We will analyze studies for the following newer AEDs: oxcarbazepine (OXC), LTG, TPM, tiagabine (TGB), GBP, and levetiracetam (LEV).
OXC is a keto homologue of CBZ with a completely different metabolic profile. In humans, the keto group is rapidly and quantitatively reduced to form a monohydroxy derivative that is the main active agent during OXC therapy. Oxcarbazepine was approved in the European Union in 1999 and is indicated for use as monotherapy or adjunctive therapy for partial seizures with or without secondarily generalized tonic-clonic seizures in patients ≥6 years of age.
The effects of OXC on cognitive function have been evaluated in one study in healthy volunteers and in four studies in patients with epilepsy. A double-blind, placebo-controlled, crossover study was conducted in 12 healthy volunteers (27). The effects of two doses of OXC (300 and 600 mg/day) and placebo on cognitive function and psychomotor performance were assessed. The treatment duration for each condition was 2 weeks. Cognitive function tests were administered before treatment initiation and 4 h after the morning doses on days 1, 8, and 15. In this study, OXC improved performance on a focused attention task, increased manual writing speed, and had no effect on long-term memory processes.
In patients with epilepsy, four monotherapy comparative studies evaluated the effects of OXC on cognitive functions in adult patients with newly diagnosed epilepsy (28–31). The first study was a double-blind, active-control study evaluating the effects of CBZ and OXC on memory and attention in 41 patients with newly diagnosed epilepsy (28). The treatment duration was 1 year. Cognitive function and intelligence tests were administered before treatment initiation and after 1 year of treatment. The results indicated no deterioration of memory or attention with either CBZ or OXC. The second study was an active-control study that evaluated the effects of CBZ, VPA, and OXC on intelligence, learning, and memory, attention, psychomotor speed, verbal span, and visuospatial construction in 32 patients with newly diagnosed epilepsy (29). The treatment duration was 4 months. Cognitive function and intelligence tests were administered before treatment initiation and after 4 months of treatment. The results indicated no deterioration of cognitive function in any treatment group. Significant improvements in learning and memory tests were found for the CBZ- and OXC-treated patients. Improvements were also found in attention and psychomotor speed tests for the VPA-treated patients and partly for the CBZ-treated patients. The third study was a double-blind, randomized, active-control study that evaluated the effects of PHT and OXC on memory, attention, and psychomotor speed in 29 patients with newly diagnosed epilepsy (30). The treatment duration was 1 year. Cognitive function tests were administered before treatment initiation and after 6 and 12 months of treatment. The results indicated no significant differential cognitive effects between PHT and OXC during the first year of treatment in patients with newly diagnosed epilepsy who achieved adequate seizure control. In the fourth study (31), three groups of 12 patients taking either CBZ, VPA, or PHT took a single 600-mg dose of OXC, followed 7 days later by 3 weeks of treatment with OXC 300 mg three times daily and matched placebo in random order. Seven untreated patients, acting as controls, were prescribed the single OXC dose and 3 weeks of active treatment only. There were no important changes in cognitive function test results during administration of OXC compared with placebo.
In summary, the results of these studies indicate that OXC does not affect cognitive function in healthy volunteers and adult patients with newly diagnosed epilepsy. However, the effects of OXC on cognitive function have not been systematically studied in children and adolescents. In accordance with the latest revision of the Committee for Proprietary Medicinal Products (CPMP) Note of Guidance (CPMP EWP/566/98 rev 1, dated November 16, 2000, Sections 2.5 and 5.2), a study has recently been launched (Protocol #: CTRI476E2337) to investigate the effects of OXC on cognitive function (i.e., psychomotor speed and alertness, mental information processing speed and attention, memory, and learning) in children and adolescents aged 6 to <17 years with partial seizures.
TPM is a sulfamate-substituted monosaccharide that has multiple mechanisms of action (32). TPM has proved to be effective in patients with refractory chronic partial epilepsies (15,33).
During the initial add-on clinical trials, central nervous system (CNS)–related “cognitive” subjective complaints were frequently reported, including mental slowing, attentional deficits, speech problems, and memory difficulties (15). It should be mentioned, however, that higher target doses and faster titration schedules were used than are now used in clinical practice (see references 34 and 35 for a discussion of dose and titration speed). Recent studies with TPM-treated patients have confirmed high levels of adverse cognitive effects based on subjective complaints (36,37). A recent follow-up study (Bootsma HPR, Coolen F, Aldenkamp AP, et al., unpublished data) showed long-term retention of 30% for a 4-year follow-up. For about half of the 70% of patients who discontinued treatment, side effects were the major reason, with cognitive side effects being most frequently mentioned. Only a few studies have psychometrically measured cognitive changes using neuropsychological tests.
A study by Martin et al. in six normal volunteers (38)used an acute dose of 2.8 mg/kg (∼200 mg/day) followed by a titration to 5.7 mg/kg (∼400 mg/day) in 4 weeks, resulting in weekly dose escalations of ∼100 mg. The rate at which TPM was escalated in this study was very similar to the dose escalation used in the initial TPM adjunctive-therapy trials, in which escalating the TPM dose to 200 or 400 mg/day over 2–3 weeks was associated with somnolence, psychomotor slowing, speech disorders, and concentration and memory difficulties (15,37; Bootsma HPR, Coolen F, Aldenkamp AP, et al., unpublished data). Martin et al. showed neuropsychometric changes commensurate with these CNS effects. The cognitive effects of the acute starting dose of 200 mg/day were impairments of verbal function (word finding and verbal fluency) of ∼2 standard deviations (which represents very serious impairment) and of sustained attention. Titration to 400 mg/day in 4 weeks resulted in impairments of verbal memory and mental speed of >2 standard deviations.
Four studies involving patients with epilepsy are available. In a study by Meador (39) with 155 patients with epilepsy, the effects of the gradual introduction of TPM as add-on (a 50-mg starting dose, followed by increments of 50 mg/week over 8 weeks) were compared with those of more rapid dose escalation (initial dose of 100 mg, followed by two consecutive weekly increments of 100 and 200 mg). In a test battery of 23 variables representing selective attention, word fluency, and visuomotor speed, the subjects who were on a slow-titration schedule and treated with one background AED displayed TPM-associated score changes of more than one third but <1 standard deviation (39). A study by Aldenkamp et al. (35) was specifically designed to compare cognitive effects of TPM and VPA added to therapeutic dosages of CBZ in 59 patients with epilepsy. In this study, a slow titration speed was used with a starting dose of 25 mg/day TPM and weekly increments of 25 mg. Moreover, the average achieved dose (∼250 mg) was relatively low. Neuropsychometric testing was conducted 8 weeks after the last dosage increase (20 weeks after the start of TPM therapy). The study therefore used optimal conditions (i.e., slow titration, relatively low dose, and a longer treatment period), allowing for patient habituation to the effects of TPM therapy. Nonetheless, cognitive impairment was found for verbal memory function both during titration and at end point. In a study by Burton and Harden (40), attention was assessed weekly in 10 subjects receiving TPM over a 3-month period. Four of nine subjects showed significant correlations between TPM dosage and forward digit span measured weekly, such that higher dosage was associated with poorer attention. In a retrospective study by Thompson et al. (41), the neuropsychological test scores of 18 patients obtained before and after the introduction of treatment with TPM (median dose 300 mg) were compared with changes in test performance of 18 patients who had undergone repeat neuropsychological assessments at the same time intervals. In those patients taking TPM, a significant deterioration in many domains was found. The largest changes were for verbal IQ, verbal fluency, and verbal learning.
In summary, there is clear clinical evidence for TPM-induced cognitive impairment. Not all studies are comparable because of the confusion about dose and titration speed (see reference 34 for a discussion). Moreover, the complete lack of controlled studies is remarkable.
LTG blocks voltage-dependent sodium channels, thereby preventing excitatory neurotransmitter release. Clinical evidence indicates that LTG is effective against partial and secondarily generalized tonic-clonic seizures, as well as idiopathic (primary) generalized epilepsy. LTG was introduced in Europe in 1991 and in the United States in 1994.
A large number of cognitive studies are available for LTG (see reference 42 for an overview). Five volunteer studies have been conducted with LTG. Doses of 120 and 240 mg did not produce a significant change in cognitive function compared with baseline when administered to 12 normal volunteers in an acute study of 1 day (43). Similarly, five volunteers received LTG (acute dose 3.5 mg/kg and then titrated to a maximum of 7.1 mg/kg) in a single-blind manner and were assessed for change in cognitive function after 2 and 4 weeks (38). There was no significant change in any of the neurocognitive measures relative to baseline performance. LTG and CBZ have been compared in 12 healthy male volunteers and associations were made between the observed cognitive effects and plasma concentrations of these drugs (44). The effects of these drugs were examined using adaptive tracking, which assesses eye–hand coordination and effects of attention, and eye movement tests. LTG treatment was not significantly different from placebo, but increased CBZ saliva concentrations were significantly associated with impaired adaptive tracking and smooth and saccadic eye movements. The long-term effects of LTG and CBZ were compared in 23 volunteers in a 10-week crossover study (45). The neuropsychological battery in this study consisted of 19 instruments yielding 40 variables, including both subjective and objective measures. LTG showed better performance or fewer side effects in 17 (42%) of the variables, while no statistically significant differences were seen in the remaining variables. Finally, a study by Aldenkamp et al. (46) in 30 volunteers (12 days of treatment, using a daily dose of 50 mg of LTG) showed evidence for a selective positive effect of LTG on cognitive activation, relative to both placebo and VPA. Although the results of these volunteer studies provide us with preliminary insight into the impact of LTG on cognition, the generalizability of the results from these studies to patients with epilepsy receiving long-term AED treatment is limited.
The effects of LTG on cognitive function have been compared with those of CBZ in patients with newly diagnosed epilepsy. Patients completed tests of verbal learning and memory, attention, and mental flexibility at baseline and then periodically for up to 48 weeks. Significant differences favoring LTG over CBZ were observed with semantic processing, verbal learning, and attention. Brodie et al. (47) concluded that LTG may have a favorable long-term effect on cognitive function when compared with CBZ. Other studies have reported positive cognitive effects of LTG used as adjunctive therapy. Two independent double-blind, randomized, crossover studies have examined the cognitive effects of LTG used as add-on therapy (48,49). Both studies included patients with a history of partial seizures (at least once weekly during the preceding 3 months) who had received no more than two other AEDs or VPA monotherapy. Both studies also used two treatment periods (12 and 18 weeks), which were separated by a washout period (4 and 6 weeks). Despite the similarity in trial design and patients, there is some inconsistency between the findings of these two studies. One study showed a marginal reduction in general “cerebral efficiency” (an indirect measure of cognitive function) after LTG treatment (49). Conversely, significant improvements were reported in the second study (48). In an uncontrolled add-on study (50) using CBZ as baseline drug, no deterioration on any of the cognitive tests was found after introducing LTG (200 mg). LTG therapy in seven patients with epilepsy and mental retardation caused both positive and negative psychotropic effects (51). These findings were based on the observations of parents and supervising staff. Positive effects included reduced irritability and increased compliance with simple instructions, while negative effects included behavioral deterioration with temper tantrums, restlessness, and hyperactivity. Similarly, a second study in 67 patients with mental retardation showed that after adjunctive treatment with LTG, social functioning was stable or improved in 90% of patients (52).
In addition to clinical studies that have assessed the impact of LTG on cognitive function, further evidence can be obtained from examining the effect of LTG on electroencephalographic (EEG) parameters. Overt EEG discharges can occur without any visible clinical correlate in many patients with epilepsy. These epileptiform episodes may be associated with transient deterioration in cognitive function (53,54). Data from several studies indicate that LTG may reduce spontaneous epileptiform discharges, which may partially explain the favorable cognitive profile of LTG. In five patients displaying spontaneous EEG discharges, a single dose of LTG (120 or 240 mg in addition to existing medication) resulted in a substantial reduction in spontaneous interictal discharges within a 24-h period (55). The long-term effects of LTG on paroxysmal abnormalities have also been monitored with a computer-based analysis system (56). Twenty-one patients with intractable epilepsy (20 of whom were receiving multiple AED therapy) were evaluated before and after LTG treatment for EEG ictal events and number of spikes in a 10-min period. Before LTG treatment, patients typically showed discharges characterized by diffuse spike-wave complexes. However, after a 4-month treatment period with LTG, ictal discharges disappeared and diffuse slow wave activity was seen with no adverse effect on background activity. Nineteen of the 21 patients also showed a reduction in seizure frequency.
The effect of LTG add-on therapy in 11 patients with refractory partial seizures with or without secondary generalization has also been reported (57). LTG was added to existing therapy consisting of CBZ with at least one additional AED. EEG recordings were made at rest with eyes closed, during an attentive task (blocking reaction induced by several episodes of eyes open lasting 8–9 s), during cognitive tasks, and while performing mental arithmetic. In addition, a battery of neuropsychological tests was carried out. Before LTG treatment, EEG data revealed a decrease in fast activity at rest and a reduction in alpha and beta bands during attentive and cognitive tasks. LTG treatment resulted in a selective increase in alpha reactivity and beta power during the attentive tasks with no other detectable changes. During cortical activation, subtle changes were observed that were taken as indicative of a slight improvement in attention. Neuropsychological evaluation revealed that after 3 months of LTG therapy, no deterioration in cognitive function had occurred.
LTG also shows a promising cognitive profile in elderly patients suffering from age-associated memory impairment (58). A neuropsychological test battery, in combination with auditory event-related potentials (ERPs), was used to measure the impact of LTG on cognitive function. LTG treatment caused a reduction in amplitude of the P300 component of the ERP, and a corresponding improvement in immediate and delayed visual memory and delayed logical memory. LTG may therefore improve simple memory functions in a memory-impaired elderly population.
Levetiracetam (LEV) is a new AED, structurally and mechanistically dissimilar to other marketed AEDs. It is effective in reducing partial seizures in patients with epilepsy, both as adjunctive treatment and as monotherapy. LEV has many therapeutic advantages for patients with epilepsy. It has favorable pharmacokinetic characteristics (good bioavailability, linear pharmacokinetics, insignificant protein binding, lack of hepatic metabolism, and rapid achievement of steady-state concentrations) and a low potential for drug interactions. It is licensed for use as adjunctive treatment for partial seizures, with or without secondary generalization, in people aged over 16 years. For its impact on cognitive function, we only have data from a small pilot study that does not allow definite conclusions (59).
TGB is a γ-aminobutyric acid (GABA) uptake inhibitor that is structurally related to nipecotic acid but has an improved ability to cross the blood–brain barrier. Clinical trials have shown that TGB is effective as add-on therapy in the management of patients with refractory partial epilepsy. Three cognitive studies are available.
Dodrill et al. (60) included 162 patients who received the following treatments: placebo (n = 57), 16 mg/day TGB (n = 34), 32 mg/day TGB (n = 45), or 56 mg/day TGB (n = 26) at a fixed dose for 12 weeks after a 4-week dose titration period. Eight cognitive tests and three measures of mood and adjustment were administered during the baseline period and again during the double-blind period near the end of treatment (or at the time of dropout). The results showed no cognitive effects of monotherapy with TGB at a low or high dose, but there was some evidence for mood effects of add-on treatment with TGB at higher dosing, possibly related to titration speed. In the add-on polytherapy study by Kälviäinen et al. (61), 37 patients with partial epilepsy were included. The study protocol consisted of a randomized, double-blind, placebo-controlled, parallel-group add-on study and an open-label extension study. During the 3-month double-blind phase at low doses (30 mg/day), TGB treatment did not cause any cognitive changes as compared with placebo. TGB treatment also did not cause deterioration in cognitive performance during longer follow-up with successful treatment on higher doses after 6–12 months (mean 65.7 mg/day, range 30–80 mg/day) and after 18–24 months (mean dose 67.6 mg/day, range 24–80 mg/day). Finally, a study by Sveinbjornsdottir et al. (62) was an open trial of 22 adult patients with refractory partial epilepsy followed by a double-blind, placebo-controlled, crossover trial in 12 subjects. Nineteen patients completed the initial open titration and fixed-dose phase of the study and 11 patients completed the double-blind phase. The median daily TGB dose was 32 mg during the open fixed dose and 24 mg during the double-blind period. Neuropsychological evaluation did not show any significant effect on cognitive function in the open or double-blind phase.
GBP is a novel AED, currently used as add-on therapy in patients with partial seizures. GBP apparently has a completely novel type of action, probably involving potentiation of GABA-mediated inhibition and possibly inactivation of sodium channels. Two volunteer studies and one clinical study are available to interpret the cognitive effects.
Martin et al. (38) used an acute dose and rapid titration in six volunteers and did not find cognitive effects of GBP. Meador et al. (63) compared the cognitive effects of GBP and CBZ in 35 healthy subjects using a double-blind, randomized, crossover design with two 5-week treatment periods. During each treatment condition, subjects received either GBP 2,400 mg/day or CBZ (mean 731 mg/day). Subjects were tested at the end of each AED treatment period and in four drug-free conditions [two pretreatment baselines and two posttreatment washout periods (1 month after each AED)]. The neuropsychological test battery included 17 measures yielding 31 total variables. Significantly better performance on eight variables was found for GBP, but on no variables for CBZ. Comparison of CBZ and GBP with the nondrug average revealed significant statistical differences for 15 (48%) of 31 variables. Leach et al. (64) studied GBP in 21 patients in an add-on polytherapy study after 4 weeks of adjunctive therapy and found no change in psychomotor and memory tests. Drowsiness was more often found in higher dosing (2,400 mg). Mortimore et al. (65) did not find a difference between continued polytherapy and an add-on with GBP in measures of quality of life.