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Show Journal of Neuro- Ophthalmology 20( 1): 5- 11, 2000. ' 2000 Lippincott Williams & Wilkins, Inc., Philadelphia Accommodative and Vergence Findings in Ocular Myasthenia: A Case Analysis Jeffrey Cooper, MS, OD, Gayle J. PoUak, OD, Kenneth J. Ciuffreda, OD, PhD, Philip Kruger, OD, PhD, and Jerome Feldman, PhD Myasthenia gravis ( MG) is a neuromuscular disorder that affects skeletal muscles, in particular, the extraocular muscles. Response variability is a hallmark sign. Detailed findings are described in a patient with MG in which the presenting sign was accommodative insufficiency. Objective accommodative findings were recorded 3 years before the onset of myasthenia, soon after the initial diagnosis was made, and then after the treatment commenced with pyridostigmine. In addition, clinical measurements were obtained periodically at different times of the day for various binocular motor functions, including near point of convergence, phoria, fusional and accommodative amplitudes, and relative accommodation. The disease adversely affected all accommodative and vergence findings, with fatigue being the primary disturbance. The therapeutic administration of pyridostigmine improved static measurements of accommodation and vergence and reduced asthenopia. The objective dynamic measurements of accommodation, vergence, and versions were less affected. These findings provide a clear demonstration that both intrinsic and extrinsic ocular muscles may be affected in the prepresbyopic myasthenic patient. Key Words: Accommodation- Accommodative insufficiency- Binocular vision- Convergence- Convergence insufficiency- Fatigue- Myasthenia gravis- Strabismus. Myasthenia gravis ( MG) is a neuromuscular disorder, which causes progressive muscular fatigue and weakness because of impairment of synaptic transmission ( 1,2). It affects approximately 1 in 10,000 individuals ( 3). This acquired autoimmunologic disorder results from a decrease in the number of available acetylcholine receptors ( 4). Myasthenia gravis is typically found in women younger and men older than 40 years of age. Ptosis and diplopia are the most common presenting symptoms, occurring in more than 70% of the cases and eventually in over 90% of all patients diagnosed with MG ( 5,6). Manuscript received March 3, 1999; accepted October 13, 1999. From the State College of Optometry, State University of New York, Departments of Clinical Sciences and Vision Sciences, New York, New York. Address correspondence and reprint requests to Jeffrey Cooper, MS, OD, State College of Optometry, State University of New York, Departments of Clinical Sciences and Vision Sciences, 100 East 24th Street, New York, NY 10010. Myasthenia gravis has a predilection for the skeletal-like ocular muscles because of the rapid contraction kinetics and high firing rates found ( 7). Because small disturbances in ocular innervation may cause clinically significant misalignments of the visual axis, the extraocular muscles are particularly sensitive to MG ( 8). Such perturbations frequently produce diplopia, which is usually noncomitant and variable. If diplopia is present, then ptosis is also usually observed. The relationship between MG and accommodation remains controversial ( 8,9). Because MG is a skeletal muscle disorder, some believe that neither accommodation nor pupillary responses should be affected ( 9,10). However, as early as 1900, Campbell and Bramwell ( 11) reported that MG affected accommodation. Later, Romano and Stark ( 12) presented a case in which pseudomyopia was the presenting sign of MG. Aird ( 13), and also Simpson ( 14) observed abnormal accommodative responses associated with MG. Rabinovitch and Vengrjenovsky ( 15) described a 25- year- old woman whose initial complaint of accommodative asthenopia occurred 13 years before the diagnosis of MG with bilateral accommodative spasm. Manson and Stern ( 16) measured accommodative amplitude in four groups of patients: 6 with systemic untreated MG; 3 with untreated ocular MG; 11 with non-myasthenic accommodative insufficiency; and 17 controls. In most of the myasthenic patients and half of the nonmyasthenic patients who manifested reduced accommodation, improvement was obtained with edrophonium chloride ( Tensilon; Zeneca, Wilmington, DE) injection. None of the controls experienced any change in accommodative amplitude. The authors concluded that the accommodative system was involved in MG, and furthermore, that those accommodative defects may represent a mild form of MG. More recently, Cooper et al. ( 17) described a patient with ocular myasthenia whose presenting sign was accommodative fatigue. They recorded accommodative responses objectively with a dynamic infrared optometer, while the patient viewed a target in a Badal optical system that moved predictably either sinusoidally or in a stepwise manner. They reported that there was little ac- 6 J. COO commodative response for a target that moved faster than 0.2 Hz. For target movement between 0.1 and 0.2 Hz, either oscillations of accommodation and/ or variable reduced responses were found, which were apparently caused by fatigue. At times, the patient exhibited an accommodative spasm of 5 to 6 diopters. The most common finding was relatively normal initial accommodative tracking, which was quickly followed by response deterioration reflecting accommodative fatigue. In the current paper, a detailed case study is presented in which the initial sign of ocular MG was also accommodative fatigue. This was followed by development of a convergence insufficiency, and months later with a ptosis. The concomitancy of the deviation and the predictability of the general findings are atypical of MG. For the first time, sequential clinical and laboratory accommodative and vergence findings related to time of day, as well as to development of the disease itself, are reported. In addition, accommodative findings before the onset of the disease, accommodative and oculomotor muscle findings concurrent with the onset of the disease, and then after the prescription of pyridostigmine ( Mestinon; Zeneca, Wilmington, DE) are provided. CASE REPORT A 25- year- old female student presented with a history of ocular fatigue associated with near work occurring over the preceding 2 years. Other than having a childhood diagnosis of asthma, for which she was taking sal-meterol xinafoate ( Serevent, GlaxoWellcome, Research Triangle Park, NC), triamcinolone acetonide ( Azmacort, Rhone- Poulenc Rorer, Collegeville, PA), and metapro-terenol sulfate ( Alupent, Boehringer Ingelheim, Ridge-field, CT), all other ocular findings and general health history were unremarkable. Both noncycloplegic and cy-cloplegic refractions were identical ( OD, - 0.75 D; sph, 20/ 20; OS, - 0.75 D; 20/ 20). There were few traditional symptoms or signs of MG at the initial examination. The patient complained of accommodative fatigue that was verified with a ± 1.50 accommodative flipper test ( see Appendix) ( 18,19). This clinical test correlates with objective dynamic accommodative measurements ( 20). An accommodative insufficiency was diagnosed on the basis of her reduced accommodative amplitudes. In addition, there was 2A of left hyperphoria. Stereopsis was present with a 660- second random dot stereogram test indicating bifoveal fixation ( 21). All other ocular findings were unremarkable. Two years later, the patient presented with similar symptoms of ocular fatigue, but now with the additional symptom of occasional diplopia. Findings included an accommodative insufficiency associated with a convergence insufficiency. Interestingly, the initially measured hyperphoria was not present. On the basis of these findings, orthoptic therapy was initiated to improve both accommodative and vergence function. Orthoptic therapy was provided once a week for 45 minutes. Therapy was designed to improve static and dynamic accommodation and vergence and their interaction. J Neuro- Ophthalmol Vol 20, No. I, 2000 ETAL. Normally, orthoptic therapy is successful in improving accommodative and vergence function with concurrent elimination of symptoms in over 90% of patients with either convergence insufficiency or various accommodative anomalies of nonorganic origin ( 22). However, in the current case, the symptoms did not decrease. Orthoptic therapy resulted in a further reduction of accommodative and vergence amplitudes, which presumably reflected a fatigue factor. This observation led to the suspicion of MG. The first author had observed this pattern in another case, in a patient who was subsequently diagnosed with MG ( 17). The patient refused to have a Tensilon ( edrophonium) test because of her history of asthma. Ocular fatigue testing ( 23) and the sleep test ( 24) were equivocal, and the ice test ( 25) was negative. Approximately 2 months later, the patient developed a 3- mm ptosis of the left eye. The patient then had a comprehensive neurologic examination, including magnetic resonance testing and visual-evoked potential. All results were negative, except for the accommodative and convergence findings, which once again showed fatigue on repetition. In addition, there was a subtle oculomotor noncomitancy of 4 prism diopters on extreme levoduction. She also reported that she experienced significant ocular and systemic fatigue by 7: 00 PM. The patient was then placed on a trial dosage of pyridostigmine ( Mestinon; Zeneca, Wilmington, DE), 60 mg twice daily, which improved both accommodative and vergence findings, as well as decreased the ptosis. The patient reported that her fatigue was now eliminated. Follow- up examination one and half years later substantiated these findings. During a short interval during which she ran out of her medication, the ptosis and ocular and systemic fatigue all reappeared. She has since remained stable with 60 mg Mestinon twice a day. RESULTS Laboratory Measurements of Accommodation The patient was examined 3 years before the onset of symptoms of MG as part of an investigation of the stimulus for normal reflex accommodation by one of the authors ( 26). Accommodation was monitored continuously with a high- speed infrared optometer while the subject viewed a high- contrast white- on- black Maltese cross. The target moved sinusoidally ( 1 to 3 D) at three temporal frequencies ( 0.1, 0.2, and 0.4 Hz) in a Badal optical system ( 27,28). Representative tracking responses are shown in Figure 1, and gains and phase- lags for the trials in Figure 1 are presented in Table 1. Trials were run in the order shown, and additional trials were run at different temporal frequencies ( data not presented). During the initial examination, the dynamic tracking responses were relatively smooth, and gain and phase lags were within the normal range ( Figure 1, top) ( 28). As expected, accommodative gain decreased and phase- lag increased as temporal frequency of target motion increased from 0.1 to 0.4 Hz. These initial findings suggested that both the sensory and motor aspects of reflex accommodation OCULOMOTOR FINDINGS IN MYASTHENIA 7 INITIAL EXAMINATION Gain = 0.92 Phase- lag = 16 deg 0.1 Hz 0.2 Hz • Gain = 0.57 Phase- lag = 73 deg CO 08 LU CO o 0_ co LU rr < Q O ooO < JAAAAAAAA/ WVVWW 0 T. kl\ rVAJ\/ Ww^ AAiVVW U SECOND EXAMINATION ! 3 C^> ti£^^ d3lW^^ 0, Hl 13 AMAM/ WWWWW » I. 4HZ 2 Hz FIG. 1. Dynamic recordings of the accommodation stimulus and response are presented at 0.2 Hz three different examination times. 4 Hz THIRD EXAMINATION 0.2 Hz 0.2 Hz : J^ LJ^^ iJ^ l^^ 0.16 Hz 10 20 30 TIME ( seconds) were reasonably normal and intact at the time of the first laboratory examination. A second examination was performed shortly after the onset of symptoms but before the diagnosis of MG was made. Sinusoidal tracking responses were recorded again at 0.1, 0.2, and 0.4 Hz ( Fig. 1, middle). In the first trial at 0.2 Hz, gain and phase- lag were normal, but sudden TABLE 1. Accommodative gain and phase- lag Session no. 1 2 3 Temporal frequency ( Hz) 0.1 0.2 0.4 0.1 0.2 0.2 0.4 0.2 0.2 Gain 0.92 0.72 0.57 0.27 0.52 0.41 0.15 0.50 0.47 Phase- lag ( degrees) 16 36 73 129 31 43 166 52 47 marked variation of accommodation was evident during some of the cycles in which large fluctuations of accommodation replaced the smooth tracking response. A second trial was run at 0.2 Hz, and tracking was again highly variable, reflecting unsuccessful attempts to track the target dynamically. For the third trial, temporal frequency was then reduced to 0.1 Hz, but responses suggesting accommodative fatigue remained. The last trial at 0.4 Hz produced marked fluctuations of accommodation that was followed by complete fatigue. A third examination followed the prescription of Mes-tinon. Examples of accommodative tracking are shown in Figure 1 ( bottom). Gain was still lower than before the onset of MG, but the large response variations prominent in the second examination were now less frequent. Responses suggestive of accommodative fatigue were still evident, as illustrated by the responses to the square-wave target changes ( Fig. 1, bottom). In the final trial, the target was stepped toward ( 0 to 2 D) or away from the eye ( 2 to 0 D) at 4- second intervals ( 0.16 Hz). The patient had great difficulty sustaining accommodation at J Neuro- Ophihalmol, Vol. 20, No. 1, 2000 /. COOPER ET AL. h i • e « « IF the near distance ( 2 D) for more than 1 to 2 seconds, and the response finally deteriorated into a series of small, variable movements. Clinical Measurements of Accommodation and Vergence Shortly after the diagnosis of MG was made, various clinical accommodative and vergence measures over the course of a day ( 9: 00 AM, 1: 00 PM, and 5: 00 PM) over a 6- month period were taken. These included accommodative amplitude, relative accommodation, relative vergence, and the phoria. Figure 2 presents monocular accommodative amplitudes as measured with a minus lens to first noted sustained blur ( 19). The patient was encouraged to exert maximum accommodative effort throughout testing. The right eye had a considerably larger amplitude of accommodation than the left eye ( mean difference, 2 D). There was progressive diminution of accommodative amplitude as the day progressed ( Fig. 2A). With the administration of pyridostigmine, the amplitude of accommodation increased from 2 to 4 D OD and from 0.50D to 3.5 D OS ( Fig. 2B). However, these values were still below the age- related clinical norm of 11 D ( 29). Figure 3 presents the relative accommodative measurements over the same period. Negative relative accommodation was normal (+ 2.50 D OU) and was relatively unaffected by time of day, course of the disease, or the instillation of Mestinon. In contrast, all of these factors clearly affected positive relative accommodation. Positive relative accommodation decreased over the course of the day and improved with the administration of pyridostigmine. Figure 4A presents the near relative convergence amplitudes at various times of day ( 9: 00 AM, 1: 00 PM, and 5: 00 PM), whereas Figure 4B depicts near relative convergence over a 1.5- year period. Convergence amplitudes were initially normal but progressively decreased over the course of the day. The mean relative convergence amplitude at 9: 00 AM was 13A with a recovery of g o & * BEFORE MESTINON /^ o- o- o^° p / O. 6 : ' D a Q- n.. d- AFTER MESTINON n a a D- a ' - O NRA_ EVE d- PRA_ EVE 10/ 8 10/ 22 11/ 21 2/ 4 2/ 11 3/ 4 3/ 13 4/ 3 10/ 15 11/ 18 11/ 26 2/ 6 2/ 2S 3/ 6 3/ 25 4/ 8 5 6.5 ^ 5.5 J 4.5 BEFORE MESTINON • D---- D.. a a - - • - • ' . a - c AFTER MESTINON ft. .. o. • o - O OO AM - Q- OO PM - 0~ OD_ EVE o- - -- o q q 10/ 8 10/ 15 10/ 22 11/ 18 11/ 21 11/ 26 2/ 4 2/ S 2/ 11 2/ 25 3/ 4 3/ 6 3/ 13 3/ 25 4/ 3 4/ 8 DATES I , BEFORE MESTINON D - . - D - . q ^ A o - o o ..< D> • - o '' 8a AFTER MESTINON v.. ' <> , / \ °' o. - Q- OS_ AM - O- OS_ PM - O- OS_ EVE o • o <> « , 10/ 8 10/ 15 10/ 22 11/ 18 11/ 21 11/ 26 2/ 4 2/ 6 2/ 11 2/ 25 3/ 4 3/ 6 3/ 13 3125 4/ 3 4/ 8 O DATES FIG. 2. Accommodative amplitudes for each eye are presented for three different times of the day. The top panel presents measurements for the right eye, and the bottom panel is for the left eye. FIG. 3. Negative relative accommodation ( NRA) and positive relative ( PRA) were measured at three different times of the day. Only the evening measurements are presented. 8A; at 1: 00 PM, the mean convergence amplitude was - 4 with a recovery of - 2A; and at 5: 00 PM the mean convergence amplitude was - 15 with a recovery of - 12 . With the introduction of Mestinon, the convergence amplitude at 5: 00 PM improved to 5A with a recovery of 2A. This was still outside normal limits ( i. e., 17/ 21/ 11; blur/ break/ recovery in prism diopters) ( 30). Figure 5 presents the change in phoria during the course of the day. The mean exophoria increased as the day progressed. At 9: 00 AM, it was 8A, and by 5: 00 PM the exophoria had increased to 16A. The increasing phoria accompanied with decreasing convergence amplitudes explains the symptom of diplopia that the patient experienced late in the day. It is of interest that neither the fusional divergence amplitudes nor concomitancy of versions varied from day to day or over the course of the day. The initial finding of a small left hyperphoria was present at only some of the test sessions. Laboratory Measurements of Eye Movements Objective eye movement recordings were performed on the subject at four separate test sessions. Horizontal eye movements ( binocular viewing; right eye recorded) were assessed using a commercially available, infrared eye movement system ( Gulf and Western, Eye Trac, Model 200). This system has a band width from dc to 250 Hz, a resolution of 0.2°, and a linear range of ± 10°; however, the frequency response of the eye movement traces was limited by the bandwidth of the strip chart recorder ( dc to 80 Hz). The target consisted of a small ( 5- minute arc), bright spot of light ( 3 log units above threshold) controlled by a function generator and presented on a display monitor 57 cm from the subject. It moved predictably at various frequencies specified below at either ± 5° or ± 10° in amplitude to the left and right of midline. Emphasis was placed on static and dynamic aspects of saccadic eye movements and their apparent ability to fatigue. After a brief calibration, 6 cycles of 0.4 Hz, 10° predictable step tracking were tested. Saccadic accuracy ( with respect to the initial saccade metric) and velocity J Neuro- Ophthalmol, Vol. 20, No. 1, 2000 OCULOMOTOR FINDINGS IN MYASTHENIA 9 BEFORE MESTINON AFTER MESTINON 10/ 8 10/ 22 11/ 21 2/ 4 10/ 15 11/ 18 11/ 26 2/ 11 3/ 4 2/ 6 2/ 25 3/ 13 3/ 6 3/ 25 BEFORE MESTINON Mean*/- SD BREAK sarW- SD RECOVERY PM A DATES ( EVENING) B TIME OF TESTING FIG. 4. A: Early evening measurements of fusional relative convergence amplitudes are presented; the trends at the other times were identical. B: Relative fusional near convergence findings at near ( 40 cm) are presented ( blur, break, recovery). Mean convergence amplitudes are depicted by • and recovery values depicted by • Measurements were taken at 9: 00 AM, 1: 00 PM, and 5: 00 PM, respectfully. profile were within normal limits. Some saccades were slightly hypometric, but the peak velocity/ amplitude relation ( i. e., main sequence) was in the normal range ( 31). This was followed by 60 cycles of 0.8 Hz predictable step tracking in an attempt to induce fatigue. Immediately after this, 20 cycles of 0.4 Hz, and then 45 cycles of 0.8 Hz of predictable step tracking were performed. There were no obvious fatigue effects either during or immediately after this fatigue paradigm, such as slowed or overlapping saccades; the metrics and velocity characteristics were as before ( 31). Testing was repeated 5 days later, in the morning. For 10° predictable step tracking at various frequencies ( 0.2- 0.8 Hz.), there was evidence of " mild" fatigue effects in 20% of the saccadic movements. Hypometria was now more marked, which reflected reduced saccadic gain. Peak velocities were reduced, with blunted velocity profiles evident. When saccadic amplitude was increased to 20°, at a relatively rapid self- paced frequency of approximately 1.0 Hz, the presence of fatigue effects was increased and now occurred in approximately 50% of the saccades. These fatigue- related abnormalities included markedly slowed saccades with very blunted velocity profiles, marked hypometria, and increased response variability. The patient was retested on the same day in the late afternoon. Using a similar 10° saccadic fatigue paradigm, there was now little evidence of any fatigue effects. The patient was retested 5 months later in the late afternoon, after she had begun taking Mestinon. Subjectively, she noticed considerable improvement with respect to overall reduction of general body and ocular fatigue. Once again, the larger 20°, self- paced saccades were tested. After 60 cycles of tracking to induce fatigue, 50 more cycles were tracked. The eye movement characteristics were then qualitatively analyzed with respect to a general profile. Numerous abnormalities were found, including moderately slow saccades, overlapping saccades, and considerable saccadic response variability ( 31). Moderately slowed saccades were found with movements to both the right and left ( Fig. 6). DISCUSSION The current results, as well as those reported earlier by two of the authors, are consistent with the notion that accommodative dysfunction may be a more common finding in the prepresbyopic myasthenic population than previously believed ( 16) Accommodation fatigued more easily than vergence, pursuit, saccades, or other skeletal muscles ( e. g., levator). This is surprising, because MG has traditionally been described as a disease that only affects striated skeletal muscles and not smooth muscles, such as those involved in the control of accommodation. Static measurements of accommodative amplitude and dynamic measurements of accommodative facility are rarely performed in the MG population. This would account for the paucity of such information in the literature, as well as the apparent lack of correlation with symptomatology. ^ f - / / ZIZ Mean+/- SD TIME OF TESTING FIG. 5. Phorias were measured at both distance and near during the day. Mean phorometric measurement and the standard deviation are presented. J Neuw- Ophthalmol, Vol. 20, No. 1, 2000 10 J. COOPER ET AL. EYE POS. EYE VEL. rt r ^ i \ 20° EYE POS. EYE VEL. i- r v i 1 1 SEC FIG. 6. Ten degree ( top) and 20° ( bottom) saccadic eye movements were recorded. The clinical and objective accommodative findings associated with MG are different from those commonly found in other functional anomalies of accommodation and vergence. In MG, there is rapid accommodative fatigue occurring within a few seconds associated with either repeated testing or sustained near work. In the nonmyasthenic patient with an accommodative or non-strabismic vergence anomaly, response amplitudes or dynamic response facilities are reduced. In contrast, they are not much affected either by repeated testing, time of day, or sustained effort ( 17). Thus, the most sensitive and specific test of accommodative fatigue is not a static measurement of accommodation, such as clinical measurements of accommodative amplitude, but rather one that measures overall dynamic accommodation facility. The patient with MG may initially show relatively normal accommodative responses to repeated, alternate- step, blur inputs to accommodation ( i. e., + 1.50 D OU or - 1.50 D OU). However, after a few cycles, the response latency usually will increase, or the gain will decrease. Unlike patients with functional accommodative anomalies, repeated testing may even result in the total absence of an accommodative response. If our findings can be generalized, then the earliest finding in MG may be accommodative insufficiency as evidenced by fatigue of accommodation in the pre- presbyopic MG population. Measurements of striated eye muscle findings showed more variable evidence of fatigue that included a relatively concomitant and progressive convergence insufficiency, a predictable increase in phoria, and vergence fatigue as the day progresses. Unlike accommodation, variability in skeletal extraocular muscle findings occurred over the day, which was not apparent when one tried to fatigue these muscles during a clinical session. In addition, neither pursuits nor saccades showed the traditional findings associated with MG, thus suggesting that our patient had a mild form of MG. This was further supported by the appearance of a mild ptosis, relative concomitancy of eye movements, and minimal fatigue associated with eye movements. Pyridostigmine decreased the ptosis, and improved static measurements of accommodation and vergence. Dynamic measures of accommodation and vergence were less affected by the drug. The prescription of Mestinon in conjunction with a spectacle correction, consisting of both plus near lenses and prisms, eliminated the symptoms in our patient. The patient has remained relatively asymptomatic 1 year after diagnosis as long as she continues to take her medication. During a short period in which she ran out of her medication, all symptoms returned. Resumption of Mestinon again eliminated her symptoms and improved static measurements of accommodation and vergence. These changes, which occurred with or without medication, further substantiated the initial diagnosis. CONCLUSION This is the second report by two of the authors in which accommodation was the presenting sign for MG. Both patients were in their 20s and showed classical muscle fatigue consistent with the diagnosis of MG. The probability of two of our patients coincidentally having atypical accommodative anomalies diagnostic of MG is remote. We believe the lack of reporting of accommodative involvement with MG is the result of infrequent measurement of dynamic accommodative facility. We suggest that all patients thought to have prepresbyopic MG should have accommodative facility tested to evaluate fatigue of the accommodative system. This may be important, because we believe that accommodative fatigue may be one of the earliest signs of MG in the prepresbyopic population. APPENDIX Accommodative facility testing is performed by presenting either a + 1.50 D or + 2.00 D in front of one or both eyes at near. As soon as the patient clears the lenses, similarly powered negative lenses replace the plus lenses ( 19). The lenses are alternated between the plus and minus powers as rapidly as possible for 60 seconds, and the number of cycles per minute is calculated. 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