Cognitive effects of seizures

Transcription

1 Seizure (2006) 15, Cognitive effects of seizures Guy Vingerhoets * Laboratory for Neuropsychology, Department of Internal Medicine-Section Neurology, Ghent University, De Pintelaan 185-4K3, B-9000 Ghent, Belgium Received 24 January 2006; accepted 15 February 2006 KEYWORDS Cognition; Seizures; Epilepsy; Neuropsychology; Intelligence Summary We aimed to review recent prospective and cross-sectional studies regarding the gradual and chronic effects of (cumulative) seizures on cognition. In contrast with the increasing evidence of structural changes in the brain associated with repeated seizures, its functional repercussions remain unclear. Methodological difficulties of cross-sectional and prospective studies are addressed. It appears that all but one of the prospective studies available on children are limited to measures of intelligence. Most studies revealed no significant adverse effects, although there appears to be a subgroup of about 10 25% of children that shows a clinically significant intellectual decline. Children with generalized symptomatic epilepsies, frequent seizures, high antiepileptic drug use, and early onset of epilepsy appear at risk, although psychosocial factors may also play an important role. Five of the six prospective studies on adults report evidence of a mild decline in cognition in patients with a (longstanding) history of pharmacoresistant epilepsy. The adverse effect on cognitive abilities, memory in particular, seems somewhat more robust than that on measures of intelligence. A significant association between cognitive decline and seizure related variables is rarely substantiated in prospective research and crosssectional studies show contradicting results. Taken together, the data suggest a mild but measurable decline of intellectual performance in children and adults. Decline of specific cognitive abilities in children is impossible to evaluate given the very little data available. In adults, memory appears to be the most vulnerable cognitive function. Due to many confounding variables, the effect of seizures per se is difficult to estimate, but appears limited. # 2006 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. Cognitive effects of seizures * Tel.: ; fax: address: guy.vingerhoets@ugent.be. Patients with epilepsy are at significant risk for cognitive impairment and behavioral abnormalities. 1 Although it appears safe to say that the likely reason for the cognitive impairment is the neuropathology underlying the epilepsy, it remains unclear whether one of its clinical manifestations, i.e. seizures, can cause cognitive decline per se. By cognitive decline we mean the gradual and chronic loss of mental abilities over time, not the /$ see front matter # 2006 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. doi: /j.seizure

2 222 G. Vingerhoets reversible postictal cognitive deterioration that can be observed shortly after focal and generalized seizures. 2 This apparently simple question has proven extraordinarily complex, and the problem has been addressed from very different angles without providing a definite answer. 3 The aim of this review is to offer a short state of affairs on this clinically and therapeutically important question by summarizing the results of recent prospective and cross-sectional studies in children and adults. The main reason for studying the data on children separately is that there are reasons to believe that the immature brain may react differently to the long-term effects of seizures than does the mature brain. 1,4 Do seizures cause brain damage? One of the first questions that come to mind is whether there is evidence that seizures can cause (permanent) brain damage that could be responsible for the cognitive decline. The substantial experimental research on chronic rodent models of epilepsy suggests that the brain s vulnerability to seizure-induced injury is age-specific: whereas the immature brain is highly prone to develop seizures, it is more resistant to seizure induced damage than the adult brain. 4 Although experimental research, in which the animals can be sacrificed to investigate the effects of seizures on the developing brain, has shown that seizure induced damage appears less prominent in the immature nervous system, there is an abundance of evidence that there are significant long-term adverse consequences of early life seizures. Kindled seizures induce progressive cellular and metabolic alterations correlated with (hippocampal) neuronal loss, neoneurogenesis and synaptic reorganization, increased susceptibility to evoked and spontaneous seizures, and behavioral and cognitive deficits that worsen as a function of the cumulative number of seizures. 3 8 Although a similar relation might be expected in humans, it has proven much more difficult to substantiate this, and different reviews of the available data have come to somewhat different conclusions. Some underline that human cross-sectional morphological and biochemical studies on brain damage following status epilepticus or brief seizures show inconsistent results, that prospective data are lacking, and that the functional significance of the structural and biochemical changes is unclear. 4 Others argue that given the emerging data from human magnetic resonance imaging and neuropsychological studies, patients can no longer be reassured with confidence that only prolonged seizures, as in status epilepticus, can cause brain damage, whereas repeated brief seizures do not. 8 In addition to the neuropathologically documented hippocampal neuronal loss in the majority of patients with temporal lobe epilepsy, magnetic resonance imaging revealed more widespread associated neuronal damage in extrahippocampal regions. Repeated magnetic resonance imaging showed progressive hippocampal reduction following repeated seizures in several case-studies, 9,10 and an association between seizure frequency and hippocampal volume loss in prospective group studies, 11,12 although this is not always confirmed A recent study compared 37 patients with childhood-onset versus 16 patients with late-onset temporal epilepsy and 62 healthy controls using magnetic resonance imaging volumetrics and neurocognitive assessment. 16 A substantial reduction in brain volume, especially evident in white matter tissue, and extending to extra-temporal regions was found among the childhood-onset patients compared to the late-onset patients and healthy controls. This reduction was also associated with significantly poorer cognitive status. It appears from these findings that the presence of recurrent seizures in the developing human brain is associated with an adverse and widespread neurodevelopmental impact on both brain structure and function if assessed after a longstanding disease history in the matured brain. Methodological issues Before going into the recent data on the relation between seizures and cognition, it is relevant to point out the methodological difficulties that are associated with this question. In patients with localization-related symptomatic epilepsy it is difficult to disentangle the effects of epilepsy as a symptom from those of the underlying lesion causing the epilepsy. This covariance provides a major disadvantage for cross-sectional studies to address the effect of a single variable (i.e. seizures) on cognition. Measuring a state rather than a change, cross-sectional research cannot differentiate between the effect of the initial underlying lesion and the long-term effects of the disease. As a result, they tend to overestimate the effects of seizures. Patients with idiopathic epilepsy might provide a better model to study the effects of seizures in the absence of a confounding identifiable cerebral disease. However, these patients usually respond well to anticonvulsive treatment and many are only mildly cognitively impaired. The few cross-sectional neuropsychological studies on idiopathic epilepsy

3 Cognitive effects of seizures 223 failed to find a relation between cognitive impairment and seizure frequency, although a significant relation with interictal epileptiform activity was observed. 17 Some cross-sectional studies, however, were able to document the contribution of seizure frequency either statistically or by strategic comparison of patient subgroups. Prospective studies may be better able to objectivate intra-individual changes over time and to correlate these changes with specific epileptic variables, but they too are subject to confounders that interfere with the interpretation. Duration of epilepsy is a composite factor that reflects the influence of several factors in combination, the relative explanatory power of each remaining to be clarified. 18,19 The longer one suffers from intractable epilepsy, the higher the (cumulative) effect of the seizures, the more prolonged the exposure to interictal discharges or anticonvulsant drugs, and the greater the risk of seizure related closed-head injuries. In addition, seizure frequency itself is often related to increased or multiple antiepileptic drug dosage and uncontrolled seizures burden the psychological and psychosocial well being of the patient which also negatively affects cognitive performance. 20 These interrelations may only be disentangled in multiple longitudinal studies with repeated assessments in carefully selected homogeneous groups of patients. And even then, homogeneous epilepsy syndromes may present with different cognitive profiles dependent on the age at onset of epilepsy. 1 Aspecificissuein longitudinal research with repeated measurements is the problem of test retest variation. In normals, repeated testing gives rise to improved cognitive performance that is attributed to learning. The magnitude of this test retest effect is dependent on the number of repetitions, the time interval between testing, the use of alternative test versions, and the cognitive function under investigation. The absence of such a test retest effect in patient groups is often interpreted as a reduced learning potential and an argument for cognitive impairment. The use of a matched control group that undergoes exactly the same procedure is the only valid way to assess the magnitude and relevance of a (absent) test retest effect. Cognitive consequences of seizures in children In a recent review, Dodrill 21 listed nine longitudinal studies done with children. Five of these studies were published prior to They used relatively short test retest intervals of 1 or 2 years, and were all using older measures of intelligence. In addition, information on seizure frequency was either completely lacking or unclear. We will not include these older studies here, but will focus on the four more recent studies in Dodrill s review and on three additional prospective studies that are of interest. Bourgeois et al. 22 investigated 72 children (mean age: 7.5 years) who suffered from active seizure disorders over a 4-year interval with age-appropriate IQ tests. No group changes in IQ were detected, but a subgroup (11%) with frequent seizures, toxic drug levels, and early onset of epilepsy showed a decline of more than 10 IQ points. Ellenberg et al. 23 tested 83 children between 4 and 7 years old with relatively few seizures with age-appropriate IQ tests over a test retest period of 3 years. No losses in intelligence were detected. Aldenkamp et al. 24 performed a study on 45 outpatients with an average of 9.3 years of age, most of them had active seizures, with a Dutch form of the WISC-R. The average test retest interval measured 4.2 years and no significant group changes were reported although a slight decrease in IQ scores was observed. In 24% of the children however, full-scale IQ losses of more than 9 IQ points were registered. Neyens et al. 25 compared the intellectual development of 11 children with epilepsy aged 7 15 years with 39 normal controls on three occasions over a 1.5-year period. Compared to controls, children with epilepsy already showed lower intelligence levels at the first assessment and showed significantly less gain in full-scale IQ over trials. The reduced gain was more frequent in children with a recent onset of seizures than in those who had a longer duration of epilepsy. Seizure frequency was not associated with differences in fullscale IQ gain. Bjornaes et al. 26 tested 17 candidates for epilepsy surgery (mean age 10.2 years) on a 3.5 years (average) interval prior to surgery with a Norwegian version of the WISC-R. All children had active seizures of moderate severity and showed a significant decrease in performance IQ and full-scale IQ. The same group published a later study that reported on the post surgical outcome of 13 of these children. 27 Although, on average, the children showed a general decline in full-scale IQ after both the drug treatment period and the subsequent surgery, children who became seizure free after surgery showed no further decline in IQ. A recent prospective study repeatedly investigated 42 children with newly diagnosed idiopathic or cryptogenic epilepsy and 30 healthy gender-matched classmate controls over a 3.5-year period using a comprehensive neuropsychological battery and behavior checklists. 28 Most of these children became seizure-free within the first 2 years after diagnosis, either spontaneously or with anti-epileptic drug treatment.

4 224 G. Vingerhoets After controlling for the possible influence of repeating a grade at school, increased susceptibility to proactive interference, the phenomenon that previous learning inhibits new learning of similar material, was the only cognitive variable on which the epileptic group performed worse. None of the epilepsy-related variables, including seizure remission or not, had clinically meaningful effects on cognition or behavior. Instead, in the 19% of children with persistent cognitive deficits, poor parenting, unhappy family situations, and prior existence of behavioral problems were overrepresented. The effect of psychosocial variables on cognition has been corroborated recently. 29 As illustrated before, cross-sectional studies face important methodological problems in evaluating the cognitive effects of unique variables of the epileptic syndrome. Recently, a number of largescale cross-sectional studies were published that looked at specific variables and may contribute to the discussion. Nolan et al. 30 investigated 169 children, aged 0 18 years, and vigorously categorized each patient according to 6 different epilepsy syndromes, with age appropriate intelligence tests. Younger age of onset, higher seizure frequency (especially if daily), and the intake of more than two antiepileptic drugs significantly were associated with a lower full-scale IQ and contributed to 26% of its variance. After accounting for these covariates, significant differences in full-scale IQ were found between the syndrome groups, with best performances for the generalized idiopathic epilepsy group, the central epilepsy group, and the temporal lobe epilepsy group. Children with generalized symptomatic epilepsy performed most poorly and children with either non-localized partial epilepsy or frontal lobe epilepsy performed in between. Every group s average full-scale IQ fell below the age-adjusted normed mean. These results seem to indicate that seizures have an impact, and that syndromal type can be used as a separate variable when considering intellectual potential. Similar findings on type of epilepsy have been reported in a recent study with educational underachievement being more prominent in children with localized and symptomatic generalized epilepsies, suggesting a dominant impact of the underlying brain dysfunction. 31 Hoie et al. 32 compared nonverbal intelligence in 183 children between 6 and 12 years old with 126 healthy controls matched for age and gender and related these data with seizure related factors. Severe non-verbal intelligence problems were present in 43% of the patients and in 3% of the controls. The problems were especially common in children with symptomatic epilepsy, undetermined epilepsy syndromes, myoclonic seizures, early seizure debut, high seizure frequency, and in children with polytherapy. Caplan et al. 33 investigated the effect of seizure related factors on intellectual and linguistic abilities in 101 children with complex partial seizures and 102 normal children between 5 and 16 years old. Interestingly, principal component analysis of the seizure related variables revealed four components: a duration/onset component, an EEG component, a prolonged seizures/ febrile convulsions component, and a seizure frequency/number of antiepileptic drugs component. Patients showed significantly lower IQ scores and linguistic abilities than controls. The components prolonged seizures/febrile convulsions and seizure frequency/number of antiepileptic drugs both contributed significantly to the IQs observed variance. Previous research in a comparable group showed that frequency of seizure activity in the past year, rather than age at seizure onset, was the best predictor for behavioral difficulties. 34 Riva et al. 35 assessed eight children (aged 6 13 years) with frontal epilepsy and regular seizures on IQ and a wide range of frontal tests. Although IQ was generally spared, the children showed a great variety of executive dysfunctions. Frequent seizures correlated with difficulties in attention and the inability to inhibit impulsive responses. Cognitive consequences of seizures in adults Dodrill s review of prospective investigations lists 13 studies on adults. 21 We will focus on the only five studies that offered precise data on seizure types and frequencies and included patients who actually suffered from uncontrolled seizures. In addition, we will present one recently published longitudinal study. Dodrill and Wilensky 36 compared nine patients with a history of status epilepticus before and after a 5-year study period with nine matched controls with no status on an intelligence test. Fullscale IQ improved significantly more in the nonstatus group than in the status group. Selwa et al. 37 investigated 28 patients with temporal lobe epilepsy and high seizure frequency on an intelligence and memory scale at intervals ranging from 1 to 8 years. A normal improvement in full-scale and performance IQ was noted and no decline in memory performance was found. Holmes et al. 38 assessed 35 patients with high frequent intractable seizures over a 10-year period with an intelligence test and a neuropsychological battery. Whereas IQ showed no change, 6 out of 17 neuropsychological variables showed subtle but significant losses, especially measures of visual memory, attention, problem solving,

5 Cognitive effects of seizures 225 and perception. Dodrill 39 compared 35 patients with detailed estimates of seizure frequency with or without secondary generalization with 35 healthy controls over a 10-year period with an intelligence test and a neuropsychological battery. He found less improvement in the epilepsy group, but the frequency of partial seizures did not correlate with changes in performance. Two out of 20 test variables correlated with the number of generalized seizures, and the 4 patients that experienced a status in the course of the study period suffered visual and verbal memory loss. Helmstaedter et al. 40 investigated 102 adults with temporal lobe epilepsy on measures of memory over an average period of 57 months. Twelve percent of these patients were seizure free at the follow-up testing. Fifty percent of the patients showed a significant decline in verbal and figural memory function. In a recent study, Andersson-Roswall et al. 41 compared 36 patients with partial epilepsy and 30 healthy controls over a 3 4-year period on measures of intelligence and verbal and visual memory. IQ scores were significantly lower in the patient group at baseline, but showed no significant changes at follow-up, whereas the controls showed increased scores at retesting. Verbal memory capacity and retention of visuospatial material was also lower in the patients at baseline. At follow-up a decline in verbal memory was observed in the patients, which was absent in the controls. An association with seizure related variables was not found. Recent cross-sectional neuropsychological studies that compared chronic epilepsy patients with healthy controls have documented impaired performances of memory, language, executive function, and motor speed. 18,42 In some studies, the degree of neuropsychological morbidity was correlated with the duration of epilepsy, 18 in others this relation was not confirmed. 42,43 Conclusions It appears that all but one of the prospective studies available on children are limited to measures of intelligence. Since IQ-tests were not designed to investigate brain behavior relationships, these measures may underestimate changes in a broader range of cognitive functions. Only in the presurgical group with refractory epilepsy 26 a significant decline of group level IQ was noted. The other studies revealed no significant adverse effects, although there appears to be a subgroup of about 10 25% of children that shows a clinically significant intellectual or cognitive decline. This subgroup contains more children with frequent seizures, high antiepileptic drug use, and early onset of epilepsy, although psychosocial factors may also play an important role. As expected, cross-sectional studies reveal more robust findings of intellectual and cognitive impairment. Children with generalized symptomatic epilepsies appear to be a high risk group for intellectual and educational underachievement. Five of the six prospective studies on adults report evidence of a mild decline in cognition in patients with a (longstanding) history of pharmacoresistant epilepsy. The adverse effect on cognitive abilities, memory in particular, seems somewhat more robust than that on measures of intelligence. A significant association between cognitive decline and seizure related variables, however, is rarely substantiated in prospective research. Cross-sectional studies report a wider variety of neurocognitive deficits, but show contradicting results regarding the influence of seizure related variables. Taken together, the data suggest a mild but measurable decline of intellectual performance in children and adults. Decline of specific cognitive abilities in children is impossible to evaluate given the very little data available. In adults, memory appears to be the most vulnerable cognitive function. Due to many confounding variables, the effect of seizures per se is difficult to estimate, but appears limited. Future prospective research should take an effort in accurately describing seizure type and frequency, and by comparing groups of different epilepsy syndromes. References 1. Elger CE, Helmstaedter C, Kurthen M. Chronic epilepsy and cognition. Lancet (Neurol) 2004;3: Helmstaedter C, Elger CE, Lendt M. Postictal courses of cognitive deficits in focal epilepsies. Epilepsia 1994;35: Sutula T, Pitkänen A. 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