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Summary: Purpose: All major antiepileptic drugs (AEDs) have been reported to be associated with cognitive side effects. Uncertainty exists regarding the degree of cognitive effects, primarily because many studies do not adhere to basic standards of methodology and design. The aim of this study was to assess the effect of discontinuation of AEDs in patients receiving monotherapy on measures of attention, reaction time, and speed of information processing.
Methods: The 150 subjects who had been seizure free >2 years on drug monotherapy went through a randomized, double-blind, placebo-controlled study. Each patient was included for 12 months or until seizure relapse. Cognitive function was assessed with the California Computerized Assessment Package at baseline and 7 months after discontinuation.
Results: The major finding in this study is that discontinuation of major AEDs significantly improved performance on tests that require complex cognitive processing under time pressure. The difference in speed of cognitive processing between the two groups on these tasks was between 24 to 43 ms. Simple tasks of attention and reaction time revealed no significant differences between the discontinuation group and the nondiscontinuation group. Most of the subjects in the study were medicated with carbamazepine (CBZ) and valproate (VPA). The outcome of discontinuation of CBZ was similar to the outcome for the total study population, whereas withdrawal of VPA revealed only a nonsignificant tendency in the same direction.
Conclusions: The results suggest that seizure-free epilepsy patients receiving monotherapy can obtain improvement in cognitive function if they discontinue AED treatment.
Antiepileptic drugs (AEDs) are given as long-term treatment, and concern about their impact on cognitive function in daily life is an important aspect in the management of people with epilepsy (Vermeulen and Aldenkamp, 1995). All major AEDs have been reported to be associated with adverse cognitive side effects (Aldenkamp, 2001). The main neuropsychological effects of AEDs involve attention/vigilance, psychomotor speed, and memory. Memory tests with a high-vigilance load are most likely to be sensitive to AED effects (Meador, 2001). Neuropsychological testing has been the major method of objectively measuring cognitive function related to the use of AEDs. Approximately 100 studies have been published on this issue in the last 30 years. Still much uncertainty remains regarding the degree of cognitive effects of AEDs and whether significant differences in adverse cognitive effects exist between the major AEDs. The reason for this uncertainty is that many studies do not adhere to basic standards of methodology, design, and neuropsychological evaluation (Meador, 1998; Baker and Marson, 2001; Brunbech and Sabers, 2002). Four major problems have been encountered:
The selection criteria of subjects in many of the studies have differed, so that results from one group cannot necessarily be compared with other groups.
The neuropsychological testing has not been consistent with regard to test selection, administration of tests, and reporting of test results. This makes comparison between the results difficult (Cochrane et al., 1998
The existing studies often lack control groups and randomization of the treatment. In many studies, results regarding the target drug are distorted by the effect of polytherapy (Vermeulen and Aldenkamp, 1995
). No reported studies fulfil the design criteria of a randomized, double-blind, placebo-controlled withdrawal study of seizure-free epilepsy patients receiving monotherapy, tested after several months of steady state treatment.
A statistical problem in many of the studies relates to sample size. Many studies involve only a few subjects and therefore lack statistical power.
In selecting tests to evaluate the possible adverse cognitive effects of AEDs, it is essential to include tests representing functions believed to be sensitive to AEDs. Furthermore, the tests must meet acceptable criteria of reliability, validity, and sensitivity to change.
In the current study, we chose to focus on previously reported neuropsychological side effects of AEDs on attention/vigilance and psychomotor speed (Meador, 2001). On the basis of a review of all randomized controlled trials evaluating neuropsychological outcomes of AEDs (Cochrane et al., 1998), Baker and Marson (2001) recommend computerized tests of attention and psychomotor speed in clinical trials of AEDs. With this background, we chose to use the California Computerized Assessment Package (CalCAP) (Miller, 1980). To our knowledge, the CalCAP test battery has not previously been used in assessment of possible cognitive side-effects of AEDs. However, it integrates a broad range of attention-related speeded cognitive measures with different levels of complexity that are sensitive to important treatment effects in both epilepsy and other patient categories. This has been shown in studies of cognitive AED effects (Gillham et al., 1988; Meador et al., 1991) and in studies of HIV-seropositive patients receiving antiretroviral therapy (Martin et al., 1999).
The CalCAP test battery consists of four subtests of simple reaction time and six subtests measuring more-complex aspects of attention, choice reaction time, psychomotor speed, and rapid information processing. Intercorrelations between simple and choice reaction time are very small (from 0.11 to 0.29) (Miller, 1995). Correlation between the same simple reaction-time task, administered at 4 separate times during the standard CalCAP procedures, are moderate to strong (0.41 to 0.68), whereas correlation between choice reaction-time measures are weak to moderate (0.31 to 0.60). Form discrimination shows the lowest intercorrelations with the other choice reaction-time measures (Miller, 1995). The choice reaction-time measures show moderate to strong 6-month test–retest reliability (0.43–0.68), which is comparable to that seen in conventional neuropsychological procedures (0.47–0.77) (Miller, 1995). The CalCAP has been shown repeatedly to discriminate cognitively impaired index cases from matched controls as well as or better than conventional neuropsychological tests. These findings have been established both cross-sectionally (Miller et al., 1989; Miller et al., 1991; Worth et al., 1993) and longitudinally (Miller et al., 1989; Miller, 1992). These data suggest sensitivity of the reaction-time measures provided by CalCAP for detecting changes in different cognitive processes like attention, motor and psychomotor functioning, and support the use of reaction-time procedures for assessment and monitoring of conditions characterized by impairment of attention and cognitive slowing, like possible effects of AEDs.
Thus the aim of this study was to assess, in a randomized, double blind, placebo-controlled study of seizure-free epilepsy patients receiving monotherapy, the possible impact of discontinuation of AEDs on attention, reaction time, and speed of information processing.
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Baseline characteristics of the two groups (discontinuation vs. nondiscontinuation) are shown in Table 2. The baseline test scores from the CalCAP are given as mean reaction time in milliseconds and as number of hits and false alarms on the different tasks.
Changes in scores on the CalCAP test battery from baseline to 7 months after intervention are shown in Table 2. Function improved significantly more in the discontinuation group than in the nondiscontinuation group on three of the six complex tests. The improvement was significant on a choice reaction-time test with digits (choice RT-digits) (p ≤ 0.001), on the task that demands rapid language discrimination (language discrimination; p = 0.003), and on the form-discrimination task (form discrimination; p = 0.013). On a verbal task demanding rapid visual scanning (response reversal), the improvement was nearly significantly (p = 0.047) better in the discontinuation group. On a somewhat simpler task in the same category (degraded words with distraction), the improvement in the same group was close to significant (p = 0.067). Only on one of the tests demanding complex cognitive function (sequential reaction time) was no significant or near-significant improvement noted in the discontinuation group. The latter test is a measure of immediate recognition memory. On all the four tests of simple reaction time, no significant changes were found in any of the groups.
With regard to true-positive responses, near-significant improvement in the withdrawal group was evident on the form-discrimination task (p = 0.020) and on the language discrimination task (p = 0.050). On the rest of the tests, no significant change was evident, but a consistent trend of more true-positive responses appeared on all the tasks in the discontinuation group. No significant differences in false-positive responses were noted between the discontinuation and the nondiscontinuation group.
In Table 3, changes in CalCAP scores for patients taking CBZ from baseline to 7 months after intervention is shown. With regard to response time, the improvement in the discontinuation group is significant on the following cognitive tasks: choice reaction time with digits (p ≤ 0.001), language discrimination (p = 0.003), and on degraded words with distraction (p = 0.012). Near-significant improvement is evident on form discrimination (p = 0.074). No significant changes appeared on sequential reaction-time task, on the response reversal task, or on any of the four simple reaction-time tasks. True-positive responses increased nearly significantly on the degraded words with distractions task (p = 0.035) in the discontinuation group. For the other tasks, no significant changes appeared, but a consistent trend of more true-positive responses on all the subtests was seen in the discontinuation group. No significant differences in false-positive responses appeared between the two groups.
Table 3. Baseline characteristics of patients
| ||No discontinuation (n = 79)||Discontinuation (n = 71)|
|Mean age (range)||37.4 (18–66)||39.2 (19–65)|
|Female (%)||40 (50.6)||40 (56.3)|
|Epilepsy onset 0–18 yr (%)||32 (41) ||26 (37) |
|Epilepsy onset 18–60 yr (%)||47 (60) ||45 (63) |
|Seizure free 2–5 yr (%)||23 (29) ||27 (39) |
|Seizure free >5 yr (%)||56 (71) ||44 (62) |
|Known etiology (%)||23 (29) ||20 (28) |
|MRI pathology (%)||21 (28) ||16 (23) |
|Normal neurologic status (%)||73 (92) ||67 (94) |
|Carbamazepine (%)||52 (66) ||41 (58) |
|Valproate (%)||18 (23) ||15 (21) |
|Phenytoin (%)||6 (8) ||7 (10)|
|Phenobarbital (%)||2 (3) ||3 (4) |
|Lamotrigine (%)||1 (1) ||5 (7) |
|Serum concentration within therapeutic range (%)||64 (82) ||54 (76) |
|Epileptiform activity on EEG (%)||35 (44) ||25 (35) |
|CalCAP: mean reaction time (ms)|
| Simple RT 1-DH ms (SD)||374.53 (117.70)||369.98 (96.67) |
| Simple RT-Nond. H ms (SD)||317.57 (58.41) ||322.63 (65.17) |
| Choice RT-Digits ms (SD)||425.83 (49.77) ||440.50 (64.75) |
| Sequential RT ms (SD)||553.13 (110.32)||542.78 (134.54)|
| Language discrimination ms (SD)||587.18 (81.47) ||590.42 (84.74) |
| Simple RT 2-DH ms (SD)||349.18 (70.15) ||347.14 (63.67) |
| Degraded words distract ms (SD)||537.46 (101.44)||561.38 (107.36)|
| Response reversal-words ms (SD)||672.28 (112.85)||692.98 (118.65)|
| Form discrimination ms (SD)||776.31 (158.59)||809.98 (167.48)|
| Simple RT 3-DH ms (SD)||340.40 (67.09) ||334.45 (54.99) |
|CalCAP: True-positive responses (n)|
| Choice RT-Digits tp (SD)||14.69 (0.73) ||14.41 (1.46) |
| Sequential RT tp (SD)||17.14 (4.01) ||17.09 (4.06) |
| Language discrimination tp (SD)||21.44 (3.91) ||21.52 (3.62) |
| Degraded words distract tp (SD)||13.64 (2.71) ||13.42 (2.65) |
| Response reversal-words tp (SD)||12.01 (3.01) ||11.44 (3.12) |
| Form discrimination tp (SD)||13.54 (4.71) ||12.69 (4.95) |
|CalCAP: False-positive responses (n)|
| Choice RT-digits fp (SD)||0.78 (0.92)||0.91 (1.17)|
| Sequential RT fp (SD)||1.44 (1.74)||1.17 (1.53)|
| Language discrimination fp (SD)||2.14 (1.93)||2.48 (4.02)|
| Degraded words distract fp (SD)||2.28 (2.91)||1.98 (2.34)|
| Response reversal-words fp (SD)||1.46 (2.43)||1.58 (2.17)|
| Form discrimination fp (SD)||5.11 (7.80)||3.77 (2.83)|
In Table 4, changes in scores for subjects on VPA from baseline to 7 months after intervention are shown. Close to significant improvement in response time was found in the discontinuation group on the form-discrimination task (p = 0.020) and on the Response-reversal task (p = 0.044). On the other subtests, no significant change was evident. Improvement in the nondiscontinuation group on the test of immediate recognition memory was close to significant (p = 0.060). True-positive responses increased nearly significantly in the discontinuation group only on the form-discrimination subtest (p = 0.030). On the immediate recognition memory task (sequential reaction time), improvement in positive responses was almost significant in the nondiscontinuation group (p = 0.065). For the other tests, no significant changes were evident. A significant decrease in false-positive responses (p = 0.013) appeared in the discontinuation group on the language discrimination task. Otherwise, no significant differences were found.
Table 4. Changes in CalCAP scores from baseline to seven months after intervention
|CalCAP: mean reaction time (ms)||No discontinuation (n = 75)||Discontinuation (n = 64)||p Value|
|Simple RT 1-DH ms (SD)||−13.38 (83.07)||−2.75 (100.27)||NS|
|Simple RT-nond. H ms (SD)||5.35 (66.45)||0.38 (56.48)||NS|
|Choice RT-digits ms (SD)||4.07 (33.29)||−24.02 (56.07)||<0.001|
|Sequential RT ms (SD)||−17.69 (93.88)||−9.28 (113.43)||NS|
|Language discrimination ms (SD)||6.99 (45.79)||−17.44 (46.58)|| 0.003|
|Simple RT 2-DH ms (SD)||2.19 (55.41)||1.94 (55.03)||NS|
|Degraded words distract ms (SD)||9.92 (65.78)||−14.11 (85.32)|| 0.067|
|Response revers.-words ms (SD)||−1.96 (66.22)||−26.19 (74.68)|| 0.047|
|Form discrimination ms (SD)||8.07 (93.37)||−34.98 (106.61)|| 0.013|
|Simple RT 3-DH ms (SD)||0.15 (54.67)||12.89 (40.33)||NS|
|CalCAP: True-positive responses (n)|
| Choice RT-digits tp (SD)||0.11 (.83)||0.36 (1.10)||NS|
| Sequential RT tp (SD)||0.67 (3.99)||0.70 (4.20)||NS|
| Language discrimination tp (SD)||0.04 (2.95)||0.94 (2.29)|| 0.050|
| Degraded words distract tp (SD)||0.31 (2.11)||0.63 (2.37)||NS|
| Response reversal-words tp (SD)||0.19 (2.35)||0.86 (2.11)|| 0.086|
| Form discrimination tp (SD)||−0.18 (2.93)||1.09 (3.37)|| 0.020|
|CalCAP: False-positive responses (n)|
| Choice RT-digits fp (SD)||−0.33 (.99)||−0.45 (1.17)||NS|
| Sequential RT fp (SD)||−0.57 (1.69)||−0.20 (1.58)||NS|
| Language discrimination fp (SD)||0.19 (2.71)||−0.02 (2.75)||NS|
| Degraded words distract fp (SD)||−0.71 (2.38)||−0.36 (2.55)||NS|
| Response reversal-words fp (SD)||−0.38 (2.17)||−0.25 (2.43)||NS|
| Form discrimination fp (SD)||−0.99 (5.97)||0.53 (3.08)||NS|
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The main finding of the present study is that discontinuation of major AEDs significantly improves performance on tests that require complex cognitive processing under time pressure, as in divided attention, rapid language discrimination, and rapid form discrimination.
The strengths of the present study is that it fulfils the design criteria of a randomized, double-blind, placebo-controlled discontinuation study of seizure-free epilepsy patients receiving monotherapy, tested after several months of steady-state treatment. Second, this study includes a large sample of subjects and therefore has good statistical power.
The present data are relevant for patients that fulfilled the described inclusion criteria: No seizures on AED monotherapy for ≥2 years, no epileptiform activity on EEG in patients with generalized epilepsy, and no patients with juvenile myoclonic epilepsy. It is reasonable to believe that the selected group of patients is representative of the majority of seizure-free epilepsy patients (Lossius et al., 1999; Kwan and Brodie, 2000). Our findings, however, cannot be extrapolated to all epilepsy patients, including patients with refractory epilepsy.
To our knowledge, this is the first randomized, double-blind, placebo-controlled study to investigate the effect on attention, reaction time, and speed of information processing after discontinuation of AEDs in seizure-free epilepsy patients. Both research design and test methods have been somewhat different from those of other reported studies. It is therefore difficult to make direct comparison of the present results with results from other studies on the cognitive influence of major AEDs.
Two previous discontinuation studies of AEDs in children are fairly similar to the current study with regard to research design: In a nonrandomized and unblinded discontinuation study of AEDs in children with epilepsy with seizure freedom of >2 years, Chen et al. (2001) did not find any improvement in IQ or on any of the subtests from WISC-R. They found, however, that P300 latencies (auditory event-related potentials) were significantly increased in children receiving phenobarbital (PB) but not in children receiving CBZ or VPA. In another discontinuation study of seizure-free children with epilepsy, Aldenkamp et al. (1993) found no cognitive effects, compared with healthy controls, in a large sample of children for a mixture of AEDs comprising mainly CBZ. However, it is interesting that in studies of healthy adult volunteers with similar test methods as in the current study, Meador et al. (1991, 1993), in direct comparison of 1-month exposure to phenytoin (PHT) and CBZ, found that both drugs produced impairment on a choice reaction-time task and that CBZ in addition impaired performance on tasks of conflict interference and memory (story recall). In another study of healthy volunteers, Meador et al. (2001) found that subjects CBZ performed poorer than did subjects taking lamotrigine (LTG) and subjects off AEDs on measures of attention, cognitive speed, memory, and graphomotor coding. These findings are challenged by studies by Thompson et al. (1980) with normal volunteers and the mentioned study by Aldenkamp et al. (1993), who both reported no cognitive effects of CBZ. Studies of VPA have resulted in findings of mild to moderate impairment of mental speed and psychomotor slowing (Thompson and Trimble, 1981; Aldenkamp et al., 1993; Craig and Tallis, 1994; Prevey et al., 1996). Comparing CBZ with VPA, Gallassi et al. (1992) found that subjects taking VPA performed worse on tasks of visuomotor function and memory. These findings are not supported by Gilham et al. (1991), who found no cognitive side effects of patients receiving VPA monotherapy compared with nonepilepsy controls.
Most of the subjects in the study used CBZ (62%). The outcome of discontinuation of CBZ was similar to the outcome for the total study population, with significant or near-significant improvement on most of the more-complex cognitive tests, and no significant changes on the repeated tests of simple reaction time. The second largest group of subjects were medicated with VPA (23%). Analysis of cognitive outcome of the discontinuation of VPA revealed the same tendency as for the whole group, and for CBZ, but less clearly. The group of subjects taking VPA was small, and it is therefore reasonable to be cautious about drawing conclusions about cognitive effects of this drug based on the present data.
The major finding in this study is that discontinuation of major AEDs significantly improves performance on tests that require complex cognitive processing under time pressure. The difference in speed of cognitive processing between the two groups on these tasks was between 24 to 43 ms. Elements of these cognitive processes are necessary in many daily-life activities, and even a subtle slowing in processes that are repeated many times in daily-life activities may have a significant impact. The results suggest that performance of certain kinds of intellectual work, tasks requiring divided attention, and fast information processing may be negatively affected by use of AEDs. Repeated testing of simple tasks of attention and reaction time revealed no significant differences between the discontinuation group and the nondiscontinuation group. These results indicate that tasks requiring simpler forms of attention and simple reaction time are not significantly affected by major AEDs.
In conclusion, the major finding is that discontinuation of major AEDs in seizure-free patients significantly improves performance on tests that require divided attention and rapid information processing. The results suggest that seizure-free epilepsy patients can obtain improvement in cognitive function if they discontinue AED treatment. All of the subjects in the study were receiving monotherapy, most of them with CBZ or VPA. The outcome of discontinuation of CBZ was similar to the outcome for the total study population, whereas discontinuation of VPA revealed only a nonsignificant tendency in the same direction.