Non-ptotic ocular myasthenia gravis: a
common presentation of an uncommon
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 which Greek, meaning "gravely weak muscles," and was causes rapid muscle fatigue and weakness. Two thirds ofall cases of myasthenia gravis (MG) initially manifest first described by Sir Thomas Willis in It was ptosis. In the absence of the characteristic variable ptosis, later considered in detail by three German physicians— MG can present a challenge to the clinician. This article Goldflam, Erb, and Jolly—in 1890. Twenty years ago, an will review the current diagnostic and management strat- animal model was developed that led to a better physio- egies for MG.
logically based understanding of the disease, and which Case Reports: Five cases will be presented that did not
resulted in new treatment initially present with ptosis. Each of these cases waspreviously misdiagnosed as a result of presentation ofatypical myasthenia gravis signs and symptoms. The first The pathophysiology of the disorder requires an under- two cases had signs and symptoms of a typical accom- standing of the neuromuscular junction (NMJ), which is modative/vergence anomaly. The others manifested dip- the point at which the nerve fiber either synapses with or lopia not normally associated with MG: one had a non- terminates on a muscle fiber. When a nerve impulse is comitant vertical deviation; another had a stable 6th nervepalsy; and the third had a basic esotropia.
initiated, it travels to the NMJ. Here the neurotransmitter acetylcholine (Ach) is then released, passes through the Conclusion: Although the hallmark findings of MG are ptosis
and eye muscle palsy with variability, MG may present NMJ, and ultimately attaches to receptors on the muscle without ptosis, affect nonstriated muscles, and/or mani- surface, thereby resulting in muscular contraction. In MG, fest either as a nonstrabismic vergence anomaly or as antibodies erroneously destroy Ach receptor sites, which comitant nonvariable strabismic deviation.
are located at the postsynaptic membrane of the NMJ. This Key Words: Accommodative insufficiency, convergence insuf-
prevents Ach from binding to muscle cells, and hence ficiency, diplopia, myasthenia gravis, oculomotor paresis, inhibiting muscle contraction. (Current thinking is that T cells derived from the thymus stimulate B cells to produce the antibodies that react at the Ach The result is a progressive muscle weakness that worsens with sustained MG occurs in approximately 14 of every 100,000 people, resulting in a prevalence of 36,000 cases in the U.S. It can occur at any age, but has a bimodal distribution that affects women below age 40 years and men more than 60 years of MG is characterized by ptosis, facial weakness, dysar- Colavito J, Cooper J, Ciuffreda KJ. Non-ptotic ocular myas-thenia gravis: a common presentation of an uncommon dis- thria, dysphagia, and Among patients who mani- ease. Optometry 2005;76:363-75.
fest ocular myasthenia gravis (OMG), generalized myasthenic VOLUME 76 / NUMBER 7 / JULY 2005 symptoms will develop in more than 50% within The first test involves "fatiguing" the extraocular two Two thirds of all cases of MG initially muscles in upgaze. The patient attempts to sus- manifest ptosis and/or diplopia. A history of a tain extreme upgaze for 30 seconds, then quickly variable ptosis makes MG the most likely differen- returns to primary position. Patients with OMG tial diagnosis. However, when the patient mani- often demonstrate either a lid-lag or an increase fests diplopia, or with an accommodative/vergence in ptosis (Darple's sign). This is repeated five insufficiency, the diagnosis of MG becomes more times, to initiate fatigue. Second, the patient is told close his or her eyes, and then there is an attempt to pry open the eyelids. In a non-OMG The exact cause of this auto-immune disease is patient, this will be difficult to perform. How- unknown; it is thought there might be a genetic ever, in the OMG patient, minimal resistance and/or viral etiology. Thymus abnormalities are will be found. Third, the eyebrow is lifted over associated with MG, but the exact relationship is the more ptotic eye. If a patient has OMG, the uncertain. The thymus produces cells involved contralateral eyelid will exhibit more ptosis, in immune responses. Approximately 10% of while in normal patients only a minimal change will occur. These three tests are specific to the patients with MG have a thymoma or tumor of patient who manifests a ptosis.
the thymus, and 70% have hyperplasia of the thymus, which is usually associated with active Similar tests of ocular fatigue can be conducted auto-immune disease. Since the thymus is the while version, vergence, and/or accommodative central organ for immunological self-tolerance, it testing are performed. It may be necessary to has been suggested that abnormalities of the place a red lens over one eye to disrupt fusion thymus may cause an immune-mediated attack and to identify a suppressing eye. Accommoda- on the Ach receptor in tive fatigue may be determined with accommo- dative facility testing (i.e., behind the phoropter Patients with MG also have an increased preva- while binocularly alternating the sphere power lence of other auto-immune diseases, such as by !1.50 D to produce large changes in accom- rheumatoid arthritis, thyroid disease, and vita- modative demand). In patients with MG, the min B-12 deficiency. Symptoms of MG, which initial response is often one of clarity. With vary day-to-day, may be exacerbated by stress, repeated changes, however, fatigue rapidly oc- systemic illness, thyroid disease, pregnancy, curs. Increased blur or diplopia on repetition is menstruation, and certain suggestive of In addition, monocular ac- commodative amplitudes may be different be- tween the eyes by at least a diopter, generally lower in the second eye tested.
The diagnosis of OMG is usually made by a combination of patient history, clinical findings, If MG is still suspected, three simple tests may and other diagnostic procedures. The first suspi- be performed at home by the patient: photo cion of OMG should come to mind during the review, the ice and the sleep The case history if the patient manifests symptoms of photo review test requires looking at previous pictures, then taking early morning and late ptosis, diplopia, and/or blur, which increases evening full-face pictures for three days. Lid with use of the ocular muscles, or as the day position and ocular alignment are noted. If a progresses. Patients with generalized systemic patient has OMG, there will be an increase in the MG may also manifest fatigue of the face, neck, ptosis and/or ocular deviation in the evening and limbs, worsening with activity. Brushing pictures, when greater fatigue would be ex- one's teeth or combing hair may become prob- pected to be present. The picture review process lematic. Head droop and down-sloping of a smile may be combined with the sleep and ice test may be noted. Variability of symptoms should described here.
further trigger suspicion. The gold standard for diagnosis of OMG is the Tensilon test. However, The ice-pack test has been shown to be both there are a number of non-invasive tests that can highly sensitive and specific for OMG in more also be used to make the diagnosis; all are sim- than 90% of the The palpebral fissure is ple, inexpensive, and highly sensitive.
measured, and then an ice-pack is applied to the VOLUME 76 / NUMBER 7 / JULY 2005 ptotic lid for a minimum of 3 minutes. An in- If Tensilon testing is contraindicated or negative crease in the palpebral fissure of 2 mm is con- in highly suspected cases, there are several elec- sidered a positive response. Non-myasthenic pa- trodiagnostic tests that can be performed to sup- tients do not demonstrate such a change. The port a diagnosis of MG. Repetitive nerve stimu- ice-pack test can also be performed to look for a lation (RNS)—as the name suggests—involves decrease in diplopia; however, the results may repetitive electrical stimulation of the nerve while recording the muscle A de- crease in the fourth or fifth response by 10% of The sleep test is also sensitive and specific for the initial value is a positive finding. While this MG. The patient sleeps for 30 minutes in the test is highly specific for disorders of neuromus- middle of the day or evening to ascertain if the cular transmission (such as MG), it is not very ptosis and/or diplopia decrease with rest. In our sensitive. A negative result does not exclude the practice, all three tests are combined at home.
diagnosis of MG. Additionally, it is much more On one of the days the MG suspect performs a sensitive for general MG (60% to 85%) than for OMG (18% to 35%).
photo review, a 30-minutes nap is taken in the evening with an ice bag placed on one eye.
Single-fiber electromyography (SFEMG) is the Pictures are taken immediately on awakening.
most-sensitive clinical test of neuromuscular The patient then brings the pictures to the doc- SFEMG shows an increased tor, who reviews them with magnification (a 20 activity in some muscles in almost all patients D condensing lens), looking for signs of reduc- with MG. Its sensitivity is 91% to 100% for tion of ptosis and/or strabismus.
generalized MG, and 80% to 88% in patients with OMG. Though the SFEMG is very sensitive In addition, the patient with suspected MG for MG and OMG, it is not very specific. The should have a blood test performed to measure SFEMG requires specialized equipment and re- the level of serum anti-acetycholine receptor an- lies heavily on the skill of the examiner, so is not tibodies. The caveat to this test is that 20% of as easily performed as the RNS test.
patients with general MG and 50% with ocular MG will be sero-negative. Another more-specific A CT or MRI of the thymus is necessary for blood test can detect the presence of anti-striated patients in whom OMG is diagnosed to rule out muscle antibodies, which is positive in about the presence of a thymoma. Lastly, all cases that 84% of patients with thymoma who are younger manifest neurological signs such as ptosis and/or than 40 years of age. In individuals more than 40 diplopia should have a threshold visual fields years, anti-striated muscle antibodies can be performed. (In the following cases presented, found in MG without Humphrey threshold 24–2 visual fields were performed and were normal.) If the diagnosis of MG is still suspected but uncon- firmed, a Tensilon Test may be performed. Tensi- lon (edrophonium chloride), an anti-cholinesterase drug, inactivates the enzyme that breaks down Treatment of OMG consists of one or more of acetylcholine. This results in an excess of acetyl- the following options: cholinesterase inhibitors, thymectomy, plasmapheresis, corticosteroids, choline in the neuromuscular junction, thus pro- and/or other immunosuppressive drugs. Treat- ducing transiently improved muscle function. Ten- ment goals are individualized according to the silon is injected at a rate of 2 cc every two minutes severity of the disease and the patient's pre- for 10 minutes, until 10 cc are injected. Immedi- dicted tolerance to specific therapies. Untreated ately following the injection, either the patient's MG has a mortality rate of 25% to 31%, usually ptosis or eye-muscle function will improve in a due to respiratory muscle paralysis; however, myasthenic patient. It should be noted that some with current treatment, the mortality rate has patients with MG will have a negative Tensilon result. However, more than 90% of patients with OMG will have a positive Tensilon test. (Atropine Oral cholinesterase inhibitors such as pyridostig- should be readily available in case of a hypersen- mine bromide (Mestinon) are the first line of treat- ment. They slow down the enzymatic destruction VOLUME 76 / NUMBER 7 / JULY 2005 of Ach at the neuromuscular This pressure and cataract formation should be mon- allows the concentration of Ach to accumulate, which, in turn, prolongs muscle contraction.
Cholinesterase inhibitors, the first line of treat- Recently, other immunosuppresive drugs have ment for OMG, may result in considerable been used effectively to treat MG, such as Cy- improvement in some patients, but little to no closporine and Azathioprine. Cyclosporine is a improvement in others. Generally speaking, cho- fungal peptide with potent immunosuppressive linesterase inhibitors work better in systemic MG.
It inhibits the T-lymphocyte-depen- In some cases, they are ineffective because they dent immune response in MG. Its maximum may only reduce but not eliminate ocular misalign- effectiveness occurs in six months, after which ment, thereby causing diplopia to be more bother- time the drug is tapered to achieve the minimal some, or they may improve a severely ptotic eye- effective dosage. Two of the most-serious side lid, which can unmask diplopia. Because of their effects of cyclosporine are hypertension and high incidence of gastrointestinal side effects, they nephrotoxicity. Azathioprine (Imuran™) may be are not well-tolerated in the elderly population.
effective in those patients who do not respond to Rarely, cholinergic medications may result in a either Prednisone or The effect cholinergic crisis.
of this drug, however, may take 6 to 8 months; therefore, the two drugs might be used simulta- A thymectomy is the surgical removal of the neously. While the Prednisone is tapered, the thymus gland. It is often performed on young Azathioprine effect begins.
people early in the course of the The surgery is performed in young patients with or A new short-term treatment currently under in- without a tumor. Unfortunately, patients more vestigation uses intravenous human immune than 60 years of age rarely show substantial globulin It saturates the body with improvement from thymectomy.
pooled gamma globulin antibodies derived from many donors, which is thought to have a non- Plasmapheresis, or plasma exchange, is used as a specific suppressive effect on the immune sys- temporary treatment for patients with sudden tem. Improvement starts within a few days and peaks in a few weeks.
worsening of Several liters of blood are removed, the plasma cells are filtered out, Recent studies by both Kupersmith et and and then the red blood cells are returned with Mee et alstrongly suggest that immunomodu- artificial plasma, in an attempt to remove the latory therapy (e.g., corticosteroids, azathio- offending antibodies. Patients feel better for a prine, thymectomy), significantly delays—or few days after the procedure, but symptomatic even prevents—generalization of the disease.
improvement only lasts several weeks.
Immunosuppressive therapy improves muscle strength by suppressing the production of abnor- mal antibodies. Oral corticosteroid therapy The pathognomonic pattern of accommodative
(Prednisone) is typically prescribed in moderate- fatigue in ocular myasthenia A 25-
to-severe cases that do not respond to cholines- year-old female reported asthenopia after 5 min- terase inhibitors and Significant utes of near work; i.e., blurred vision, pulling improvement occurs in more than 75% of the sensations, and headaches. The symptoms had cases. The patient is started on a high daily dose been occurring for 12 years prior to the initial of Prednisone (60 to 80 mg), which is then sys- examination. Her hyperopia was corrected to tematically reduced until the minimal effective 20/20 OU with spectacles. Extraocular muscle dosage is reached. Long-term treatment may movements were full and concomitant. Cover cause either remission or significant improve- testing revealed orthophoria at distance and 4" ment in most patients in 1 to 4 months. How- exophoria at near. The near point of conver- ever, long-term use may predispose patients to gence was 2/4". Suppression was noted on first- significant problems such as hyperglycemia, os- and second-degree targets, thus suggesting an teoporosis, gastric ulcer disease, weight gain, oculomotor anomaly of long duration. Vergence and Cushing's syndrome. Ocularly, intraocular amplitudes were reduced and without elicitation VOLUME 76 / NUMBER 7 / JULY 2005

Case 2
Ocular myasthenia gravis masquerading as ac-
commodative and convergence insufficiency
A 25-year-old female optometry student came to us with a history of ocular fatigue, associated with near work, occurring over the preceding two years. She had a childhood diagnosis of asthma for which she was taking salmeterol xinafoate (Ser- event, GlaxoWellcome, Reasearch Triangle Park, North Carolina), triamcinolone acetonide (Asma- cort, Rhone–Poulenc Rorer, Collegeville, Pennsyl- Figure 1 Accommodative findings of a patient with ocular myasthenia gravis are presented. The top tracing depicts the sinusoidal vania), and metaproterenol sulfate (Alupent, stimulus and the bottom the response. Note, the initial re- Boehringer Ingelheim, Ridgefield, Connecticut).
sponses were reasonability robust with a delayed latency.
Non-cycloplegic and cycloplegic refractions were After a complete response, accommodative fatigue is evident, identical (–0.75 sph 20/20 O.D.; –0.75 sph 20/20 becoming flat over a short period of time. (Reprinted withpermission of Binocul Vis Eye Muscle Surg Q. 1988:3 p.145).
At her initial vision examination, as a first-year of blur (BO X/9/4 and BI X/8/5), but with asthe- student, she reported difficulty focusing while nopia induced on testing. Accommodative facil- reading. This was verified with an abnormal ity was initially normal, with ! 1.50 flippers monocular and binocular ! 1.50 accommodative performed both monocularly and binocularly at flipper test result and reduced accommodative 40 cm, but rapidly showed fatigue with amplitudes of 2 D sphere right eye and 0.5 D sphere left eye. The age-related clinical norm was 11 D. (By chance, this patient also partici- These findings suggested an overall accommoda- pated in a study in which dynamic accommoda- tive and fusional-vergence insufficiency with as- tive measurements were performed and were sociated asthenopia. Vision therapy was begun, found to be normal.) Phorometric findings re- which included activities to improve smooth fu- vealed 2" of left hyperphoria. Random-dot ste- sional capabilities, step or jump ductions, and reopsis was present, but reduced (660 sec arc), accommodative facility and amplitude training.
thus indicating bifoveal fixation. All other ocular Paradoxically, training increased her signs and findings were normal. The record did not suggest symptoms. Two months after the initial exami- any treatment or further testing based on these nation, a re-evaluation was performed that dem- abnormal findings.
onstrated a variable extraocular muscle paresis and mild ptosis with repeated eye movement Two years later, the patient returned with simi- lar symptoms of ocular fatigue, but now with the additional symptom of occasional diplopia. Find- A Tensilon test was performed, which was ings again suggested an accommodative insuffi- equivocal. However, single-fiber electomyogra- ciency now associated with convergence insuffi- phy tests were positive for MG. To document the ciency. Both near point of convergence and presence of an accommodative deficit objec- fusional amplitudes were reduced. Interestingly, tively, a high-speed infra-red optometer was the initially measured hyperphoria of two years used to measure accommodative responses dy- earlier was not present. On the basis of these namically to sinusoidally moving accommoda- findings, weekly vision therapy was initiated to tive targets. presents the recording.
improve both accommodative and fusional ver- Initially, accommodation was robust and accu- gence function. The therapy was designed to rate. With repetition, effects of fatigue were ev- improve static and dynamic accommodation, ident. Accommodation initially displayed a lag, vergence, and their interactions. Normally, vi- and eventually showed fatigue to the point that sion therapy is successful in improving accom- no change in accommodation occurred in re- modative and vergence function with concur- sponse to the blur stimulation.
rent elimination of symptoms in more than 90% VOLUME 76 / NUMBER 7 / JULY 2005 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 zero Figure 2 Accommodative amplitudes were measured using pushup before Mestinon, but improves with Mestinon. (Reprinted with methods on the right and left eye in the morning, afternoon, permission of Neuro-Ophthalmol 2000;20:p8) 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) of patients with either convergence insufficiency or various accommodative anomalies In this case, however—and as in Case 2—vision therapy 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 from therapy. A review of her record by JC noted that her pattern of fatigue occurring during therapy morning, afternoon, and early evening. The phoria in- was suggestive of MG. Ocular fatigue testing and creases dramatically during the course of testing from 8"to 16". The phoria decreased after administration of the sleep test were equivocal, and the ice test Mestinon. (Reprinted with permission of Neuro-Ophthalmol was negative. Approximately two months later, a 3-mm ptosis of the left eye developed. She then had a comprehensive neurological examination, On the basis of these findings, the consulting including magnetic resonance testing. The pa- neurologist agreed with our suggestion of plac- tient refused to have a Tensilon test because of ing the patient on a diagnostic trial of Mestinon her history of asthma. On initial testing, her (Zeneca, Wilmington, Delaware) in an attempt to accommodative and convergence findings were mimic the results of Tensilon testing. We contin- initially normal, but showed fatigue on repeti- ued to measure accommodative and vergence tion. There was also a subtle oculomotor non- after the administration of Mestinon. It is clear comitancy of 4" on extreme levoduction.
from the results that all accommodative/ver- gence measurements exhibited significant reduc- We measured accommodation (positive relative tion from morning to evening. In addition, Mes- accommodation, negative relative accommoda- tinon clearly improved both accommodative and tion and accommodative amplitudes); vergence vergence amplitudes and facility. These findings (positive fusional amplitudes and their respected are diagnostic for MG—since Mestinon is similar recoveries); and cover tests in the morning, af- to Tensilon—except for having a longer duration ternoon, and evening (see through VOLUME 76 / NUMBER 7 / JULY 2005 Case 3
Ocular myasthenia gravis masquerading as a
non-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 the previous two months. The diplopia worsened as the day progressed, and improved when he tilted his head to the left. He had been seen previously for this symptom of the dip- lopia without resolution. Other than Crohn's disease, all other history was unremarkable.
He mentioned he was going through a stress- ful time in his personal life.
Figure 5 Convergence amplitudes (break) and recovery were measured with the Risley prisms in the morning, afternoon, and early Best-corrected vision with a low hyperopic cor- evening. The convergence amplitude decreased dramatically rection was 20/20 in each eye. Distance cover from morning to evening from 15 to -8". One third of the testing revealed a 3" left hypertropia in primary decrease may be attributed to a change in phoria. Improve- gaze, orthophoria in right gaze, and a 9" left ment occurred with the administration of Mestinon. (Reprintedwith permission of Neuro-Ophthalmol 2000;20:p9) hypertopia in left gaze. Diplopia was worse on right head tilt. A Park's 3-Step Test indicated a left inferior rectus (IR) palsy. (It should be noted that isolated nontraumatic, noncongenital palsy of the IR is very 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 were unremarkable. Due to the recent onset of his symptoms, as well as the presentation of a non- comitant vertical muscle deviation, a blood work-up was ordered, which included Acetyl- choline Receptor Antibody Titers, TSH, T3,T4 ESR, RPR, Lyme serology, and a fasting blood sugar test. The patient was instructed to perform Figure 6 Convergence amplitudes (break and recovery) in the evening are presented by date. It is apparent that the amplitude varies daily, a home sleep/ice pack test with picture review.
but is improved with the administration of Mestinon. (Reprinted He was also prescribed a 3" Fresnel press-on with permission of Neuro-Ophthalmol 2000;20:5-11) prism base-down over the left eye, to alleviate his diplopia.
Prior to taking Mestinon, the patient experi- enced significant ocular and systemic fatigue On a follow-up examination, the blood test re- by 7:00 PM. After taking Mestinon (60 mg sults were abnormal for the acetylcholine-recep- daily), there was an immediate improvement tor antibody level (i.e., 1.4 nmol/L—reference in both accommodative and vergence find- range is less than 0.7 nmol/L); Striated Muscle ings, as well as a decrease in the ptosis. In Antibody Titers (i.e., 1:160—reference range is addition, she reported elimination of her 1:40); and TSH (i.e., 6.94 mIU/L—reference general fatigue. Follow-up examination one range, 0.40 to 5.50 mIU/L). All other blood find- and a half years later substantiated these ings were normal. The patient reported improve- findings. During a short interval in which ment of his diplopia after performing an ice-pack she ran out of her medication, the ptosis and test at home on two separate occasions. These ocular and systemic fatigue all reappeared.
findings were consistent with acquired autoim- She has since remained stable with a regimen mune MG and thyroiditis. A CT scan of the of 60-mg Mestinon twice a day.
thymus was ordered, and the patient was re- VOLUME 76 / NUMBER 7 / JULY 2005 ferred to a neurologist who specialized in neuro- 3" exophoria at near. The ice pack test was muscular disease, and to an endocrinologist.
equivocal in reducing the patient's diplopia.
Blood tests were negative. Due to the unex- There was no evidence of a thymoma or thymic plained hyperphoric deviation associated with hyperplasia on a chest CT scan. A Tensilon test the horizontal deviation, the patient was re- was performed, which was positive. The patient ferred to a neuro-ophthalmologist for evaluation.
was placed on a regimen of 40-mg Prednisone The neuro-ophthalmologist wanted to rule out every other day, later tapered by 5 mg per day.
MG by performing a Tensilon test. A diagnosis After two weeks of treatment, the patient re- of OMG was made on the basis of a positive ported a decrease in the frequency and magni- Tensilon test, and a diagnosis of hypothyroidism tude of his diplopia. Subsequently, the patient as indicated by a repeated blood test. The patient moved out of state and was lost to followup.
was placed on a regimen of 60-mg Mestinon q.i.d. for the OMG and Synthroid for the hypo- thyroidism. On follow-up examination 3 months later, the patient stated that her diplopia was no Ocular myasthenia gravis masquerading as a
longer present with her current spectacles and stable, longstanding 6th nerve palsy. A 66-year-
that she was doing well with current medica- old woman came to us with a history of horizon- tions. Cover testing with correction revealed or- tal diplopia for the previous 5 years. She noted thophoria at distance and near. The patient was that the diplopia was worse when looking into instructed to continue with her current specta- the distance than at near. The patient was taking cles and medication regimen to maintain her hormone replacement therapy. She had a history positive status.
of a surgical ptosis repair of her left eyelid two years earlier for cosmetic reasons. The etiology of the ptosis was not investigated at the time, nor was the diplopia, despite numerous previous Ocular myasthenia gravis masquerading as a
visits to eye doctors.
concomitant esotropia. A 22-year-old man with
best-corrected visual acuities of 20/20 OU was With a slight hyperopic prescription, best cor- referred to author JC for vision therapy. The rected visual acuities were 20/25 in each eye.
referring optometrist noted a basic esotropia of Distance cover test measured 10" left esotropia recent onset. She had ordered an MRI, which with 2" left hyperphoria, and the near cover test was negative. At the initial examination, a 16" measured 12" esophoria with 4" left hyperpho- constant esotropia with 2" of hypertropia was ria. Vertical vergence ranges were normal at found at distance and near. Since the patient was distance and near. Near vergence ranges were BI leaving for college, he was prescribed a pris- x/–4/–14 and BO x/25/12. All other findings were matic correction and was referred for vision within normal limits.
therapy in the city in which he attended college.
A few months later, he returned from college The diagnosis of a longstanding 6th nerve palsy and returned to JC for a followup. He stated that was made, and the patient was given prism with the prism correction initially eliminated the dip- her prescription of #2.25 D –0.75 D $ 85 % 11 " lopia, which lasted for only a short period of BU % 31 " BO right eye and #1.25 D sph % time. After the patient returned to college, the 11 " BD % 31 " BO left eye with an add of #2.75 optometrist—who initially provided the vision D in a progressive addition lens design. Blood tests therapy—advised the patient that the initial pris- were ordered, including thyroid function tests matic correction was incorrect.
(T3,T4, TSH) sed-rate (ESR), and Acetylcholine re- ceptor antibody titers. Given the length of time the On the patient's return to JC, the variability of patient was experiencing symptoms, an MRI was his measured deviation led us to suspect the not immediately indicated.
possibility of MG. We performed an ice/sleep test and ordered an Ach Receptor Antibody On follow-up examination two weeks later, the blood test. The ice/sleep test was positive for MG patient stated that the diplopia was eliminated (see A and B), while the antibody level with the prism spectacles. Cover testing with was negative. A subsequent cover testing re- correction revealed 3" esophoria at distance and vealed a concomitant 20" left esotropia at dis- VOLUME 76 / NUMBER 7 / JULY 2005

of his lids was noted.
tance and 10" of esophoria at near. Versions The patient returned to us six months later, were concomitant.
taking 60-mg Mestinon q.i.d. p.o. He reported less ptosis with the medication; however, the The patient had a neuro-ophthalmological abdominal side effects forced him to discontinue examination; nerve-conduction studies, and the medication. Cover testing revealed a con- EMG results, all of which were normal. The comitant 16" esotropia at distance and or- neuro-ophthalmologist concluded that OMG thophoria at near. Accommodative amplitudes was not present. However, a Tensilon test— were 6.5 diopters in each eye. A thymectomec- which we requested—was not performed at tomy was performed; the patient discontinued that time. We saw him again and noted the Mestinon and was treated with 60-mg Pred- variable esotropia. We conferred with a sec- nisone, with some improvement. His deviation ond neuro-ophthalmologist, who agreed with stabilized and he was advised to wear a distance our tentative diagnosis of MG. We referred prism correction.
the patient back to the neuro-ophthalmolo- gist located in his college town who subse- quently noted a new ptosis and performed a Tensilon test, which was positive. The pa- MG usually manifests a recently acquired, vari- tient was started on a regimen of 30-mg able ptosis, greater in one eye than the other.
Mestinon q.i.d. p.o. and advised to have a When this occurs, the diagnosis is straightfor- chest CT scan.
ward and is readily confirmed by the gold stan- VOLUME 76 / NUMBER 7 / JULY 2005 dard—the Tensilon test. Previous studies have bell and demonstrated that accom- suggested that 90% of all patients with myasthe- modation may be involved in the MG syndrome.
nia gravis manifest a ptosis, and that a general- We have presented and published two case stud- ized MG will eventually develop (within two ies that objectively demonstrate accommodative years) in 50% of those who manifest an ocular insufficiency as the presenting We be- In dealing with relatively stable acquired lieve that the paucity in reporting of accommo- ptosis is more difficult to ascertain the origin; dative anomalies is related to the lack of testing however, even in those cases, MG must be con- of accommodative amplitude, and/or facility of sidered. We believe that patients manifest non- accommodation. It is important that those pro- ptotic signs of MG more frequently than previ- viding vision therapy recognize the pattern of ously reported. When the presenting sign is accommodative findings associated with MG.
other than ptosis—such as an accommodative/ There are a few caveats in making the diagnosis vergence insufficiency, or a concomitant or non- comitant oculomotor paresis—then diagnosis of of accommodative insufficiency secondary to MG is much more elusive. For the patient with MG, since these accommodative findings are myasthenia gravis who manifests nonclassical unique. First, asymmetrical accommodative am- symptoms, MG may be overlooked by the plitudes between the eyes are present. Second, neuro-ophthalmolgists, ophthalmologists, op- the amplitudes are usually reduced and will de- tometrists, and primary care practitioners.
crease further on repeated testing. Third, accom- modative facility as measured with ! 1.50 D Perhaps the primary reason that patients who lenses in the phoropter demonstrates fatigue initially manifest MG-induced accommodative with repeated testing. Fourth, the general accom- and vergence deficits are not appropriately diag- modative (and related vergence) findings fatigue nosed is that the ophthalmic community is not by the end of the day, and thus their respective sensitive to the subtle initial signs and symptoms amplitudes and/or facility will be less in the of MG—i.e., asthenopia, blur, diplopia, and vi- evening, as compared to the morning. Fifth, the sual fatigue. The most-common finding of MG is findings will vary from day to day. And sixth, fatigability of either striated or non-striated ocu- Tensilon or Tensilon equivalent medications lar motor muscles—accommodation, vergence, (such as Mestinon) will have a positive effect on and levator palpebrae. This fatigability may oc- cur with minimal usage: within minutes, from morning to evening, and/or from day to day. No After the classical sign of ptosis, the most com- other condition manifests such variable findings.
monly described sign of MG is variable diplopia.
Thus, any patient suspected of having MG The classical myasthenic patient will manifest a should have morning baseline testing to estab- non-comitant, oculo-motor paresis varying as the lish lid position and accommodative/vergence day progresses. This myasthenic patient will functioning. Measurement should be repeated in have motor fields that are not indicative of a the evening to assess fatigability.
specific oculomotor paresis; variability is the hallmark of MG. Like accommodation, in- There are a variety of non-invasive, simple office and home tests that we have discussed previously creased variability is usually noted with re- to support the diagnosis of MG (see . If peated testing or time of day. The patient may ptosis is present, the clinician should attempt to manifest a subtle ptosis, so the external exami- fatigue the orbicularis muscles. Also, 2.5% neo- nation must be carefully performed. Fatigue, synephrine may be used to differentiate senile induced by repeated versions or vergence testing ptosis from other forms of ptosis. The patient with a prism bar, will result in increased diplo- should be instructed to perform the photo test at pia and/or a change in the cover test value.
home. If a patient has diplopia, atypical oculo- Version and vergence testing may be enhanced motor fatigue, and/or demonstrates a decrement with the use of a red lens. The red lens serves of findings during or immediately after vision three functions: to disrupt binocularity, to elim- therapy, MG should be suspected.
inate suppression, and to determine the diplopia direction. The sleep/ice test usually results in It has been assumed that MG only affects stri- improvement of the diplopia, as noted in two of ated muscles. As early as 1900, however, Camp- VOLUME 76 / NUMBER 7 / JULY 2005 with a photo review, are sensitive and specific to myasthenia gravis.
Myasthenia may masquerade as a convergence plained diplopia—particularly under the age of insufficiency, a divergence insufficiency, or a 60 years—should include MG in the differential concomitant hyperdeviation. Myasthenia both diagnosis, even if another health care practitio- follows and breaks the rules. Thus, any unex- ner has dismissed the diagnosis of MG. Although VOLUME 76 / NUMBER 7 / JULY 2005 four of the five cases had variable findings which lead to a more-detailed investigation of possible 1. Conti–Fine BM, Protti MP, Belone M, et al. Myasthenia MG, one did not. This patient was particularly gravis and its experimental model. The immunobiology of elusive, since the ptosis was previously elimi- an autoimmune disease. Georgetown: Landes Bioscience nated by surgery, and her deviation was con- Publishers, 1997.
comitant and unchanging over a course of sev- 2. Porter NC, Salter BC. Ocular myasthenia gravis. Curr Treat Options Neurol 2005;7:79-88.
3. Engel AG. Myasthenia gravis and myasthnic syn- dromes. Ann Neurol 1984;16:519-34.
If the patient is still not confirmed as having MG 4. Sampson JA. Myasthenia gravis and myasthenic syn- after simple, non-invasive office and home tests, dromes. In: Walton J, ed. Disorders of voluntary muscle.
Boston: Churchill–Livingstone, 1981:585.
further testing is warranted. A blood workup 5. Kurland IT, Ater M. Current status in epidemiology and should include a MG antibody test, thyroid test- genetics of myasthenia gravis. In: Viets HR, ed. Myasthe- ing, fasting blood sugar, Lyme titer, and ESR in nia gravis: the Second International Symposium proceed- those over 60 years of age. If intracranial disease ings. Springfield, Ill.: Charles Thomas, 1961:307-36.
6. Somnier FE, Keiding N, Paulson OB. Epidemiology of is suspected, an MRI with contrast should be myasthenia gravis in Denmark: a longitudinal and com- performed. The radiologist should be advised to prehensive study. Arch Neurol 1991;48:733-9.
carefully examine the pathways of 3rd, 4th, or 6th 7. Kalb B, Matell G, Pirskanen R, et al. Epidemiology of N from the eye to the midbrain, and the higher myasthenia gravis a population-based study in Stock- holm, Sweden. Neuroepidemiology 2002;21:221-5.
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8. Kupersmith MJ, Latkany R. Development of general- Lastly, a neuro-ophthalmological consult is in ized disease at 2 years in patients with ocular myasthe- order with Tensilon testing and single-fiber myo- nia gravis. Arch Neurol 2003;60:243-8.
graphy to make the final differential diagnosis.
9. Evoli A, Minisci C, Schino D. Thymoma in patients with MG: characteristics and long-term outcome. Neurology After stabilization with medication, patients 10. Cooper J, Kruger P, Panariello G. The pathognomic with MG should have a re-evaluation of their pattern of accommodative fatigue in myasthenia gravis.
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vergence defects may benefit from prismatic cor- 12. Golnik KC, Pena R, Lee AG, et al. The ice test in the rection incorporated into a progressive lens. A diagnosis of myasthenia gravis. Ophthalmology 1999; progressive lens provides the advantage of com- 13. Kubis KC, Danesh–Meyer HV, Savino PJ, et al. The ice pensating for the variable accommodative ampli- test versus the rest test in myasthenia gravis. Ophthal- tudes noted during the day and from day to day.
One must remember, for the young patient, that 14. Ellis FD, Hoyt CS, Ellis FJ, et al. Extraocular muscle the add power should be determined monocu- responses to orbital cooling (Ice Test) for ocular myas- thenia gravis diagnosis. Am Assoc Pediatr Ophth Surg larly before prism is determined (by relaxing accommodation, there is a relaxation of conver- 15. Soliven BC, Lange DJ. Seronegative myasthenia gravis.
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18. Howard JF, Sanders DB. The electrodiagnosis of myas- In summary, MG should be considered when thenia gravis and the Lambert–Eaton myasthenic syn- examining the patient with unexplained ocular drome. Neurol Clin North Am 1994;12:305-30.
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Alcohol studies in translational models: behavioural consequences of adolescent exposure and novel approaches to reduce the propensity to relapse. The research described in this thesis was conducted at the department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands and at the department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands. My research was supported by ZONMW Topgrant 912-06-148. Cover: artwork by Martijn C.L. Van Roovert. Layout by Esger Brunner. Printed by GVO drukkers & vormgevers B.V. P+L ISBN: 978-90-6464-703-1 Copyright © J.A. Wouda (, 2013. Al rights reserved. No part of this thesis may be reproduced, stored in a retrieval system, transmitted in any form without prior permission from the author.

The Journal of Neuroscience, August 1, 2002, 22(15):6321–6324 Caffeine Induces Dopamine and Glutamate Release in the Shell ofthe Nucleus Accumbens Marcello Solinas,1 Sergi Ferre´,1 Zhi-Bing You,2 Marzena Karcz-Kubicha,1 Patrizia Popoli,3 andSteven R. Goldberg1 Sections of 1Preclinical Pharmacology and 2Behavioral Neuroscience, Behavioral Neuroscience Branch, National Instituteon Drug Abuse, National Institutes of Health Intramural Research Program, Baltimore, Maryland 21224, and3Department of Pharmacology, Istituto Superiore di Sanita, 00161 Rome, Italy