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Show Journal of C/ illieal Neuro- ol'hthalmology 11( 4): 288- 292, 1991 The Sleep Test for Myasthenia Gravis A Safe Alternative to Tensilon Jeffrey G. Odel, M. D., Jacqueline M. S. Winterkorn, Ph. D., M. D., and Myles M. Behrens, M. D. © 1991 Raven Press, Ltd., New York The diagnosis of myasthenia gravis is usually confirmed by a Tensilon test, which can be complicated by cholinergic side effects that include cardiopulmonary arrest. An alternative, the Sleep test, based on the characteristic of myasthenia that symptoms and signs worsen with fatigue and improve after a period of rest, is safe, moderately sensitive, and specific. The diagnosis of myasthenia can be confirmed by observing resolution of ptosis or ophthalmoparesis immediately after a 3D- minute period of sleep; the reappearance of the myasthenic signs over the next 3D seconds to 5 minutes adds further confirmation, Key Words: Myasthenia gravis- OphthalmoparesisPtosis- Sleep test- Tensilon. From the E. S. Harkness Eye Institute a. G. O., M. M. B.). Columbia- Presbyterian Medical Center, New York, and Department of Ophthalmology a. M. S. W.), North Shore University Hospital- Cornell University Medical College, Manhasset, New York, U. S. A. This paper was presented by Dr. Jacqueline M. S. Winterkorn, with videotape documentation, at the International Neuro- Ophthalmology Symposium ( INOS), Winchester, England, June 1990. Address correspondence and reprint request to Dr. Jacqueline M. S. Winterkorn at North Shore University HospitalCornell University Medical College, Department of Ophthalmology, 300 Community Drive, Manhasset, NY 1l030, U. S. A. 288 Myasthenia gravis is characterized by muscular weakness worsened with repeated or sustained effort. It is attributed to a defect in neuromuscular transmission caused by antibodies to acetylcholine receptors at the motor end plate ( 1). Myasthenic patients often present with ptosis and may be found to have lid twitch ( 2), ophthalmoparesis, orbicularis weakness ( 3), slow or occasionally superfast saccades ( 4), and nystagmus ( 5). All of these conditions are worsened with sustained performance. Improvement upon awakening or after rest is also characteristic of myasthenia. A transient reversal of abnormal signs by intravenous edrophonium, the Tensilon test, is the standard procedure for the diagnosis of myasthenia gravis. Edrophonium increases the safety factor of neuromuscular transmission ( 6), by inhibiting acetylcholine esterase, making more acetylcholine available to stimulate the limited receptor population. Unfortunately, the Tensilon test for myasthenia has several drawbacks. Results of the Tensilon test may be equivocal. False negative tests occur when patients with myasthenia do not improve after injection of Tensilon. False positive tests have been reported in patients with botulism, the Eaton- Lambert syndrome, amyotrophic lateral sclerosis, transverse myelitis, poliomyelitis, Guillain- Barre syndrome and myositis ( 7- 9), as well as in rare patients with compressive lesions such as aneurysm or meningioma ( 10). The lack of specificity has a physiologic basis. Botulism and the Eaton- Lambert syndrome produce presynaptic neuromuscular transmission defects, whereas compression produces axonal conduction block. Either defect may be overcome temporarily, as in myasthenia, when neuromuscular transmission is MYASTHENIA SLEEP TEST 289 facilitated by increasing the ratio of acetylcholine molecules to available receptors. Physicians are hesitant to give edrophonium to patients who are elderly or have bradycardia or arrythmia, since cholinergic actions of edrophonium produce not only nicotinic but also muscarinic effects ( 11). In addition to bradycardia, abdominal cramps, tearing, salivation, flushing, and sweating, cardiopulmonary arrest can occur. Although administration of atropine to block these effects may increase the safety and comfort of the Tensilon test, atropine itself can be dangerous, and it may also be deferred to allow signs of adequacy of Tensilon dosage. The same disadvantages are present with intramuscular Prostigmin testing, although to a lesser extent. In children, edrophonium testing is technically difficult to administer while one is reassuring and observing a child, unless there is a preplaced intravenous drip. We therefore decided to study the utility of a noninvasive test to screen for myasthenia- the " Sleep test." METHODS We studied the effects of a 3D- minute period of sleep or rest on 42 patients with Tensilon- positive myasthenia gravis and 26 patients with other causes of ptosis or ophthalmoparesis. The sleep test was performed on patients with ptosis or pupil- sparing ophthalmoparesis, after they were examined, photographed, and had ocular deviations measured. Each patient was left in a quiet, darkened room with instructions to close the eyes and try to sleep. Thirty minutes later, the physician aroused the patient ( from sleep or resting state) and immediately photographed and measured the patient's palpebral fissures and ocular motility function. Photographs and measurements were taken repeatedly over the next 5- 10 minutes. An instant camera was of value in immediate comparison of the findings before and after the periods of sleep. Video tape was also used to record results. RESULTS The Sleep test was positive in every patient who had a positive Tensilon test. In addition, ocular myasthenia gravis was diagnosed in 2 ~ atients after negative Tensilon test. In the patients who were administered the Sleep test and who had ptosis and ophthalmoparesis from causes other than myasthenia ( for example, ocular mot~ r nerve palsies or levator dehiscence, where patients do not typically report diurnal fluctuation) there was no improvement after sleep. Although we refer to the procedure as the Sleep test, it is not essential that the patient actually sleep for improvement to be noted. This is particularly true in testing for ptosis; keeping the eyes closed for a period of time is the critical factor. The degree of recovery and the duration of the recovery were similar in Sleep test and Tensilon test. However, on several occasions, the Sleep test gave a more dramatic result and the period of remission was longer lasting- several minutes instead of 3040 seconds. CASE EXAMPLES Case 1. A 49- year- old woman complained of a drooping left lid for 2 weeks. Examination revealed complete ptosis on the left despite elevation of brows. Ocular motility was intact. After 30 minutes in a quiet, dark room with eyes closed in attempt to sleep, the patient was found to have almost complete resolution of ptosis, which then FIG. 1. A: Patient in Case 1 with complete left ptosis. B: Ptosis resolves after 3D- minute Sleep test. C: Ptosis returns 5 minutes later. JClin Neuro- ilphthalmol, Vol. 11, No. 4, 1991 290 J. G. ODEL ET AL. 8 FIG. 2. A: Patient in Case 2 with right ptosis and left hypertropia. B: After 3D- minute Sleep test, palpebral fissures are both 11 mm and hypertropia resolved. gradually redeveloped over the next 5 minutes ( see Fig. 1). The suggested diagnosis of ocular myasthenia gravis was confirmed by a Tensilon test at a later date. Case 2. A 48- year- old man with diabetes and colitis complained of blurred vision, especially at near and in downgaze. His ophthalmologist suggested a diagnosis of diabetic cranial neuropathy and referred him for neuro- ophthalmic examination. He was found to have palpebral fissures of 8 mm 00 and 10 mm as and a left hypertropia of lO PO in primary position, increasing in downgaze, left gaze, and left head tilt to 14 PD. There was no vertical deviation in right gaze. Myasthenia was suspected, not only because of ptosis, but also because of a vertical deviation that did not fit a neurogenic pattern. The patient reclined in the examining chair, fell asleep, and was allowed to remain sleeping for 30 minutes. He was then awakened, but told to keep his eyes closed until measurements were about to be taken. Immediately upon eye opening, the palpebral fissures were both 11 mm ( Fig. 2). The patient commented that he had no blur on downgaze and reading was comfortable, without diplopia. Measurements taken in primary position using Maddox rod and prisms revealed only 1 PO left hypertropia. Three minutes after eye opening, the patient commented that hi~ vision was beginning to blur and double. Left hypertropia of 4 PO was measured in primary position at that time. At the end of 5 minutes, his palpebral fissures were again 8 mm 00 and 10 mm as. The previous degree of left hypertropia, 9- 10 PO, was found again. A Tensilon test done a month later was positive. Case 3. A lO- year- old girl presented with bilateral ptosis and ophthalmoparesis, with flat facial expression. The patient had a marked restriction of ocular movement in all directions. After measurements and photographs were taken in primary and cardinal positions of gaze, the room was darkened and the patient was encouraged to sleep. Thirty minutes later, she was awakened and showed striking resolution of both ptosis and ophthalmoparesis in comparison to photographs and measurements made prior to sleep ( Figs. 3 and 4). A Prostigmin test later confirmed the diagnosis of myasthenia gravis. Case 4. A 48- year- old man presented with left ptosis and vertical diplopia, with limited elevation and depression of the left eye, in the pattern of a left 3rd nerve paresis. Computerized tomography of the head was normal, and his diplopia resolved. He enjoyed single vision for 1 month, and then A FIG. 3. A: Ct? ild in C~ 5e 3 - A'rur dght ptosis, dMplM 1} t" Ow ellwatiol' 1. B: Ptosis resolves and brows relax after 3D- minute Sleep test. 1Clin Neuro- ophtludmol, Vol. 11, No. 4, 1991 MYASTHENIA SLEEP TEST 291 A B FIG. 4. A: Child in Case 3 has right gaze deficit. B: Right gaze improves after sleep. returned with left ptosis and vertical diplopia in the pattern of a right 4th nerve paresis. A Tensilon test performed at that time produced complete resolution of the ptosis and of the vertical deviation. The patient declined systemic treatment and was given a vertical prism, which he used for 2 weeks and then discarded. He had single vision for 3 months and then returned with a bilateral ptosis and vertical diplopia, now in the pattern of a left 4th nerve paresis. This time, the vertical deviation had persisted for several weeks before he sought consultation. A Sleep test was undertaken to confirm the diagnosis. Prior to sleep, the palpebral fissures were 10 mm 00 and 8 mm as ( Fig. SA), and there was 8- 10 00 left hypertropia in primary position ( Fig. 6A). The patient was encouraged to sleep for 30 minutes. Upon awakening, he was found to have ptosis resolved, with palpebral fissures of 11 mm au ( Fig. 5B). There was only trace left hypertropia of 0- 1 PO in primary position and no subjective diplopia ( Fig. 6B). Between 3- 5 minutes after awakening, the ptosis and left hypertropia gradually recurred. DISCUSSION We have presented in detail 4 of our many cases in which the Sleep test was used to diagnosis my-asthenia gravis and for which there was subsequent confirmation with a positive Tensilon test. We believe that the sleep test is at least as specific and as sensitive as the Tensilon test, since it was positive in every case of Tensilon positivity and also positive in cases where the Tensilon test was equivocal. Although Sleep tests on patients with cranial nerve palsies from ischemia or compression have been negative so far, the Sleep test, like the Tensilon test, might be expected to produce falsepositives in the future. We believe the mechanism of action of the Sleep test is analogous to that of the Tensilon test. Edrophonium ( Tensilon) increases the likelihood of acetylcholine- receptor interaction by preventing the destruction of acetylcholine, whereas sleep increases the chances of acetylcholine- receptor interaction by transiently making more receptors available. The transient recovery of function after a 30minute Sleep test appears to decay almost at the same rate that response to edrophonium does, although perhaps lasting slightly longer- that is, for a period of 2- 5 minutes. Capturing the improvement by photography allows the transient recovery to be documented. Thus, the Sleep test provides an absolutely safe alternative to the Tensilon test, producing improvement in ptosis and ophthalmoparesis similar in both magnitude and time A 8 _. FIG. 5. A: Patient in Case 4 with bilateral ptosis. B: Ptosis resolves after 30- minute Sleep test. JClin Neuro- ophthalmol, Vol. 11, No. 4, 1991 292 A J. G. GOH ET AL. FIG. 6. A: Patient in Case 4 with 8 PD left hypertropia measured on prism bar. B: Left hypertropia resolves to 0- 1 PD after 30 minutes of sleep. B course. A Sleep test can be used for confirmation of myasthenia gravis at the time of examination in cases where it is preferred that the Tensilon test be deferred for any reason. Acknowledgment: The authors would like to thank Drs. Ann Ziffer and Stephen Berger for assisting with our early sleep tests, and Ms. Deborah Siegel for her assistance in preparing the manuscript. REFERENCES 1. Lindstrom, JM, Seybold, ME, Lennon, VA, Wittingham, S, et al. Antibody to acetylcholine receptor in myasthenia gravis: prevalence, clinical correlates and diagnostic value. Neurology 1976; 26: 1054- 59. 2. Cogan, DG. Myasthenia gravis: a review of the disease and description of lid twitch as a characteristic sign. Arch Ophthalmol 1965; 74: 217- 21. J elin Neuro- ophtlullmol, Vell. 11, No. ;!, " 992 3. Osher, RH, Griggs, RC. Orbicularis fatigue: the " peek" sign of myasthenia gravis. Arch OphthalmoI1979; 97: 677- 9. 4. Cogan, DG, Yee, RD, Gittinger, J. Rapid eye movements in myasthenia gravis. 1. Clinical observations. Arch Ophtha/ mol 1976; 94: 1083- 85. 5. Finelli, PF, Hoyt, WF. Myasthenic abduction nystagmus in a patient with hyperthyroidism. Neurology 1976; 26: 289-- 90. 6. 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