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Show Journal of Nemo- Ophthalmology 18( 3): 182- 186, 1998. & 1998 Lippincoll Williams & Wilkins, Philadelphia Autonomic Nervous System Involvement in Behcet's Disease A Pupillometric Study Hiiseyin Bayramlar, M. D., Ibrahim F. Hepsen, M. D., Murat Uguralp, M. D., Ayhan Boliik, M. D., and Cemal Ozcan, M. D.. The aim of this study was to elucidate whether autonomic nervous system dysfunction exists in patients with Behcet's disease by pupillometric tests. Thirty- one patients with Behcet's disease with a mean age of 41.3 years ( range 21- 64) and 41 control subjects with a mean age of 39.5 years ( range 18- 66) were selected for the study. To test the autonomic nervous system, four pupillometric techniques were used: pupil cycle time ( PCT), dark- adapted pupil size ( DAPS), 0.05% pilocarpine drop test, and 1% phenylephrine drop test. In all four tests, there were significant differences between the patients and controls. Mean PCTs were 1,156 ms ( range 856- 1,560 ms) and 919 ms ( range 650- 1,261 ms) in the patients and controls, respectively ( p < 0.0001). The mean DAPS was 0.45 ( range 0.31- 0.66) in the patients, whereas it was 0.56 ( range 0.42- 0.67) in controls ( p < 0.001). Iris sensitivity to both 0.05% pilocarpine and 1% phenylephrine showed significant differences between patients and controls, respectively ( p < 0.05, p < 0.05). Among all four tests, only 0.05% pilocarpine sensitivity was correlated with the duration of Behcet's disease ( p < 0.05). The results suggest that the autonomic nervous system innervating the iris is affected in Behcet's disease. This involvement may be due to the vasculitic nature of Behcet's disease. Key Words: Autonomic nervous function- Behcet's disease- Pupil- Pupillomelry. Behcet's disease was first described by Hulusi Behcet in 1937 as a syndrome characterized by oral and genital ulcers and hypopyon uveitis ( 1). Neurologic manifestations of the disease, which constitute minor criteria for diagnosis, are the consequences of focal areas of necrosis within neural tissue. The disease could involve cortical or subcortical areas, cranial nerves, pyramidal and extrapyramidal systems, cerebellum, medulla spinalis, and peripheric nerves ( 2,3). Neurologic signs include poliomyelitis with brain stem involvement, meningoencepha- Manuscript received February 1997; accepted November 1997. From the Departments of Ophthalmology ( H. B., i. F. H., M. U.) and Neurology ( A. B., CO.), Inonii University School of Medicine, Malatya, Turkey. Address correspondence and reprint requests to Dr. Hiiseyin Bayramlar, Inonii Universitcsi Tip Fakiiltesi, Turgut ozal Tip Merkezi, Goz Hastaliklari Anabilim Dali, Malatya, Turkey. litis with cerebrospinal fluid pleocytosis and elevated protein, cerebellar dysfunction, pyramidal and extrapyramidal disease, dementia, and confusional states ( 2). Both neurologic involvement and vasculitis are minor diagnostic criteria of Behcet's disease ( 4). Therefore, there also may be autonomic nervous dysfunction in the disease. However, attention has rarely focused on the autonomic nervous system in Behcet's disease. In this study, we determined whether autonomic nervous function was disturbed in patients with Behcet's disease via four pupillometric tests: pupil cycle time ( PCT), dark-adapted pupil size, 1% phenylephrine drop test, and 0.05% pilocarpine drop test. MATERIALS AND METHODS Subjects The study group was composed of 31 patients with Behcet's disease: 18 women and 13 men. Mean age was 41.3 ± 10.6 ( range 21- 64). The control group obtained from hospital staff was composed of 41 healthy age- and sex- matched volunteers ( 22 women, 19 men) who did not use any drug or contact lenses. They were from hospital staff, and the mean age was 39.5 ± 12.4 ( range 18- 66). The subjects we selected for inclusion in this study were those who ( a) had visual acuity better than II 1 0 and normal light reflexes, ( b) had no any history of uveitis, ( c) had no irregular pupillary margin or any signs or sequelae of anterior or posterior uveitis ( cells in anterior chamber, synechia, irideal pigment on anterior lens capsule etc.), ( d) had not used any topical drug, ( e) had no diabetes mellitus or any history of intraocular surgery or trauma, ( f) had no ocular pathology that could impair pupillary response such as glaucoma or atrophic iris, and ( g) had no any pupillary abnormality such as afferent pupil defect. The subjects received no drugs such as cholinergics, anticholinergics, sympathomimetics, antidepressants, antihystaminics, or corticosteroids 72 hours before the study. The subjects were asked to not consume excess food, drink, coffee, or tea and not smoke for 3 hours 182 AUTONOMIC NERVOUS SYSTEM INVOEVEMENT IN BEHCET'S DISEASE, l, SJ I8OO1 1600 •' 1400- p 1200 C T IOOO- 800' 600- 400'. .__ , . - N - 31 41 Behcet's Controls before and not drink alcohol for 12 hours before the study. Informed consent was obtained from each subject. Methods Pupil cycle time was measured as follows. The subjects were seated in front of the slit lamp and looked at any distant object to prevent accommodation. The slit beam of light width was focused at the pupillary margin 45 degrees obliquely from the temporal side, and the time required to see 10 pupillary cycles was determined. The procedure was repeated five times, and the time required for one complete oscillation was calculated in milliseconds ( 5). For dark- adapted pupil size and pharmacologic tests, we used a computerized \ ideo- pupillomelry technique that provided direct and continuous measurement of the pupil si/. e in darkness. A video camera ( f: 4.6- 46: objective 1: 1.8 lx) was positioned 2 cm from the eye. for each subject, the mean pupillary response of the left and right eye was used for analysis. In all eases the subject was resting, sealed, and fixating on a distant object in a dim room (~ 3 lux). The measurements were performed blindly by a single observer. No difference was observed between light and dark colored irises. Only round irises were chosen for the study. In the dark- adapted pupil size test, the pupil and iris sizes were measured in the vertical plane on the computer in a dark room, and pupillary diameter, measured as the pupil/ iris ratio, was estimated ( 6). For pharmacologic tests, ocular drug solutions were freshly prepared on each experimental day by diluting in the appropriate volume of 0.9% sterile saline. The eye drops were instilled into the conjuctival sac and subjects were asked to close their eyes for - 10 seconds. Iris cholinergic sensitivity was tested with 0.05% pilocarpine F1C1 after 30 seconds of uninterrupted darkness and 1 hour after instillation by measuring the degree of pupillary constriction ( 7). Irideal adrenergic sensitivity was tested by measuring the extent to which a pupil dilates in " bright light" I hour after instillation of two drops of I % phenylephrine ( 8). The interval between application of pilocarpine and phenylephrine was at least 48 hours. Because phenylephrine sensitivity of the pupil increases FIG. 1. Pupil cycle time ( PCT) test results are illustrated ( in milliseconds) in patients with Behcet's disease and in control subjects. Data represent the difference between the patients and controls ( p < 0.0001). by 0.23 mm per decade, the results were adjusted after three decades accordingly ( 9). Statistical Analysis Pharmacologic test results were not normally distributed according to the Kolmogorov- Smyrnov test; therefore, nonparametric statistics were used ( 10). The Mann- Whitney U test was used to compare the results of pharmacologic tests in two groups. For PCT and dark-adapted pupil size tests. Student's / lest was used. RESULTS In patients with Behcet's disease, the mean PCT ( I. 155 ± 28.3) was significantly higher than controls ( 91 9 ± I 9.5) ( p < 0.01)? The mean PCI' was also higher than the level of 600- 900 ins given as normal in the literature ( 5). Figure I illustrates the results of PCT in two groups. Mean dark- adapted pupil size was found 0.45 ± 0.09 in the patients, whereas it was 0.56 ± 0.06 in controls. The difference was significant ( p < 0.00 l). Figure 2 illustrates the results of the dark- adapted pupil size lest. When the data concerning iris sensitivity to 0.059; pilocarpine were compared, the mean sensitivity of the pupils of patients with Behcet's disease ( 0.9 ± 0.09) was significantly greater than the mean of normal controls ( 0.39 ± 0.03Mp < 0.05: Fig. 3). Analysis of iris sensitivity to l% phenylephrine also showed a significant difference between the patients ( mean 0.75 ± 0.07) and controls ( mean 0.36 ± 0.03) ( p < 0.05; Fig. 4). There was no difference in sensitivity between pupillary pairs of greater than 0.4 mm for 0.05%) pilocarpine or 0.7 mm for l% phenylephrine accepted as an abnormality of the corresponding autonomic innervation of the more sensitive pupil ( 9). The mean duration of Behcet's disease was I 1.5 ± 8 years in the patients. The duration of the disease did not correlate with PCT. dark- adapted pupil size, and I %- phenylephrine test results but did correlate with cholinergic sensitivity ( p < 0.05). There was no correlation between patients age and test results. Of 31 patients with Behcet's disease, five were diag- .1 Xairc- Ophlluihmil. Vol. IS. \,,. .<. I< W 184 H. BAYRAMLAR ET AL, FIG. 2. Dark- adapted pupil size test ( DAPS) results are illustrated in patients with Behcet's disease and control subjects ( pupil/ iris ratio). Pupillary dilatation in darkness in the patients is significantly lower than controls ( p < 0.0001). nosed as having neuro- Behcet. There was no patient with thrombosis of cavernous sinus; optic atrophy or optic neuropathy might disturb the pupillometric tests, however. DISCUSSION Behcet's disease has been studied extensively. Both vasculitis and central nervous system ( CNS) involvement are minor criteria for Behcet's diagnosis, and the disease might affect the CNS extensively ( 2- 4,11,12). So it is probable that the disease also has autonomic dysfunction. However, there are limited reports about autonomic nervous system involvement in Behcet's disease. Although it is not invariable, pupillometry is a valuable method in the examination of autonomic neuropathy because it provides information on the function of cranial autonomic pathways. During the past 10 years, there have been several reports on the use of pupillometric methods in the assessment of autonomic function ( 9,13- 21). Pupil cycle time is a well- known pupillometric test that measures the speed of neural conduction in the reflex arc. It does not distinguish well between sympathetic and parasympathetic damage, but an increase of PCT may show a probable dysfunction of the autonomic nervous system. Osipova et al. studied 262 patients with nine different somatic or neurologic diseases and concluded that PCT was a reliable test to show autonomic nervous dysfunction in various stages of both central and peripheric autonomic nervous system disorders ( 13). Using PCT, MacLean et al. also observed a subclinical autonomic involvement in patients with acquired immunodeficiency syndrome ( 14). In our study, the increased PCT is consistent with autonomic nervous dysfunction in patients with Behcet's disease. Dark- adapted pupil size also was lower in patients with Behcet's disease than in normal individuals. A small pupil size in the dark could be due to a lack of sympathetic tone in the dilator. It has been shown that the size decreased in diabetic patients and was accepted as an indicator of sympathetic dysfunction ( 15,16). In combination with PCT, dark- adapted pupil size is a reliable indicator to determine the presence of autonomic ( especially sympathetic) disease ( 5). The pharmacologic pupillometric tests also have been used successfully to investigate the autonomic nervous system in various diseases such as Horner's and Adie's syndromes ( 9,17- 19). Similar to PCT and dark- adapted pupil size tests, we found both cholinergic and adrenergic hypersensitivity in patients with Behcet's disease. This result could be interpreted as a denervation hypersensitivity. Our results showed that there was some autonomic nervous involvement in Behcet's disease. To the best of M i o FIG. 3. Pupillary constriction caused by 0.05% pilocarpine is shown ( in millimeters) in patients with Behcet's disease and control subjects. Constriction is significantly higher in the patients than in the controls ( p < 0.05). Behcet's ./ Neum- Opliilialiiml. Vol. 18, No. 3, 1998 AUTONOMIC NERVOUS SYSTEM INVOLVEMENT IN BEHCET'S DISEASE 1X5 2.0 M 1.5 y d m 0,0 -. 51 Behcet's 41 Controls FIG. 4. Pupillary dilatation caused by 1% phenylephrine is shown ( in millimeters) in patients with Behcet's disease and control subjects. Dilatation is significantly higher in the patients than in the controls ( p < 0.05). our knowledge, there are only two reports about autonomic nervous involvement in Behcet's disease. In 1975, using methacholine, Saito et al. found that the frequency of a sympathetic hyporeaclor pupil was much higher in patients with Behcet's disease than it was normal controls and was higher in the exacerbation than in the remission ( 20). They concluded that the sympathetic hy-pofunclion probably contributed to the exacerbation of the disease. In 1992, Shirakawa et al. observed involvement of the cholinergic nerve to the iris sphincter muscle in Behcet's disease ( 21). Our results arc comparable with these two studies. Our study showed that both the sympathetic and parasympathetic autonomic nervous systems were affected in patients with Behcet's disease. Among all the tests we used, only pilocarpine supersensitivity correlated with the duration of the Behcet's disease. Because of this, we can conclude that the disease becomes more dominant on the cholinergic system cumulatively as the duration of the disease increases. This result is not consistent with the results of Saito et al. ( 20). They noted a mild slope to parasympathetic leading in their patients with Behcet's disease. Further studies are needed to corroborate the various findings. Using only pilocarpine and phenylephrine tests, we cannot predict pre- or postganglionic involvement ( 19). There was no significant difference between the two pupils of the subjects. We also found no distinct focal lesion in the central or peripheral nervous system via computerized tomography or magnetic resonance imaging. Thus, we can conclude that focal lesions do not play a role in the pathogenesis of abnormal test results. Rather, a generalized autonomic hypofunction is more likely. The essential lesion in Behcet's disease is a focus of chronic inflammation, typically in the vicinity of a small vessel ( II). Lesions in the CNS resemble those in other organ systems. Characteristically there are multiple small foci of softening that correspond to myelin loss. However, the lesions are not fundamentally demyelinative and more closely resemble minute ischemic foci ( 22). Thereore, we concluded that the vasculitic nature of the disease may contribute to autonomic neuropathology. Because of some overlap of the test results between the patient and control groups, these four pupillometric tests may not be able to sufficiently diagnose autonomic neuropathy in an individual patient. Rather, this study may indicate that as a group the patients with Behcet's disease show some evidence of autonomic neuropathy based on pupil function. 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