the role of drug treatment in children with strabismus and amblyopia

The Role of Drug Treatment in Children with Strabismus and AmblyopiaKlio I. Chatzistefanou and Monte D. Mills

Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison MedicalSchool, Madison, Wisconsin, USA

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 911. Botulinum Toxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

1.1 Therapeutic Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 932. Miotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94

2.1 Therapeutic Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 952.1.1 Accommodative Esotropia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 952.1.2 Postoperative Miotic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 962.1.3 Amblyopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

2.2 Diagnostic Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 963. Atropine Penalisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 964. Levodopa/carbidopa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 985. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

Abstract Strabismus, or misalignment of the eyes, is a common ophthalmic problem inchildhood, affecting 2 to 5% of the preschool population. Amblyopia is an im-portant cause of visual morbidity frequently associated with strabismus, and bothconditions should be treated simultaneously. Pharmacological means for treatingstrabismus and amblyopia can be divided into 3 categories: paralytic agents (bot-ulinum toxin) used directly on the extraocular muscles to affect eye movements;autonomic agents (atropine, miotics) used topically to manipulate the refractivestatus of the eye and thereby affect alignment, focus and amblyopia; and centrallyacting agents, including levodopa and citicoline, which affect the central visualsystem abnormalities in amblyopia.Botulinum toxin, the paralytic agent that causes the clinical symptoms of

botulism poisoning, can be injected in minute quantities to achieve controlledparalysis of the extraocular muscles. Although the role of botulinum toxin isestablished in adults with paralytic strabismus, its usefulness in the treatment ofcomitant childhood strabismus (primary esotropia and exotropia) is not univer-sally accepted. Botulinum injections tend to be more effective with smaller de-grees of strabismus, in patients with good binocular fusion, and in managingovercorrections or undercorrections after traditional muscle surgery. Inadvertent

REVIEW ARTICLE Paediatr Drugs 2000 Mar-Apr; 2 (2): 91-1001174-5878/00/0003-0091/$20.00/0

© Adis International Limited. All rights reserved.

ptosis and paralysis of adjacent muscles, unpredictable responses and technicalconstraints of the injections limit its use in children.Miotic therapy, by altering the refractive state of the treated eye, offers an

alternative to optical correction with bifocals in treating esotropia due to exces-sive accommodative convergence. It is also effective in treating residual esotropiafollowing surgery. The ease of use of glasses restricts the wide application ofmiotics in these common strabismus syndromes.Atropine, an anticholinergic agent, paralyses the ability of the eye to focus or

accommodate. In amblyopia therapy, atropine is used to blur vision in the non-amblyopic eye and offers a useful alternative to traditional occlusion therapywithpatching, especially in older children who are not compliant with patching.The neurotransmitter precursor levodopa and the related compound citicoline

have been demonstrated to improve vision in amblyopic eyes. The therapeuticrole of these centrally acting agents in the clinical management of amblyopiaremains unproven.

Strabismus in childhood encompasses a varietyof entities affecting the alignment of the eyes, theability of the two eyes to work together in process-ing the visual information as a single perception(binocular single vision and depth perception).Amblyopia is an acquired maldevelopment of cen-tral visual pathways resulting in reduced vision.Strabismic amblyopia occurs when misalignmentof the eye interrupts binocular single vision. Con-versely, sensory esotropia is a misalignment whichmay result from amblyopia. In both cases, strabismusand amblyopia occur in association. The therapeuticobjectives of treating children with strabismus in-clude reversal of amblyopia, development of equalvision, and the proper alignment of the eyes. Thesuccessful treatment of both strabismus and ambly-opia is critical for obtaining the advantage of usingboth eyes simultaneously (perception of depth, bin-ocular fusion and enlargement of the visual field).The standard methods of treatment for strabis-

mus include surgery on the extraocular muscles,optical treatment with glasses and various methodsof occlusion for amblyopia. Pharmacological treat-ments for strabismus and amblyopia in general playa useful auxiliary role in this therapeutic inventory.

1. Botulinum Toxin

The idea of replacing surgery with a pharmaco-logical means of altering the balance of extraocularmuscle forces to correct misalignment of the eyes

has tempted clinicians for a long time. ConradBehrens is cited as the first to attempt injectingalcohol into human extraocular muscles in the 19thcentury, but the results were inadequate and thecomplications severe. Since Scott et al.[1] introducedthe use of botulinum toxin A in ocular motility dis-orders, the toxin has proved effective for a widevariety of neuromuscular conditions in both oph-thalmology and neurology such as blepharospasm,focal dystonias and strabismus.[2,3] Botulinum toxintype A, 1 of 7 immunologically distinct toxins pro-duced by Clostridium botulinum and one of themost lethal biological toxins, is a dichain proteinof molecular weight 150 000.[2]The first report of the efficacy of botulinum

toxin in correcting strabismus was from a studyconducted in rhesus monkeys with incomitant stra-bismus (induced by paralysis of the medial rectusmuscle).[1] When the paralysis resolved, a concom-itant exodeviation persisted. It appeared that inthese animals the agonist/antagonist muscle balancehad been altered permanently. On this basis thetechnique appeared to be a possible alternative tostrabismus surgery.Botulinum toxin acts selectively on peripheral

cholinergic nerve endings to inhibit acetylcholinerelease.[4] The toxin binds to specific receptors onthe cell surface, thus inducing powerful musclepalsy without causing damage to the muscle or theperipheral nerve.[5] Neither nerve nor muscle suf-

92 Chatzistefanou & Mills

© Adis International Limited. All rights reserved. Paediatr Drugs 2000 Mar-Apr; 2 (2)

fers impairment of electrical excitability or con-ductivity.[6] By preventing release of acetylcholinethe muscle is functionally denervated for 2 to 4months, then fully recovers its action. Apermanentchange in ocular alignment may occur, even thoughthe injected rectus muscle is no longer paretic. Thismay be accomplished by removal of sarcomeresfrom the shortened injected muscle with an addi-tion of sarcomeres to its contralateral (paretic) an-tagonist.[7]When a very small quantity of a purified, recon-

stituted solution of botulinum A toxin (Oculinum)is injected locally into a given muscle group, itbinds very rapidly and quite firmly to the muscle,leaving little toxin to pass into the circulatory sys-tem. The palsy persists for a period of 2 to 4months.[8] No systemic adverse effects or antibod-ies to botulinum toxin have been demonstrated inpatients treated for strabismus.[5]The injections are performed under local or gen-

eral anaesthesia and under electromyographic con-trol through a needle that doubles as an electrode.When general anaesthesia is used, as is usuallynecessary in children, ketamine or insufflation nit-rous oxide are used to preserve the electromyo-graphic signal required tomonitor placement of theneedle in the muscle.[1]Initial doses of botulinum toxin for individual

muscles may be selected from a range of 1.0 to5.0U based on the degree of deviation, bodyweightand the particular muscle injected.[9] Similar initialdoses are administered over a wide range of agesand body sizes. This is probably due to 2 factors:the eye and adjacent structures are precocious indevelopment, attaining over 50% of adult size by1 year of age, and the number of muscle fibres andmyoneural junctions within the muscles is evenhigher in infants than in adults.[9]

1.1 Therapeutic Use

Data are limited on the use of botulinum toxinin childhood strabismus, partly because the elec-tromyography-guided injection is best performedwith local anaesthetic and is less predictable undergeneral anaesthesia.[10] Complications can occur

as a result of diffusion of the drug into the orbit,causing undesirable effects. Adverse effects due tospread of the solution to other extraocular musclesand the levator palpebrae tend to be more commonin children because of the small orbit.[10] The re-ported incidence of ptosis in children is 31[9] to66%,[11] versus 7 to 53%[9,12,13] in adults, and thatof secondary vertical strabismus is 16 to 17%.[9,14]Positioning the patient vertically during and afterthe injection may decrease the incidence of blephar-optosis.[15] Most cases of ptosis are reported to bemild and transient, rarely requiring treatment forinduced amblyopia. Perforation of the globe andretrobulbar haemorrhage, although very uncommon,have also been reported.[16] Absolute contraindica-tions are amyotrophic lateral sclerosis or allergy tobotulinum toxin A.[15] The need for re-treatment re-ported in a large series of paediatric patients reaches85%[17] and is much higher than the average 40%[16]reported in adults.The strabismic indications for the use of botuli-

num toxin vary greatly among different authors.Botulinum toxin has been investigated with vari-able success in a variety of ocular motility prob-lems affecting childhood, including infantile eso-tropia, sensory esotropia, residual accommodativeesotropia, intermittent exotropia, sensory exotropia,paralytic and neurological deviations, congenitaland acquired nystagmus and oscillopsia.The use of botulinum toxin therapy in children

with acute sixth nerve palsy has not been investi-gated extensively. It holds the theoretical advan-tage of allowing a rapid return of single binocularvision and fusion in patients sensitive to develop-ing amblyopia and rapidly losing some binocularfusion ability.[5] In adults, its use in the treatmentof both acute and chronic sixth nerve palsy is wellrecognised, although not universally accepted.[5]Botulinum toxin injection of the ipsilateral medialrectus muscle may allow the patient to obtain anarea of single binocular vision while waiting forpotential recovery during the 6-month period fol-lowing acute onset of the sixth nerve palsy. It alsohelps prevent contracture of themedial rectus mus-cle during this time.[18-22]

Drugs in Strabismus 93


Infantile esotropia is a common form of strabis-mus defined as a manifest esodeviation in a neuro-logically normal infant with an onset between birthand 6 months of age.[23] Botulinum toxin injectioninto the medial rectus has been recommended byseveral investigators as an alternative to incisionalsurgery for treatment of patients with essential in-fantile esotropia. The rate of achievement of satis-factory alignment after one or more injections var-ies from 33 to 89%.[11,24-26] On the other hand,normal-appearing eye alignment is the outcome inmore than 80% of infants after conventional ex-traocular muscle surgery.[27] For its supporters, bi-lateral medial rectus injections of 2.5U of botuli-num toxin have an effective, reliable modality for themanagement of infantile esotropia in infants andyoung children,[25,26] producing binocular alignmentof the visual axes with the potential for achievingsatisfactory binocular function and acceptable longterm effects.[28] 40% of patients received multiple(2 or more) bilateral injections.[26]Less satisfactory results have been reported by

others,[11,24] suggesting that the requirement forfrequent reinjection and the prolonged period ofmisalignment after injection [large angle exotropiaaveraging 30 prism diopters (PD) initial overcor-rection of at least 1 month duration after the injec-tion] may interfere with the goal of achieving earlyalignment and binocular vision.[24] Furthermore,the frequency of associated vertical strabismus (in-ferior oblique overaction and dissociated verticaldeviation) requiring surgery limits the applicationof botulinum. Together with the patients requiringmultiple botulinum toxin injections, these patientsrequiring surgery after botulinum treatment sug-gest that the total number of procedures requiredper patient may be greater with botulinum than pri-mary surgical therapy.[10,29]The effectiveness of botulinum treatment in in-

termittent exotropia in children has been reportedto vary from45%[9] to 69%.[30] This is also lower thanthe expected rate of success with incisional surgery.The clinical use of botulinum toxin A as a post-

operative adjustment procedure has been sug-gested in an attempt to circumvent multiple surgi-

cal procedures in strabismus.[31] In a prospectiverandomised study of children needing re-treatmentafter previous surgery for acquired esotropia, therewas no difference in themotor and sensory outcomesbetween those treated with botulinum toxin andthose reoperated. The treatment was well tolerated,effective and did not produce adverse effects.[14]Botulinum toxin injected into multiple horizon-

tal rectus muscles or retrobulbar injection has of-fered some limited benefit in improving the visualacuity of patients with congenital[32] and acquirednystagmus and oscillopsia.[33]Overall, botulinum injections tend to be more

effective in the treatment of smaller degrees of stra-bismus,[5,15,24] in patients who have good fusion,and when there is a functioning direct antagonist toput stretch on the injected muscle. It seems to beparticularly helpful inmanaging overcorrections orundercorrections after traditional muscle surgery.Results are compromised by the presence of fibro-sis, as in the congenital fibrosis syndrome or scartissue after multiple surgical interventions.[5,15]

2. Miotics

The refractive status of the eye is critical in thepathogenesis and therapy of strabismus. This isparticularly true for a form of childhood strabismusknown as accommodative esotropia, the most com-mon form of childhood esotropia. In normal pa-tients, accommodation (focusing the eyes for nearobjects) is linked to convergence (rotation of theeyes inwardly) in order to keep the object centred inthe visual axis of each eye. The ratio of accommoda-tive convergence to accommodation (AC/A ratio)is generally fixed by this central reflex mechanism.Patients with normal AC/Aratioswho requiremoreaccommodation because of an underlying hyper-opic refractive error may develop esotropia whenfocusing on near as well as on distant objects. Thisis known as refractive accommodative esotropia.Other patients with an abnormally high AC/A ratiomay develop esotropia on near objects, known asnonrefractive accommodative esotropia.Parasympathetic innervation, mediated through

the neurotransmitter acetylcholine, induces constric-



tion of the pupil and contraction of the ciliary mus-cle to produce accommodation. Acetylcholine israpidly hydrolysed and inactivated by the enzymeacetylcholinesterase. One may, therefore, simulatethis parasympathetic effect by using either acetyl-choline or an analogous drug that directly acts onthe end plate, or by allowing acetylcholine to ac-cumulate by preventing cholinesterase from inac-tivating it.The use of physostigmine (eserine) and pilocar-

pine in the treatment of strabismus dates as far backas the 1870s.[34-35] It was not until 1949, though,that the development of the newer, long acting an-ticholinesterase drugs triggered a renewed interestin their clinical usefulness in strabismus.[35]The vast bulk of experiencewith long-acting anti-

cholinesterase drugs has been obtained with ecothi-opate iodide (phospholine iodide) and di-isopropylfluorophosphate although demecarium bromide anddiethyl-phosphoric-acid-p-nitrophenol ester havebeen investigated as well.Ecothiopate iodide and di-isopropyl fluoro-

phosphate are available in concentrations of 0.06to 0.25% and 0.01 to 0.1%, respectively. The min-imal dosage required to produce the desired effectsshould be titrated, starting with a weak solution,such as ecothiopate iodide 0.03%, 1 drop per dayin each eye, and using stronger concentrations ifthe patient fails to respond.[36]Maintaining binocular vision may necessitate

instillation every night, every other night or twicea week, and occasionally even less frequently.[34]When binocular vision is achieved, the medicationmay be continued until contraindicated by compli-cations or until the patient can be weaned off it.Miotic agents have been shown to be beneficial

in therapeutic and diagnostic settings.

2.1 Therapeutic Use

2.1.1 Accommodative Esotropia

Refractive Accommodative Esotropia (Normal AC/A Ratio)Refractive accommodative esotropia is defined

as an esotropia that is restored to orthotropia at allfixation distances and in all gaze positions by

optical correction of the underlying hypermetropicrefractive error. Usually correction with spectaclesis the preferred treatment. Although miotics havebeen shown to be effective in certain patients withrefractive accommodative esotropia,[37-39] it has beenestablished[34,38,39] that glasses and miotics are notinterchangeable. Furthermore, in none of the casesstudied have miotics been more effective thanglasses.[39] Most clinicians would reserve the useof miotics for hyperactive or extremely uncooper-ative children who do not wear spectacles success-fully, or occasionally substitute drops for glassesduring summer vacation when play and physicaloutdoor activity occupy most of the day.[36]

Nonrefractive Accommodative Esotropia (Abnormally High AC/A Ratio)

While bifocal glasses are the most common ap-proach to this problem, miotics are very useful incases without significant hypermetropia and a highAC/A ratio. By pharmacologically causing accom-modation, and reducing the amount of centralaccommodative stimulus, less associated conver-gence and therefore less esotropia occurs. Such al-teration of the AC/A ratio is the desired effect ofdrug therapy.[34] It has been suggested that drug-induced miosis, increasing the depth of focus, maycontribute to the therapeutic effect, although forthis to happen a pupil of 1.0mmdiameter or smalleris required.[40] Pupil diameters <1.5mm are almostnever encountered in children under miotic therapy.The choice of miotics or bifocals is more a mat-

ter of preference of the physician than one of a uni-versally approved advantage of one method overthe other.[36] The reluctance of some children to prop-erly use the lower segment of bifocals or glasses al-together and the long term effects of wearing bifo-cal spectacles on the ability to accommodate[41] areimportant considerations and must be comparedwith the adverse effects of miotics. The reported‘cure rate’ of accommodative strabismus with mi-otics, defined as the presence of binocular visionwithout the use of drops or drugs, varies from3.6%[42] to 55 to 72%.[43,44] Better results are ob-tained in patients with moderate hypermetropia.[44]This compares with 61.5% effectiveness of bifocal



therapy for nonrefractive accommodative esotro-pia.[45,46]

2.1.2 Postoperative Miotic TherapyMiotics may be used to control a residual amount

of postoperative esotropia after surgery for esotro-pia[47-49] or exotropia.[34,38]Overall, miotics for accommodative esotropia:

• tend to be more effective when binocularity ispresent

• are more useful in cases with an abnormal AC/Aratio

• are more effective in reducing the near than thedistance deviation

• tend to be less effective in the presence of am-blyopia

• are generally not indicated unless some degreeof binocularity can be achieved.[34,47]

2.1.3 AmblyopiaAlthough the use of miotics in combinationwith

atropine has been advocated in the past for thetreatment of amblyopia,[50] this combination is notsupported by current literature, nor is it in generalclinical use. The combined use of miotics and atro-pine would increase the refractive advantage of theamblyopic eye relative to the cyclopleged, non-amblyopic eye.

2.2 Diagnostic Use

Miotics can be used as a diagnostic trial foraccommodative esotropia. A significant reduction ofthe deviation at near fixation under the influence ofmiotics may be a strong[36] but not infallible[34,47]indicator of the presenceof either refractive accom-modative esotropia or accommodative esotropiawith a high AC/A ratio. The more standard way ofidentifying an accommodative component in eso-tropia is measuring the angle of deviation after thefull cycloplegic refractive error has been given inglasses.Adverse effects of miotic therapy are com-

mon[51] and necessitate awareness and close mon-itoring. Local adverse effects include conjunctivalhyperaemia, lacrimation, brow ache, allergic bleph-aroconjunctivitis and iris cysts. The incidence of

iris cysts may be as high as 50%. They first appearat the nasal pupillary margin and they may becomelarge enough to partially occlude the pupil, inter-fering with vision. Rapid regression occurs afterdiscontinuation of treatment. They may also be ef-fectively prevented with concomitant topical use ofphenylephrine 2.5%, preferably administered simul-taneously with the miotic drops. Retinal detach-ment, closed angle glaucoma and lens opacities arerarely a concern in children, as they are in olderindividuals.[52]Other visual adverse effects include generalised

darkening of the field of vision and induced tran-sient myopia with blurring of vision. It has beensuggested that if drops are used at bedtime, myopiais usually less than 1 dioptre in the morning.Systemic adverse reactions include lacrimation,

salivation, sweating, intestinal cramps with waterydiarrhoea, bradycardia, nausea, vomiting, urinaryurgency and general fatigue. They are rarely severeenough to warrant discontinuation of treatment. Apotential risk exists when children receivingmiotictherapy are undergoing general anaesthesia. Themore potent anticholinesterase drugs, such as eco-thiopate iodide, lower cholinesterase in red bloodcells and this effect persists for several weeks afterthe last administration of drops. Since cholinester-ase is required for hydrolysis of succinylcholine,patients may develop prolonged paralysis followinggeneral anaesthesia using this agent. Succinylchol-ine should be avoided for up to 6 weeks after dis-continuation of therapy with miotics.[36]

3. Atropine Penalisation

The most common cause of vision loss in chil-dren with strabismus is strabismic amblyopia. Am-blyopia, when recognised within the first 7 to 8years of life, can usually be reversed by forcingpreferential use of the amblyopic eye. Amblyopiatherapy is an integral part of management of youngchildren with strabismus.Occlusive patching of the normal eye has been

described for the treatment of amblyopia as earlyas AD 900, and remains the mainstay of amblyopiatreatment.[53] In practice, though, occlusion treatment



is subject to serious limitations of compliance dueto children’s dislike of occlusion for visual, skinirritation and social/psychological effects of an eyepatch.[54] Compliance is the primary determinantof success in amblyopia treatment.[55,56]Atropine, an anticholinergic agent, acts by re-

laxing the ciliary muscle and the iris sphincter mus-cle, resulting in paralysis of accommodation anddilation of the pupil. This lack of accommodationleads to refractive blur in treated eyes at any focaldistance other than the resting focal length, in theabsence of corrective lenses.This amblyopia therapy has become popular

under the term ‘penalisation’. The principle of pen-alisation is to decrease near or distance vision ofthe fixating eye, i.e. to ‘penalise’ it by atropinisa-tion and/or appropriate spectacle overcorrection.The objective of this treatment is to force the pa-tient to develop alternation between the amblyopiceye for near fixation and the sound eye for distanceor vice versa.Three principal methods of penalisation are

used in clinical practice, although several othervariations have also been described.[57]• Near penalisation: Atropine sulfate 1% dropsare instilled once a day into the sound eye, blur-ring it for near vision and forcing the amblyopiceye to be used for near tasks. Switch of fixationto the amblyopic eye at near vision usually willoccur if visual acuity in the amblyopic eye is20/100 or better. The cycloplegic distance cor-rection is usually provided for the better eye,allowing focused vision for distance from eithereye.[54,57]

• Distance penalisation: Penalisation for distanceis achieved through atropinisation with over-correction of +3.00 diopters of the sound eyeand optical correction for distance of the ambly-opic eye. In this way the sound eye is focusedfor near vision but blurred for distance vision.

• Total penalisation: Total penalisation is achievedthrough atropinisation of the sound eye withminus lenses or 4.00 to 5.00 diopters un-dercorrection in hypermetropes and optical cor-rection for distance of the amblyopic eye. This

would increase the refractive blur in the cyclo-pleged eye both at distance and near.An intermittent form of penalisation was re-

cently proposed by Simons et al.,[54] consisting ofonly 1 drop of atropine 1% each week in patientswith blue iris and the same amount for 2 to 3 con-secutive days a week in patients with dark iris. Theeffectiveness of the cycloplegia wanes over theperiod of treatment, allowing recovery of vision inthe penalised eye during part of each treatment cycle.Advantages of pharmacological penalisation

for amblyopia include consistency (it is physicallyimpossible to peek around the effect of the atro-pine) and compliance monitoring (compliance usu-ally can be checked by inspection of pupil size andreactivity).[58,59] Furthermore, the social stigma ofwearing a patch as well as the skin irritation isavoided. There is no blockage of peripheral visualfield. It is also recommended in cases of latent nys-tagmus, as induced nystagmus is minimal ifany.[57,60] Hypersensitivity to atropine is an obvi-ous contraindication, but is rare.The efficacy of penalisation as a primary treat-

ment of moderate (20/100 or better acuity) ambly-opia has been demonstrated in several studies, withconsiderable improvement of visual acuity occur-ring in 59 to 76% of treated patients.[57,59,61-64] Thetreatment benefit tended to remain stable 2 or moreyears after discontinuation of treatment.[54,62] At-ropine penalisation has also been shown to be aseffective as part-time occlusion therapy in thetreatment of amblyopia.[59,64] Penalisation mayalso be combined with part-time occlusion. It hasbeen shown to be effective in significantly improv-ing binocularity,[54] although no evidence of a dif-ference in binocular outcome was shown whencomparing penalisation with part-time occlusion.[64]Penalisation is usually not effective with severe

amblyopia (vision less than 20/100). Except in mod-erate or high hypermetropia, atropine does not suf-ficiently decrease visual acuity of the sound eye sothat the patient may still prefer the amblyopic eyefor fixation.[53]Penalisation does not avoid the potential of

reversing the amblyopia (inadvertently causing a



decrease of the visual acuity of the atropinised, pre-viously ‘good’ eye).[54,65,66] Furthermore, the rateof vision improvement with penalisation may beslower than with occlusion.[63]

4. Levodopa/carbidopa

Amblyopia represents a functional loss of visualacuity, usually in 1 eye, due to maldevelopment ofthe central visual neuro-anatomic substrate duringearly childhood.Historically, Bietti andSorsonelli[67]noted that anoxia deepens all suppression phenom-ena, including amblyopia, whereas inhalation ofoxygen alleviates them. Claims have been madethat local or systemic application of strychnine canimprove vision in various conditions of the retinaand the optic nerve.[68,69] It has also been suggestedthat central nervous system depressant drugs mayweaken and even completely abolish retinal riv-alry.[70] Since amblyopia was conceived as a phe-nomenon of suppression, closely related to retinalrivalry with the fixating eye inhibiting the affectedeye, alcohol has been tried as a therapeutic agent.[71]None of these agents have proven clinical utility.Recently, the effect of neurotransmitters (espe-

cially levodopa), has been studied extensively onamblyopic vision. Levodopa is a precursor for thecatecholamine neurotransmitters, dopamine andnoradrenaline. It is most frequently used in thetreatment of Parkinson’s disease to replace the re-duction of striatal dopamine. Adverse effects arefrequently encountered with the therapeutic use oflevodopa, including nausea and emesis. To mini-mise the conversion of levodopa to dopamine atperipheral sites, reduceadverse effects, andmaximisecentral nervous system uptake, a peripheral decar-boxylase inhibitor, such as carbidopa or benseraz-ide, is frequently coadministeredwith levodopa.[72]Although levodopa has been shown to influence

the visual system at the retina[73,74] and cortical lev-els,[75] the specific sites of action on the visual sys-tem remain uncertain.[76]Gottlob and Stangler-Zuschrott[77] first reported

that a single 200/50mg dose of levodopa/benseraz-ide temporarily improved contrast sensitivity anddecreased the scotoma size in the amblyopic eyes

of 9 adults. Several subsequent studies investigatedthe potential of lowering the dose[78,79] to achievea longer term beneficial effect in the visual func-tion of the amblyopic eye.[79] An average dose of0.48/0.12 mg/kg levodopa/carbidopa is well toler-ated with minimal adverse effects, and has demon-strated improvement in visual acuity and contrastsensitivity in amblyopic eyes.[78] The improvementin vision persisted at least 6 weeks after cessationof the drug, but did not improve acuity to normallevels.[76] Surprisingly, this improvement was seenin older children (>6 years of age) or adults, whohad previously been considered stable amblyopeswho no longer had potential to improve using usualamblyopia treatments.[72,76-78] The overall improve-ment in vision, however, is small, not exceeding 3lines of visual acuity. Thus, whether pharmacolog-ical treatment will become a useful mode of ther-apy for amblyopia is unclear.[71]Another agent, citicoline, which improves the

level of consciousness in patients with head traumaand parkinsonism, has been reported to have aneffect similar to levodopa. The small improvementin vision in amblyopic eyes is reported to last aslong as 4 months with citicoline.[80]

5. Conclusions

The primary therapeutic methods currently usedto treat strabismus are surgery to the extraocularmuscles and optical manipulations with glasses.Drugs play a secondary but important role in stra-bismus and amblyopia therapy.Botulinum toxin, delivered directly to extraocu-

lar muscles by injection, causes paralysis of themuscles and affects the eye position. The unpre-dictability of botulinum toxin effects, local compli-cations and the limited duration of the paralysismake this drug therapy generally secondary to sur-gery in most clinical practices.Autonomic medications, including both miotics

and mydriatics, are useful in manipulating the re-fractive status of the eye for strabismus and ambly-opia therapy. Specific indications for miotic therapyinclude accommodative esotropia and post-surgical



esotropia. Atropine is generally used therapeuti-cally in amblyopia treatment for optical penalisa-tion.Drugs affecting central neurotransmitters, in-

cluding levodopa/carbidopa and citicoline, havebeen demonstrated experimentally to improve visionin amblyopic eyes. However, the role of these agentsin clinical strabismus and amblyopia therapy hasnot been established.

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Correspondence and offprints: Monte D. Mills, AssociateProfessor of Ophthalmology, Director, Pediatric Ophthal-mology and Strabismus, Department of Ophthalmologyand Visual Sciences, University of Wisconsin, Madison,2870 University Ave, Suite 206, Madison, WI 53705, USA.E-mail: [email protected]



the role of drug treatment in children with strabismus and amblyopia

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