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I. Introduction II. Historical Perspective Key words. botulinum toxin botulism blepharospasm Botox chemodenervation Clostridium botulinum hemifacial spasm Myobloc strabismus In 1822, Justinius Kerner, a German physician, collated data on 230 cases of botulism, a disorder he called ‘‘sausage poisoning.’’ The Latin word for sausage is botulus, and it was long known to be associated with a form of food poisoning. In fact, in the 800s Emperor Leo VI of Byzantine forbade the 13
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MAJOR REVIEW Botulinum Toxin in Ophthalmology Jonathan J. Dutton, MD, PhD, and Amy M. Fowler, MD Department of Ophthalmology, University of North Carolina, Chapel Hill, NC, USA Abstract. Since its introduction into clinical medicine in 1980, botulinum toxin has become a major therapeutic drug with applications valuable to many medical sub-specialties. Its use was spearheaded in ophthalmology where its potential applications have expanded to cover a broad range of visually related disorders. These include dystonic movement disorders, strabismus, nystagmus, headache syndromes such as migraine, lacrimal hypersecretion syndromes, eyelid retraction, spastic entropion, compressive optic neuropathy, and, more recently, periorbital aesthetic uses. Botulinum toxin is a potent neurotoxin that blocks the release of acetylcholine at the neuromuscular junction of cholinergic nerves. When used appropriately it will weaken the force of muscular contraction, or inhibit glandular secretion. Recovery occurs over 3 to 4 months from nerve terminal sprouting and regeneration of inactivated proteins necessary for degranualtion of acetylcholine vesicles. Complica- tions are related to chemodenervation of adjacent muscle groups, injection technique, and immunological mechanisms. (Surv Ophthalmol 52:13--31, 2007. Ó 2007 Elsevier Inc. All rights reserved.) Key words. botulinum toxin botulism blepharospasm Botox chemodenervation Clostridium botulinum hemifacial spasm Myobloc strabismus I. Introduction Botulinum toxin is an exotoxin produced by the bacterium Clostridium botulinum, an anaerobic Gram-positive sporulating organism. It is consid- ered to be the most potent biological toxin in nature. 87 It is the causative agent of the deadly food poisoning, botulism, which when untreated results in a high rate of mortality. During the past three decades it has been commercially produced as preparations that have found wide application in medical therapy. 31,165 Since its early clinical trials for the treatment of strabismus in the 1970s, the use of botulinum toxin has been expanded to eyelid spasticity, pain syndromes, and facial aes- thetics. It has proven to be easy to administer with only rare local and transient side effects, and it has achieved a very high patient acceptance. The use of botulinum toxin in ophthalmology spearheaded the use of this drug for widespread application in medical therapy, and ophthalmic and aesthetic conditions continue to head the list of its current uses. In this article, we review the history of its development, its pharmacology and mode of action, and its indications for ophthalmic-related disorders. II. Historical Perspective In 1822, Justinius Kerner, a German physician, collated data on 230 cases of botulism, a disorder he called ‘‘sausage poisoning.’’ The Latin word for sausage is botulus, and it was long known to be associated with a form of food poisoning. In fact, in the 800s Emperor Leo VI of Byzantine forbade the 13 Ó 2007 by Elsevier Inc. All rights reserved. 0039-6257/07/$--see front matter doi:10.1016/j.survophthal.2006.10.003 SURVEY OF OPHTHALMOLOGY VOLUME 52 NUMBER 1 JANUARY–FEBRUARY 2007
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Page 1: 2007 Dutton BTX ophth review

SURVEY OF OPHTHALMOLOGY VOLUME 52 � NUMBER 1 � JANUARY–FEBRUARY 2007

MAJOR REVIEW

Botulinum Toxin in OphthalmologyJonathan J. Dutton, MD, PhD, and Amy M. Fowler, MD

Department of Ophthalmology, University of North Carolina, Chapel Hill, NC, USA

Abstract. Since its introduction into clinical medicine in 1980, botulinum toxin has become a majortherapeutic drug with applications valuable to many medical sub-specialties. Its use was spearheaded inophthalmology where its potential applications have expanded to cover a broad range of visuallyrelated disorders. These include dystonic movement disorders, strabismus, nystagmus, headachesyndromes such as migraine, lacrimal hypersecretion syndromes, eyelid retraction, spastic entropion,compressive optic neuropathy, and, more recently, periorbital aesthetic uses. Botulinum toxin isa potent neurotoxin that blocks the release of acetylcholine at the neuromuscular junction ofcholinergic nerves. When used appropriately it will weaken the force of muscular contraction, orinhibit glandular secretion. Recovery occurs over 3 to 4 months from nerve terminal sprouting andregeneration of inactivated proteins necessary for degranualtion of acetylcholine vesicles. Complica-tions are related to chemodenervation of adjacent muscle groups, injection technique, andimmunological mechanisms. (Surv Ophthalmol 52:13--31, 2007. � 2007 Elsevier Inc. All rightsreserved.)

Key words. botulinum toxin � botulism � blepharospasm � Botox � chemodenervation �Clostridium botulinum � hemifacial spasm � Myobloc � strabismus

I. Introduction

Botulinum toxin is an exotoxin produced by thebacterium Clostridium botulinum, an anaerobicGram-positive sporulating organism. It is consid-ered to be the most potent biological toxin innature.87 It is the causative agent of the deadly foodpoisoning, botulism, which when untreated resultsin a high rate of mortality. During the past threedecades it has been commercially produced aspreparations that have found wide application inmedical therapy.31,165 Since its early clinical trialsfor the treatment of strabismus in the 1970s, theuse of botulinum toxin has been expanded toeyelid spasticity, pain syndromes, and facial aes-thetics. It has proven to be easy to administer withonly rare local and transient side effects, and it hasachieved a very high patient acceptance. The use of

13

� 2007 by Elsevier Inc.All rights reserved.

botulinum toxin in ophthalmology spearheadedthe use of this drug for widespread application inmedical therapy, and ophthalmic and aestheticconditions continue to head the list of its currentuses. In this article, we review the history of itsdevelopment, its pharmacology and mode ofaction, and its indications for ophthalmic-relateddisorders.

II. Historical Perspective

In 1822, Justinius Kerner, a German physician,collated data on 230 cases of botulism, a disorder hecalled ‘‘sausage poisoning.’’ The Latin word forsausage is botulus, and it was long known to beassociated with a form of food poisoning. In fact, inthe 800s Emperor Leo VI of Byzantine forbade the

0039-6257/07/$--see front matterdoi:10.1016/j.survophthal.2006.10.003

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Surv Ophthalmol 2007;52(1):13-31 2007010105
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14 Surv Ophthalmol 52 (1) January--February 2007 DUTTON AND FOWLER

manufacture of sausage. Kerner identified a fattyacid as the poisonous agent, and he speculated thatthe toxin might have a therapeutic role in medicineto treat diseases associated with an overactivenervous system. Some years later Muller, anotherGerman physician, described the symptoms ofbotulism as Kerner’s Disease. In 1895 ProfessorEmile Pierre Marie van Ermengen, a student ofKoch, first isolated the bacterium Clostridium botuli-num from the remnants of a preserved ham mealthat killed three musicians in Belgium. He em-ployed Koch’s postulates to determine the cause ofthe disease. Botulinum neurotoxin was first purifiedas a stable acid precipitate by Herman Sommer atthe University of California, San Francisco, in 1928,and during World War II Edward Schantz, stationedat the US National Academy of Sciences laboratoriesat Camp Detrick, Maryland, prepared large quanti-ties of the drug for use by the government andacademic institutions.

In 1949 A.S. Burgen discovered that botulinumtoxin blocks neurotransmitter release at the neuro-muscular junction, and in the 1950s Vernon Brooksdetermined that the blocked neurotransmitter atthe nerve terminal was acetylcholine. Encouraged bystudies by D.B. Drachman in the use of botulinumtoxin to paralyze the hind limb in chicks, Alan Scottof the Smith-Kettlewell Eye Research Foundation,collaborating with Schantz, tested botulinum toxinin monkeys to determine its effectiveness in treatingstrabismus, and in 1980 he published the first reportof its clinical use. Shortly thereafter Scott formed hisown company to produce botulinum toxin type Aunder the name Oculinum, and initiated FDA-sponsored clinical trials for its use in strabismusand blepharospasm. Scott’s original batch of toxinamounted to a mere 150 mg, which provided thesole source for Oculinum used worldwide for almost20 years. In 1989 the FDA approved Oculinum as anorphan drug to treat strabismus, blepharospasm,and hemifacial spasm in patients 12 years of age andolder. Allergan Inc. purchased the right to marketthe toxin in 1991 and changed the name to Botox,and in 1997 they produced a new bulk batch witha higher specific potency that lowered the amountof neurotoxin protein used, thus reducing itsantigenic potential. Subsequent FDA approval wasgranted for its use in cervical dystonia and spasticdysphonia in 2000. Also in 2000, Elan Pharmaceu-ticals gained FDA approval to market botulinumtoxin type B under the name Myobloc for cervicaldystonia.

Observations that patients treated with botulinumtoxin for blepharospasm had the additional effect ofproducing ‘‘an unworried, untroubled appearance’’inspired additional studies for potential cosmetic

applications. In 1987 Alastair Carruthers, a Canadiandermatologist, published the first paper on thetreatment of forehead frown lines with Botox, andin 2002 the FDA approved this drug for thetreatment of glabellar furrows. FDA approval ispending for other aesthetic applications, althoughbotulinum toxin is currently widely used off-label forlateral eyelid rhytids, forehead folds, and otherfacial wrinkles.

Since 1989 botulinum toxin has been demon-strated to be a safe and effective therapy for morethan 100 clinical disorders characterized by involun-tary muscle activity, excessive muscle tone, painsyndromes, and hypersecretory conditions. Novelapplications in neurological and non-neurologicaldisorders continue to emerge at an exponential rate.Table 1 lists the major applications that have beenreported. Numerous ophthalmic conditions fall intothis group, and for several, botulinum toxin hasbecome the first line of management.

III. Pharmacology and Biochemistry

A. STRUCTURE

Botulinum toxin exists as seven distinct serotypes,designated A--G, each with differing terminalbinding configurations.38,112 With few exceptionseach strain of Clostridium produces only one type oftoxin. Clinical botulism in humans is caused by typesA, B, E, F, and potentially G.49 The macromolecularcomplex of each serotype ranges in size from w300kDa to w900 kDa, and is composed of a neurotoxinmolecule with one or more associated non-toxinproteins that surround and protect the toxin. Theneurotoxin molecule is synthesized by the Clostrid-ium bacterium as a single-chain polypeptide ofw150 kDa. To become active, the 150-kDa moleculeis endogenously cleaved, or ‘‘nicked,’’ by bacterialprotease-mediated cleavage into two unequal poly-peptide fragments that remain linked by a disulfidebond (Fig. 1).100 This results in a zinc-dependent 50-kDa light chain fragment and a 100-kDa heavy chainfragment. The heavy chain contains two functionaldomains, each of 50 kDa.

B. MECHANISM OF ACTION

Botulinum toxin acts on cholinergic nerve termi-nals.161 At the neural bouton there are synapticvesicles containing acetylcholine (ACh), a neuro-transmitter that crosses the neuromuscular junctionto stimulate the muscle to contract. The AChvesicles are associated with a protein aggregatecalled the SNARE complex (soluble N-ethylmalei-mide-sensitive fusion attachment protein receptor)(Fig. 2). In order to effect signal transmission across

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BOTULINUM TOXIN IN OPHTHALMOLOGY 15

the neuromuscular junction, vesicles of ACh in thepre-synaptic neural bouton must be released intothe synaptic cleft. Here the neurotransmitter bindsto specific receptors on the muscle plate that triggeropening of sodium ion channels, resulting in

TABLE 1

Current and Potential Clinical Applications ofBotulinum Toxin Therapy

Movement DisordersFocal dystonias

BlepharospasmOromandibular dystoniaCervical dystoniaLaryngeal dystonia

Regional dystoniaMeige syndrome

Essential tremorMyoclonusParkinson disease spasticityTic disordersTardive dyskinesiaPost seventh nerve palsy synkinesis

Other Neuromuscular DisordersMyokymiaNeuromyotoniaTrismusCerebral palsyStroke

Pain SyndromesBack PainCervicogenic painHeadacheTrigeminal neuralgiaMyofascial pain

Ophthalmic DisordersEyelid retractionLacrimal hypersecretionNystagmusOscillopsiaSpastic entropionStrabismusProtective ptosis

Genitourinary DisordersAchalasiaAnal fissuresAnismusIntractable hiccups

Oromandicular DisordersBruxismMasseter hypertrophyTemporomadibular joint dysfunction

Other DisordersApraxia of eyelid openingHemifacial spasmHyperhidrosisSpastic dysphagiaSpastic dysphoniaSynkinesis from facial nerve palsy

Aesthetic ApplicationsWrinkle reductionBrow elevationPlatysmal bands

depolarization and contraction in the adjacentstriated muscle (Fig. 3). This ACh release requiresthe participation of the SNARE proteins thatmediate the fusion of synaptic vesicles with theneuronal plasma membrane.

It is generally accepted that the SNARE proteinsform the core of the machinery for the intracellularmembrane fusion necessary for actelycholine exo-cytosis.76 The SNARE complex consists of at leastfive proteins that play differing roles in the exo-cytosis process. For example, VAMP (vesicle associ-ated membrane protein)—also known assynaptobrevin—is associated with the synaptic vesi-cles, whereas SNAP-25 (synaptosome associatedprotein of molecular weight of 25 kDa) becomeassociated with the synaptic membrane. Under the

Zn

NH2

NH2 COOH

COOH

S--S

light chainheavy chain

cleavage site

Fig. 1. Structure of the botulinum neurotoxin molecule.The native molecule is cleaved to form a light and heavychain, joined by a disulfide bond, and the molecule issurrounded by protective proteins.

synaptic cleft

snap-25

VAMP/synaptobrevin

syntaxin

neurexin

synaptotagmin

Ach synaptic vesicle

SNAR

E co

mpl

ex

Fig. 2. Terminal bouton of a neuron at the neuromus-cular junction. Synaptic vesicles containing acetycholineare associated with SNARE proteins required for release ofthe neurotransmitter into the synaptic cleft.

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16 Surv Ophthalmol 52 (1) January--February 2007 DUTTON AND FOWLER

influence of an action potential in the neuron,calcium channels open and calcium binds to theSNARE proteins. This causes them to spontaneouslyassemble into a soluble ternary complex that movesto the neuronal plasma membrane where theSNARE complex enables the ACh vesicle to fusewith the cell membrane.

The fundamental mode of action of botulinumtoxin is to inhibit neuromuscular transmission byblocking the extracellular release of acetylcholine.86

After injection of botulinum toxin in the region ofthe target muscle, the C-terminal half of the100-kDatoxin heavy chain binds externally to gangliosidesand protein acceptors on the bouton of the terminalnerve cell surface membrane.48 These high affinityacceptors are specific for the various distinctserotypes. The toxin molecules then become in-ternalized within vesicles by the process of endocy-tosis.147 These vesicles become more acidic in theprocess and this leads to a conformational change inthe structure of the neurotoxin, where the N-terminal of the heavy chain can then enabletranslocation of the active 50-kDa light chain acrossthe membrane of the vesicle into the cytosol of theneural pre-synaptic bouton.93 Once in the cytosolthe light chain acts as a zinc-dependant endopepti-dase that cleaves specific SNARE proteins necessaryfor the exocytosis of acetylcholine molecules, thusattenuating neurotransmitter release.20

The various botulinum toxin serotypes differ ineither the SNARE protein they cleave or the specificsite they act on (Fig. 4).4,68 Botulinum toxins A andE cleave SNAP-25. Botulinum toxins B, D, F, and Gcleave VAMP/synaptobrevin. Toxin serotype Ccleaves syntaxin. This endopeptidase protein cleav-

synaptic cleft

muscle fiber

K+

Na+

acetylcholine

ion channel

SNARE complex

Fig. 3. Depolarization of the nerve membrane by anadvancing action potential activates aggregation of theSNARE proteins, with fusion and exocytosis of thesynaptic vesicles at the pre-synaptic membrane. ACh bindsto receptors on the muscle end plate, opening ionchannels that initiate muscle contraction.

age acts to destabilize the SNARE complex render-

ing it non-functional, thereby inhibiting the releaseof acetylcholine into the synaptic cleft. The fewerthe number of vesicles released into the synapticcleft, the lower the probability that an actionpotential will propagate and result in muscle fibercontraction. The resulting local chemodenervationof the muscle causes a flaccid paralysis.

Inhibition of ACh exocytosis by botulinum toxinis temporary and neurotransmission is eventuallyrestored. The process of functional recovery is notcompletely understood, but in part appears to occurby several mechanisms. Most important is the non-collateral sprouting of nerve fibers from the non-myelinated terminal axon immediately proximal tothe end plate, and from nodes of Ranvier of themyelinated parent pre-terminal axons.83 Uponrestoration of synaptic function to the parentterminal some 90 days after exposure to botulinumtoxin type A, there is a concomitant retraction ofthese outgrowths.113 The SNARE proteins can alsobe regenerated in the cell body from where theymigrate to the nerve terminals. In addition, extra-junctional acetylcholine receptors and sodiumchannels appear,9 and the levels of junctionalacetylcholinesterase fall.158 The duration of clinicaleffect depends upon the time it takes to effect theserecovery steps. The time for recovery of functiondiffers between the botulinum toxin serotypes.Effects of botulinum toxin type A last for an averageof three months, whereas recovery from botulinumtoxin type E tends to be more rapid, over severalweeks. Several studies have suggested that theduration of effect does, in part, appear to be dose-related, with higher doses correlating with longerdurations of action. However, other studies have notshown such a correlation.71,139

snap-25

VAMP/synaptobrevin

syntaxin

neurexin

synaptotagmin

Botulinum toxinA,E

B,D,F,G

C

Fig. 4. Botulinum neurotoxin binds to specific mem-brane acceptors allowing internalization of the lightchain. The various toxin serotypes cleave and inactivatedifferent SNARE proteins, blocking their function.

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BOTULINUM TOXIN IN OPHTHALMOLOGY 17

C. ACTIVITY AND DOSING

Biologic effect of botulinum toxin is expressed interms of units (U). Units do not correspond toa specific weight or volume of protein. Rather, 1 U isdefined as the amount of toxin that is lethal in 50%of female Swiss-Webster mice following intraperito-neal injection, defined as the mouse LD50. ForBotox the specific activity is approximately 0.05 ngof neurotoxin protein complex per mouse LD50unit. The LD50 for humans is about 1 ng/kg orapproximately 1,400 mouse LD50 units. This is fargreater than the typical dose of 50--100 units usedclinically. The determination of the mouse LD50 isspecific to methods of preparation and assaytechnique, and therefore there is no simpleconversion factor to compare one serotype orpreparation of toxin to another. Biological effectdepends more on specific activity, which is a measureof toxin potency expressed as nannograms of activetoxin per unit. Thus, in our experience the bi-ological effect of 5 U botulinum toxin type A willgive approximately equivalent clinical results as 500U botulinum toxin type B.

During manufacture, botulinum toxin type A(Botox in the USA; Dysport in the UK) is mixedwith sodium chloride and human albumin is thenadded to prevent loss from surface adsorption.Finally, the toxin is dried and stored frozen. For useit must be reconstituted with saline prior to in-jection, usually in concentrations of 5--10 U per 0.1ml. Despite the fact that the product label recom-mends non-preserved saline for dilution, in ourexperience preserved saline reduces the pain ofinjection for most patients with no detectable loss ofclinical effect. Botulinum toxin type B (Myobloc) isstable in solution at acidic pH, and is stored in thisform. It is provided in a stock concentration of 500U per 0.1 ml, but diluting it with preserved saline at1:1 to 1:2 can very significantly reduce the pain ofthe acidic injection.

The onset of clinical effect with either serotype isgenerally between 1 and 3 days, with full benefitachieved by about 5 days.56,163 However, it is notunusual for the onset to be delayed for 1--2 weeks ormore, and peak effect may be at 2--4 weeks. Theclinical benefit lasts about 3--4 months in mostpatients, but can vary from a few weeks to 6 monthsor greater.

IV. Immunology

A. THE CHALLENGE OF PROTEIN THERAPEUTICS

The immune system frequently presents hurdlesto the success of medical therapeutics. Because it isunable to distinguish beneficial foreign materials

from those that are harmful, significant challengesarise with the use of protein-based biologicaltherapies, such as botulinum toxin. The develop-ment of an immune response to an antigen isinfluenced by several factors, including humanversus non-human origin, molecular size, presenceof an adjuvant, persistence of the antigen in thetissues, antigen quantity, and exposure fre-quency.7,40,88 Botulinum toxins, by virtue of theirlarge size and bacterial origin, are highly immuno-genic. Large doses of botulinum toxin type A ($250U per session of Botox or its equivalent dose forother preparations), large cumulative doses, andinjections administered at less than 3-month in-tervals are possible risk factors for the developmentof antibodies and increased risk of secondarytreatment failure (i.e., patients who had clinicaleffects initially, but later develop treatment re-sistance).19,79,81 However, smaller doses of less than100 U and a dosing interval of not more than every 3months carries a very low risk of developing block-ing antibodies.87 Rollnik et al129 compared patientswith antibodies against type A toxin to a matchedgroup of patients without antibodies. They foundthat those who developed antibodies had a cumula-tive dose more than twice as high, and were youngerin age.

B. ANTIBODIES AGAINST BOTULINUM TOXIN

The large botulinum protein complexes aredegraded into many smaller protein fragments 9--20 amino acids in length that serve as antigenicstimuli. Antibodies may develop against portions ofthe toxin protein but most of these will notattenuate its effect on the neuromuscular junction.These are termed non-neutralizing antibodies, andhave no clinical relevance. Most of these antibodiescross-react between botulinum toxin type A andother forms such as type B. Only a very smallpercentage of antibodies formed will neutralize theneurotoxin at the functional site of the heavy chainthus preventing binding to the neuronal mem-brane. Such antibodies, by definition, are termedneutralizing antibodies and block toxin function.50

To date, no cross-reactive neutralizing antibodieshave been recognized between different serotypes.For this reason patients who become resistant tobotulinum toxin type A usually will respond to typeB, and vice versa. In those patients who do developa low titer of blocking antibodies and only a partialtreatment failure, beneficial treatment response canbe achieved by increasing the injected toxin dose.53

Once complete therapy failure occurs with highantibody titers, even massive doses will not over-come the situation. However, it has been shown that

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18 Surv Ophthalmol 52 (1) January--February 2007 DUTTON AND FOWLER

in the majority of such patients cessation of toxintreatment results in a slow decrease in antibodytiters over 2--8 years to a level where re-initiation oftoxin therapy may again give beneficial results.51

Atassi7 suggested that once a patient developsantibodies against one serotype of botulinum toxin,switching them to another type is likely to be short-lived due to the more rapid development ofresistance. This appears to be born out by clinicalobservations52 and by our own studies where sometype A-resistant patients switched to type B showedonly a temporary benefit.

Clostridium tetani is a closely related bacteriumspecies to C. botulinum. Cloning and sequencingstudies show a 27--51% amino acid sequence homol-ogy between tetanus and botulinum toxins, creatinga potential risk of immunologic cross-reactivity inpatients who have received tetanus vaccine. However,although antibodies against tetanus toxin do cross-react with botulinum toxin and the cross reactivitywith botulinum toxin type B is almost twice that oftype A, experimental studies have suggested thatinjection of botulinum toxin in patients with a pre-vious active immunity to tetanus toxin is not very likelyto mount an antibody response.47

V. Clinically Available Forms ofBotulinum Toxin

Botulinum toxin serotype A was introduced forclinical use in 1983 and is currently FDA-approvedfor a variety of spastic disorders.105 In 2000 type B,an antigenically distinct seroform, became available,approved for cervical dystonia. Type A (Botox,Allergan Inc., and Dysport, Speywood BiopharmLTD [the latter is not approved for use in the USA])is a lyophilized powder that must be reconstitutedwith normal saline prior to use. The resulting pH is7.4, which allows for a rapid release of the toxinfrom the protein complex. Although initial recom-mendations were to use the drug within 4 hours ofpreparation when using non-preserved saline (seeBotox package insert), in our practice when dilutedwith preserved saline it can be used safely for up to7--10 days with only minimal loss of potency.

Botulinum type B (Myobloc in the USA, Neuro-bloc in the UK, Elan Pharmaceuticals) is structurallyand functionally similar to type A. However, type Bhas specific differences in molecular size, neuronalacceptor binding sites, intracellular enzymatic sites,and species sensitivities suggesting that it is a distinctpharmacologic entitiy.23,133 Myobloc is available ina ready-to-use liquid form at pH 5.6, which gives ita long shelf-life that can be used for up to 9 months.However, it causes considerable discomfort on

injection unless it is diluted with saline. Type Btoxin also prevents ACh exocytosis by selectiveSNARE proteolysis, but it acts on a different protein,synaptobrevin.68 Studies have shown that both typesA and B are equivalent in inhibiting neuromusculartransmission,.2,66,134,138 but we have found a shorterduration of action and a higher complication ratewith type B toxin (Myobloc for the treatment of BEB.Ophthal Plast Reconstr Surg (in press).

VI. Clinical Uses of Botulinum Toxin inOphthalmology

Botulinum toxin has found numerous uses inmedicine, with new indications continuing to beadded. This agent has become the treatment ofchoice for a number of movement disorders, and isadvocated as an alternative treatment for manyother conditions. The use of Botox in the aestheticreduction of facial wrinkles currently is expandingrapidly.

A. MOVEMENT DISORDERS AND FOCAL

DYSTONIAS

1. Benign Essential Blepharospasm

Benign essential blepharospasm is a focal cranialdystonia involving the eyelid and forehead muscles.It manifests as involuntary orbicularis musclecontraction resulting in increased frequency andforcefulness of blinking (Fig. 5). In severe cases,blinking may be so repetitive and forceful that thepatient is unable to open their eyes, resulting infunctional blindness. The etiology remains un-known, but may involve dysfunction of the centralcoordination of visual sensory input and motor

Fig. 5. A patient with essential blepharospasm involvingthe orbicularis muscle and the protractors of the medialbrow. Reprinted with permission from Dutton andBuckley.57 Copyright � American Medical Association,1986. All rights reserved.

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BOTULINUM TOXIN IN OPHTHALMOLOGY 19

output to the eyelids. Under this scenario patientshave increased sensitivity to visual stimuli (such asocular surface irritation, or photophobia), and anexaggerated motor response manifested as excessiveblinking and forced eyelid closure.

Botulinum toxin, used in the treatment ofblepharospasm since 1983, has become the treat-ment of choice, and is very successful in controllingeyelid spasms.22,37,54,56,57,59,60,77,89,99,110,120,142,154 Ina review of 29 published series on blepharospasm,type A toxin was shown to be effective in 75--100% ofpatients (mean 93.3%).54 Average doses of toxintype A are 12.5--25 U per eye for Botox and 50--100U for Dysport, injected just beneath the skin intothe orbicularis muscle. The most common injectionpattern is into the medial and lateral portion of theupper and lower lid pre-septal orbicularis, avoidingthe central lid region so as to minimize the risk ofptosis (Fig. 6). Cakmur et al21 reported a betterresponse and fewer complications when injectingthe toxin into the pre-tarsal portion of the muscle.Treatment benefit lasts an average of 13 weeks,although in some patients it may be significantlyshorter or longer. Although some authors havereported decreasing effectiveness with prolongeduse,60,71 others have not seen this for mostpatients.56,75 There is no evidence that prolongedtreatment carried any adverse effects, and we havetreated patients for 22 consecutive years withoutdifficulty. One recent report noted 3 of 178 patients(1.7%) had total remission of blepharospasmfollowing treatment with botulinum toxin.22

5555

5 5

55551

11

1

1

1

11

Fig. 6. Average injection pattern of botulinum toxin typeA for benign essential blepharospasm.

We reserve type B toxin (Myobloc) for thosepatients who develop resistance to type A, frompresumed antibody formation. As long as type Aremains effective, we believe it is important not toimmunologically expose patients to type B until it isnecessary for therapeutic effect. The typical dose oftype B is 1,200 to 2,500 U per eye, in general 50 to100 times the dose of type A. In our experienceusing the same injection technique and sites ofinjection as for Botox, type B has a shorter durationof effect (8--10 weeks) and shows a greater tendencyto diffuse into adjacent areas. Also, patients experi-ence more pain and burning on injection due to thelow pH of the preparation. This discomfort can bereduced considerably by diluting the toxin 2:1 withpreserved saline prior to injection. Although greaterdilutions can be used, this will require a largeraliquot injection and distortion of tissue.

Potential adverse effects following the use ofbotulinum toxin around the eye are shown in Table2. One or more side effects occur in 30% in ofpatients treated for blepharospasm.54 These relateboth to the chemodenervation effect of the toxin onadjacent non-target muscle groups, and to theinjection technique. Complications include local-ized bruising, ecchymosis, ptosis, exposure keratop-athy, diplopia, mid-facial weakness, lagophthalmos,and dry eye. In most cases, complications are mildand transient, resolving when muscle functionrecovers.

The most common complication is ptosis, seenfollowing 10--15% of injections. Although the risk ofptosis is low for any single set of injections, wepreviously reported that the risk of experiencingptosis at least once increases with the number ofinjection sessions, so that after 10 sessions the riskrises to 74%.56 Also, the incidence of ptosis increases

TABLE 2

Most Frequent Complications of Botulinum Toxin forEssential Blepharospasm

Side EffectMean

Incidence (%)Reported

Range (%)

Ptosis 13.4 0--52.3Keratitis 4.1 0--46.2Epiphora 3.5 0--20.0Dry eyes 2.5 0--18.2Dipolpia 2.1 0--17.2Lid edema 1.6 0--30.4Facial weakness 0.9 0--4.6Lagophthalmos 3.0 0--63.6Ecchymosis 0.3 0--9.0Ectropion/entropion 0.3 0--6.7Local pain 0.2 0--100Blurred vision 0.2 0--2.1Facial numbness 0.1 0--4.0

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20 Surv Ophthalmol 52 (1) January--February 2007 DUTTON AND FOWLER

significantly with increasing periorbital injectiondose.30,56 Ptosis is related to spread of the chemo-denervation effect to the levator muscle, resultingfrom placement of the toxin beneath the orbitalseptum. However, even with superficial injectionsthe toxin can diffuse through thin areas in theseptum. When evaluating patients in follow-up afterinjection, they may complain that the toxin has hadno effect. However, patients frequently do notdistinguish between the eyelids being closed fromspasm vs closed from ptosis. The clinician mustdetermine the difference in order to avoid un-necessary early retreatment.

Symptomatic dry eye is another common sideeffect of botulinum toxin for blepharospasm, oftenassociated with superficial keratopathy, photopho-bia, and epiphora. This results from a poor blinkfrom orbicularis muscle weakening and lagophthal-mos, seen in up to 64% of patients.110,145 Artificialtears should be used routinely during toxin therapy.

2. Oromandibular Dystonia

Oromandibular dystonia is a focal movementdisorder affecting the lower face. It is characterizedby spasms along the sides of the nose, the mouth,and chin.64 It can have a profound influence oneating and speaking. Treatment is with small doses(1--2 U) into the affected facial muscles, with nomore than 10 U on each side. Because these musclesare so tiny, overdosage and facial weakness, withdrooling or cheek biting, are potential risks. Athorough knowledge of facial anatomy and experi-ence in injecting the face is important. Oromadib-ular dystonia is sometimes associated with jawclosure dystonia characterized by strong jaw clench-ing. This can be treated with 50--100 U into eachmasseter muscle as needed.

3. Meige Syndrome

Meige syndrome is a term used for a regionaldystonia consisting of the two adjacent focaldystonias: benign essential blepharospasm andoromandibular dystonia (Fig. 7). It is not uncom-mon for clinical manifestations to begin withorbicularis muscle spasm, spreading to the lowerface and even the neck after months to a few years.Frequently, the facial spasms become less severe withbotulinum toxin treatment of the orbicularis musclealone. In many cases, however, the lower facialmuscles will require additional injections as notedfor oromandibular dystonia.

4. Hemifacial Spasm

Hemifacial spasm is characterized by unilateralrecurrent fasciculations and twitches of the face

muscles innervated by the seventh cranial or facialnerve. Onset is usually in the 5th and 6th decades,and is usually unilateral. Unlike blepahrospasm, thespasms in hemifacial spasm persist during sleep, andare not related to hypersensory input. The anatom-ical basis for the spasms is usually a mechanicalirritation of the facial nerve at its exit root bya sagging arterial vascular branch. The latter can bedemonstrated radiographically in 85--90% of cases.The condition may be bilateral in rare instances.Although neurosurgical treatment is available, mostpatients opt for medical management with botuli-num toxin, which is highly successful (Fig. 8).Injection is as for blepharospasm and oromandibulardystonia, with an average of 25--35 U on the affectedside. The duration of beneficial effect is longer thanfor blepharospasm, typically about 16 weeks.

5. Cervical Dystonia

Cervical dystonia is a form of focal dystonia that isassociated with significant musculoskeletal painresulting from the repetitive twisting and turningmovements of the cervical and/or shoulder muscles.A variety of neck muscles can be involved, but in our

Fig. 7. A patient with Meige Syndrome, combiningblepharospasm and oromandibular dystonia. This patientalso shows a significant degree of cervical dystonia.

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BOTULINUM TOXIN IN OPHTHALMOLOGY 21

experience, retrocollis more commonly accom-panies blepharospasm. Injection of 30--60 U toxininto each muscle gives gratifying results. Treatmentof anterocollis and torticollis carries a risk ofdysphagia, and should be undertaken with caution.

B. APRAXIA OF EYELID OPENING

Apraxia is an inability to perform learnedcomplex movements in the absence of paralysis,sensory loss, or disturbance of coordination.Apraxia of eyelid opening is a poorly understoodentity, and the concept has been greatly misused inthe literature. It generally refers to a non-paralyticinability to raise the upper eyelid in the absence ofdiscernable orbicularis muscle contraction or leva-tor muscle injury. The inability to initiate levatormuscle contraction and failure to sustain lidelevation suggests an abnormality of central motorcontrol.44 Many authors inappropriately apply thisdiagnosis to any patient with eyelid closure associ-ated with minimal force of orbicularis contraction,or to those who respond poorly to botulinum toxin.

The original description of this disease referred topatients with supranuclear injury in which activationof the levator muscle could not be achieved. Sincethat time, apraxic-like eyelids have been found tooccur with several different disorders. These includedystonic Parkinson syndrome, progressive super-anuclear palsy, and isolated loss of levator musclecontrol. A fourth type, which we refer to asblepharospastic apraxia, is seen in many patients withblepharospasm. This is not a true apraxia, buta specific type of eyelid dystonia. Here, sub-clinicalcontractions of the pretarsal orbicularis musclepersist into the post-blink phase, suppressing levatormuscle contraction.69 In such cases, the usual

Fig. 8. A patient with hemifacial spasm (A) before and(B) two weeks after injection with botulinum toxin.Reprinted with permission from Dutton and Buckley.57

Copyright � American Medical Association, 1986. Allrights reserved.

injection sites of botulinum toxin will have littleclinical effect. Because the residual orbicularismuscle tone seems to be confined to the pre-tarsalportion of the muscle and the muscle of Riolan,injection of 5 U botulinum toxin into these regionsalong the upper eyelid margin will often showbeneficial results.18,44,98,125 It is unclear whether theproblem here is an abnormal co-contraction of thelevator and orbicularis muscles or a failure atrelaxation of the orbicularis during early levatorcontraction. In either case chemodenervation of thepretarsal portion of the orbicularis with botulinumtoxin seems to help eyelid opening in patients witheyelid apraxia.

C. STRABISMUS

Botulinum toxin was first used in ophthalmologyby Alan Scott to treat strabismus. The theory was toweaken the force of contraction of specific opposingmuscles to straighten the eye. It was also hoped thatpermanent muscle weakness would result. Injectiongenerally requires the use of EMG-guided place-ment of the needle to ensure the toxin is accuratelydelivered to the target muscle, although an open skytechnique is often employed.

For infantile esotropia, McNeer and others haveshown that early intervention using simultaneousbimedial rectus muscle injection with botulinumtoxin can reestablish motor and sensory fusion withgood long term results comparable with thatreported for surgical correction.111 Other studieshave shown that 70--75% of treated children can becorrected to less than 10 prism diopters deviation atdistance.103,156 Ruiz et al132 noted a higher successrate with botulinum toxin in patients over 18months of age, but disappointing results in youngerchildren. On the contrary, Campos et al24 foundbetter results in children younger than 7 months ofage, compared to those who were older at initialtreatment. Spielmann152 noted good initial resultsafter botulinum toxin, but significant long-termrecurrence of esotropia ultimately requiring surgery.These varying findings are due in part to differencesin patient population and injection patterns.

For acquired esotropia in children, botulinumtoxin has been shown to give some measure ofsuccess that increases with repeat injections.155

More than 70% of children can achieve at leastperipheral fusion. Dawson et al43 looked at the useof botulinum toxin on older children (mean age 5.4years) with acute onset esotropia, and noted goodresults in 79%, with 57% maintaining high-gradestereopsis. Others have demonstrated a beneficialrole for botulinum toxin in the treatment of smallangle esotropia in older children and adults, with

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22 Surv Ophthalmol 52 (1) January--February 2007 DUTTON AND FOWLER

most patients showing improvement and someachieving binocular vision.42 For larger angle de-viations, increasing the dose of toxin per injectionmay give better results, but this is associated witha higher incidence of complications such as ptosis.

Intermittent exotropia has been difficult tomanage, and surgery is associated with a highrecurrence rate. Nevertheless, Spencer et al150

reported a 69% success rate in managing thesepatients with botulinum toxin, at least as good aswith surgery.

Botulinum toxin has also been advocated toweaken the medial rectus muscle in patients withsixth nerve palsy from trauma, ischemia, inflamma-tion, or tumors.35 Results have been reported asbetter than the expected spontaneous recovery rateof 12--54% reported in the literature. When treatedwith botulinum toxin less than 6 months from onset,recovery has been reported in 38--70% of cases, witha significant number achieving binocular fu-sion.34,74 Kao and Chao91 demonstrated a similarlysatisfactory result using a sub-Tenon’s injectionwithout EMG-controlled intramuscular injection.They reported a higher rate of recovery using thistechnique then in patients managed more conser-vatively in their series. However, in a prospectivestudy of the effectiveness of botulinum toxin com-pared to conservative management, Holmes et al84

failed to show any significant difference in recoveryrate. In a prospective study of conservative manage-ment for sixth nerve palsy, Holmes et al85 founda higher rate of spontaneous recovery (73%) thanpreviously reported, more in line with the ratesnoted using botulinum toxin.

In cases of sensory strabismus, Han et al78

reported correction in 73% of cases, where thetoxin was used to prevent muscle contracture.Bessant and Lee13 treated five cases of diplopiafrom orbital myositis with botulinum toxin. Theydemonstrated improvement in diplopia in four outof five patients.

Not all attempts at managing ocular deviationshave been successful. Kerr et al94 showed nosignificant benefit in treating sixth nerve palsies inchildren with brain tumors. For the treatment offourth nerve palsy, Garnham et al72 injectedbotulinum toxin into the inferior oblique musclebut found a poor rate of improvement, with 83% oftheir patients ultimately requiring surgery.

D. CHRONIC DRY EYES

Chronic dry eyes from lacrimal hyposecretion orpoor tear quality is difficult to manage. Topicallubrication, punctal plugs, or permanent punctalocclusion have been the mainstay of medical

therapy. Sahlin et al135 injected 2.5--3.75 U botuli-num toxin into the medial portion of the orbicularismuscle of the lower lid or to both the upper andlower lids to reduce the effectiveness of theorbicularis muscle pump mechanism around thecanaliculi. They reported a decreased mean blinktear output of up to 62%, and a subjective improve-ment in dry eye symptoms in 70% of their patients.Although this study has not been confirmed, it mayoffer an alternative treatment choice for patientswith severe dry eyes.

E. ELEVATED INTRAOCULAR PRESSURE FROM

RESTRICTIVE MYOPATHY

Patients with restrictive myopathy from thyroidophthalmopathy may have increased intraocularpressure (IOP), particularly in upgaze. This maybe very difficult to manage with topical medications,and occasionally may require orbital decompressionto relieve vascular congestion. Kikkawa et al95 havereported a reduction in IOP in eight patientsfollowing injection of 10--15 U botulinum toxin intothe inferior rectus muscle. The mean decrease was2 mm Hg in primary gaze and 5 mm Hg in upgazelasting 2--4 months. Presumably, this effect resultsfrom a decreased tone in the extraocular musclesand possibly reduced orbital volume.

F. CONGENITAL AND ACQUIRED NYSTAGMUS

AND OSCILLOPSIA

Nystagmus is a rare condition that has beendifficult to treat.151 Patients may suffer fromoscillopsia and blurred vision from inability tomaintain foveal fixation. Identification of thenystagmus pattern is important in directing therapy.For example, pendular nystagmus associated withmultiple sclerosis may benefit from the druggabapentin, whereas periodic alternating nystagmususually responds better to baclofen.8 Studies haveadvocated injecting botulinum toxin directly intomultiple rectus muscles.27,41,102,126 Oleszezynska-Prost117 reported a diminished amplitude of nystag-mus and improved visual acuity in 43% and 50% ofpatients with congenital nystagmus and eostropia orexotropia, respectively. Retrobulbar injection ofbotulinum toxin also has been reported to resultin improved visual acuity in up to 66% ofpatients.80,130,131 Ptosis was the most common sideeffect, and Tomsak et al158 felt that injection of toxininto the retrobulbar space was not as effective inrelieving nystagmus because of the frequent com-plications of symptomatic diplopia and ptosis.159

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BOTULINUM TOXIN IN OPHTHALMOLOGY 23

G. TREATMENT OF TICS, TREMORS,

AND MYOKYMIA

Several investigators have reported the use ofbotulinum toxin for the treatment of motor tics,including those associated with Tourette syn-drome.148 Improvement has also been demon-strated in patients with essential tremor and headmovements associated with cervical dystonia.

Eyelid myokymia is an uncontrollable twitching ofthe orbicularis muscle, typically involving the lowerlids, and less commonly the upper lid. Unlikemyokymia affecting other facial muscles, isolatedeyelid myokymia is believed to be a benign, self-limited disorder that does not progress to otherneurologic conditions.10 It is sometimes triggered bystress, fatigue, caffeine, or alcohol. The mechanismcausing this condition is not well understood. In somecases it appears to be generated peripherally by thespontaneous discharge of signals in hyperexcitableaxon membranes, where a self-perpetuating rever-berating circuit is produced. The affected muscleshows a slow, undulating fine movement in the mostsuperficial muscle layers. EMG studies show rhythmicbursts of normal-appearing potentials in groupdischarges. Injection of 5 U botulinum toxin intothe superficial orbicularis muscle temporarily relaxesthe muscle until the condition resolves spontane-ously.90,143

Tremor is an oscillatory movement produced byalternating or synchronous contractions of antago-nistic muscles. Essential tremor is the most commonmovement disorder that may involve the head, andwhen of high amplitude, becomes visually disabling.Botulinum toxin may be useful and the dose andsites of injection must be tailored to each patientdepending upon the muscles involved.

H. POST-PERIPHERAL FACIAL NERVE SYNKINESIS

Facial nerve palsy is usually a benign neurologiccondition that resolves spontaneously. However, itcan result in long-lasting motor dysfunction.162

Early after presentation with facial nerve palsy thepatient may show increased blinking and blepha-rospasm-like activity on the non-paralytic side,possibly from increased excitability of facialmotoneurons mediating trigeminal reflexes. Axo-nal regeneration inevitably leads to clinicallyevident hyperactivity of the previously paralyzedmuscles. Abnormal axonal branching leads tosynkinesis, characterized by involuntary contrac-tion of muscles innervated by one branch of thefacial nerve when attempting to voluntary activatemuscles previously innervated by other branches.The condition can result in facial deformity,inappropriate eyelid closure, drooling, and twitch-

ing or muscle spasms. Botulinum toxin has beenshown to be highly effective in reducing thesynkinetic movements for 3--9 months after a singleset of injections.5,33,65,115,128

I. CORNEAL PROTECTIVE PTOSIS

Corneal exposure resulting from a poor blink orlagophthalmos may require a surgical tarsorrhaphyto aid medical therapy. However, this can makefrequent examinations difficult, and can causesome eyelid margin deformity when the adhesionis taken down. Botulinum toxin not uncommonlyresults in the complication of ptosis, from in-advertent chemodenervation of the levator muscle.This complication may be beneficial in creatinga protective ptosis to cover the cornea withoutsurgically altering the eyelid margin.1 The tech-nique is performed by injecting 2.5--5 U toxindirectly into the levator muscle through a trans-cutaneous injection in the superior sulcus orthrough a transconjunctival approach. In 75--80%of cases a ptosis results that is sufficient to allowcorneal healing.58 This procedure offers a valuableadjunct to the management of corneal diseasesthat would otherwise requiring long-term patchingor tarsorrhaphy.108

J. HEADACHE SYNDROMES

The use of botulinum toxin for headachesyndromes followed from observations that patientstreated for forehead frown lines showed improve-ment in headache. Because migraine and otherheadaches often are associated with visual distur-bances, management can be of ophthalmic signifi-cance. Smuts et al149 showed that althoughbotulinum toxin could reduce the frequency ofmigraines by 50%, this did not correlate with theobserved decrease on corrugator muscle actionpotential. They suggested that other mechanismsmight also be responsible for the pain reduction.

Our understanding of migraine has been chang-ing in recent years thanks to the use of functionalneuroimaging techniques. The activation of brain-stem structures preceding activation of the occipitalcortex has been demonstrated, although its signifi-cance is uncertain.6 The transmission of pain signalsfrom the periphery to the central nervous system inmigraine headache is not completely understood,but in part involves the activation of trigeminalnociceptive afferent fibers on vessel walls by tissuedamage or extravasated algesiogenic vasoactiveneuropeptides, leading to propagation of pain. Morerecently, data have pointed to an antinociceptiveeffect of botulinum toxin that is separate from itsneuromuscular activity, but also mediated through

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24 Surv Ophthalmol 52 (1) January--February 2007 DUTTON AND FOWLER

enzymatic blockade of neurotransmitter release.3

Botulinum toxin may act to reduce pain by bothreducing peripheral and central sensitization, bothof which seem to be implicated in the etiology ofmigraine. In experimental studies, a hybrid proteinderived from botulinum toxin type A, LH(N)/A-ECL, was able to selectively target nociceptor afferentneurons and thereby inhibit the release of neuro-transmitters involved in pain transmission.70 Thisappears to be independent of its effect on AChblockade at cholinergic nerve endings. This de-rivative has been shown to produce prolongedanalgesic activity in vivo. Several studies, includingrandomized double blind trials, have confirmed thebenefit of botulinum toxin in lessening the fre-quency and intensity of tension headaches,12 cervi-cogenic headaches, and fibromyalgia--myfascial painsyndromes, with a reduction in the use of chronicpain medication for headache syndromes of 40--75%.15,17,46,157 However, some other clinical trialshave failed to demonstrate any significant benefit inpain control.61,62,122,137

Although the exact dosing regimen and place-ment sites remain to be determined, in ourexperience botulinum toxin can significantly reducethe severity and frequency of painful migraineepisodes for 3--9 months. In our clinical experiencewe inject 50--100 U into the frontalis muscle, stayingat least 2 cm above the brow to prevent brow ptosis.In addition, we inject 30--40 U into the temporalismuscle on each side, and, if needed, 20 units to theoccipitalis muscle.

K. HYPERHIDROSIS AND LACRIMAL

HYPERSECRETION SYNDROMES

Hyperhidrosis is an idiopathic condition charac-terized by exaggerated sweat production by eccrineglands.109 It affects approximately 1% of thepopulation. Early in the clinical use of botulinumtoxin it was observed that some patients withhemifacial spasm experienced decreased facialsweating on the treated side. Since then, botulinumtoxin has been used in the management ofhyperhidrosis of the face, axilla, and palms.73,96,109

In Frey syndrome, gustatory facial sweating followsfrom aberrant regeneration of facial nerve secreto-motor fibers to sweat glands following parotidec-tomy. For treatment with botulinum toxin,postganglionic sympathetic cholinergic nerves toeccrine sweat glands are targeted in the affectedareas. Typically, 0.5--0.8 U/cm2 is injected intrader-mally at 10--25 sites. Although the reported experi-ence is limited, several studies including one largeclinical trial noted up to 82% of treated patientsshowed greater than 50% reduction in sweating

compared to baseline.101 The benefits typically lastfor 3--5 months, and higher doses may extend thisup to a year.

Gustatory epiphora, often called crocodile tears, isa rare condition characterized by excessive lacrima-tion associated with salivatory stimulation.11 It mayfollow from proximal facial nerve injury withaberrant regeneration of secretomotor fibers origi-nally destined for the salivary glands to the lacrimalgland. This can be very troublesome and embarrass-ing to affected patients. Secondary lacrimal hyper-secretion syndrome is a more common problem thatmay be secondary to ocular surface irritation, suchas with trichiasis and eyelid malpositions, cornealexposure, or blepharitis. Primary idiopathic lacrimalhypersecretion, often intermittent, may also be seenin the absence of any obvious ocular surfaceabnormality. This can result in epiphora withoutevidence of nasolacrimal duct abnormality, eyelidlaxity, or ocular surface irritation.

In cases of lacrimal hypersecretion from anycause, injection of 2.5--5 U botulinum toxin intothe palpebral lobe of the lacrimal gland results ina clinically significant reduction in tear productionand improvement in symptoms of epiphora in theup to 75% of patients.16,82,92,127 Although injectioninto the orbital lobe may make more sense, this canbe associated with a risk of diplopia, which we havenot seen with injection into the palpebral lobe.Mean Schirmer’s values fall by 4--5 mm, but we haverecorded as much as 8 mm of reduction. Relief ofepiphora lasts 3 to 4 months. Whittaker et al164

reported improvement in symptoms in 73% of their14 patients; however, they found no correlationbetween the degree of reduction in the Schirmer’stest vs. the degree of resolution of subjectivesymptoms.

L. EYELID RETRACTION

Upper eyelid retraction associated with thyroideye disease may result in corneal exposure, and insome cases corneal ulceration. It also is a majorcontributor to the aesthetic deformities associatedwith this disease. Surgical recession gives excellentresults in 90--95% of patients, but is not usuallyrecommended until the ophthalmopathy has beenstable for 6--12 months. Botulinum toxin canprovide significant improvement in lid retraction.141

We inject 5--10 U into the levator muscle, eithertranscutaneously or transconjunctivally. Studies haveshown an average drop in lid position of 2--3 mm,for a duration of 8--14 weeks.14,34,45,114,121,144 Theprocedure carries a 5--10% risk of overcorrectionresulting in ptosis, and up to a 10% risk of transientdiplopia,160 generally from weakening of the

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BOTULINUM TOXIN IN OPHTHALMOLOGY 25

superior rectus muscle. Morgenstern et al notedthree cases of Hering induced contralateral lidretraction associated with lowering of the treatedeyelid.

Patients with Gravess’ orbitopathy may alsoexhibit an overaction of periorbital muscles suchas the procerus and corrugator muscles. Thiscontributes to the aesthetic deformities, such asglabellar frown lines, associated with this disease.Botulinum toxin can be effective in reducing thesedynamic furrows.118

M. ENTROPION

Spastic entropion is a term previously used fora form of entropion in which the lower eyelidmargin is turned in with a riding up of the pre-tarsalorbicularis muscle. The condition is also often seenwith involutional entropion. It can be associatedwith any horizontal lid laxity where fixation betweenthe anterior and posterior lamellae is lost ordisrupted, often commonly seen with laxity ordisinsertion of the lower eyelid retractors. Occasion-ally following ocular surgery in older patients withpre-existing lid laxity, ocular irritation can causea reflexive orbicularis muscle spasm resulting inmuscle override and entropion. This tends to betransient, often resolving after weeks to months.Temporary relief can be achieved by weakeninglower eyelid muscle tone with 5--10 U botulinumtoxin injected into the pretarsal or pre-septalorbicularis muscle.30,36,116,153 This can completelyeliminate the entropion for up to 3--4 months.

N. COMPRESSIVE OPTIC NEUROPATHY

IN GRAVES’ DISEASE

Compressive optic neuropathy seen in thyroid eyedisease results from enlargement of extraocularmuscles, especially in the orbital apex. In earlystages, systemic steroids or local radiotherapy mayhelp reduce muscle edema with good recovery ofvision. In more advanced cases surgical decompres-sion is required to allow the muscles to expand intothe adjacent paranasal sinuses. In a recent reportfollowing failed bony decompression persistentnerve compression was successfully treated usingbotulinum toxin injected into the retrobulbar space.Neuroimaging showed narrowing of the extraocularmuscle bellies due to reduction of contraction.146

This appears to have reduced the mechanicalcompression of the optic nerve by the musclebellies. Although this does not appear to be a usefullong-term therapeutic option, in selected cases, itmight buy some time prior to initiation of moredefinitive treatment.

O. AESTHETIC USES

In recent years the utility of botulinum toxin infacial rejuvenation has been nothing short ofrevolutionary.25,67,97 Initially, the treatment of facialwrinkles with botulinum toxin focused on thereduction of dynamic rhytids—wrinkles presentduring muscular contraction. Furrows created byrepetitive corrugator supercillii contraction, orglabellar frown lines, were the first to be shown toimprove with localized botulinum toxin injection.26

Fifteen to 25 U toxin are injected into thecorrugator muscle in a V-shaped pattern to includeboth the transverse and oblique heads (Fig. 9). Off-label applications have now expanded to thetreatment of many other areas of the face andinclude ‘‘crows feet’’ (lateral periocular rhytids),transverse brow and forehead furrows, ‘‘smokerslines’’ (perioral rhytids), ‘‘marionette lines’’ (meso-labial folds), and platysmal bands.28,29,63,97,107 Al-though most effective at reducing dynamic rhytids,botulinum toxin can often reduce the appearanceof static rhytids as well by relaxing static muscletone.

Botulinum toxin is also useful in creating a chem-ical brow lift by targeting the brow depressors(depressor supercillii medially, and tail of the orbicularislaterally). Thus, patients can achieve an improvedalthough minor brow re-positioning even withouta surgical brow lift.32 Treatment strategies foraesthetic uses vary widely, but it is important toapproach each patient judiciously and err on theside of caution, because side effects—while

555

5

5

4

555 5

55

55

44

44

4lateral rhytids

glabellarfrown lines

forehead furrows

Fig. 9. Typical injection pattern of botulinum toxin typeA for aesthetic reduction of facial wrinkles.

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26 Surv Ophthalmol 52 (1) January--February 2007 DUTTON AND FOWLER

temporary—can result in significant morbidity andgreat patient dissatisfaction.

VII. Complications of Botulinum Toxin

There are a number of potential complicationswith the use of all clinical preparations of botulinumtoxin. Most of these result from its ability tochemodenervate striated muscles.54,55,124 However,almost all of these side effects are mild andtransient. In our studies the frequency of complica-tions overall is nearly 30% for botulinum type A(Botox) and 54% for type B (Myobloc). But for themost clinically important ones, the incidence isgenerally rather low, and rarely significant enoughto make the patient discontinue treatment. Table 2summarizes the most common complications.

Virtually all patients will experience some degreeof pain or discomfort with botulinum toxin in-jection. However, reports of local pain significantenough to produce an unfavorable patient responseare few and are estimated at 0.2% of treatments.Pretreatment with topical analgesic creams, such as4% lidocaine (ELA-Max) can be very useful.Application of ice to the skin for 10 minutes priorto treatment can also reduce the pain of injection.

Local bruising is another potential side effect,reported with an overall incidence of less than 1%.However, this is likely more common and under-reported in most publications. This tends to occurmore commonly in patients with telangectasias,friable blood vessels, and those on medications thatpredispose to easy bruisability (aspirin, prednisone).Careful placement of injections, immediate gentlelocal pressure following injection, or pretreatmentwith ice packs can help lessen the occurrence ofecchymosis.

Ptosis is one of the more frequent complicationsand results from passage of the toxin through theorbital septum, either by diffusion or inadvertentplacement. The incidence has been reported asfrom only a few percent to as much as 50%, withan average of 13.4%.54 The duration of the ptosistends to last several weeks, but is typically less thanthe duration of the therapeutic benefit on theorbicularis muscle. To reduce the risk of ptosis it isbest to avoid the levator muscle by not injectinginto the central portion of the upper lid. Wheninjecting the brow or forehead areas, one shouldtake care to stay at least 1.5 to 2 cm above thesuperior orbital rim, and aim the needle bevel awayfrom the orbit. Additionally, keeping the volume oftoxin low (i.e., increased concentration) helpsreduce uncontrolled diffusion from the injectionsite.

Surgical treatment for ptosis resulting frombotulinum toxin is clearly contraindicated becausthis effect is almost always temporary and resolvesafter several months. If visually significant, apraclo-nidine 0.5% ophthalmic solution (iopidine) maysuccessfully manage the ptosis until levator musclefunction returns.119,136

Diplopia is an uncommon complication and mostcommonly results from inferior oblique muscleparalysis. It can be associated with other muscles aswell. Because the inferior oblique lies just inside theinferior orbital rim behind the orbital septum, it canbecome exposed to toxin injected deep into themid-portion of the lower eyelid. If this occursrepeatedly, this site can be omitted, because goodefficacy for blepharospasm treatment has beendemonstrated with the elimination of injections tothis region.

Other common side effects of botulinum toxintreatment include dry eye and epiphora. Manypatients will develop an impaired blink with result-ing lagophthalmos from orbicularis muscle weaken-ing. This has been reported in as many of 63% ofpatients, and is likely underreported. Poor blinkleads to corneal exposure and desiccation, resultingin characteristic signs and symptoms of dry eye.These include burning, foreign-body sensation,photophobia, reflex tearing, and redness. Clinicalevaluation can demonstrate punctate epithelialerosions, superficial punctate keratopathy and, insevere cases, sterile ulceration. Reduced lower eyelidtone also impairs lacrimal pump function and canworsen epiphora.

Ectropion can result from weakening of orbicu-laris muscle tone in the face of a pre-existinghorizontal laxity of the lower eyelid supportstructures, particularly the lateral canthal tendon.This is an uncommon side effect, with an overallincidence of less than 1%.

Injections below the level of the lower eyelidsmust be carefully placed to avoid undesirable lowerfacial weakness. The muscles for facial expression liewithin the SMAS (superficial muscular and aponeu-rotic system), a connective tissue layer separatedfrom deeper tissues by a loose areolar layer that canpermit drug to easily diffuse into the mid and lowerface. The incidence of mouth droop and drooling isabout 0.9% when the drug is administered to thelower lid orbicularis alone, but is about 12% wheninjecting in the mid and lower face for hemifacialspasm and oromandibular dystonia. Keeping thedose to only 1--2 U per site and remaining verysuperficial will minimize this risk.

Other rare local side effects include facialnumbness in the distribution of the infraorbitalnerve. This most likely results from a direct

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BOTULINUM TOXIN IN OPHTHALMOLOGY 27

mechanical effect on the nerve as it exits theinfraorbital canal. Blurred vision mostly results froman incomplete blink and resultant corneal exposure,but there is some experimental evidence to suggestthat deep posterior orbital effects of toxin on theciliary ganglion can cause subtle accommodativeinsufficiency.104 One case of acute angle closureglaucoma following botulinum injection was re-ported, felt to result from mydriasis from para-sympathetic effect at the ciliary ganglion.39 One caseof inadvertent intraocular injection resulting ina retinal tear has been reported.106

Brow droop can be seen in patients with earlybrow ptosis where excessive weakening of thefrontalis muscle results. This is avoided by placingforehead injections no closer than 2 cm above thebrows.

VIII. Future Directions

Current research is being directed toward newerclinical applications of botulinum toxin. Toxin typesE and F are effective, but give much shorterdurations of action. They may be useful for patientswho develop antibodies to types A and B. Type C isunder investigation but is not yet available for trial.A search is ongoing for longer acting preparationsby preventing reactivation of the SNARE complex,and short acting forms have shown potential fortreating sports injuries.

The management of complications has beendifficult, and in most cases little can be offeredexcept to wait for muscle recovery. Early attempts atdeveloping anti-botulinum toxin A antibodiesproved successful, but had to be injected withinfour hours of the toxin injection to be effective. 140

Spurred by the recent threats of bioterrorism,there has been renewed interest in developingvaccines against botulinum toxin. Some progresshas been made in creating an inhalation vaccine toneutralize the effects of the toxin.123 It is based onthe discovery of a polypeptide that can be absorbedfrom the airway and that is only one-third of the sizeof the toxin molecule. This peptide stimulates animmune reaction against botulinum toxin, but doesnot itself elicit any of the toxic effects. If the use ofsuch a vaccine ever becomes widespread, it couldhave significant implications for the medical appli-cations of botulinum toxin.

IX. Conclusions

The use of botulinum toxin in ophthalmology hassignificantly altered our ability to manage a numberof difficult medical problems. It has seen its greatest

benefit in the treatment of movement disorders andin aesthetic wrinkle reduction. Additional uses aredescribed annually, and its value in our therapeuticarmamentarium is expected to grow. Although therisks are low and generally well-tolerated, they arenot inconsequential, and the treating physician iswell advised to develop the skills needed toappropriately administer this drug. When properlydelivered, botulinum toxin can provide safe andgratifying results.

X. Method of Literature Search

The literature search for this review was based ona search of the MEDLINE database. Our searchstrategy included key words related to botulinumtoxin, Botox, Myobloc, Dysport, chemodenervation, bleph-arospasm, hemifacial spasm, myokymia, facial tics,migraine, apraxia, dystonia, and various combinationsof these words. Older literature was identified fromthose obtained in our search and most referenceswere obtained and examined. For foreign languagepublications, those in German and Spanish weretranslated. For those in other languages, the Englishabstract was utilized.

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The authors reported no proprietary or commercial interest inany product mentioned or in any concept discussed in this article.Supported by an unrestricted grant from Research to PreventBlindness to the Department of Ophthalmology, University ofNorth Carolina, Chapel Hill.

Reprint address: Jonathan J. Dutton, MD, PhD, Department ofOphthalmology, 130 Mason Farm Road, 5111 BioinformaticsBuilding, CB # 7040, Chapel Hill, NC, 27599-7040.

Outline

I. IntroductionII. Historical perspective

III. Pharmacology and biochemistry

A. StructureB. Mechanism of actionC. Activity and dosing

IV. Immunology

A. The challenge of protein therapeutics

B. Antibodies against botulinum toxin

V. Clinically available forms of botulinum toxinVI. Clinical uses of botulinim toxin in ophthal-

mology

A. Movement disorders and focal dystonias

1. Benign essential blepharospasm2. Oromandibular dystonia3. Meige syndrome4. Hemifacial spasm5. Cervical dystonia

B. Apraxia of eyelid openingC. StrabismusD. Chronic dry eyesE. Elevated intraocular pressure from restric-

tive myopathyF. Congenital and acquired nystagmus and

oscillopsiaG. Treatment of tics, tremors, and myokymiaH. Post-peripheral facial nerve synkinesisI. Corneal protective ptosisJ. Headache syndromes

K. Hyperhidrosis and lacrimal hypersecretionsyndromes

L. Eyelid retractionM. EntropionN. Compressive optic neuropathy in Graves

diseaseO. Aesthetic uses

VII. Complications of botulinum toxinVIII. Future directions

IX. ConclusionsX. Method of literature search


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