The cognitive impact of antiepileptic drugs
13 Sep 2011-Therapeutic Advances in Neurological Disorders (SAGE Publications)-Vol. 4, Iss: 6, pp 385-407
TL;DR: The data reviewed suggest that the effects exerted by an AED could vary depending on both patient characteristics and drug-related variables, and longitudinal studies are needed to improve the understanding of the influence of factors such as age, tolerance and the stability of cognitive effects.
Abstract: Effective treatment of epilepsy depends on medication compliance across a lifetime, and studies indicate that drug tolerability is a significant limiting factor in medication maintenance. Available antiepileptic drugs (AEDs) have the potential to exert detrimental effects on cognitive function and therefore compromise patient wellbeing. On the other hand, some agents may serve to enhance cognitive function. In this review paper, we highlight the range of effects on cognition linked to a variety of newer and older AEDs, encompassing key alterations in both specific executive abilities and broader neuropsychological functions. Importantly, the data reviewed suggest that the effects exerted by an AED could vary depending on both patient characteristics and drug-related variables. However, there are considerable difficulties in evaluating the available evidence. Many studies have failed to investigate the influence of patient and treatment variables on cognitive functioning. Other difficulties include variation across studies in relation to design, treatment group and assessment tools, poor reporting of methodology and poor specification of the cognitive abilities assessed. Focused and rigorous experimental designs including a range of cognitive measures assessing more precisely defined abilities are needed to fill the gaps in our knowledge and follow up reported patterns in the literature. Longitudinal studies are needed to improve our understanding of the influence of factors such as age, tolerance and the stability of cognitive effects. Future trials comparing the effects of commonly prescribed agents across patient subgroups will offer critical insight into the role of patient characteristics in determining the cognitive impact of particular AEDs.
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TL;DR: Responsive neurostimulation decreases the frequency of disabling seizures when used as an adjunctive therapy in patients with medically refractory partial‐onset seizures.
Abstract: SummaryObjective
Responsive neurostimulation decreases the frequency of disabling seizures when used as an adjunctive therapy in patients with medically refractory partial-onset seizures. The effect of long-term responsive neurostimulation on neuropsychological performance has not yet been established.
Methods
Neuropsychological data were collected from subjects participating in the open-label arm of a randomized controlled trial of responsive neurostimulation with the RNS® System. Primary cognitive outcomes were the Boston Naming Test (BNT) and Rey Auditory Verbal Learning (AVLT) test. Neuropsychological performance was evaluated at baseline and again following 1 and 2 years of RNS System treatment. Follow-up analyses were conducted in patients with seizure onset restricted to either the mesial temporal lobe or neocortex.
Results
No significant cognitive declines were observed for any neuropsychological measure through 2 years. When examined as a function of seizure onset region, a double dissociation was found, with significant improvement in naming across all patients (p < 0.0001), and for patients with neocortical seizure onsets (p < 0.0001) but not in patients with mesial temporal lobe (MTL) seizure onsets (p = 0.679). In contrast, a significant improvement in verbal learning was observed across all patients (p = 0.03), and for patients with MTL seizure onsets (p = 0.005) but not for patients with neocortical onsets (p = 0.403).
Significance
Treatment with the RNS System is not associated with cognitive decline when tested through 2 years. In fact, there were small but significant beneficial treatment effects on naming in patients with neocortical onsets and modest improvements in verbal learning for patients with seizure onsets in MTL structures. These results suggest that there are modest cognitive improvements in some domains that vary as a function of the region from which seizures arise.
136 citations
TL;DR: Successful management of epilepsy requires a holistic approach to care, with treatment tailored to the individual patient's needs, and this can only be achieved through effective doctor–patient communication and the full involvement of a multidisciplinary care team.
Abstract: The impact of epilepsy is multifaceted and extensive on its effects. The
occurrence of seizures is unpredictable and often dangerous,
increasing the risk of injury, hospitalization and mortality, and
adversely affecting a patient’s mental health, often resulting in
anxiety, depression or cognitive impairment. Seizures can also result
in stigmatization and social exclusion, with detrimental effects on an
individual’s confidence and self-esteem. However, the burden of
epilepsy extends beyond the effects of seizures themselves. In
particular, individuals with epilepsy are significantly more likely to
have medical or psychiatric comorbidities than those without epilepsy,
and comorbidity in patients with epilepsy has been shown to be
strongly correlated with negative impacts on subjective health status
and quality of life (QoL). In addition, antiepileptic drug (AED)
treatment is commonly associated with side effects, which further
impair patients’ QoL. Patient surveys provide valuable insights into
what matters to patients in their daily lives and highlight important
discrepancies between the perceptions of patients and their physicians.
For example, survey data show that physicians underestimate the
number of patients experiencing AED side effects and the impact of
these on patients. Screening questionnaires can help physicians to
quickly identify problems with treatment side effects; also, to
recognize comorbidities such as depression that are otherwise difficult
to identify in a time-limited consultation. Ultimately, successful
management of epilepsy requires a holistic approach to care, with
treatment tailored to the individual patient’s needs; this can only be
achieved through effective doctor–patient communication and the full
involvement of a multidisciplinary care team.
100 citations
Cites background from "The cognitive impact of antiepilept..."
...In addition to the potentially injurious effects of seizures themselves (8), injury in patients with epilepsy may result from comorbid conditions (9, 10), or adverse cognitive effects of AED treatment (11)....
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TL;DR: It is concluded that Curcumin has the ameliorative effect on seizure severity, depression like behavior and memory impairment in pentylenetetrazole kindled mice, possibly via central monoaminergic modulation and inhibitory effect on nitrosative stress and acetylcholinesterase activity.
99 citations
Cites background or result from "The cognitive impact of antiepilept..."
...Several research reports suggesting the detrimental effect of chronic treatment of phenytoin on cognition in normal and epileptic subjects (Ogura et al., 2002; Park and Kwon, 2008; Eddy et al., 2011), supports the outcome of this study....
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...The conventional antiepileptic drugs, used to manage epilepsy can also produce these psychiatric comorbidities (Arroyo and de la Morena, 2001; Motamedi and Meador, 2003; Lagae, 2006; Vinayan, 2006; Schmidt, 2009; Eddy et al., 2011; Kanner et al., 2012)....
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TL;DR: Physicians should not only be aware of the late and chronic AEs of AEDs but should systematically enquire and screen for these according to the individual AED AE profile, and care should be taken for individuals with comorbid conditions that may render them more susceptible to specific AEs.
Abstract: Antiepileptic drugs (AEDs) are used by millions of people worldwide for the treatment of epilepsy, as well as in many other neurological and psychiatric conditions. They are frequently associated with adverse effects (AEs), which have an impact on the tolerability and success of treatment. Half the people who develop intolerable AEs discontinue treatment early on after initiation, while the majority of people will continue to be exposed to their effects for long periods of time. The long-term safety of AEDs reflects their potential for chronic, cumulative dose effects; rare, but potentially serious late idiosyncratic effects; late, dose-related effects; and delayed, teratogenic or neurodevelopmental effects. These AEs can affect every body system and are usually insidious. With the exception of delayed effects, most other late or chronic AEs are reversible. To date, there is no clear evidence of a carcinogenic effect of AEDs in humans. While physicians are aware of the long-term AEs of old AEDs (the traditional liver enzyme-inducing AEDs and valproate), information about AEs of new AEDs (such as lamotrigine, levetiracetam, oxcarbazepine, topiramate or zonisamide), particularly of their teratogenic effects, has emerged over the years. Sporadic publications have raised issues about AEs of the newer AEDs eslicarbazepine, retigabine, rufinamide, lacosamide and perampanel but their long-term safety profiles may take years to be fully appreciated. Physicians should not only be aware of the late and chronic AEs of AEDs but should systematically enquire and screen for these according to the individual AED AE profile. Care should be taken for individuals with comorbid conditions that may render them more susceptible to specific AEs. Prevention and appropriate management of long-term AED AEs is expected to improve adherence to treatment, quality of life and control of epilepsy.
88 citations
Cites background from "The cognitive impact of antiepilept..."
...AEs are expected to subside following discontinuation of the responsible AED [219]....
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...Studies in healthy volunteers and people with epilepsy have shown negative effects of AEDs in a variety of neuropsychological tests [219]....
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...Development of tolerance to cognitive AEs after long-term use has been reported for VGB [232] but information about other AEDs is lacking [219]....
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...In addition, special populations, such as children, the elderly, people with LD or previous cognitive difficulties, may be more vulnerable to cognitive AEs [219]....
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...The risk of cognitive AEs increases with rapid titration, higher AED doses and concentrations, and use of polytherapy [219, 226]....
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References
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TL;DR: Ethosuximide and valproic acid are more effective than lamotrigine in the treatment of childhood absence epilepsy and are associated with fewer adverse attentional effects.
Abstract: Background Childhood absence epilepsy, the most common pediatric epilepsy syndrome, is usually treated with ethosuximide, valproic acid, or lamotrigine. The most efficacious and tolerable initial empirical treatment has not been defined. Methods In a double-blind, randomized, controlled clinical trial, we compared the efficacy, tolerability, and neuropsychological effects of ethosuximide, valproic acid, and lamotrigine in children with newly diagnosed childhood absence epilepsy. Drug doses were incrementally increased until the child was free of seizures, the maximal allowable or highest tolerable dose was reached, or a criterion indicating treatment failure was met. The primary outcome was freedom from treatment failure after 16 weeks of therapy; the secondary outcome was attentional dysfunction. Differential drug effects were determined by means of pairwise comparisons. Results The 453 children who were randomly assigned to treatment with ethosuximide (156), lamotrigine (149), or valproic acid (148) wer...
504 citations
TL;DR: It is concluded that phenobarbital depresses cognitive performance in children treated for febrile seizures and that this disadvantage may outlast the administration of the drug by several months and is not offset by the benefit of seizure prevention.
Abstract: Phenobarbital is widely used in the treatment of children with febrile seizures, although there is concern about possible behavioral and cognitive side effects. In 217 children between 8 and 36 months of age who had had at least one febrile seizure and were at heightened risk of further seizures, we compared the intelligence quotients (IQs) of a group randomly assigned to daily doses of phenobarbital (4 to 5 mg per kilogram of body weight per day) with the IQs of a group randomly assigned to placebo. After two years, the mean IQ was 7.03 [corrected] points lower in the group assigned to phenobarbital than in the placebo group (95 percent confidence interval, -11.52 to -2.5, P = 0.0068 [corrected]). Six months later, after the medication had been tapered and discontinued, the mean IQ was 5.2 points lower in the group assigned to phenobarbital (95 percent confidence interval, -10.5 to 0.04, P = 0.052). The proportion of children remaining free of subsequent seizures did not differ significantly between the treatment groups. We conclude that phenobarbital depresses cognitive performance in children treated for febrile seizures and that this disadvantage, which may outlast the administration of the drug by several months, is not offset by the benefit of seizure prevention.
497 citations
"The cognitive impact of antiepilept..." refers background in this paper
...However, studies involving children with epilepsy have linked this agent to lower IQ [Farwell et al. 1990; Camfield et al. 1979], and discontinuation of the drug can improve total IQ (mainly affecting nonverbal items) in children [Tonekaboni et al....
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...However, studies involving children with epilepsy have linked this agent to lower IQ [Farwell et al. 1990; Camfield et al. 1979], and discontinuation of the drug can improve total IQ (mainly affecting nonverbal items) in children [Tonekaboni et al. 2006]....
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TL;DR: LTG is effective in reducing seizure frequency and has additional favorable effects on seizure severity, mood, and perceived internal control, according to simple correlation and multiple‐regression analyses.
Abstract: The need for new antiepileptic drugs (AEDs) and more sensitive methods of assessing their efficacy is well recognized. This study was designed to evaluate the efficacy and safety of lamotrigine (LTG), a potential new AED and to develop and test new outcome measures. A health-related quality of life (HRQL) model was developed which contains previously validated measures of anxiety, depression, happiness, overall mood, self-esteem, and mastery and a specifically designed seizure severity scale with patient- and caregiver-based components. This HRQL model was used in a randomized, placebo-controlled, double-blind, cross-over study of LTG in 81 patients with refractory partial seizures. Seizure frequency was the primary measure and seizure severity and the HRQL were secondary measures of efficacy. The reduction in seizure frequency with LTG, relative to placebo, was 29.7% [95% confidence interval (CI) 17.8%, 39.9%] for total seizure count, 33.4% (95% CI 14.8%, 47.9%) for complex partial seizures (CPS) and 20.3% (95% CI 0.3%, 36.2%) for secondarily generalized tonic-clonic seizures (GTCS). However, although 41 patients elected to continue with LTG, only 11 experienced at least 50% reduction in total seizures, indicating that other factors influenced their decision. The score with LTG, relative to placebo, was significantly lower for the ictal (p = 0.017) and caregivers (p = 0.035) subscales of the seizure severity scale and significantly higher for happiness (p = 0.003) and mastery (p = 0.003). Simple correlation and multiple-regression analyses indicate that the effects on seizure frequency, seizure severity, and psychological variables appear to be independent of each other. This study indicates that LTG is effective in reducing seizure frequency and has additional favorable effects on seizure severity, mood, and perceived internal control. Some of the scales used indicate the potential of secondary measures of efficacy to enhance the sensitivity of trials of new AEDs.
323 citations
"The cognitive impact of antiepilept..." refers result in this paper
...adverse effect on cognition in association with lamotrigine [Smith et al. 1993], and other studies have reported similar findings [Bootsma et al....
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...…placebo-controlled crossover study of 81 patients with refractory partial seizures demonstrated no adverse effect on cognition in association with lamotrigine [Smith et al. 1993], and other studies have reported similar findings [Bootsma et al. 2008b; Gillham et al. 2000; Aldenkamp et al. 1997]....
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TL;DR: Additional, more sensitive, methods of monitoring patients while receiving these drugs is necessary because subtle but significant changes in intellectual function and behavior may be occurring.
Abstract: Traditional clinical monitoring of children with epilepsy does not appear to be sufficiently sensitive to cognitive functioning and behavioral problems. Although subtle, these changes may alter a child's ability to perform well in school and in society. Physicians must prevent seizures without producing intolerable side effects, and ways of more appropriately assessing these side effects must be developed. In this double-blind, counter-balanced, crossover study of 21 children, the effects of phenobarbital and valproic acid on cognitive functioning and behavior were measured. There was no difference in seizure control between the drugs, and each medication was maintained in the therapeutic range for 6 months (mean phenobarbital level, 21.2 micrograms/mL; mean valproic acid level, 94.1 micrograms/mL). Children were treated with each drug for 6 months. Differences between the drugs were seen on measurements of cognitive function and behavior. On four tests of neuropsychologic function, children performed significantly less well while receiving phenobarbital (P less than .01). There was no evidence that the patients were sedated or less able to perform continuous performance tasks while receiving phenobarbital. Parental assessment of behavior indicated significantly worse behavior with the phenobarbital regimen for three items (P less than .01) and children were measurably more "hyperactive" (P less than .05). Routine clinical assessment of the patients did not reveal differences between the drugs with respect to routine laboratory measurements or side effects as assessed by history or physical examination. Although children may appear to tolerate a medication without clinically apparent problems, subtle but significant changes in intellectual function and behavior may be occurring. Additional, more sensitive, methods of monitoring patients while receiving these drugs is necessary.
257 citations
"The cognitive impact of antiepilept..." refers background in this paper
...Phenobarbital is considered to have worse cognitive effects than valproate or carbamazepine [Calandre et al. 1990; Vining et al. 1987]....
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...In relation to the effects of other AEDs on cognitive function, valproate has been suggested to be preferable to carbamazepine [Forsythe et al. 1991], phenobarbital [Vining et al. 1987] and topiramate [Sun et al. 2008; De Araujo Filhou 2006; Meador et al. 2003]....
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TL;DR: To evaluate pregabalin (PGB), 150 mg/day, and PGB, 600 mg/ day, as an add‐on treatment for patients with refractory partial seizures concurrently treated with one to three AEDs.
Abstract: Summary: Purpose: To evaluate pregabalin (PGB), 150 mg/day, and PGB, 600 mg/day, as an add-on treatment for patients with refractory partial seizures concurrently treated with one to three anticonvulsants (AEDs).
Methods: An international (13 countries), multicenter (45 centers), 12-week, double-blind, randomized study in which patients with partial seizures received placebo (n = 96); PGB, 150 mg/day (n = 99); or PGB, 600 mg/day (n = 92); given 3 times a day (t.i.d.). The primary efficacy criterion was reduction in seizure frequency during treatment as compared with baseline, as measured by RRatio, the symmetrical percentage change in seizure rates determined from daily seizure diaries. The RRatio between the 8-week baseline (pretreatment phase) and the 12-week treatment period were compared between each of the PGB groups and the placebo group by using an analysis of variance analysis of the intent-to-treat population.
Results: PGB, 150 mg/day and 600 mg/day, were both significantly more effective than placebo in reducing the RRatio [–11.5 (p = 0.0007) and –31.4 (p ≤ 0.0001), respectively, vs. 0.9]. These RRatio values correspond to seizure-frequency reductions from baseline of –1.8, 20.6, and 47.8% for placebo, 150 mg/day, and 600 mg/day, respectively. PGB efficacy was significantly dose related (p ≤ 0.0001). Secondary efficacy variables corroborated the findings of the primary analysis. Significantly more patients were responders (≥50% reduction in seizure frequency) in the PGB, 600 mg/day (43.5%), group than in the placebo group (6.2%) (p ≤ 0.001). PGB was well tolerated. Dose-related, treatment-emergent adverse events (≥10%), mostly mild or moderate in intensity, were somnolence, dizziness, ataxia, diplopia, and weight gain. The withdrawal rate due to adverse events was 10% of patients at 150 mg/day and 18.5% of patients at 600 mg/day, compared with 6.2% of patients receiving placebo.
Conclusions: PGB, 150 mg/day and 600 mg/day, is highly effective and well-tolerated add-on therapy in patients with partial seizures.
251 citations
Additional excerpts
...Other reports indicate that abnormal thinking may be rare [Arroyo et al. 2004], although one report indicated this CAE could be 9–12 times more likely with pregabalin than with placebo [Beydoun et al....
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...Other reports indicate that abnormal thinking may be rare [Arroyo et al. 2004], although one report indicated this CAE could be 9–12 times more likely with pregabalin than with placebo [Beydoun et al. 2005]....
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