Journal of Neuro-Ophthalmology, September 2001, Volume 21, Issue 3

Evaluation of Transdermal Scopolamine as Treatment for Acquired Nystagmus

We conducted an unmasked evaluation of transdermal scopolamine in seven patients with acquired nystagmus for whom other treatments had been unsatisfactory. We measured eye speed and visual acuity before and several hours after starting treatment. Median eye speed decreased slightly in three patients but increased in two; no change in visual acuity occurred in any patient. One patient was unable to tolerate the side effects of scopolamine after two hours, but the others continued the scopolamine treatment for 48 hours; only one reported minor improvement. We conclude that transdermal scopolamine is not likely to be an effective treatment of acquired nystagmus. Patients should be monitored during the first few hours of treatment to determine whether vision is improved or made worse and whether side effects occur.

Journal of Neuro- Ophthalmology 21( 3): 188- 192, 2001. • 2001 Lippincott Williams & Wilkins, Inc., Philadelphia Original Contribution Evaluation of Transdermal Scopolamine as Treatment for Acquired Nystagmus Jae- Il Kim, MD, PhD, Lea Averbuch- Heller, MD, and R. J. Leigh, MD We conducted an unmasked evaluation of transdermal scopol­amine in seven patients with acquired nystagmus for whom other treatments had been unsatisfactory. We measured eye speed and visual acuity before and several hours after starting treatment. Median eye speed decreased slightly in three patients but increased in two; no change in visual acuity occurred in any patient. One patient was unable to tolerate the side effects of scopolamine after two hours, but the others continued the sco­polamine treatment for 48 hours; only one reported minor im­provement. We conclude that transdermal scopolamine is not likely to be an effective treatment of acquired nystagmus. Pa­tients should be monitored during the first few hours of treat­ment to determine whether vision is improved or made worse and whether side effects occur. Key Words: Nystagmus-movements. - Scopolamine- Gabapentin- Eye A prerequisite for clear vision is that images of the world be held steadily on the retina. Acquired forms of nystagmus cause excessive motion of retinal images, which often degrades vision and causes oscillopsia- illusory motion of the seen world ( 1). At present, several drug treatments may alleviate specific types of nystag­mus. Thus, baclofen is often effective therapy for peri- Manuscript received April 24, 2001; accepted July 16, 2001. Supported by a research fund provided by the Korea Research Foun­dation, Support for Faculty Research ( J- IK); the German- Israeli Foun­dation for Scientific Research and Development ( LA- H); NIH grant EY06717, Office of Research and Development, Medical Research Service, Department of Veterans Affairs and the Evenor Armington Fund ( RJL). From the Department of Neurology, Veterans Affairs Medical Cen­ter and University Hospitals; and Case Western Reserve University, Cleveland, Ohio. Dr. Kim is currently at the Department of Neurology, Dankook University Hospital, Cheonan, Korea. At the time of her death ( 26 September 2000), Dr. Averbuch- Heller was a member of the Depart­ment of Neurology, Rabin Medical Center, Tel Aviv, Israel. Address correspondence and reprint requests to R. John Leigh, MD, Department of Neurology, University Hospitals, 11100 Euclid Avenue, Cleveland, OH 44106- 5040. E- mail: rjl4@ po. cwru. edu odic alternating nystagmus ( 2) and acetazolamide sup­presses the nystagmus associated with familial episodic vertigo and ataxia type 2 ( 3). Patients with acquired pen-dular nystagmus, in association with multiple sclerosis or as a component of oculopalatal tremor, may benefit from either gabapentin ( 4), or memantine ( 5). Some patients with upbeat or downbeat nystagmus benefit from baclo­fen ( 6) or clonazepam ( 7). However, not all patients are helped or able to tolerate these agents. For example, a side effect of gabapentin is that it may make ataxia worse. Thus, there is a need to identify and evaluate new potential treatments for nystagmus and its visual conse­quences ( 8). Basic studies using the technique of pharmacologic inactivation have presented evidence that the neurotrans­mitters gamma- aminobutyric acid ( GABA) and glutamate play an important role in the normal mecha­nism by which gaze is held steady during visual fixation ( 9,10), and which depends on structures in the rostral medulla ( nucleus prepositus hypoglossi, medial vestibu­lar nucleus), and their cerebellar connections. In addi­tion, both muscarinic and nicotinic receptors have been demonstrated in the medial vestibular nucleus ( 11). Pre­vious trials of drugs with cholinergic effects in patients with acquired nystagmus produced mixed results. A double- blind evaluation of trihexyphenidyl showed little benefit and concluded that the side effects outweighed the benefits of the drug in most patients ( 12). However, intravenous scopolamine ( hyoscine) has been reported to suppress both pendular nystagmus and downbeat nystag­mus ( 13,14). Scopolamine can also be administered transdermally and has been reported to help occasional patients with pendular nystagmus associated with mul­tiple sclerosis ( 5). We studied seven patients with various forms of acquired nystagmus, making precise measure­ments of the oscillations before and during scopolamine therapy. Our goal was to determine whether transdermal scopolamine improved vision and suppressed nystagmus in this group of patients for whom other treatments had proved unsatisfactory. 188 TREATMENT OF NYSTAGMUS 189 TABLE 1. Summary of clinical findings in patients studied No./ age/ gender/ diagnosis/ duration* Visual acuity optic fundif Drug Nystagmus features^ Effects of other treatments P1/ 37/ F/ MS/ 11 P2/ 37/ M/ OPT/ 2 P3/ 47/ F/ MS/ 3 P4/ 49/ F/ RML/ 9 P5/ 41/ M/ Chiari/ 4 P6/ 55/ M/ OPT/ 4 P7/ 42/ F/ MS/ 11 R: 0.29; L: 0.01; bilateral OP R > L R: 0.4; L: 0.8; normal R: 0.67; L: 0.9; normal R: 0.8; L: 0.8; normal R: 1.0; L: 1.0; normal R: 0.5; L: 0.67; normal R: 0.1; L: 0.29; bilateral OP R > L Alprazolam Verapamil Lorazepam Amitriptyline Tranyl- cypromine None Fluoxetine 4.5 Hz pendular; right- and CW- beating; H > V > T; R = L 2 Hz pendular; V > H; R > L Upbeat with divergent horizontal component Torsional, CW- beating, with downbeat component, R > L Divergent- beating horizontal 1.5 Hz pendular, V > T> H; R> L 3.0 Hz pendular, R > L; H> V Gabapentin: reduced nystagmus, worsened ataxia; Trihexyphenidyl: minor effect Gabapentin; reduced nystagmus, worsened ataxia Gabapentin, trihexyphenidyl, clonazepam: minor effects Gabapentin, clonazepam, amantidine, lamotrigine, riluzol, baclofen: minor effects Gabapentin, clonazepam, balcofen: minor effects Gabapentin, clonazepam: minor effects Gabapentin, clonazepam: minor effects * Age and duration are in years. f Visual acuity is expressed as decimal values. Bilateral indicates bilateral evidence of demyelination and worst affected eye ( e. g., R > L: right worse than left), as judged by optic disc pallor ( OP), color vision, or relative afferent pupillary responses to light. % Predominant frequency of pendular components, presence of any jerk or other superimposed waveform ( CW, clockwise); relative amplitude of horizontal ( H), vertical ( V), and torsional ( T) components. Chiari, Chiari malformation; MS, multiple sclerosis; OPT, oculopalatal tremor after brainstem stroke; RML, right medullary lesion, undetermined ( possible arteriovenous malformation). METHODS We studied seven patients with acquired nystagmus, all of whom complained of oscillopsia that interfered with daily activities such as reading. The features of their illness, characteristics of their nystagmus, current medi­cations, and prior treatments for nystagmus are summa­rized in Table 1. All patients had been tried on a variety of other drugs, including gabapentin, but either these drugs were ineffective or produced undesirable side ef­fects. None had glaucoma or general medical disorders that would be a contraindication to administering sco­polamine. All patients gave informed consent in accor­dance with our Institutional Review Board and the tenets of the Declaration of Helsinki. Before starting treatment, we performed a general neuro- ophthalmologic examination and measured eye movements using the magnetic search coil technique, as previously described ( 4). In Patient 2, who had filamen­tary keratitis, we used an infrared video eye move­ment monitor. We were able to measure movements of both eyes before and during scopolamine in Patients 1 and 2 , and the eye with the greater nystagmus in the other patients. Measurements of visual acuity are sum­marized in Table 1. Patients were also asked to view a light- emitting diode in a dark room to characterize their oscillopsia. We tested fixation ( small target at 1.2 or 15 cm), sac-cades, smooth pursuit, and the vestibulo- ocular reflex, as previously described ( 4). Eye position signals were dig­itized at 200 Hz and differentiated. For pendular nys­tagmus, saccades were removed interactively and the first 10 seconds of these records of nystagmus velocity ( array size, 2,000 points) were then converted to eye speed ( absolute value of velocity measurements) and the median value was computed. We also measured the predominant frequency of pendular oscillations, using a fast- Fourier transform. For jerk nystagmus waveforms, we interactively measured slow- phase velocity. We compared the eye speed of each directional component of nystagmus during similar fixation conditions from corresponding eyes before and after each treatment using the Wilcoxon signed- rank test ( because some of the data were not normal in distribution). In the case of Patient 5, who had divergent nystagmus ( convergent slow phases), we compared the eye speed during epochs when the measured convergence angle ( during far or near viewing) was similar ( 27- 31 degrees), before and during treatment. After making these baseline measurements, a 1.5- mg scopolamine patch ( Transderm Scop; Novartis, East Hanover, NJ) was applied to an area of skin behind one ear, as recommended by the manufacturer. Patients were subsequently monitored for any side effects, such as con­fusion or unsteadiness. Measurements of visual function and eye movements were repeated after approximately four hours ( range, 2- 5.5). We repeated measurements in Patient 1 after only two hours because she reported sys­temic effects and wanted to end the session. All except Patient 1 continued to wear the patch for another two days and then reported whether there had been any sub­jective improvement of their symptoms. RESULTS No patient showed any change- improvement or de­terioration- of visual acuity after wearing the scopol­amine treatment for approximately four hours. Patients 1, 2, and 6 reported modest improvement of their oscillop­sia. Comparisons of the effects of scopolamine on each J Neuro- Ophthalmol, Vol. 21, No. 3, 2001 190 J. KIM ETAL. directional component of nystagmus in each patient are summarized in Fig. 1. Eye speed showed small but sig­nificant ( p < 0.01) decreases in Patients 1, 4, and 6. Patients 5 and 7 both showed significant ( p < 0.01) in­creases of eye speed. For Patient 5, the increase in his divergent- beating nystagmus mainly occurred during near viewing. In Patient 7, the increase in median hori­zontal and vertical eye speed was greater than 70%; rep­resentative records are shown in Fig. 2. No changes in the predominant frequency of any of the cases of pen-dular nystagmus were noted. Side effects from the scopolamine were noted by four patients at the time of the second recording, including mild dizziness ( Patient 2), blurring of vision ( Patient 3), change in balance ( Patient 6), and a feeling " similar to having a glass of wine" ( Patient 1). Patient 1 preferred not to continue wearing the scopolamine patch. Of the patients who continued the scopolamine treatment for another 48 hours, only Patient 6 reported modest benefits consisting of reduced oscillopsia and improved balance for the first few weeks. However, after wearing a sco­polamine patch each weekend for approximately three months, the effect decreased, and he has stopped using it. DISCUSSION Transdermal scopolamine had inconsistent effects on the nystagmus in our patients, including modest de­creases or increases of eye speed. Modest decreases are consistent with a previous study of pendular nystagmus in multiple sclerosis ( 5) but contrast with the substantial effects that intravenous scopolamine is reported to have in suppressing acquired pendular or downbeat nystag­mus ( 13,14). The increase in eye speed was unexpected and not clearly related to the underlying disorder. Thus, Patients 1 and 7, both of whom had acquired pen­dular nystagmus in association with multiple sclerosis, showed a decrease of approximately 15% and increase of approximately 70% in eye speed, respectively. Nys­tagmus also increased in Patient 5 during convergence ( increased speed of converging slow phases) when he was taking scopolamine. How can these disparate results be explained? Scopolamine is a nonspecific antagonist of muscarinic receptors in the central nervous system ( 15). Acetylcho­line plays only an efferent role in the peripheral vestib­ular system ( 16), but both muscarinic and nicotinic re­ceptors have been demonstrated in the medial vestibular nucleus ( 11), which contributes to the gaze- holding net­working ( 9,10). Thus, it seems possible that scopolamine might be acting at the level of the gaze- holding mecha­nism ( brainstem neural integrator), for which the medial vestibular nucleus is an important component. Microin­jection of the GABA- ergic agents muscimol and bicu-culline may produce either a deficient or unstable inte­gration of ocular motor signals ( 9,10), depending on which part of the network of neurons in the rostral me­dulla is inactivated. In analogy, therefore, it seems pos­sible that scopolamine by transdermal administration might produce different effects, depending on absorption and pathology affecting the gaze- holding mechanism. Much larger doses of scopolamine ( owing to intrave- Summary of effects of scopolamine on nyslagmus • o • • n A T V T + o • ~ D a PI Horizontal * PI Vertical * PI Tors km Ed * P2 Horizontal P2 Vertical P3 Vertical P4 Horizontal* P4Vericar P4 Torskmal * P5 Venjence ad far P5 Veigence ai near4' P6 Horizontal* P6 Vertical * P?" Horizontal* P7 Vertical* : significantly decreased after scopolamine ( p < OJQ1) >- signScanrly increased after scopolamine ( p < 0- Q1) Eye Speed Before Treatment ( deg/ sec) FIG. 1. Comparison of median eye speed of nystagmus before during treatment with scopolamine. Each data point compares corre­sponding measurements for each plane of movement OU for each patient ( P). Data from both eyes of Patients 1 and 2 are shown. The solid line at 45 degrees represents no change between pretreatment and treatment values. Data points below the line represent reduction of nystagmus with treatment and those above represent increase with treatment. / Neuro- Ophthalmol, Vol. 21, No. 3, 2001 TREATMENT OF NYSTAGMUS 191 BEFORE SCOPOLAMINE DL RING SrOPOLAMI N E 3 - S =-- •--. z=. 5. - L : 5 : s : s 1 : Horizontal Vertical HJ - 05 - 1.0 Horizontal cm ;? O. J 06 Tire ( sec) : = : : : • : ; : M OB Time [ sec) ? E 1 : B C^ S D " L ™ - 0T5 - 0T5 • 0.75 - 0.50 - 3 3 P'X : • : = 050 0.75 41.75 - O. S0 - OM OJU ; : : : 5t • 0.75 Horizontal Position ( tfeg) Horizjonlal Poston ( deg) FIG. 2. Representative data from Patient 7 comparing her nystagmus before and during administration of scopolamine. A, B: One- second epochs as time plots; horizontal and vertical records have been offset for convenience of display. C, D: Corresponding data sets are plotted as " scan paths" to allow comparison of the amplitude of the oscillations. Positive deflections indicate rightward and upward eye rotations. nously administration) are effective in suppressing nys­tagmus ( 13,14), but side effects make this mode of treat­ment unfeasible. Indeed, scopolamine is known to produce a variety of side effects on the nervous system, especially confusion in patients with neurologic disease ( 17). In general, our patients tolerated scopolamine well apart from Patient 1, who after two hours, found the effects on her sensorium undesirable. Intravenous scopolamine is also reported to suppress downbeat nystagmus ( 14); conversely, intravenous ad­ministration of the acetylcholinesterase inhibitor physo-stigmine worsens such nystagmus ( 6). None our patients had downbeat nystagmus, but it was recently demon­strated that transdermal scopolamine has little effect on the " chin- beating" nystagmus that normal subjects de­velop when they are placed in an upside- down position in darkness ( 18). Based on the results from our Patient 5, it seems possible that scopolamine may have effects on vergence mechanisms ( increased gain), but more studies are required to confirm this. In conclusion, scopolamine by the transdermal route is not likely to be an effective treatment, including patients who are unresponsive to or unable to tolerate gabapentin. Although we only compared effects of scopolamine on eye speed during one session, none of our patients who wore the scopolamine patch for several days thought that J Neuro- Ophthalmol, Vol. 21, No. 3, 2001 192 J. KIM ETAL. it was a worthwhile treatment. Patients with neurologic disease who desire a treatment trial should be monitored during the first few hours that they take the medication to check whether the drug makes their nystagmus better or worse or causes undesirable side effects. Acknowledgment: We are grateful to Drs. D. Mann, R. Tomsak, M. Devereaux, J. Johnston, T. Hain, A. Epstein, and P. Kinkel for referring patients. 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