Briar

Allergan: Botox Therapeutic Div

G. Davidovic

D. Hoppenbrouwer