J7ournal ofNeurology, Neurosurgery, and Psychiatry 1993;56:1271-1275 1271 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.12.1271 on 1 December 1993. Downloaded from Effect of vigabatrin on sedation and cognitive function in patients with refractory

R A Gillham, J Blacklaw, P J W McKee, M J Brodie

Abstract Vigabatrin was the first 'designer' drug to be Twenty-four patients with refractory used for the treatment of epilepsy. It is an epilepsy on one or more antiepileptic irreversible suicide inhibitor of y-aminobu- drugs were given additional vigabatrin tyric acid (GABA) transaminase, the (1 g twice daily for six weeks, followed by responsible for the breakdown of the 1-5 g twice daily for a further six weeks) inhibitory neurotransmitter GABA.1 Thus, it and matched placebo in a double blind, increases the concentration of GABA in the randomised, crossover study. A battery brain. Efficacy trials have been largely con- of neuropsychological tests was adminis- fined to patients with refractory epilepsy tered at baseline and at weeks two, six already receiving other antiepileptic drugs. and 12 of both treatment periods. No sig- Overall, a 50% reduction in frequency of the nificant differences were found between has been reported in around 50% of vigabatrin and placebo at any time point treated patients.24 The benefits were particu- Department of for any of the objective tests of cognitive larly apparent in patients with partial seizures Clinical Psychology, Institute of function. Patients, however, reported a (unpublished observations).5 Good, long term Neurological Sciences, greater degree of sedation after two and efficacy has been reported with the drug over Southern General six weeks on vigabatrin than during the a number of years.f5 Hospital and Epilepsy Research Unit, equivalent placebo phase (p < 0 01), The safety of vigabatrin has come under University although no such difference was appar- particular scrutiny because it produced Department of ent at 12 weeks. Follow up over a mean of intramyelinic oedema in the dog and rat,l617 Medicine and Therapeutics, 14-75 months in 12 responders, who con- although there is no evidence in support of a Western Infirmary, tinued on vigabatrin, revealed a signifi- similar lesion in man.4 '>'9 Vigabatrin is Glasgow, UK cant improvement (all p < 001) on each known to be sedative in some patients, partic- R A Gillham J Blacklaw of three composite scales (three psy- ularly during early treatment.4 Few objective P J W McKee chomotor tests, four memory tests, three data are available on cognitive function, M J Brodie self rating scales) compared with their although one non-randomised, non-blinded Correspondence to: scores during the double blind trial. study with a parallel control group did not Dr M J Brodie, Epilepsy Research Unit, Department Vigabatrin did not cause cognitive support a major deleterious effect with the of Medicine and impairment either acutely or in the long drug.20 In this study, our standard battery of Therapeutics, Western Infirmary, Glasgow GIl term. Phased introduction, however, cognitive function tests21-23 was administered 6NT, United Kingdom seems a prudent policy to allow tolerance to patients with refractory epilepsy who were Received 31 July 1992 and to early subjective sedation. taking part in an add-on, dose ranging, in revised form 15 January 1993. placebo controlled, crossover trial (unpub- Accepted 1 February 1993 (7 Neurol Neurosurg Psychiatry 1993;56: 1271-1275) lished observations). Measures were made in http://jnnp.bmj.com/ the short term and after prolonged adminis- Table 1 Clinical characteristics of24 patients with refractory epilepsy tration of vigabatrin in responders. Age Duration Patient Sex (years) type (years) Treatment 1 F 24 GTCS 16 CBZ 2 F 53 CPS 43 CBZ Methods 3 M 27 CPS/GTCS 8 CBZ/VPA PATENTS 4 F 38 CPS/GTCS 24 CBZ on September 24, 2021 by guest. Protected copyright. 5 F 24 CPS/GTCS 24 CBZ/PRIM Twenty-four patients (16 women, 8 men; 6 F 17 CPS/GTCS 6 CBZ 7 F 31 CPS 30 CBZ/PRIM aged 17-53 years) with refractory epilepsy 8 F 45 CPS 42 PHT/PB entered the trial (table 1). Fourteen suffered 9 F 46 CPS/GTCS 22 VPA/PB 10 F 27 CPS 20 PHT complex partial seizures with secondary gen- 11 F 36 CPS/GTCS 33 CBZ/VPA eralisation (PSG), eight had complex partial 12 F 34 CPS/GTCS 23 CBZ 13 F 20 CPS/GTCS 9 CBZ/VPA seizures (CPS) alone and two reported only 14 F 32 CPS 30 PHT/PRIM generalised tonic-clonic seizures (GTCS). 15 M 49 CPS 27 CBZ/PRIM 16 M 22 GTCS 20 CBZ/PHT Each averaged at least one seizure per week 17 M 43 CPS/GTCS 8 CBZ/PRIM during the three months before recruitment. 18 M 26 CPS 19 CBZ Eleven patients were being treated with anti- 19 F 24 CPS/GTCS 4 CBZ convulsant monotherapy (nine took carba- 20 M* 26 CPS/GTCS 6 CBZ 21 M* 35 CPS/GTCS 9 CBZ/PHT mazepine, one , and one sodium ) and the other 13 took two drugs in 22 Mt 44 CPS/GTCS 9 CBZ/PRIM six 23 Ft 27 CPS 7 VPA combination (10 had , 24 Ft 39 CPS/GTCS 36 CBZ , four sodium valproate, four two All Patients excluded from seizure analysis. phenytoin, and ). gave tPatients who failed to complete the study. written consent to their participation in the GTCS = generalised tonic-clonic seizures; CPS = complex partial seizures; CBZ = carba- which had the approval of the local mazepine; VPA = sodium valproate; PHT = phenytoin, PRIM = primidone; PB= pheno- trial, barbital. ethical committee. 1272 Gillham, Blacklaw, McKee, Brodie J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.12.1271 on 1 December 1993. Downloaded from PROTOCOL level and the task was discontinued when The study was a double blind, randomised, both were failed. crossover, add-on trial of two consecutive The backward digit span measured the doses of vigabatrin and matched placebo. maximum number of digits the patient could After an initial four week run-in, two 12-week recall in reverse order immediately following treatment periods (phase one: six weeks of oral presentation. He or she was allowed two 1 g vigabatrin/matched placebo twice daily; trials at each level and, again, the task was phase two: six weeks of 1-5 g vigabatrin/ discontinued when both were failed. matched placebo twice daily) were separated The paired associate learning test mea- by a four-week washout. Neuropsychological sured the number of trials to reach the crite- testing was performed immediately before rion of three correct answers, when learning each schedule and after two, six and 12 weeks three, unrelated word pairs. of treatment. Patients were given individual In the Rivermead behavioural memory test, appointment times, which were kept constant the 'screen score' of this standardised psycho- throughout the trial. Patients were asked to metric battery was used. take their medication at the same times each day. Seizures were recorded using standard Selfreporting scales description and frequency charts with which The general health questionnaire was the the patients were familiar. At each hospital standard 28 question version, which gave a visit, compliance with medication was 'cut off' point for psychiatric cases. checked by a tablet count. The sedation score assessed the patient's rating of level of alertness using a 10 cm line TEST BAT-tERY where zero was 'wide awake' and 10 'nearly The test battery consisted of measures of ver- asleep'. bal and performance IQ, psychomotor func- The patient was also presented with a list tion, visual attention, memory, and subjective of 10 commonly reported antiepileptic drug side effect rating scales as below: side effects-for example, dizziness, , and nausea. He or she rated each Intelligence quotients one on a 10 cm line with 'don't have it' at The verbal IQ was calculated from the score one end and 'very severe' at the other. The on the National Adult Reading Test. The distances from the left hand side of the scales performance IQ was calculated by a standard were measured in centimetres and summated method from the score on Raven's standard to produce a subjective side effect score. progressive matrices. DRUG ASSAYS Psychomotor tests Blood was withdrawn at each review appoint- The decision time was the time in milli- ment for measurement of antiepileptic drug seconds to respond to a light coming on by concentrations. Samples were centrifuged removing the finger from the base button in a immediately and plasma stored at -20° for choice reaction time task. The mean of 30 batch analysis. Vigabatrin was extracted into trials was recorded. The movement time was ethyl acetate from plasma heated with dansyl the time in milliseconds to move the finger chloride to form a fluorescent derivative at

from the base button to extinguish a light. high pH and quantified using high pressure http://jnnp.bmj.com/ The mean of 30 trials was recorded. liquid chromatography with phenyl-GABA as In another test, an array of small rectangles the internal standard. The interassay coeffi- was displayed on a visual display unit. After a cient of variation over the range 1-100 mg/l brief period an extra rectangle was added to was 5% and the lower limit of detection was the array. The patient was required to indi- 0 1 mg/l. Concentrations of other anti- cate which it was. The 'threshold' was the epileptic drugs were measured by enzyme minimum time gap in frame units between immunoassay (Emit, Syva, Palo Alto, United the presentation of the array and the addi- States). on September 24, 2021 by guest. Protected copyright. tional stimulus that the patient required to perceive that an extra rectangle had been STATISTICS added. Analysis of variance was employed to explore Finally, the tracking task measured the the possibility of a practice effect for all tests. amount of time the patient was able to keep Student's t testing for paired values was used on the track of a moving target presented on to compare placebo and treatment condition a visual display unit using a joystick. scores on the psychomotor and memory tests, Decision and movement time tests were because these have been standardised and carried out using the choice reaction time scores in sample populations are normally facility of the Leeds psychomotor tester. distributed. Scores on the three 'self report' Threshold detection and the tracking task scales were compared with the Wilcoxon were administered using an Apple IIe micro- matched pairs test. Correlations (Spearman) computer. were performed to test the hypothesis that sedation influenced test performances. Memory tests Comparisons of seizure frequencies between The forward digit span test measured the vigabatrin and placebo phases were made maximum number of digits the patient could using the Wilcoxon rank test for matched recall immediately following oral presenta- pairs. Frequencies of seizures during follow tion. He or she was allowed two trials at each up were compared using Friedman's test. Effect ofvigabatrin in patients with refractory epilepsy11273 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.12.1271 on 1 December 1993. Downloaded from The composite scores used in a long term (r = 0-72, p < 0-01) doses, suggesting good part of the study are Z-scores and may be compliance with treatment. This was sup- considered to be normally distributed. These ported by the tablet counts. Vigabatrin did were examined by repeated measures analysis not alter total or free concentrations of any of variance. Paired t tests were then used to concomitant antiepileptic drug (unpublished identify the point where significant changes observations). There were no significant dif- had occurred. Significance levels were set ferences in vigabatrin or other antiepileptic conservatively at 1%. drug concentrations between responders ( > 25% reduction in frequency) and non- responders following treatment with both Results doses. PATIENTS Twenty-one patients completed the trial; 11 NEUROPSYCHOLOGICAL ASSESSMENT (group 1) took vigabatrin during the first Neuropsychological testing and data analysis phase, and 10 (group 2) took the placebo from the short term study were performed first. One patient discontinued treatment blind to treatment. This was not possible dur- because she thought that she was pregnant, ing long term follow up as only patients another because he felt no benefit after two responding to vigabatrin were included. weeks, and a third following a psychotic episode.24 Between patient analysis There were no significant differences between SEIZURE CONTROL groups 1 and 2 in terms of age, duration of There was a significant overall reduction epilepsy or seizure frequency at base-line. No (median) in partial seizures over the treat- differences between the two groups were ment period with 2 g (placebo 22, vigabatrin found for any of the neuropsychological mea- 13, p < 0-05, 95% CI -0-5 to -16-5) but not sures at base line, or at any of the subsequent with 3 g (placebo 28, vigabatrin 22, not sig- testing points. There was an improvement in nificant, 95% CI-18 to + 11) vigabatrin performance on the tracking task over the daily compared with placebo. Eight out of 19 first three testings regardless of treatment (p patients who documented their episodes satis- < 0.005). This test was, therefore, excluded factorily, reported a greater than 50% from further analysis. No other test revealed a improvement in seizure frequency. These significant practice effect. results will be discussed in detail elsewhere. Within patient analysis DRUG CONCENTRATIONS Scores on vigabatrin were compared with There was large interindividual variation in those on placebo. Patients rated their seda- serum vigabatrin levels. Mean (SD) concen- tion level significantly higher (p < 0-01) when trations of the drug at the same time after they had been taking vigabatrin for two and dosing were higher following six weeks' treat- six weeks compared with placebo. This effect ment with 3 g (15-5 (8 9) mg/l) than with 2 g was not sustained at 12 weeks (fig). There (13-9 (11 2 mg/l) daily. Significant negative were no significant differences between the correlations were obtained between vigabatrin treatments for any other test in the battery

concentrations and times after dosing with (data available from the authors). http://jnnp.bmj.com/ both the 2 g (r= 0-75, p < 0-01) and 3 g Correlations with sedation score During treatment with vigabatrin, the seda- tion scores correlated significantly with side 10. effect scoring during the sixth and 12th week and with backward digit span during the 12th 0 Placebo week (all p < 0 05). Sedation scoring corre- lated significantly during the placebo phase on September 24, 2021 by guest. Protected copyright. E 8 * Vigabatrin 0 with the side effect score during the second, sixth and 12th weeks, with decision time and CD general health questionnaire in the second 0L. 0 6. week and with backward digit span in the CO) 12th week (all p < 0 05). cn p < 0.01 0 NS p <0.01 _ 4- Long term follow up -o Twelve patients (mean age 33 years), whose cD seizure frequency had diminiished by more than 25%, were continued on the drug and 2. followed up for a mean of 14-75 months without any subsequent change in antiepilep- tic medication. Their test scores were con- 0 verted to standard (Z) scores, with a mean of zero and standard deviation of 1. Three 0 2 4 6 8 1 0 1 2 'composite' scales were produced, made up Weeks of the three remaining psychomotor tests Figure Mean sedattion scores during the double blind, placebo controlled part of thestudy (decision and movement times, threshold in 21 patients with refractry epilepsy. NS = not significant. detection), the four memory tests (forward 1274 Gillham, Blacklaw, McKee, Brodie J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.12.1271 on 1 December 1993. Downloaded from Table 2 Composite Z-scores (mean 0, SD 1) for long identified cognitive impairment with carba- term study in responders mazepine and phenytoin,22 it was not sensitive Psychomotor Memory Self rating to the deleterious effects of vigabatrin. Baseline -0-14 -0-42 0.19 With the exception of the memory tests, Placebo 2 -0 53 1-02 scores tended to be lower during treatment (weeks) 6 -0-56 0-75 12 -0-27 -0 19 -0-27 with vigabatrin although these differences Vigabatrin 2 -0 19 -0-25 were not statistically significant. This trend, (weeks) 6 -0-38 -0-32 12 _1.09a 0-15 -0-9lf however, cannot simply be ignored. There are Follow up 1 0-12 _0*84d -0-48 considerable difficulties in measuring small (months) 3 0 53 -0-82 -0-60 6 043 -0-52 0-58 changes in neuropsychological functioning in 9 0-92 0-08 -0 45 this patient population. Impairment due to 12 l Olb 1-20 1-299 15 1-28c 1-35e 0.93h epilepsy related factors, other than anticon- vulsant drugs, can be identified when patients a-b, a-c; d-e; f-g, f-h; p <001 with epilepsy are contrasted with healthy con- trols.22 23 25 Even standardised tests become less sensitive at the upper and lower ends of and backward digit span, paired associate the scale, so that small changes in function learning, Rivermead test) and the three self become difficult to detect unless the sample report scales (general health questionnaire, size is large. Thus, the possibility that vigaba- sedation and side effect scores). Significant trin does impair cognitive performance can- improvement over the follow-up period not be excluded entirely, although it seems occurred with all three scales (table 2). This clear that any such effect must be small. change took place at week 12 of the vigaba- The most consistently reported side effect trin treatment phase during the placebo con- with vigabatrin is tiredness4 which, if marked, trolled trial and the end of follow up for the could reasonably be expected to influence psychomotor and self rating scales and some of the tasks in the battery. In this study, between the beginning and end of follow up patients reported significantly greater seda- for the memory scale (all p < 0-01). There tion during weeks two and six of the treat- was no further improvement in seizure con- ment phase compared with the same number trol during the follow up period (table 3) and of weeks on placebo. Our data, however, no correlation was found between numbers of revealed fewer significant correlations seizures and cognitive test performances. between sedation scores and performances in other tests during the vigabatrin phase than on the placebo, even though patients reported Discussion more sedation while taking the active drug. TEST SENSITIVITY AND SPECIFICITY Hence sedation itself did not bring about During the first and second leg of the trial impairment of cognitive performance. The there was no significant difference between difference between sedation score during the the group taking vigabatrin and those taking treatment phase and placebo phase at week placebo for any test in the battery. There zero was not statistically significant and was were no changes in performance when the too small to be clinically significant. dose of vigabatrin was increased or when Interestingly, patients did not report sedation

patients were changed from placebo to active after six weeks' treatment with the higher http://jnnp.bmj.com/ treatment. This finding is consistent with an vigabatrin dose. This supports the rapid early report suggesting that vigabatrin does development of tolerance to the sedative not produce cognitive impairment.20 Such a effect of this drug. conclusion, however, cannot be drawn with- out regard to other possibilities. It could LONG TERM RESULTS be argued that, although our test battery All three composite scales showed significant improvement during follow up in the 12 responders who took vigabatrin long term. on September 24, 2021 by guest. Protected copyright. The temporal history of these changes was Table 3 Seizurefrequencies in responders to vigabatrin during long term follow up inconsistent with a practice effect or with Visit Total n Partial n Tonic-clonic n regression to the mean. If there had been a it would have Baseline 17-0 12 15-5 12 5-5 11 marked learning effect, (5-55) (7-55) (0-46) occurred during the first phases of the trial During trial 13-0 12 14-0 12 3-5 11 (4-98) (0-90) (0-11) when the tests were administered eight times 3 months 110 12 12-0 12 1.0 11 over 28 weeks. (1-132) (0-132) (0-8) 6 months 10-5 12 100 12 1 0 11 Improvement in test scores in patients (0-31) (0-31) (0-10) responding to vigabatrin continued during 9months 90 12 90 12 1-5 11 (0-71) (0-61) (0-10) longer term follow up. If the drug brought 12 months 8-5 11 9 0 11 1-5 10 about a small performance decrement, it is (0-30) (0-30) (0-6) 15 months 8-0 11 7 0 11 4 0 10 possible that tolerance developed during fol- (0-33) (0-33) (0-8) low up and that this, together with an 18 months 9 0 11 11 0 11 3 0 10 (0-40) (0-40) (1-7) improvement in well being brought about by 21 months 13-5 8 13-0 8 3-5 7 better seizure control, provides the explana- (3-40) (1-22) (0-7) 24months 11 0 7 11 0 7 1-5 6 tion for this observation. Tolerance may not (4-30) (3-23) (0-7) necessarily be a pharmacological phenome- Values are median (range) per month. Patients were assessed every three months following non, but may simply reflect the patient's abil- completion of the double blind, placebo controlled, crossover trial. ity to adapt psychologically to slight, drug Effiect ofvigabatrin in patients with refractory epilepsy 1275 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.12.1271 on 1 December 1993. Downloaded from induced deterioration in functioning. It seems Vigabatrin in complex partial seizures: a long-term study. Epiepsy Res 1989;3:160-6. most likely, however, that the major factor 10 Remy C, Beaumont D. Efficacy and safety of vigabatrin in responsible for the improvement was better the long-term treatment of refractory epilepsy. Br J Clin Pharmacol 1989;27(Suppl l):S125-9. seizure control. 11 Tartara A, Manni R, Galimberti CA, Mumford JP, Iudice In conclusion, the results of the short term A, Perucca E. Vigabatrin in the treatment of epilepsy: a long-term follow-up study. J Neurol Neurosurg Psychiatry part of the study suggest that treatment with 1989;52:467-71. vigabatrin did not produce significant cogni- 12 Dam M. Long-term evaluation of vigabatrin (gamma vinyl GABA) in epilepsy. Epilepsia 1989;30(Suppl 3):S26-30. tive impairment. Patients reported early seda- 13 Sander JW, Trevisol-Bittencourt PC, Hart YM, Shorvon tion, but this had disappeared by the 12th SD. Evaluation of vigabatrin as an add-on drug in the management of severe epilepsy. J Neurol Neurosurg week of treatment. Longer term follow up Psychiatry 1990;53: 1008-10. allowed the identification of a further small 14 Reynolds EH, Ring HA, Farr IN, Heller AJ, Elwes RD. Open, double-blind and long-term study ofvigabatrin in improvement in overall performance. The chronic epilepsy. Epilepsia 1991;32:530-8. sustained reduction in seizure frequency may 15 Sivenius J, Ylinen A, Murros K, Mumford JP, Reikkinen PJ. Vigabatrin in drug-resistant partial epilepsy: a 5-year have contributed to its development. From follow-up study. Neurology 1991;41:562-5. the practical viewpoint, phased introduction 16 Butler WH. The neuropathology of vigabatrin. Epilepsia 1989;30(Suppl 3):S15-17. of vigabatrin seems a prudent policy to permit 17 Gibson JP, Yarrington JT, Loudy DE, Gerbig CG, Hurst tolerance to subjective sedation during early GH, Newbeme JW. Chronic toxicity studies with viga- batrin, a GABA-transaminase inhibitor. Toxicol Pathol treatment. 1990;18:225-38. 18 Agnosti T, Yasargil G, Egil M, Wieser HG, Wiestler OD. Our grateful thanks go to Moya Dewar for expert secretarial Neuropathology of a human hippocampus following assistance and to Marion Merrell Dow for supplying the drug long-term treatment with vigabatrin: lack of micro- and placebo and for financial support. vacuoles. Epilepsy Res 1990;6:166-70. 19 Cannon DJ, Butler WH, Mumford JP, Lewis PJ. Neuropathologic findings in patients receiving long- term vigabatrin for chronic intractable epilepsy. J Child 1 Editorial. Vigabatrin. Lancer 1989;1:532-3. Neurol 1991;6(suppl 2) S17-25. 2 Mumford JP, Dam M. Meta-analysis of European 20 McGuire AM, Duncan JS, Trimble MR. Effect ofvigaba- placebo-controlled studies ofvigabatrin in drug-resistant tin on cognitive function and mood when used as add- epilepsy. Br J Clin Pharmacol 1989;27(Suppl 1):S101-7. on therapy in patients with intractable epilepsy Epilepsia 3 Ring HA, Heller AJ, Farr IN, Reynolds EH. Vigabatrin: 1992;33: 128-34. rational treatment for chronic epilepsy. J Neurol 21 Gillham RA, Williams N, Wiedmann K, Butler E, Larkin Neurosurg Psychiaty 1990;53:1051-5. JG, Brodie MJ. Concentration-effect relationships with 4 Grant SM, Heel RC. Vigabatrin. Drugs 1991;41:889-926. carbamazepine and its epoxide on psychomotor and 5 Michelucci R, Tassinari CA. Response to vigabatrin in cognitive function in epileptic patients. J Neurol relation to seizure type. Br J Clin Pharmacol Neurosurg Psychiatry 1988;51:929-33. 1989;27(Suppl l):S1 19-24. 22 Gillham R, Williams N, Wiedmann K, Butler E, Larkin 6 Pedersen SA, Klosterkov P, Gram L, Dam M. Long-term JG, Brodie MJ. Cognitive function in adult epileptic study of gamma-vinyl GABA in the treatment of patients established on monotherapy. epilepsy. Acta Neurol Scand 1985;72:295-8. Epilepsy Res 1990;7:219-25. 7 Sivenius MR, Ylinen A, Murros K, Matkainen R, 23 Gillham RA, Read CL, McKee PJW, Larkin JG, Brodie Riekkinen P. Double-blind dose reduction study ofviga- MJ. Cognitive function in adult epileptic patients on batrin in complex partial epilepsy. Epilepsia 1987;28: long-term sodium valproate. J7 Epilepsy 1991;4:205-10. 688-92. 24 Brodie MJ, McKee PJW. Vigabatrin and . Lancet 8 Browne TR, Mattson RH, Penry JK, et al. Vigabatrin for 1990;335: 1279. refractory complex partial seizures: multicenter single 25 Brodie MJ, McPhail E, Macphee GJA, Larkin JG, Gray blind study with long-term follow-up. Neurology 1987; JMB. Psychomotor impairment and anticonvulsant 37:184-9. therapy in adult epileptic patients. EurJ Clin Pharmacol 9 Cocito L, Maffini M, Perfumo P, Roncallo F, Loeb C. 1987;31:655-60. http://jnnp.bmj.com/

Historical description ofprimary writer's tremor Although this description probably also includes patients with writer's cramp, the mention of absence Tremor elicited by writing may be a feature of several of uncomfortable or painful sensations and male pre- neurological diseases. In rare occasions it presents as a dominance refers, undoubtedly, to primary writer's unique symptom, and its independent nosological tremor. identity is frequently discussed. In other patients it is J CASTIILLO

F MARTINEZ on September 24, 2021 by guest. Protected copyright. combined with essential tremor' or focal dystonia. A GONZALEZ-QUINTELA The modem description of this entity corresponds to M NOYA Rothwell, Traub and Marsden.3 However, we have Servicio de Neurologia, Hospital General de Galicta-Clinico Universitano, encountered a description by Grisolle4 in 1848 that Santiago de Compostela, Spain exactly resembles writer's tremor: "The affection consists ofa particular tremor ofthe right handfingers only Correspondence to: Professor J Castillo, Servicio de observed when writing, and absent in all other Neurologia, Hospital General de Galicia-Clinico circumstance. The patient is able to cut the pen and hold it Universitario, Santiago de Compostela, Spain. with his fingers a long while, as if he were to write; he is able to wash himself, shave and play piano without difficulty. But as soon as he begins to write he is affected by tremor. When writing is interrupted, tremor ceases. On many ocasions patients do not experience discomfort or 1 Kachi T, Rothwell JC, Cowan JMA, Marsden CD. pain. In others, these do exist." Writing tremor: its relationship to benign essential "This affection seems to develop slowly; until now it has tremor. J Neurol Neurosurg Psychiatry 1985;48:545-50. 2 Elble RJ, Moody C, Higgins C. Primary writing tremor. only been observed in males and all were above the age of A form of focal dystonia? Mov Disord 1990;5:1 18-26. 30. " 3 Rothwell JC, Traub MM, Marsden CD. Primary writing "Alcohol spirits, moral affections and seminal losses are tremor. Jf Neurol Neurosurg Psychiatry 1979;42: all to increase tremor. 1106-14. believed the The symptoms have 4 Grisolle A. Tratado de Patologia Interna. Tomo sesto. De las never been ascribed to a certain disease; therefore, it has neurosis. Madrid: Imprenta de Francisco Andres y been compared with chorea. " Companiia, 1848:93-4.