non-ptotic ocular myasthenia gravis: a common...

Non-ptotic ocular myasthenia gravis: acommon presentation of an uncommondisease

Jennifer Colavito, O.D.,a Jeffrey Cooper, O.D., M.S.,a,b andKenneth J. Ciuffreda, O.D., Ph.D.c

aPrivate practice, 539 Park Avenue, New York, New York; and bState University of New York, College of Optometry,Department of Clinical Sciences and cDepartment of Visual Sciences, New York, New York

Background: Myasthenia gravis (MG) is an acquired auto-immune disease of the neuromuscular junction whichcauses rapid muscle fatigue and weakness. Two thirds ofall cases of myasthenia gravis (MG) initially manifestptosis. In the absence of the characteristic variable ptosis,MG can present a challenge to the clinician. This articlewill review the current diagnostic and management strat-egies for MG.

Case Reports: Five cases will be presented that did notinitially present with ptosis. Each of these cases waspreviously misdiagnosed as a result of presentation ofatypical myasthenia gravis signs and symptoms. The firsttwo cases had signs and symptoms of a typical accom-modative/vergence anomaly. The others manifested dip-lopia not normally associated with MG: one had a non-comitant vertical deviation; another had a stable 6th nervepalsy; and the third had a basic esotropia.

Conclusion: Although the hallmark findings of MG are ptosisand eye muscle palsy with variability, MG may presentwithout ptosis, affect nonstriated muscles, and/or mani-fest either as a nonstrabismic vergence anomaly or ascomitant nonvariable strabismic deviation.

Key Words: Accommodative insufficiency, convergence insuf-ficiency, diplopia, myasthenia gravis, oculomotor paresis,strabismus

The name myasthenia gravis (MG) is derived from theGreek, meaning “gravely weak muscles,” and wasfirst described by Sir Thomas Willis in 1672.1 It was

later considered in detail by three German physicians—Goldflam, Erb, and Jolly—in 1890. Twenty years ago, ananimal model was developed that led to a better physio-logically based understanding of the disease, and whichresulted in new treatment options.1

The pathophysiology of the disorder requires an under-standing of the neuromuscular junction (NMJ), which isthe point at which the nerve fiber either synapses with orterminates on a muscle fiber. When a nerve impulse isinitiated, it travels to the NMJ. Here the neurotransmitteracetylcholine (Ach) is then released, passes through theNMJ, and ultimately attaches to receptors on the musclesurface, thereby resulting in muscular contraction. In MG,antibodies erroneously destroy Ach receptor sites, whichare located at the postsynaptic membrane of the NMJ. Thisprevents Ach from binding to muscle cells, and henceinhibiting muscle contraction. (Current thinking is that Tcells derived from the thymus stimulate B cells to producethe antibodies that react at the Ach sites.)2 The result is aprogressive muscle weakness that worsens with sustainedactivity.3,4

MG occurs in approximately 14 of every 100,000 people,resulting in a prevalence of 36,000 cases in the U.S. It canoccur at any age, but has a bimodal distribution that affectswomen below age 40 years and men more than 60 years ofage.5-7 MG is characterized by ptosis, facial weakness, dysar-thria, dysphagia, and dyspnea.2 Among patients who mani-fest ocular myasthenia gravis (OMG), generalized myasthenic

Colavito J, Cooper J, Ciuffreda KJ. Non-ptotic ocular myas-thenia gravis: a common presentation of an uncommon dis-ease. Optometry 2005;76:363-75.

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symptoms will develop in more than 50% withintwo years.8 Two thirds of all cases of MG initiallymanifest ptosis and/or diplopia. A history of avariable ptosis makes MG the most likely differen-tial diagnosis. However, when the patient mani-fests diplopia, or with an accommodative/vergenceinsufficiency, the diagnosis of MG becomes moreelusive.

The exact cause of this auto-immune disease isunknown; it is thought there might be a geneticand/or viral etiology. Thymus abnormalities areassociated with MG, but the exact relationship isuncertain. The thymus produces cells involvedin immune responses. Approximately 10% ofpatients with MG have a thymoma or tumor ofthe thymus, and 70% have hyperplasia of thethymus, which is usually associated with activeauto-immune disease. Since the thymus is thecentral organ for immunological self-tolerance, ithas been suggested that abnormalities of thethymus may cause an immune-mediated attackon the Ach receptor in MG.9

Patients with MG also have an increased preva-lence of other auto-immune diseases, such asrheumatoid arthritis, thyroid disease, and vita-min B-12 deficiency. Symptoms of MG, whichvary day-to-day, may be exacerbated by stress,systemic illness, thyroid disease, pregnancy,menstruation, and certain drugs.3

DiagnosisThe diagnosis of OMG is usually made by acombination of patient history, clinical findings,and other diagnostic procedures. The first suspi-cion of OMG should come to mind during thecase history if the patient manifests symptoms ofptosis, diplopia, and/or blur, which increaseswith use of the ocular muscles, or as the dayprogresses. Patients with generalized systemicMG may also manifest fatigue of the face, neck,and limbs, worsening with activity. Brushingone’s teeth or combing hair may become prob-lematic. Head droop and down-sloping of a smilemay be noted. Variability of symptoms shouldfurther trigger suspicion. The gold standard fordiagnosis of OMG is the Tensilon test. However,there are a number of non-invasive tests that canalso be used to make the diagnosis; all are sim-ple, inexpensive, and highly sensitive.

The first test involves “fatiguing” the extraocularmuscles in upgaze. The patient attempts to sus-tain extreme upgaze for 30 seconds, then quicklyreturns to primary position. Patients with OMGoften demonstrate either a lid-lag or an increasein ptosis (Darple’s sign). This is repeated fivetimes, to initiate fatigue. Second, the patient istold close his or her eyes, and then there is anattempt to pry open the eyelids. In a non-OMGpatient, this will be difficult to perform. How-ever, in the OMG patient, minimal resistancewill be found. Third, the eyebrow is lifted overthe more ptotic eye. If a patient has OMG, thecontralateral eyelid will exhibit more ptosis,while in normal patients only a minimal changewill occur. These three tests are specific to thepatient who manifests a ptosis.

Similar tests of ocular fatigue can be conductedwhile version, vergence, and/or accommodativetesting are performed. It may be necessary toplace a red lens over one eye to disrupt fusionand to identify a suppressing eye. Accommoda-tive fatigue may be determined with accommo-dative facility testing (i.e., behind the phoropterwhile binocularly alternating the sphere powerby !1.50 D to produce large changes in accom-modative demand). In patients with MG, theinitial response is often one of clarity. Withrepeated changes, however, fatigue rapidly oc-curs. Increased blur or diplopia on repetition issuggestive of MG.10 In addition, monocular ac-commodative amplitudes may be different be-tween the eyes by at least a diopter, generallylower in the second eye tested.

If MG is still suspected, three simple tests maybe performed at home by the patient: photoreview, the ice test,11,12 and the sleep test.13 Thephoto review test requires looking at previouspictures, then taking early morning and lateevening full-face pictures for three days. Lidposition and ocular alignment are noted. If apatient has OMG, there will be an increase in theptosis and/or ocular deviation in the eveningpictures, when greater fatigue would be ex-pected to be present. The picture review processmay be combined with the sleep and ice testdescribed here.

The ice-pack test has been shown to be bothhighly sensitive and specific for OMG in morethan 90% of the cases.12 The palpebral fissure ismeasured, and then an ice-pack is applied to the

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ptotic lid for a minimum of 3 minutes. An in-crease in the palpebral fissure of 2 mm is con-sidered a positive response. Non-myasthenic pa-tients do not demonstrate such a change. Theice-pack test can also be performed to look for adecrease in diplopia; however, the results maybe less dramatic.14

The sleep test is also sensitive and specific forMG. The patient sleeps for 30 minutes in themiddle of the day or evening to ascertain if theptosis and/or diplopia decrease with rest. In ourpractice, all three tests are combined at home.On one of the days the MG suspect performs aphoto review, a 30-minutes nap is taken in theevening with an ice bag placed on one eye.Pictures are taken immediately on awakening.The patient then brings the pictures to the doc-tor, who reviews them with magnification (a 20D condensing lens), looking for signs of reduc-tion of ptosis and/or strabismus.

In addition, the patient with suspected MGshould have a blood test performed to measurethe level of serum anti-acetycholine receptor an-tibodies. The caveat to this test is that 20% ofpatients with general MG and 50% with ocularMG will be sero-negative. Another more-specificblood test can detect the presence of anti-striatedmuscle antibodies, which is positive in about84% of patients with thymoma who are youngerthan 40 years of age. In individuals more than 40years, anti-striated muscle antibodies can befound in MG without thymoma.15,16

If the diagnosis of MG is still suspected but uncon-firmed, a Tensilon Test may be performed. Tensi-lon (edrophonium chloride), an anti-cholinesterasedrug, inactivates the enzyme that breaks downacetylcholine. This results in an excess of acetyl-choline in the neuromuscular junction, thus pro-ducing transiently improved muscle function. Ten-silon is injected at a rate of 2 cc every two minutesfor 10 minutes, until 10 cc are injected. Immedi-ately following the injection, either the patient’sptosis or eye-muscle function will improve in amyasthenic patient. It should be noted that somepatients with MG will have a negative Tensilonresult. However, more than 90% of patients withOMG will have a positive Tensilon test. (Atropineshould be readily available in case of a hypersen-sitivity reaction.)17

If Tensilon testing is contraindicated or negativein highly suspected cases, there are several elec-trodiagnostic tests that can be performed to sup-port a diagnosis of MG. Repetitive nerve stimu-lation (RNS)—as the name suggests—involvesrepetitive electrical stimulation of the nervewhile recording the muscle response.18 A de-crease in the fourth or fifth response by 10% ofthe initial value is a positive finding. While thistest is highly specific for disorders of neuromus-cular transmission (such as MG), it is not verysensitive. A negative result does not exclude thediagnosis of MG. Additionally, it is much moresensitive for general MG (60% to 85%) than forOMG (18% to 35%).

Single-fiber electromyography (SFEMG) is themost-sensitive clinical test of neuromusculartransmission.19,20 SFEMG shows an increasedactivity in some muscles in almost all patientswith MG. Its sensitivity is 91% to 100% forgeneralized MG, and 80% to 88% in patientswith OMG. Though the SFEMG is very sensitivefor MG and OMG, it is not very specific. TheSFEMG requires specialized equipment and re-lies heavily on the skill of the examiner, so is notas easily performed as the RNS test.

A CT or MRI of the thymus is necessary forpatients in whom OMG is diagnosed to rule outthe presence of a thymoma. Lastly, all cases thatmanifest neurological signs such as ptosis and/ordiplopia should have a threshold visual fieldsperformed. (In the following cases presented,Humphrey threshold 24–2 visual fields wereperformed and were normal.)

TreatmentTreatment of OMG consists of one or more ofthe following options: cholinesterase inhibitors,thymectomy, plasmapheresis, corticosteroids,and/or other immunosuppressive drugs. Treat-ment goals are individualized according to theseverity of the disease and the patient’s pre-dicted tolerance to specific therapies. UntreatedMG has a mortality rate of 25% to 31%, usuallydue to respiratory muscle paralysis; however,with current treatment, the mortality rate hasdecreased to 4%.21

Oral cholinesterase inhibitors such as pyridostig-mine bromide (Mestinon) are the first line of treat-ment. They slow down the enzymatic destruction

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of Ach at the neuromuscular junction.22,23 Thisallows the concentration of Ach to accumulate,which, in turn, prolongs muscle contraction.Cholinesterase inhibitors, the first line of treat-ment for OMG, may result in considerableimprovement in some patients, but little to noimprovement in others. Generally speaking, cho-linesterase inhibitors work better in systemic MG.In some cases, they are ineffective because theymay only reduce but not eliminate ocular misalign-ment, thereby causing diplopia to be more bother-some, or they may improve a severely ptotic eye-lid, which can unmask diplopia. Because of theirhigh incidence of gastrointestinal side effects, theyare not well-tolerated in the elderly population.Rarely, cholinergic medications may result in acholinergic crisis.

A thymectomy is the surgical removal of thethymus gland. It is often performed on youngpeople early in the course of the disease.24 Thesurgery is performed in young patients with orwithout a tumor. Unfortunately, patients morethan 60 years of age rarely show substantialimprovement from thymectomy.

Plasmapheresis, or plasma exchange, is used as atemporary treatment for patients with suddenworsening of symptoms.23 Several liters of bloodare removed, the plasma cells are filtered out,and then the red blood cells are returned withartificial plasma, in an attempt to remove theoffending antibodies. Patients feel better for afew days after the procedure, but symptomaticimprovement only lasts several weeks.

Immunosuppressive therapy improves musclestrength by suppressing the production of abnor-mal antibodies. Oral corticosteroid therapy(Prednisone) is typically prescribed in moderate-to-severe cases that do not respond to cholines-terase inhibitors and thymectomy.25 Significantimprovement occurs in more than 75% of thecases. The patient is started on a high daily doseof Prednisone (60 to 80 mg), which is then sys-tematically reduced until the minimal effectivedosage is reached. Long-term treatment maycause either remission or significant improve-ment in most patients in 1 to 4 months. How-ever, long-term use may predispose patients tosignificant problems such as hyperglycemia, os-teoporosis, gastric ulcer disease, weight gain,and Cushing’s syndrome. Ocularly, intraocular

pressure and cataract formation should be mon-itored.

Recently, other immunosuppresive drugs havebeen used effectively to treat MG, such as Cy-closporine and Azathioprine. Cyclosporine is afungal peptide with potent immunosuppressiveactivity.26 It inhibits the T-lymphocyte-depen-dent immune response in MG. Its maximumeffectiveness occurs in six months, after whichtime the drug is tapered to achieve the minimaleffective dosage. Two of the most-serious sideeffects of cyclosporine are hypertension andnephrotoxicity. Azathioprine (Imuran™) may beeffective in those patients who do not respond toeither Prednisone or cyclosporine.27 The effectof this drug, however, may take 6 to 8 months;therefore, the two drugs might be used simulta-neously. While the Prednisone is tapered, theAzathioprine effect begins.

A new short-term treatment currently under in-vestigation uses intravenous human immuneglobulin (IVIG).28 It saturates the body withpooled gamma globulin antibodies derived frommany donors, which is thought to have a non-specific suppressive effect on the immune sys-tem. Improvement starts within a few days andpeaks in a few weeks.

Recent studies by both Kupersmith et al.29 andMee et al.30 strongly suggest that immunomodu-latory therapy (e.g., corticosteroids, azathio-prine, thymectomy), significantly delays—oreven prevents—generalization of the disease.

Case ReportsCase 1The pathognomonic pattern of accommodativefatigue in ocular myasthenia gravis.10 A 25-year-old female reported asthenopia after 5 min-utes of near work; i.e., blurred vision, pullingsensations, and headaches. The symptoms hadbeen occurring for 12 years prior to the initialexamination. Her hyperopia was corrected to20/20 OU with spectacles. Extraocular musclemovements were full and concomitant. Covertesting revealed orthophoria at distance and 4"exophoria at near. The near point of conver-gence was 2/4”. Suppression was noted on first-and second-degree targets, thus suggesting anoculomotor anomaly of long duration. Vergenceamplitudes were reduced and without elicitation

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of blur (BO X/9/4 and BI X/8/5), but with asthe-nopia induced on testing. Accommodative facil-ity was initially normal, with ! 1.50 flippersperformed both monocularly and binocularly at40 cm, but rapidly showed fatigue withrepetition.31

These findings suggested an overall accommoda-tive and fusional-vergence insufficiency with as-sociated asthenopia. Vision therapy was begun,which included activities to improve smooth fu-sional capabilities, step or jump ductions, andaccommodative facility and amplitude training.Paradoxically, training increased her signs andsymptoms. Two months after the initial exami-nation, a re-evaluation was performed that dem-onstrated a variable extraocular muscle paresisand mild ptosis with repeated eye movementtesting.

A Tensilon test was performed, which wasequivocal. However, single-fiber electomyogra-phy tests were positive for MG. To document thepresence of an accommodative deficit objec-tively, a high-speed infra-red optometer wasused to measure accommodative responses dy-namically to sinusoidally moving accommoda-tive targets. Figure 1 presents the recording.Initially, accommodation was robust and accu-rate. With repetition, effects of fatigue were ev-ident. Accommodation initially displayed a lag,and eventually showed fatigue to the point thatno change in accommodation occurred in re-sponse to the blur stimulation.

Case 2Ocular myasthenia gravis masquerading as ac-commodative and convergence insufficiency.32

A 25-year-old female optometry student came to uswith a history of ocular fatigue, associated withnear work, occurring over the preceding twoyears. She had a childhood diagnosis of asthma forwhich she was taking salmeterol xinafoate (Ser-event, GlaxoWellcome, Reasearch Triangle Park,North Carolina), triamcinolone acetonide (Asma-cort, Rhone–Poulenc Rorer, Collegeville, Pennsyl-vania), and metaproterenol sulfate (Alupent,Boehringer Ingelheim, Ridgefield, Connecticut).Non-cycloplegic and cycloplegic refractions wereidentical (–0.75 sph 20/20 O.D.; –0.75 sph 20/20O.S.).

At her initial vision examination, as a first-yearstudent, she reported difficulty focusing whilereading. This was verified with an abnormalmonocular and binocular ! 1.50 accommodativeflipper test result and reduced accommodativeamplitudes of 2 D sphere right eye and 0.5 Dsphere left eye. The age-related clinical normwas 11 D. (By chance, this patient also partici-pated in a study in which dynamic accommoda-tive measurements were performed and werefound to be normal.) Phorometric findings re-vealed 2" of left hyperphoria. Random-dot ste-reopsis was present, but reduced (660 sec arc),thus indicating bifoveal fixation. All other ocularfindings were normal. The record did not suggestany treatment or further testing based on theseabnormal findings.

Two years later, the patient returned with simi-lar symptoms of ocular fatigue, but now with theadditional symptom of occasional diplopia. Find-ings again suggested an accommodative insuffi-ciency now associated with convergence insuffi-ciency. Both near point of convergence andfusional amplitudes were reduced. Interestingly,the initially measured hyperphoria of two yearsearlier was not present. On the basis of thesefindings, weekly vision therapy was initiated toimprove both accommodative and fusional ver-gence function. The therapy was designed toimprove static and dynamic accommodation,vergence, and their interactions. Normally, vi-sion therapy is successful in improving accom-modative and vergence function with concur-rent elimination of symptoms in more than 90%

Figure 1 Accommodative findings of a patient with ocular myastheniagravis are presented. The top tracing depicts the sinusoidalstimulus and the bottom the response. Note, the initial re-sponses were reasonability robust with a delayed latency.After a complete response, accommodative fatigue is evident,becoming flat over a short period of time. (Reprinted withpermission of Binocul Vis Eye Muscle Surg Q. 1988:3 p.145).

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of patients with either convergence insufficiencyor various accommodative anomalies.34

In this case, however—and as in Case 2—visiontherapy produced a transient reduction in ac-commodative and vergence function. The stu-dent at this point contacted one of the authors(JC), since her symptoms had not abated fromtherapy. A review of her record by JC noted thather pattern of fatigue occurring during therapywas suggestive of MG. Ocular fatigue testing andthe sleep test were equivocal, and the ice testwas negative. Approximately two months later,a 3-mm ptosis of the left eye developed. She thenhad a comprehensive neurological examination,including magnetic resonance testing. The pa-tient refused to have a Tensilon test because ofher history of asthma. On initial testing, heraccommodative and convergence findings wereinitially normal, but showed fatigue on repeti-tion. There was also a subtle oculomotor non-comitancy of 4" on extreme levoduction.

We measured accommodation (positive relativeaccommodation, negative relative accommoda-tion and accommodative amplitudes); vergence(positive fusional amplitudes and their respectedrecoveries); and cover tests in the morning, af-ternoon, and evening (see Figures 2 through 6).

On the basis of these findings, the consultingneurologist agreed with our suggestion of plac-ing the patient on a diagnostic trial of Mestinon(Zeneca, Wilmington, Delaware) in an attempt tomimic the results of Tensilon testing. We contin-ued to measure accommodative and vergenceafter the administration of Mestinon. It is clearfrom the results that all accommodative/ver-gence measurements exhibited significant reduc-tion from morning to evening. In addition, Mes-tinon clearly improved both accommodative andvergence amplitudes and facility. These findingsare diagnostic for MG—since Mestinon is similarto Tensilon—except for having a longer durationof action.

Figure 2 Accommodative amplitudes were measured using pushupmethods on the right and left eye in the morning, afternoon,and early evening. It is readily apparent that amplitudedecreases from morning to evening. Also, note the discrep-ancy between the right and left eyes. (Reprinted with permis-sion of Neuro-Ophthalmol 2000;20:p8)

Figure 3 NRA and PRA measurements were performed morning, after-noon, and early evening. This figure depicts NRA and PRA overtime. The NRA is normal and unchanged with Mestinon.However, the PRA is reduced (normal for age -2.50) to zerobefore Mestinon, but improves with Mestinon. (Reprinted withpermission of Neuro-Ophthalmol 2000;20:p8)

Figure 4 Phorias were measured with the VonGraffe technique in themorning, afternoon, and early evening. The phoria in-creases dramatically during the course of testing from 8"to 16". The phoria decreased after administration ofMestinon. (Reprinted with permission of Neuro-Ophthalmol2000;20:p9)

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Prior to taking Mestinon, the patient experi-enced significant ocular and systemic fatigueby 7:00 PM. After taking Mestinon (60 mgdaily), there was an immediate improvementin both accommodative and vergence find-ings, as well as a decrease in the ptosis. Inaddition, she reported elimination of hergeneral fatigue. Follow-up examination oneand a half years later substantiated thesefindings. During a short interval in whichshe ran out of her medication, the ptosis andocular and systemic fatigue all reappeared.She has since remained stable with a regimenof 60-mg Mestinon twice a day.

Case 3Ocular myasthenia gravis masquerading as anon-comitant vertical muscle palsy. A 50-year-old man was referred to author JC for eval-uation of his recent-onset diplopia. The pa-tient had a history of vertical diplopia for theprevious two months. The diplopia worsenedas the day progressed, and improved whenhe tilted his head to the left. He had beenseen previously for this symptom of the dip-lopia without resolution. Other than Crohn’sdisease, all other history was unremarkable.He mentioned he was going through a stress-ful time in his personal life.

Best-corrected vision with a low hyperopic cor-rection was 20/20 in each eye. Distance covertesting revealed a 3" left hypertropia in primarygaze, orthophoria in right gaze, and a 9" lefthypertopia in left gaze. Diplopia was worse onright head tilt. A Park’s 3-Step Test indicated aleft inferior rectus (IR) palsy. (It should be notedthat isolated nontraumatic, noncongenital palsyof the IR is very rare.)35 The patient’s left supra-duction was 5/3, and left infraduction was –1/–3.This is consistent with a recent-onset deviation,since there was no evidence of prism adaptation.No ptosis was present. All other findings wereunremarkable. Due to the recent onset of hissymptoms, as well as the presentation of a non-comitant vertical muscle deviation, a bloodwork-up was ordered, which included Acetyl-choline Receptor Antibody Titers, TSH, T3,T4ESR, RPR, Lyme serology, and a fasting bloodsugar test. The patient was instructed to performa home sleep/ice pack test with picture review.He was also prescribed a 3" Fresnel press-onprism base-down over the left eye, to alleviatehis diplopia.

On a follow-up examination, the blood test re-sults were abnormal for the acetylcholine-recep-tor antibody level (i.e., 1.4 nmol/L—referencerange is less than 0.7 nmol/L); Striated MuscleAntibody Titers (i.e., 1:160—reference range is1:40); and TSH (i.e., 6.94 mIU/L—referencerange, 0.40 to 5.50 mIU/L). All other blood find-ings were normal. The patient reported improve-ment of his diplopia after performing an ice-packtest at home on two separate occasions. Thesefindings were consistent with acquired autoim-mune MG and thyroiditis. A CT scan of thethymus was ordered, and the patient was re-

Figure 5 Convergence amplitudes (break) and recovery were measuredwith the Risley prisms in the morning, afternoon, and earlyevening. The convergence amplitude decreased dramaticallyfrom morning to evening from 15 to -8". One third of thedecrease may be attributed to a change in phoria. Improve-ment occurred with the administration of Mestinon. (Reprintedwith permission of Neuro-Ophthalmol 2000;20:p9)

Figure 6 Convergence amplitudes (break and recovery) in the evening arepresented by date. It is apparent that the amplitude varies daily,but is improved with the administration of Mestinon. (Reprintedwith permission of Neuro-Ophthalmol 2000;20:5-11)

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ferred to a neurologist who specialized in neuro-muscular disease, and to an endocrinologist.

There was no evidence of a thymoma or thymichyperplasia on a chest CT scan. A Tensilon testwas performed, which was positive. The patientwas placed on a regimen of 40-mg Prednisoneevery other day, later tapered by 5 mg per day.After two weeks of treatment, the patient re-ported a decrease in the frequency and magni-tude of his diplopia. Subsequently, the patientmoved out of state and was lost to followup.

Case 4Ocular myasthenia gravis masquerading as astable, longstanding 6th nerve palsy. A 66-year-old woman came to us with a history of horizon-tal diplopia for the previous 5 years. She notedthat the diplopia was worse when looking intothe distance than at near. The patient was takinghormone replacement therapy. She had a historyof a surgical ptosis repair of her left eyelid twoyears earlier for cosmetic reasons. The etiologyof the ptosis was not investigated at the time, norwas the diplopia, despite numerous previousvisits to eye doctors.

With a slight hyperopic prescription, best cor-rected visual acuities were 20/25 in each eye.Distance cover test measured 10" left esotropiawith 2" left hyperphoria, and the near cover testmeasured 12" esophoria with 4" left hyperpho-ria. Vertical vergence ranges were normal atdistance and near. Near vergence ranges were BIx/–4/–14 and BO x/25/12. All other findings werewithin normal limits.

The diagnosis of a longstanding 6th nerve palsywas made, and the patient was given prism withher prescription of #2.25 D –0.75 D $ 85 % 11

4 "BU % 31

2 " BO right eye and #1.25 D sph %11

4 " BD % 312 " BO left eye with an add of #2.75

D in a progressive addition lens design. Blood testswere ordered, including thyroid function tests(T3,T4, TSH) sed-rate (ESR), and Acetylcholine re-ceptor antibody titers. Given the length of time thepatient was experiencing symptoms, an MRI wasnot immediately indicated.

On follow-up examination two weeks later, thepatient stated that the diplopia was eliminatedwith the prism spectacles. Cover testing withcorrection revealed 3" esophoria at distance and

3" exophoria at near. The ice pack test wasequivocal in reducing the patient’s diplopia.Blood tests were negative. Due to the unex-plained hyperphoric deviation associated withthe horizontal deviation, the patient was re-ferred to a neuro-ophthalmologist for evaluation.The neuro-ophthalmologist wanted to rule outMG by performing a Tensilon test. A diagnosisof OMG was made on the basis of a positiveTensilon test, and a diagnosis of hypothyroidismas indicated by a repeated blood test. The patientwas placed on a regimen of 60-mg Mestinonq.i.d. for the OMG and Synthroid for the hypo-thyroidism. On follow-up examination 3 monthslater, the patient stated that her diplopia was nolonger present with her current spectacles andthat she was doing well with current medica-tions. Cover testing with correction revealed or-thophoria at distance and near. The patient wasinstructed to continue with her current specta-cles and medication regimen to maintain herpositive status.

Case 5Ocular myasthenia gravis masquerading as aconcomitant esotropia. A 22-year-old man withbest-corrected visual acuities of 20/20 OU wasreferred to author JC for vision therapy. Thereferring optometrist noted a basic esotropia ofrecent onset. She had ordered an MRI, whichwas negative. At the initial examination, a 16"constant esotropia with 2" of hypertropia wasfound at distance and near. Since the patient wasleaving for college, he was prescribed a pris-matic correction and was referred for visiontherapy in the city in which he attended college.A few months later, he returned from collegeand returned to JC for a followup. He stated thatthe prism correction initially eliminated the dip-lopia, which lasted for only a short period oftime. After the patient returned to college, theoptometrist—who initially provided the visiontherapy—advised the patient that the initial pris-matic correction was incorrect.

On the patient’s return to JC, the variability ofhis measured deviation led us to suspect thepossibility of MG. We performed an ice/sleeptest and ordered an Ach Receptor Antibodyblood test. The ice/sleep test was positive for MG(see Figure 7, A and B), while the antibody levelwas negative. A subsequent cover testing re-vealed a concomitant 20" left esotropia at dis-

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tance and 10" of esophoria at near. Versionswere concomitant.

The patient had a neuro-ophthalmologicalexamination; nerve-conduction studies, andEMG results, all of which were normal. Theneuro-ophthalmologist concluded that OMGwas not present. However, a Tensilon test—which we requested—was not performed atthat time. We saw him again and noted thevariable esotropia. We conferred with a sec-ond neuro-ophthalmologist, who agreed withour tentative diagnosis of MG. We referredthe patient back to the neuro-ophthalmolo-gist located in his college town who subse-quently noted a new ptosis and performed aTensilon test, which was positive. The pa-tient was started on a regimen of 30-mgMestinon q.i.d. p.o. and advised to have achest CT scan.

The patient returned to us six months later,taking 60-mg Mestinon q.i.d. p.o. He reportedless ptosis with the medication; however, theabdominal side effects forced him to discontinuethe medication. Cover testing revealed a con-comitant 16" esotropia at distance and or-thophoria at near. Accommodative amplitudeswere 6.5 diopters in each eye. A thymectomec-tomy was performed; the patient discontinuedMestinon and was treated with 60-mg Pred-nisone, with some improvement. His deviationstabilized and he was advised to wear a distanceprism correction.

DiscussionMG usually manifests a recently acquired, vari-able ptosis, greater in one eye than the other.When this occurs, the diagnosis is straightfor-ward and is readily confirmed by the gold stan-

Figure 7 Patient with unequal ptosis secondary to ocular myasthenia gravis. Ice was applied for five minutes over both eyes after which a dramatic elevationof his lids was noted.

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dard—the Tensilon test. Previous studies havesuggested that 90% of all patients with myasthe-nia gravis manifest a ptosis, and that a general-ized MG will eventually develop (within twoyears) in 50% of those who manifest an ocularsign.8 In dealing with relatively stable acquiredptosis is more difficult to ascertain the origin;however, even in those cases, MG must be con-sidered. We believe that patients manifest non-ptotic signs of MG more frequently than previ-ously reported. When the presenting sign isother than ptosis—such as an accommodative/vergence insufficiency, or a concomitant or non-comitant oculomotor paresis—then diagnosis ofMG is much more elusive. For the patient withmyasthenia gravis who manifests nonclassicalsymptoms, MG may be overlooked by theneuro-ophthalmolgists, ophthalmologists, op-tometrists, and primary care practitioners.

Perhaps the primary reason that patients whoinitially manifest MG-induced accommodativeand vergence deficits are not appropriately diag-nosed is that the ophthalmic community is notsensitive to the subtle initial signs and symptomsof MG—i.e., asthenopia, blur, diplopia, and vi-sual fatigue. The most-common finding of MG isfatigability of either striated or non-striated ocu-lar motor muscles—accommodation, vergence,and levator palpebrae. This fatigability may oc-cur with minimal usage: within minutes, frommorning to evening, and/or from day to day. Noother condition manifests such variable findings.Thus, any patient suspected of having MGshould have morning baseline testing to estab-lish lid position and accommodative/vergencefunctioning. Measurement should be repeated inthe evening to assess fatigability.

There are a variety of non-invasive, simple officeand home tests that we have discussed previouslyto support the diagnosis of MG (see Figure 8). Ifptosis is present, the clinician should attempt tofatigue the orbicularis muscles. Also, 2.5% neo-synephrine may be used to differentiate senileptosis from other forms of ptosis. The patientshould be instructed to perform the photo test athome. If a patient has diplopia, atypical oculo-motor fatigue, and/or demonstrates a decrementof findings during or immediately after visiontherapy, MG should be suspected.

It has been assumed that MG only affects stri-ated muscles. As early as 1900, however, Camp-

bell and Bramwell36 demonstrated that accom-modation may be involved in the MG syndrome.We have presented and published two case stud-ies that objectively demonstrate accommodativeinsufficiency as the presenting sign.10,33 We be-lieve that the paucity in reporting of accommo-dative anomalies is related to the lack of testingof accommodative amplitude, and/or facility ofaccommodation. It is important that those pro-viding vision therapy recognize the pattern ofaccommodative findings associated with MG.There are a few caveats in making the diagnosisof accommodative insufficiency secondary toMG, since these accommodative findings areunique. First, asymmetrical accommodative am-plitudes between the eyes are present. Second,the amplitudes are usually reduced and will de-crease further on repeated testing. Third, accom-modative facility as measured with ! 1.50 Dlenses in the phoropter demonstrates fatiguewith repeated testing. Fourth, the general accom-modative (and related vergence) findings fatigueby the end of the day, and thus their respectiveamplitudes and/or facility will be less in theevening, as compared to the morning. Fifth, thefindings will vary from day to day. And sixth,Tensilon or Tensilon equivalent medications(such as Mestinon) will have a positive effect onaccommodative functioning.

After the classical sign of ptosis, the most com-monly described sign of MG is variable diplopia.The classical myasthenic patient will manifest anon-comitant, oculo-motor paresis varying as theday progresses. This myasthenic patient willhave motor fields that are not indicative of aspecific oculomotor paresis; variability is thehallmark of MG. Like accommodation, in-creased variability is usually noted with re-peated testing or time of day. The patient maymanifest a subtle ptosis, so the external exami-nation must be carefully performed. Fatigue,induced by repeated versions or vergence testingwith a prism bar, will result in increased diplo-pia and/or a change in the cover test value.Version and vergence testing may be enhancedwith the use of a red lens. The red lens servesthree functions: to disrupt binocularity, to elim-inate suppression, and to determine the diplopiadirection. The sleep/ice test usually results inimprovement of the diplopia, as noted in two ofthe cases.

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Myasthenia may masquerade as a convergenceinsufficiency, a divergence insufficiency, or aconcomitant hyperdeviation. Myasthenia bothfollows and breaks the rules. Thus, any unex-

plained diplopia—particularly under the age of60 years—should include MG in the differentialdiagnosis, even if another health care practitio-ner has dismissed the diagnosis of MG. Although

Figure 8 Testing sequence for suspected myasthenia gravis. Most testing can be easily performed in the office. Ice and sleep tests, which can be combinedwith a photo review, are sensitive and specific to myasthenia gravis.

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four of the five cases had variable findings whichlead to a more-detailed investigation of possibleMG, one did not. This patient was particularlyelusive, since the ptosis was previously elimi-nated by surgery, and her deviation was con-comitant and unchanging over a course of sev-eral years.

If the patient is still not confirmed as having MGafter simple, non-invasive office and home tests,further testing is warranted. A blood workupshould include a MG antibody test, thyroid test-ing, fasting blood sugar, Lyme titer, and ESR inthose over 60 years of age. If intracranial diseaseis suspected, an MRI with contrast should beperformed. The radiologist should be advised tocarefully examine the pathways of 3rd, 4th, or 6th

N from the eye to the midbrain, and the higherneurological centers if a gaze palsy is noted.Lastly, a neuro-ophthalmological consult is inorder with Tensilon testing and single-fiber myo-graphy to make the final differential diagnosis.

After stabilization with medication, patientswith MG should have a re-evaluation of theiraccommodative and vergence functions. StableMG patients who manifest accommodative andvergence defects may benefit from prismatic cor-rection incorporated into a progressive lens. Aprogressive lens provides the advantage of com-pensating for the variable accommodative ampli-tudes noted during the day and from day to day.One must remember, for the young patient, thatthe add power should be determined monocu-larly before prism is determined (by relaxingaccommodation, there is a relaxation of conver-gence; i.e., increase in exophoria). The add,which may be determined by conventionalmeans (i.e., cross cylinder, balancing PRA/NRA,etc.) should be prescribed monocularly to elim-inate asymmetry in accommodative findings.

In summary, MG should be considered whenexamining the patient with unexplained ocularand general fatigue, unexplained accommoda-tive fatigue or vergence fatigue, unexplained pto-sis, or diplopia. There are a multitude of simpleclinical tests that help make the diagnosis of thisoften elusive disease. Early diagnosis and treat-ment of MG is beneficial, to eliminate costlyneurological testing and to improve the qualityof life of our patients.

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Corresponding author:

Jeffrey Cooper, O.D., M.S.Dept. of Clinical Sciences

33 W. 42nd StreetNew York, New York 10036

[email protected]

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non-ptotic ocular myasthenia gravis: a common...

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