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Keywords:

  • Antiepileptic drugs;
  • AED;
  • Cognitive side effects;
  • CalCAP;
  • Carbamazepine;
  • Valproate

Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

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:

  • 1
    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.
  • 2
    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).
  • 3
    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.
  • 4
    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.

METHODS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Selection of patients: inclusion/exclusion criteria

The patients in the study were selected from the epilepsy registry at the Akershus University Hospital and from six neurologic outpatient clinics in the Oslo area; 241 appeared to fulfil the inclusion criteria (Table 1) and were invited to participate. Of these patients, 13 still had seizures, 20 were dismissed related to other exclusion criteria, and 17 patients did not appear. Of the remaining 191 eligible patients, 23 declined to participate in the study for various reasons. Thus at inclusion, only 168 patients were included. Before randomization, another 18 patients left the study. Of these, 12 changed their minds and withdrew. Two patients experienced seizures, three patients had generalized epileptiform activity on their EEGs, and one patient had an acute disease (subarachnoidal hemorrhage). These patients were withdrawn from the study, and 150 patients went through randomization. Eleven of these patients had seizure relapses during the study period and left the study. Therefore we report baseline and retest results only for the remaining 139 patients that completed the study.

Table 1. Inclusion and exclusion criteria
Inclusion criteria:
 Epilepsy (two unprovoked seizures or more)
 Two years of seizure freedom
 Monotherapy
 18–67 years
 Five years seizure freedom if prior unsuccessful discontinuation
Exclusion criteria
 Juvenile myoclonic epilepsy (JME)
 Polypharmacy
 Paroxysmal epileptiform activity in patients with primarily generalized epilepsy
 Two prior discontinuation attempts
 Pregnant or seeking pregnancy
 Mental retardation
 Progressive neurologic disease
 Other serious disease that may influence the health status of the patient in the study period
 Comedication (except postmenopausal hormone substitution), ASA, and thyroxin

Design

The study was prospective, randomized, controlled, and double-blinded. Each patient was included in the study for 12 months or until seizure relapse. Criteria for breaking the code were seizure relapse or acute disease. The neuropsychological assessments were done before and after intervention (withdrawal/not withdrawal). Both assessments were conducted by an experienced specialist in clinical neuropsychology (E.H.). The investigator was blinded during the whole study period.

Randomization was done by a statistician. The discontinuation period lasted 12 weeks. Patients were then examined about possible seizure relapse and supplied with medication or placebo. Seven months after discontinuation start, the patients were reassessed with the same neuropsychological tests. Twelve months after the start of discontinuation, the code was broken. Those who had not been discontinued from medication were offered an ordinary discontinuation at the outpatient clinic.

Cognitive testing

Cognitive function was assessed with the California Computerized Assessment Package (CalCAP) (Miller, 1980). The stimulus material includes both verbal and nonverbal stimuli. Instructions vary in complexity, and responses are precisely measured and include mean reaction times and total numbers of true-positive responses (hits) and false-positive responses (false alarms). The 10 different subtests provide measures in the following cognitive domains:

  • 1
    Simple Reaction Time. Patients are asked to press a key as soon as they see anything at all on the screen. The procedure provides a basal measure of simple reaction time. The task is given 3 times with the dominant hand and once with the nondominant hand.
  • 2
    Choice Reaction Time for Single Digits. Patients are asked to press a key as soon as they see the number “7”; otherwise, they are to do nothing. The procedure adds a simple element of memory to the task.
  • 3
    Sequential Reaction Time. In this task, patients are asked to press a key only when they see two of the same number in sequence; for example, if they see the number “5” followed by a second occurrence of the number “5.” The procedure implies a more-complex element of memory because the subject must remember the last number that was seen.
  • 4
    Language Discrimination. In this task, patients are asked to press a key when they see an animal name, but not when they see a word that fits into a category of nonanimals. The procedure introduces an additional level of language skills by requiring differentiation between semantic categories. The task requires rapid language processing.
  • 5
    Visual Selective Attention. Patients are asked to press a key as soon as they see a specific word such as “SEVEN” in the center of the screen. An additional set of the words is displayed around the periphery of the target stimulus. The distractors require that the subject focus his or her attention much more narrowly.
  • 6
    Response Reversal and Rapid Visual Scanning. In this task, patients must ignore the stimuli presented in the middle of the screen while responding to target stimuli displayed around the periphery of the computer screen. The task challenges the patient's ability to change cognitive set from the previous task and requires more rapid visual scanning across the entire screen.
  • 7
    Form Discrimination. Patients are shown three geometric figures simultaneously and asked to press a key only when two of the figures are identical. The task requires rapid comparison of nonnameable forms.

Order of administration of the 10 subtests and the different cognitive domains measured by the CalCAP are shown in Table 2.

Table 2. Order of administration of subtests and cognitive domains measured by the CalCAP
OrderSimple reaction timeComplex tests of attention/information processing
 1Simple RT 1 dom. hand 
 2Simple RT 2 nond. hand 
 3 Choice RT for single digits
 4 Sequential RT for similar digits in sequence
 5 Language discrimination: rapid language processing
 6Simple RT 2 dom. hand 
 7 Degraded words distract: visual selective attention
 8 Response reversal: rapid visual scanning
 9 Form discrimination: comparison of nonnameable forms
10Simple RT 3 dom. hand 

Statistical analysis

Two sets of statistical analyses were performed with the Statistical Package for Social Sciences for Windows (SPSS, version 11.0). First, descriptive statistics of the demographic, clinical, and cognitive characteristics of the patient population were computed. Then a series of independent t tests were performed comparing mean differences between the cognitive variables measured before and after discontinuation of AEDs. To adjust for multiple comparisons, a strict significance criterion of p < 0.01 was chosen.

RESULTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

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
  1. Lower scores on the mean reaction-time measures indicate improvement in milliseconds from baseline to retest. Increased true-positive responses indicate improvement from baseline to retest. Decreased false-positive responses indicate improvement from baseline to retest.

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

DISCUSSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

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.

REFERENCES

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • Aldenkamp AP. (2001) Effects of antiepileptic drugs on cognition. Epilepsia 42(suppl 1):4649.
  • Aldenkamp AP, Alpherts WCJ, Blennow G, Elmqvist D, Heijbel J, Nilsson HL, Sandstedt P, Tonnby B, Wahlander L, Wosse E. (1993) Withdrawal of antiepileptic medication: effects on cognitive function in children: the results of the multicentre “Holmfrid” study. Neurology 43:4151.
  • Baker GA, Marson AG. (2001) Cognitive and behavioural assessments in clinical trials: what type of measure? Epilepsy Research 45:163167.
  • Brunbech L, Sabers A. (2002) Effect of antiepileptic drugs on cognitive function in individuals with epilepsy. Drugs 62:593604.
  • Chen YJ, Chow JC, Lee IC. (2001) Comparison the cognitive effect of anti-epileptic drugs in seizure-free children with epilepsy before and after drug withdrawal. Epilepsy Research 44:6570.
  • Cochrane HC, Marson AG, Baker GA, Chadwick DW. (1998) Neuropsychological outcomes in randomized controlled trials of antiepileptic drugs: a systematic review of methodology and reporting standards. Epilepsia 39:10881097.
  • Craig I, Tallis R. (1994) Impact of valproate and phenytoin on cognitive function in elderly patients: results of a single blind randomized comparative study. Epilepsia 35:381390.
  • Gallassi R, Morreale A, Di Sarro R, Marra M, Lugaresi E, Baruzzi A. (1992) Cognitive effects of antiepileptic drug discontinuation. Epilepsia 33:4144.
  • Gilham RA, Read CL, McKee PJW, Larkin JG, Brodie MJ. (1991) Cognitive function in adult epileptic patients on long-term sodium valproate. Journal of Epilepsy 4:205210.
  • Gillham RA, Williams N, Wiedman K, Butler E, Larkin JG, Brodie MJ. (1988) Concentration-effect relationships with carbamazepine and its epoxide on psychomotor and cognitive function in epileptic patients. Journal of Neurology, Neurosurgery, and Psychiatry 51:929933.
  • Kwan P, Brodie MJ. (2000) Early identification of refractory epilepsy. New England Journal of Medicine 342:314319.
  • Lossius MI, Stavem K, Gjerstad L. (1999) Predictors for recurrence of epileptic seizures in a general epilepsy population. Seizure 8:476479.
  • Martin EM, Pitrak DL, Novak RM, Pursell KJ, Mullane KM. (1999) Reaction times are faster in HIV-seropositive patients on antiretroviral therapy: a preliminary report. Journal of Clinical and Experimental Neuropsychology 5:730735.
  • Meador KJ. (1998) Cognitive and behavioural assessments in AED trials. Antiepileptic Drug Devevelopment: Advances in Neurology 76:231238.
  • Meador KJ. (2001) Cognitive effects of epilepsy and of antiepileptic medications. In WyllieE (Ed) The treatment of epilepsy: principles and practice. 3rd ed. Lippincott Williams & Wilkins, Philadelphia , pp. 12151225.
  • Meador KJ, Loring DW, Abney OL, Allen ME, Moore ME, Moore EE, Zamrini EY, King DW. (1993) Effects of carbamazepine and phenytoin on EEG and memory in healthy adults. Epilepsia 34:153157.
  • Meador KJ, Loring DW, Allen ME, Zamrini EY, Moore EE, Abney OL, King DW. (1991) Comparative cognitive effects of carbamazepine and phenytoin in healthy adults. Neurology 41:15371540.
  • Meador K, Loring DW, Ray PG, Murro AM, King DW, Perrine KR, Vazquez BR, Kiolbasa T. (2001) Differential cognitive and behavioural effects of carbamazepine and lamotrigine. Neurology 56:11771182.
  • Miller EN. (1980) California Computerized Assessment Battery (CalCAP) Manual. Norland Software, Los Angeles .
  • Miller EN. (1992) Use of computerized reaction time in the assessment of dementia [Abstract]. Neurology 42(suppl 3):220.
  • Miller EN. (1995) Cognitive testing using reaction time and traditional neuropsychological procedures. Journal of the International Neuropsychological Society 1:393.
  • Miller EN, Satz P, Visscher B. (1989) Computerized neuropsychological assessment for HIV-related encephalopathy: symposium on novel and traditional approaches for early detection of HIV-1 related dementia (Vancouver, Canada). Journal of Clinical and Experimental Neuropsychology 11:3435.
  • Miller EN, Satz P, Visscher B. (1991) Computerized and conventional neuropsychological assessment of HIV-1 infected homosexual men. Neurology 41:16081616.
  • Prevey ML, Delaney RC, Cramer JA, Cattanach L, Collins JF, Mattso RH. (1996) Effect of valproate on cognitive function: comparison with carbamazepine: the Department of Veterans Affairs Epilepsy Cooperative Study 264 Group. Archives of Neurology 53:10081016.
  • Thompson PJ, Huppert F, Trimble MR. (1980) Anticonvulsant drugs, cognitive function and memory. Acta Neurologica Scandinavica S80:7580.
  • Thompson PJ, Trimble MR. (1981) Sodium valproate and cognitive function in normal volunteers. British Journal of Clinical Pharmacology 12:819824.
  • Vermeulen J, Aldenkamp AP. (1995) Cognitive side-effects of chronic antiepileptic drug treatment: a review of 25 years of research. Epilepsy Research 22:6595.
  • Worth JL, Savage CR, Baer L, Esty EK, Navia BA. (1993) Computer-based neuropsychological screening for AIDS dementia complex. AIDS 7:677681.