Treatment of blepharospasm with apraclonidine

Dhanya Vijayakumar MD, Subhashie Wijemanne MD, Joseph Jankovic

MD

PII: S0022-510X(16)30733-X
DOI: doi: 10.1016/j.jns.2016.11.029
Reference: JNS 14941

To appear in: Journal of the Neurological Sciences

Received date: 27 July 2016

Revised date: 31 October 2016
Accepted date: 13 November 2016

Please cite this article as: Dhanya Vijayakumar, Subhashie Wijemanne, Joseph Jankovic,
Treatment of blepharospasm with apraclonidine, Journal of the Neurological Sciences
(2016), doi: 10.1016/j.jns.2016.11.029

This is a PDF file of an unedited manuscript that has been accepted for publication.
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Treatment of Blepharospasm with Apraclonidine

Title: Treatment of Blepharospasm with Apraclonidine

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Authors: Dhanya Vijayakumar, MD, Subhashie Wijemanne, MD, Joseph Jankovic, MD

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Affiliation: Parkinson’s Disease Center and Movement Disorder Clinic

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Department of Neurology, Baylor College of Medicine, Houston, Texas

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Address correspondence to:
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Joseph Jankovic, MD
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Professor of Neurology
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Distinguished Chair in Movement Disorders

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Director, Parkinson’s Disease Center

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and Movement Disorders Clinic

Department of Neurology

Baylor College of Medicine

7200 Cambridge, Suite 9A

Houston, TX 77030-4202

Tel: 713-798-5998

Fax: 713-798-6808

E-mail: josephj@bcm.edu

Web: www.jankovic.org

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Treatment of Blepharospasm with Apraclonidine

Word count: 1435

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Financial disclosure/Conflict of Interest:

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No conflict of interest to report. Please see the end of the manuscript for full financial

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disclosures.

Funding sources for study:

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This research did not receive any specific grant from funding agencies in the public,
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commercial, or not-for-profit sectors.
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Treatment of Blepharospasm with Apraclonidine

Abstract

Objective: To describe improvement in blepharospasm with apraclonidine.

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Background: Blepharospasm is a focal dystonia involving chiefly the orbicularis oculi and

periocular muscles resulting in involuntary sustained eyelid closure. Botulinum toxin injection is

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the mainstay of treatment with meaningful improvement in over 85% of patients, but the effects

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often wear off within 3-4 months. Apraclonidine is an alpha-2 adrenergic receptor agonist, which

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causes contraction of superior tarsal (Müller) muscle which may improve blepharospasm-related

eyelid closure. We propose that apraclonidine may be a useful short-term treatment in patients
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with blepharospasm, particularly during wearing off from botulinum toxin injection.

Methods: Patients who had pre-mature wearing off of botulinum injection effect were evaluated
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before and after the administration of 2 drops of apraclonidine 0.5%-1% solution to each eye.

Subjective patient impressions and examiner’s impression of symptoms pre and post-
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apraclonidine administration were recorded. A blinded rater evaluated the videos and provided
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an independent assessment of the severity of symptoms pre- and post-administration, using a 0-4
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scale.

Results: Our study included 7 patients (4 male) with a mean age of 61 years and mean duration

of blepharospasm of 3.6 years. There was a subjective, albeit transient (about 2-4 hours)

improvement in blepharospasm reported by all patients and by the examiner. The mean severity

scores, based on blinded video ratings, showed a reduction from of 3.4 pre-administration to 2.3

post-administration of apraclonidine (p <0.025). No adverse effects were noted.

Conclusions: Apraclonidine is a potentially useful medication for short term management of

blepharospasm symptoms while awaiting botulinum toxin injection.

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Treatment of Blepharospasm with Apraclonidine

Key words: Apraclonidine, blepharospasm, botulinum toxin

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Treatment of Blepharospasm with Apraclonidine

1. Introduction

Blepharospasm is a form of focal dystonia affecting the orbicularis oculi muscle and periorbital

muscles resulting in increased frequency of blinking and involuntary eyelid closure (Jankovic,

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2016). In addition to forced eyelid closure, most patients with blepharospasm also develop

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abnormal contractions of other facial, jaw and neck muscles (cranial-cervical dystonia) (Weiss et

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al., 2006).

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Blepharospasm was the first indication for which BoNT was approved by the US Food and Drug

Administration (FDA) in 1989 (Ramirez-Castaneda and Jankovic, 2014). Response rate of

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blepharospasm symptoms to BoNT is more than 90% (Kollewe et al., 2015). The peak effect is

usually observed after about 5 days, but sometimes it can be delayed by 1-2 weeks (Dutton and
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Fowler, 2007). The effects of BoNT last 3-4 months in most patients but can vary from anywhere
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between few weeks to 6 months (Dutton and Fowler, 2007, Dashtipour et al., 2015). Surveys of
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patients receiving therapeutic BoNT have indicated that about half of the patients prefer being
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injected more frequently in order to prevent a wearing off effect (Sethi et al., 2012). Currently,
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there is no treatment modality used in the interim while patients are awaiting the onset of BoNT

benefit or after the effects have worn off, thereby resulting in troublesome symptoms similar to

the untreated state in blepharospasm patients.

The treatment of choice for blepharospasm is local injection with botulinum toxin (BoNT)

(Hallett et al., 2013, Evidente et al., 2014). Using various outcome measures, including the

Jankovic Rating Scale (JRS) and Blepharospasm Disability Index (Jankovic et al., 2009), several

studies have shown that treatment with BoNT resulted in a significant improvement in their

blepharospasm. One study of incobotulinumtoxinA in 102 patients with blepharospasm found

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Treatment of Blepharospasm with Apraclonidine

that the most frequently reported adverse events were eyelid ptosis (31.4 %) and dry eye

symptoms (17.6 %) (Evidente et al., 2014). Similar side effects were reported in other studies of

BoNT in patients with blepharospasm. Furthermore, many patients experience recurrence of their

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blepharospasm between 2 and 3 months, often before their next treatment visit.

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Apraclonidine, ophthalmological solution currently approved by the FDA for short term use in

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decreasing intra-ocular pressure (IOP), acts as an alpha-2 adrenergic receptor agonist with weak

alpha-1 agonist effects (Brown et al., 2003). Apraclonidine has its onset of action on reducing

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IOP within an hour of administration and peaks in its effects between 3 to 5 hours; hence it is
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usually prescribed as a three times a day dosing. In addition to reducing intra-ocular pressure,

apraclonidine, through its alpha-2 adrenergic activity, also leads to contraction of the superior
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tarsal or Müller muscle, a smooth muscle innervated by the sympathetic nerves, and elevates the
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eyelid, typically by 1-3 mm (Scheinfeld, 2005). There are reports of using apraclonidine to treat

ptosis in Horner’s syndrome and botulinum toxin induced ptosis (Scheinfeld, 2005, Garibaldi et
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al., 2006, Chu and Byrne, 2007). There are also reports about using acetylcholinesterase

inhibitor, edrophonium chloride, to ameliorate symptoms of blepharospasm (Matsumoto et al.,

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2016) but lack of consistent efficacy and potential side effects, such as bradycardia, sweating,

lacrimation and salivation limit its usefulness. We hypothesize a new potential use of

apraclonidine to ameliorate eyelid closure associated with blepharospasm. The contraction of

Müller’s muscle following administration of apraclonidine is likely responsible for this effect.

We describe here the results of a pilot study of apraclonidine in the treatment of blepharospasm.

2. Methods

Patients with blepharospasm followed at the Parkinson’s Disease Center and Movement Disorder

clinic (PDCMDC) at Baylor College of Medicine were evaluated before and after administration

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Treatment of Blepharospasm with Apraclonidine

of apraclonidine ophthalmic solution in their eyes. Patients included in this study were

experiencing wearing off of BoNT effect and recurrence of their blepharospasm or were waiting

for insurance approval for the first BoNT injection. They were videotaped according to a

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standardized protocol used at PDCMDC and evaluated before and 20-30 minutes after the

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administration of 2 drops of apraclonidine 0.5%-1% solution to each eye. Individual segments of

pre and post videos were labelled with fourteen numbers and these numbered segments were sent

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to a blinded rater. Based on the duration of eye closure and frequency of blinking, an overall

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impression was noted by the blinded rater and the severity was marked by a modified JRS on a

0-to-4 scale: 1 = slight increase in blinking, 2 = mild fluttering of eyelids without actual eyelid
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spasms, 3 = moderate, noticeable, eyelid spasms but not sustained spasms and 4 = definite,

sustained eyelid spasms. Patients were then asked about their impression about their symptoms
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pre and post administration. Subjective impression by the examiner pre and post-apraclonidine

administration was also recorded with the degree of improvement rated as 0 = no improvement,
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1= mild improvement, 2=moderate improvement, 3= marked improvement and 4 = complete

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resolution. A “blinded” rater evaluated the videos which were randomly presented to provide an
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independent assessment of the severity of symptoms pre- and post-administration. Unpaired t test

was used to determine statistical significance for the differences observed in the data.

3. Results

Seven patients (4 males), mean age 58 (range: 48 to 71) years and mean duration of

blepharospasm 3.6 (range: 1 to 8) years, were included in the study. All patients were

experiencing wearing off of benefit from BoNT injections at the time of inclusion in the

apraclonidine trial. Improvement in blepharospasm was noted in all patients by the examiner.

There was a subjective improvement reported by all patients, lasting about 2-4 hours. In 4 of 7

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Treatment of Blepharospasm with Apraclonidine

patients there was mild improvement (rating of 1), 2 had moderate improvement (rating of 2),

and one had marked improvement (rating of 3). Mean duration of the videos pre-apraclonidine

administration was 34 seconds and post-apraclonidine administration was 40 seconds. The mean

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severity scores, based on blinded video ratings, showed a reduction from a mean of 3.4 JRS

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score pre-administration to 2.3 post-administration of apraclonidine (p <0.025) (Table). No

adverse effects were noted in any of the patients during the immediate post administration period

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or any reported during the two weeks that this medication was used in this study population.

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Video of patient #1 with a response rating of 3 is included to illustrate the response to
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apraclonidine (Video).

4. Discussion
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Intra-ocular administration of apraclonidine was associated with improvement in blepharospasm

in all 7 patients. The severity scores, based on a review of videos by a “blinded” rater, were
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lower post administration of apraclonidine with the difference being statistically significant
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(p<0.025) (Table). This pilot data provides support for the conclusion that administration of
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apraclonidine may alleviate blepharospasm, but a larger prospective, double-blind, placebo-

controlled trial is warranted.

No adverse effects were reported by the patients in this cohort during the two weeks that this

medication was used. Potential adverse reactions include local eye discomfort, redness, itching,

blurred vision, follicular conjunctivitis and contact dermatitis. Earlier studies have reported a risk

of about 36% in developing an allergic reaction with the use of this medication for three months

(Nagasubramanian et al., 1993, Butler et al., 1995).

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Treatment of Blepharospasm with Apraclonidine

Apraclonidine is a peripherally acting agent that does not cross the blood brain barrier, making

systemic side effects very rare, but they may include dry mouth, dry nose, cardiac arrhythmia,

chest pain, nausea and myalgia. (Yazici and Beden, 2008). Long-term use of apraclonidine has

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been associated with a loss of acuity, allergic conjunctivitis, blurred vision, eye discomfort and

hyperemia but when used for only ≤4 weeks the risk of side effects is very small (Araujo et al.,

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1995). In addition to these side effects seen with chronic use of apraclonidine, there is also a

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potential for tachyphylaxis, as seen during its use in treatment of glaucoma that further

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discourages the chronic use of this agent (Apatachioae and Chiselita, 1999). This could be a brief

intermediary treatment modality for infrequent use in patients who experience premature
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wearing off of BoNT injection effects. Though the response seen here is modest, this may be

beneficial in patients with severe blepharospasm that limits their activities of daily living.
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We conclude that apraclonidine may be beneficial in patients with blepharospasm, but larger and

randomized, placebo-controlled studies are needed before it can be recommended as a routine

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treatment for patients with untreated blepharospasm or in patients whose BoNT effects wear off.
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Authors’ roles:

Dhanya Vijayakumar, MD: Author of the first draft and subsequent edits

Subhashie Wijemanne, MD: Blinded rater and also provided review and critique on the

manuscript

Joseph Jankovic, MD: Co-authored the manuscript and provided review and critique on the

manuscript

Full Financial Disclosures:

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Treatment of Blepharospasm with Apraclonidine

Joseph Jankovic, MD

Dr. Jankovic has received grants from Adamas Pharmaceuticals, Inc; Allergan, Inc; CHDI

Foundation; Civitas/Acorda Therapeutics; Huntington Study Group; Ipsen Limited; Kyowa

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Haako Kirin Pharma, Inc; Lundbeck Inc; Medtronic; Merz Pharmaceuticals; Michael J Fox

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Foundation for Parkinson Research; National Institutes of Health; National Parkinson

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Foundation; Omeros Corporation; Parkinson Study Group; Pfizer; Prothena Biosciences Inc;

Psyadon Pharmaceuticals, Inc; St. Jude Medical; Teva Pharmaceutical Industries Ltd. Dr.

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Jankovic receives consulting fees from Adamas Pharmaceuticals, Inc; Allergan, Inc; Teva
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Pharmaceutical Industries Ltd. Dr. Jankovic has received royalties from Cambridge; Elsevier;

Future Science Group; Hodder Arnold; Lippincott Williams and Wilkins; Wiley-Blackwell.
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Dhanya Vijayakumar, MD
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None to report
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Subhashie Wijemanne, MD
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None to report

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References

Apatachioae I, Chiselita D (1999) [Alpha-2 adrenergic agonists in the treatment of glaucoma].

Oftalmologia 47:35-40.
Araujo SV, Bond JB, Wilson RP, Moster MR, Schmidt CM, Jr., Spaeth GL (1995) Long term

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effect of apraclonidine. The British journal of ophthalmology 79:1098-1101.
Brown SM, Aouchiche R, Freedman KA (2003) The utility of 0.5% apraclonidine in the
diagnosis of horner syndrome. Archives of ophthalmology 121:1201-1203.

RI
Butler P, Mannschreck M, Lin S, Hwang I, Alvarado J (1995) Clinical experience with the long-
term use of 1% apraclonidine. Incidence of allergic reactions. Archives of ophthalmology

SC
113:293-296.
Chu EA, Byrne PJ (2007) Pharmacologic reversal of Horner's syndrome-related ptosis with
apraclonidine. Ear, nose, & throat journal 86:270, 273.

NU
Dashtipour K, Chen JJ, Frei K, Nahab F, Tagliati M (2015) Systematic Literature Review of
AbobotulinumtoxinA in Clinical Trials for Blepharospasm and Hemifacial Spasm.
Tremor and other hyperkinetic movements (New York, NY) 5:338.
MA
Dutton JJ, Fowler AM (2007) Botulinum toxin in ophthalmology. Survey of ophthalmology
52:13-31.
Evidente VG, Truong D, Jankovic J, Comella CL, Grafe S, Hanschmann A (2014)
IncobotulinumtoxinA (Xeomin(R)) injected for blepharospasm or cervical dystonia
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according to patient needs is well tolerated. J Neurol Sci 346:116-120.

Garibaldi DC, Hindman HB, Grant MP, Iliff NT, Merbs SL (2006) Effect of 0.5% apraclonidine
TE

on ptosis in Horner syndrome. Ophthal Plast Reconstr Surg 22:53-55.

Hallett M, Albanese A, Dressler D, Segal KR, Simpson DM, Truong D, Jankovic J (2013)
Evidence-based review and assessment of botulinum neurotoxin for the treatment of
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movement disorders. Toxicon 67:94-114.

CE

Jankovic J (2016) Blepharospasm. In: Medlink Neurology

Jankovic J, Kenney C, Grafe S, Goertelmeyer R, Comes G (2009) Relationship between various
clinical outcome assessments in patients with blepharospasm. Movement disorders :
AC

official journal of the Movement Disorder Society 24:407-413.

Kollewe K, Mohammadi B, Kohler S, Pickenbrock H, Dengler R, Dressler D (2015)
Blepharospasm: long-term treatment with either Botox(R), Xeomin(R) or Dysport(R). J
Neural Transm 122:427-431.
Matsumoto S, Murakami N, Koizumi H, Takahashi M, Izumi Y, Kaji R (2016) Edrophonium
Challenge Test for Blepharospasm. Front Neurosci 10:226.
Nagasubramanian S, Hitchings RA, Demailly P, Chuniaud M, Pannarale MR, Pecori-Giraldi J,
Stodtmeister R, Parsons DG (1993) Comparison of apraclonidine and timolol in chronic
open-angle glaucoma. A three-month study. Ophthalmology 100:1318-1323.
Ramirez-Castaneda J, Jankovic J (2014) Long-term efficacy, safety, and side effect profile of
botulinum toxin in dystonia: a 20-year follow-up. Toxicon 90:344-348.
Scheinfeld N (2005) The use of apraclonidine eyedrops to treat ptosis after the administration of
botulinum toxin to the upper face. Dermatology online journal 11.
Sethi KD, Rodriguez R, Olayinka B (2012) Satisfaction with botulinum toxin treatment: a cross-
sectional survey of patients with cervical dystonia. J Med Econ 15:419-423.

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Weiss EM, Hershey T, Karimi M, Racette B, Tabbal SD, Mink JW, Paniello RC, Perlmutter JS
(2006) Relative risk of spread of symptoms among the focal onset primary dystonias.
Movement disorders : official journal of the Movement Disorder Society 21:1175-1181.
Yazici B, Beden U (2008) Use of 0.5% apraclonidine solution in evaluation of blepharoptosis.
Ophthal Plast Reconstr Surg 24:299-301.

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Table 1: Patient demographics

Blinded rating

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Response to apraclonidine blepharospasm

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Strength of
Duration of severity (0-4
Apraclonidine

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Pt # Age Sex blepharospasm Clinical information scale)
administered

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(years) Examiner’s Pre- Post-
in both eyes Patient noted
impression Rx Rx

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subjective
of

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improvement
improvement
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1 67 M 5 0.5% Wearing off effect from BoNT;
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prior history of ptosis and

Yes 3 4 2
diplopia limiting increase in

BoNT dose.

2 51 M 1 0.5% Recurrent blepharospasm after

Yes 1 3 2
8 weeks of BoNT injection.

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3 55 F 6 0.5% Tardive blepharospasm from

use of aripiprazole with

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wearing off of BoNT effect Yes 1 3 2

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within 6 weeks after last

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injection.

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4 48 F 1 0.5% Patient with blepharospasm and

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bruxism as a part of cranial-

cervical dystonia, who is Yes 2 2 1

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awaiting insurance approval for

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BoNT injection.
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5 60 F 3 0.5% Cranial-cervical dystonia with
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recurrence of blepharospasm 8 Yes 1 4 3

weeks after BoNT injection.

6 55 M 8 1% Cranial-cervical dystonia with

insufficient benefit from BoNT, Yes 2 4 3

S/P bilateral GPi DBS, with

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suboptimal control of

blepharospasm.

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7 71 M 1 0.5% Blepharospasm and cervical

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dystonia with sustained eyelid

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Yes 1 4 3
closure with limited benefit

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from last BoNT injection.

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Mean 58.1 4M 3.57 1.57 3.4 2.3

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Rating scale for examiner:
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0 = no improvement
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1 = mild improvement

2 = moderate improvement

3 = marked improvement

4 = complete resolution

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Blinded rater’s scale of blepharospasm severity:

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0 = no symptoms

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1 = slightly increased blinking

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2 = mild fluttering of eyelids without actual eyelid spasms

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3 = moderate, noticeable eyelid spasms but not sustained

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4 = definite, sustained eyelid spasms

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Highlights

 Blepharospasm results in involuntary forceful eyelid closure that causes functional

blindness


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Botulinum toxin injection is the preferred treatment of blepharospasm but the effects
could wear off prior to the next scheduled injection
 Ophthalmic apraclonidine administration results in contraction of the Muller’s muscles

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and results in 1-3mm eyelid elevation, which reduces functional blindness in patients
with severe sustained blepharospasm

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