The interest in the cognitive side-effects of antiepileptic drug treatment is of relatively recent origin and the first studies are from the 1970s,probably stimulated bythe widening range of possibilities for drug treatment during that period; valproate and carbamazepine were clinically introduced in this same period and many studies compare these drugs with phenytoin (combination of phenytoin). A first paragraph of this chapter reviews the literature in lines of evidence-based medicine, that is, reviewing the empirical data that were published in peer-reviewed journals. Potentially relevant studies were identified through computerized and manual searches of the English-language literature published from January 1970 through December 1994. A computerized search of the DIMDI database was conducted. In addition, the bibliographies of several reviews on the same topic were examined. Criteria for selection of the papers were:
1 English-language report of original research, published in peer-reviewed journals in the period 1970-1994; studies after 1970 were all done at a time when most of the current antiepileptic drugs had become available and modern cognitive tests had come into widespread use.
2 Studies that report psycho metrically assessed cognitive functions (excluding for example clinical observations).
3 Only current antiepileptic drugs (excluding experimental drugs that have been removed from study programmes, such as zonisamide, felbamate or flunarizine).
4 Only studies on patients with epilepsy (excluding antiepileptic drug studies in for example psychiatric patients). The resulting meta-analysis has been published on the data concerning monotherapy. Here we focus on the results for combination therapy or polytherapy.
In the meta-analysis, studies were classified into the polytherapy category if subjects were treated with more than one drug at a time and no comparisons between individual drugs, or single drug vs. no antiepileptic drug, were possible. Studies that were identified through the aforementioned procedure and involving polytherapy are listed in Table Review summary of polytherapy polytherapy studies (1970-1994)
1 Treatments. This section shows the treatment conditions associated with assessment points. The nomenclature and abbreviations for individual antiepileptic drugs comply with the recommendations in Epilepsia, 1993,34,1151. In addition: P, polytherapy; SAD, single additional dose; Mono, monotherapy; plac, placebo; none, no antiepileptic drugs. Subscripts: AEDcr, controlled release formulation; AEDDhi/Dme/Di0, high, medium, low dosage; AEDshi/si0, high vs. low serum (or saliva) levels; Pred,mod> P reduction [c.q.], other modification; Paed+/-> P wmivs– without a particular antiepileptic drug; Ptox+/-> P with toxic vs. non-toxic serum levels. Slashes (/) indicate contrasts under study in a parallel group or post-test-only design. Crosses (X) indicate crossover elements. Arrows (—>) indicate change of one treatment to another. Plus signs ( +) indicate that medication is added to an existing regimen.
2 Number of subjects. The numbers are shown separately for each treatment condition and untreated controls; they indicate the number of subjects who completed the trial and for who test data were available. A range is given for n when not all subjects completed all tests. Occasionally, we were unable to determine these numbers for the separate treatments (e.g. when only an overall n was provided), or for one or more outcome measures. This is indicated by a question mark.
3 Drop-out rate. This gives a rough indication as to whether a selection artefact might have developed during the trial. An overall rate is given separately for subjects on antiepileptic drugs and untreated controls. About half the studies reviewed mention dropout losses and present sufficient data to compute a drop-out rate for each outcome measure. A range may be given here as well as due to incompletion in various degrees. A few studies explicitly state that no dropout losses occurred (-). In others, dropout losses are mentioned but insufficient data is provided to compute a loss rate (?). Often, dropout losses or their absence are not mentioned (n.m.)> which may or may not mean that no such losses occurred. Sometimes a minimum rate is quoted (5s), more subjects may have been lost, but the data are unclear or ambiguous in this regard.
4 Design. (Table 22.2 gives an overview of the general design types encountered.) The term design as used here refers to the scheduling of treatments (i.e. antiepileptic drugs, placebo, no treatment) and outcome measurement sessions, and to the way subjects were assigned to treatment groups (i.e. on a random basis or not). Occasionally, we were unable to discover a consistent principle underlying
Table Review summary of polytherapy polytherapy studies (1970-1994)
|On antiepileptic drugs||Untreatedcontrols||Drop-outrate||Design||Cognitivevariables (N)||Time onantiepileptic drug|
|(Pdw -» PDme -> PDlo)/none||8-12||6ne||n.m.||Parallel||6||14-20 days|
|P + (valproate X plac)||8-20||–||33-73%||X-over (R)||30||12 weeks|
|P/(P/(Pred/Pred + carbamazepine))||10/20/15||–||n.m.||Parallel||6||6 months|
|combination of phenytoin + (CLZ X phenobarbital)||43||–||22%||X-over (R)||?||4 months|
|P -» Mono||12||–||33%||Single||17||1 year|
|P/(Pred + zonisamide)||9||–||18%||Single||16||24 weeks|
|P/carbamazepine/valproate/combination of phenytoin||66||25||n.m.||Single||20||?|
|P-P mod||13||–||n.m.||Single||18||5 days|
|P/(P + vigabatrin)||15/15||–||n.m.||Parallel||7||4 weeks|
|carbamazepine -(carbamazepine + valproate)||16||–||33%||Single||7||5 days|
|PpHT+/(PpHT+ PpHT-)||12/17||–||n.m.||Parallel||15||10 weeks|
|(Pcbz -> PcBZcr)/none||15||15ne||6%||Parallel||22||4 weeks|
|phenobarbital + (combination of phenytoin/carbamazepine)||50||–||15%||Parallel||?||6 months|
|P + (vigabatrin X plac)||24||–||13%||X-over(R)||10||12 weeks|
|P + (lamotrigine Xplac)||40-44||–||46-51%||X-over(R)||9||18 weeks|
|P -» (P + (vigabatrin/plac))||83/85||–||8%||Parallel (R)||19||12 weeks|
|carbamazepine + (OCBZ X plac)/valproate +(OCBZ X plac)/ |
combination of phenytoin + (OCBZ X plac)/OCBZ
Randomized treatment allocation, or treatment sequencing in a crossover and parallel design, is indicated by the suffix (R).
Table Design nomenclature and classification
|Abbreviated designation||Design name||Definition|
|Post-test||Post-test-only||One or more groups of subjects are tested after (but not before) receiving treatment|
|Single||Single group pre-test-post-test||A single group is tested both before and after the treatment period|
|Parallel||Parallel groups||Two or more groups are assigned to different treatment conditions and tested both before and after the treatment period|
|X-over||Crossover||The same subjects are tested under different treatment conditions, counterbalancing the order of treatments|
Randomized treatment allocation, or treatment sequencing in a crossover design, is indicated by the suffix (R).
The scheduling of treatments and assessment points, or different schedules were employed for different subjects. In such cases the design was classified as unclear (?).
5 Number of cognitive variables. This gives an indication of the possible scope of the study with respect to cognitive functioning; also, this is a statistically relevant characteristic. Uncertainty as to the number of variables actually employed (?) in analysing the data may occur even if the tests used are mentioned; often multiple outcome variables may be derived from a single test (e.g. response speed, accuracy, subscales in intelligence tests).
6 Time on antiepileptic drug. This characteristic is important in judging the relevance of the results to chronic antiepileptic drug use. Its meaning depends on the particular design employed. In a post-test-only design the figures quoted relate to the duration of treatment prior to the assessment point. In repeated measurement designs with one or more groups (i.e. single and parallel) this refers to the duration of the experimentally changed antiepileptic drug-treatment or the continuous medication interval studied. With multiple assessment points during the trial, the maximum interval studied is given. In a crossover design where multiple antiepileptic drugs or dosages are given, this refers to the time on each antiepileptic drug [c.q.] dosage.
Closer inspection of the studies that we identified shows many methodological problems, most of which are inherent to polytherapy as such. These methodological problems must be taken into consideration carefully because they restrict the validity of the information from these studies.
Polytherapy is by nature a heterogeneous treatment category; thus, one finds treatment descriptions such as ‘various combinations of the three major antiepileptic drugs’ or ‘combination of phenytoin and one or more other antiepileptic drugs’ [c.q.], ‘drug regimens exclusive of combination of phenytoin’, or even ‘no attempt was made to standardize drug therapy as part of the study’. Obviously, widely different drug regimes would fit such descriptions, and results established with one regimen may not apply to another. Also, the polytherapy manipulations used in many studies are actually quite complex, making replication problematical. For example, all polytherapy reduction studies are done as part of individualized programs of therapy rationalization. That is, patients did not have their medications changed for research purposes, and different types of medication change were not subjected to randomization. Rather, changes were typically made ‘according to the individual needs of each patient’. The clinical considerations underlying the medication changes are a major ingredient of the treatment package, albeit one that may not be easily reproduced.
Combinations of antiepileptic drugs may alter metabolism to produce changes in the level of active and/or toxic metabolites. Examples include the decrease in carbamazepine levels due to the increased elimination of the drug when given together with combination of phenytoin and/or phenobarbital. Such interactions can alter seizure control efficacy and maybe relevant to cognitive functioning. With multiple drugs, identifying the components of a treatment most responsible for any observed effects presents a difficult problem.
Serum concentration-effect relationships
Cognitive antiepileptic drug effects may be examined through an analysis of the relationship between test scores of subjects and their individual serum drug levels, and this approach seems to offer a way out of the problem mentioned above. In fact, a number of studies report such relationships suggesting that, generally, higher serum levels are associated with lower cognitive scores. However, in patients with epilepsy, higher serum concentrations maybe the reflection of higher antiepileptic drug doses prescribed for more severe epilepsy, perhaps with seizures not fully controlled. Also, antiepileptic drugs may interact on receptor sites (pharmacodynamics), which would not necessarily be reflected in the pharmacokinetics expressed in serum concentrations. Such factors greatly reduce the interpretability of relationships between serum concentrations and cognitive performance.
Polytherapy is typically given to patients with refractory epilepsy, and separating seizure effects from antiepileptic drug effects may thus be very difficult, particularly in add-on studies, where the cognitive evaluation is usually made in connection with an efficacy trial. That is, adverse cognitive antiepileptic drug effects may be masked by beneficial effects of better seizure control. Also, patients with refractory seizures may not be representative of the general population with epilepsy.
Discussion of cognitive effects
Due to the validity threats described above, acting singly or simultaneously, drawing conclusions about the cognitive effects of polytherapy studies is not without complications. Moreover, the anecdotal-type of information is best illustrated by the large number of question marks both in the column expressing numbers of patients, for the dropout rates and even for design, number of cognitive variables, and time on antiepileptic drugs. Starting from the principles of evidence-based medicine we can therefore only proceed carefully. Conclusions will be drawn on a general level. Reviewing the literature, five types of studies can be distinguished:
• The first type of study is the single measurement polytherapy study. Corbett et al. (1985) is an example of studies that analyze polytherapy in a single measurement design. Patients who received polytherapy are analysed for cognitive impairments. Although, without exception all these studies report severe cognitive impairment the design does not allowthe isolation of drug effects from the effects of the epilepsy.
• The second type consists of studies comparing monotherapy with polytherapy. Brodie et al. (1987) showed no difference between monotherapy carbamazepine, valproate, combination of phenytoin and polytherapy at a single assessment study. Other studies did, however, show serious impairments for polytherapy. Bittencourt et al. (1993) used a complex add-on with a polytherapy at baseline (with either combination of phenytoin or carbamazepine added to an existing low-dose phenobarbital regime) and monotherapy (combination of phenytoin or carbamazepine) at endpoint. The study shows statistically significant improvements on measures of memory and attention after withdrawal from polytherapy. As for the former type of study, it is extremely difficult to avoid the seizure confound here as polytherapy is mostly given to different patients.
• A convincing group of studies showed the effect of reduction of polytherapy. Durwen etal. (1989) showed that reduction of polytherapy resulted in improvements of verbal memory. Duncan etal. (1990) used a rather interesting design in which separate drugs (combination of phenytoin, carbamazepine, valproate) were removed from polytherapy regimes showing consistent improvements in cognitive function, irrespective of the type of drug that was discontinued. Thompson and Trimble (1980,1982) Ludgate etal.(1985) and Van Rijckervorsel etal. (1990) are other examples of studies that showed marked improvement after reduction of polytherapy.
• In contrast, the fourth type of study does not show convincing effects of polytherapy. In these add-on studies a new drug is added to either monotherapy or to an existing polytherapy. Berents et al. (1987) showed impaired verbal learning when a new drug was added to an already existing polytherapy. Most other studies, however, showed no effects of newer drugs to an existing polytherapy. These are, however, all studies within the context of drug trials in refractory epilepsy, where the added effects of a new drug are difficult to entangle from the beneficial effects of improved seizure control.
• Finally, the last type of study that we could distinguish analyzed the relationship between cognitive impairment in polytherapy with serum level. Dekaban and Lehman (1975) claim a relationship but the study does not control interfering factors such as dose and seizure confound and, hence, does not guarantee valid interpretation. The same situation occurs for other studies such as Reynolds and Travers (1974), Matthews and Harley (1975) and Thompson and Trimble (1983).
The existing evidence from especially the reduction studies, therefore suggests the possibility of potentiation of tolerability problems in polytherapy and specifically an increase of cognitive problems. It may therefore be hypothesized that drug interactions maybe responsible for this potentiation. This seems to be a general effect as it occurs in many combinations of drugs and so far not a specific combination has been identified.