- Email: [email protected]
Summary: Neuropsychological consequences of human epilepsy
T. Sutula and A. Pitk~inen (Eds.) Progress in Brain Research, Vol. 135 © 2002 Published by Elsevier Science B.V.
CHAPTER 41
Summary: Neuropsychological consequences of human epilepsy Thomas Sutula 1,2,, and Asia Pitk~inen 3,4 I Department of Neurology and 2 Department of Anatomy, University of Wisconsin, Madison, W1 53792, USA 3 The Epilepsy Research Laboratory, A.I. Virtanen Institute for Molecular Sciences and 4 Department of Neurology, Kuopio University Hospital, Kuopio, Finland
In Sections I-IV, evidence has been presented in both experimental models and in human epilepsy that prolonged and repeated brief seizures are associated with a variety of long-term structural and functional alterations in neural circuitry. This volume has attempted to address whether some of the long-term alterations associated with epilepsy are not only caused by the primary etiology of the epileptic syndrome, but may also be induced by the seizures themselves. Seizure-induced alterations that are regarded as possible indicators of 'damage' include molecular and cellular markers (e.g. TUNEL staining, Fluoro-Jade B staining, silver staining, etc.), and morphological measures (e.g. reduction in numbers or density of neurons in histological sections, or reduction in volume of a particular neural structure by volumetric MRI). When these 'markers' are observed in association with an evolving macroscopic lesion following recent seizures, observers are generally comfortable in concluding that the seizures played a causal role in the 'damage'. When the 'markers' are observed after seizures that are brief and do not produce an overt macroscopic lesion (Chapters 8, 9, 29, 31), there is less comfort or even
* Correspondence to: T. Sutula, Department of Neurology H6/570, University of Wisconsin, Madison, WI 53792, USA. Tel: +1-608-263-5448; Fax: +1-608-263-0412; E-mail: [email protected]
reluctance to conclude that damage has occurred. When gradually evolving, cumulative adverse functional effects are observed in people with poorly controlled epilepsy experiencing repeated brief seizures, should these effects be regarded as 'damage' even in the absence of overt seizure-induced lesions? A conclusive answer to this question would have potentially important clinical implications. In addressing this question, what is the evidence in human epilepsy that repeated brief seizures have cumulative adverse effects? Neuropsychological assessment is essential to address this question. As background to assess how brief seizures might cumulatively contribute to adverse long-term neuropsychological performance, it is also useful to consider the perspective provided by studies of neural plasticity and the capacity of neural circuits to undergo modification in response to neural activity. There is abundant evidence that neural circuits in both development and adulthood undergo numerous shortterm and long-term alterations in response to both normal neural activity and synchronous neural activity during seizures. These activity-dependent and seizure-induced effects occur at virtually every level of neural organization, from molecular to circuit alterations, and are important for normal function and behavior. It is likely that some activity-dependent and seizure-induced alterations may also contribute to pathology and dysfunction, including cognitive or behavioral dysfunction.
466 A great deal of attention in epilepsy research has been placed on the role of pathology-associated or seizure-induced alterations in neural circuits that promote neuronal synchronization and epileptogenesis. Relatively less attention has been paid to how seizures can produce subtle alterations in neural circuits that may cumulatively result in 'systems level' dysfunction. Relatively subtle but cumulative long-term alterations may be extremely important in regard to the consequences of uncontrolled or repeated seizures, and may account for the remarkable observation that brief seizures, which typically last only seconds to minutes, can produce prolonged disruption of normal functions persisting beyond the seizures and disproportionate long-term disability. Are 'systems level' neural functions and cognitive/behavioral functions gradually compromised by subtle cumulative long-term alterations in neural circuits when seizures are repeated or poorly controlled? Neuropsychological studies are addressing this question in people with epilepsy, and some of the issues that are encountered in attempting to answer this question are addressed in this section. A substantial subset of people with epilepsy show evidence of neurobehavioral dysfunction, which has a significant impact on their daily functioning and quality of life. There are undoubtedly marked individual variations in the effects of seizures, probably as a result of genetic background (Chapter 12), that are likely to influence relationships between seizure frequency and cognitive dysfunction. Multiple cross-sectional studies have provided evidence that the severity of cognitive impairment increases as a function of the life-time number of generalized tonic-clonic seizures (Chapter 35), but the possibility that the primary etiology and other factors may play a role in this effect cannot be excluded in cross-sectional studies. In the relatively more limited number of longitudinal studies that are available, mild but definite relationships between seizures and cognitive decline have been observed (Chapter 35). These relationships were noted only for generalized tonic-clonic seizures, which is of interest given evidence in experimental models of a causal relationship between number of secondary generalized seizures and memory dysfunction (Chapter 8) and the MR spectroscopy evidence in humans of a
relationship between neuronal loss/dysfunction and generalized tonic-clonic seizures (Chapter 25). In studies of cognitive and memory function in patients with intractable temporal lobe epilepsy, cross-sectional studies have suggested that there is an adverse generalized neurodevelopmental impact of childhood onset temporal lobe epilepsy (Chapter 38) and continuing slowly progressive cognitive decline involving memory but also some other measures of general intellectual ability that becomes evident with long duration of epilepsy ('-~20-30 years; Chapters 38-40). This neuropsychological observation is reminiscent of the phenomenon of initial precipitating injury and slowly progressive cellular changes in intractable human temporal lobe epilepsy (Chapter 21). Patients with shorter durations of epilepsy show less cognitive decline, and there is evidence that 'cerebral reserve' or the effects of prior level of functioning and prior educational experience may forestall or delay the cognitive decline associated with duration of temporal lobe epilepsy (Chapter 40). The indications that there may be a phenomenon of 'cerebral reserve' or a threshold for observation of cognitive decline in chronic epilepsy is of interest, as the phenomenon of 'cerebral reserve' has been noted in aging and dementia (Chapter 40), and a threshold for seizureinduced memory dysfunction has also been observed in experimental animal models (Chapter 8). Prospective studies with long duration of observation are necessary to address the cumulative longterm effects of poorly controlled epilepsy. In the relatively limited number of prospective studies, there is accumulating evidence that implicates seizures in the long-term cognitive declines (Chapter 39). Prospective studies using rating of behavioral problems in children with new onset seizures have indicated that children with multiple untreated seizures occurring prior to the rating measure have worse behavior problems than those whose initial rating measure was obtained at the time of the first seizure (Chapter 37). While the possible contribution of anticonvulsant drugs to adverse cognitive performance is a concern in cross-sectional studies, prospective studies have also indicated that the effects of antiepileptic drugs on cognitive and behavior problems appear to be negligible (Chapter 37). Neuropsychological studies are critical for understanding the long-term consequences of poorly
467 controlled seizures. The increasing appreciation of long-term adverse cognitive and behavioral effects of seizures in experimental models (Chapters 8, 32) and in human studies (Chapters 35-40) makes attention to this issue a necessary and compelling priority for epilepsy research. In human studies, prospective designs and long durations of observation are neces-
sary to address the issues of possible adverse cognitive effects of repeated brief seizures. This is likely to be challenging for both investigators and funding agencies, but such studies are ultimately critical for both clinical decision-making and understanding of the personal and social impact of epilepsy.
CHAPTER 41
Summary: Neuropsychological consequences of human epilepsy Thomas Sutula 1,2,, and Asia Pitk~inen 3,4 I Department of Neurology and 2 Department of Anatomy, University of Wisconsin, Madison, W1 53792, USA 3 The Epilepsy Research Laboratory, A.I. Virtanen Institute for Molecular Sciences and 4 Department of Neurology, Kuopio University Hospital, Kuopio, Finland
In Sections I-IV, evidence has been presented in both experimental models and in human epilepsy that prolonged and repeated brief seizures are associated with a variety of long-term structural and functional alterations in neural circuitry. This volume has attempted to address whether some of the long-term alterations associated with epilepsy are not only caused by the primary etiology of the epileptic syndrome, but may also be induced by the seizures themselves. Seizure-induced alterations that are regarded as possible indicators of 'damage' include molecular and cellular markers (e.g. TUNEL staining, Fluoro-Jade B staining, silver staining, etc.), and morphological measures (e.g. reduction in numbers or density of neurons in histological sections, or reduction in volume of a particular neural structure by volumetric MRI). When these 'markers' are observed in association with an evolving macroscopic lesion following recent seizures, observers are generally comfortable in concluding that the seizures played a causal role in the 'damage'. When the 'markers' are observed after seizures that are brief and do not produce an overt macroscopic lesion (Chapters 8, 9, 29, 31), there is less comfort or even
* Correspondence to: T. Sutula, Department of Neurology H6/570, University of Wisconsin, Madison, WI 53792, USA. Tel: +1-608-263-5448; Fax: +1-608-263-0412; E-mail: [email protected]
reluctance to conclude that damage has occurred. When gradually evolving, cumulative adverse functional effects are observed in people with poorly controlled epilepsy experiencing repeated brief seizures, should these effects be regarded as 'damage' even in the absence of overt seizure-induced lesions? A conclusive answer to this question would have potentially important clinical implications. In addressing this question, what is the evidence in human epilepsy that repeated brief seizures have cumulative adverse effects? Neuropsychological assessment is essential to address this question. As background to assess how brief seizures might cumulatively contribute to adverse long-term neuropsychological performance, it is also useful to consider the perspective provided by studies of neural plasticity and the capacity of neural circuits to undergo modification in response to neural activity. There is abundant evidence that neural circuits in both development and adulthood undergo numerous shortterm and long-term alterations in response to both normal neural activity and synchronous neural activity during seizures. These activity-dependent and seizure-induced effects occur at virtually every level of neural organization, from molecular to circuit alterations, and are important for normal function and behavior. It is likely that some activity-dependent and seizure-induced alterations may also contribute to pathology and dysfunction, including cognitive or behavioral dysfunction.
466 A great deal of attention in epilepsy research has been placed on the role of pathology-associated or seizure-induced alterations in neural circuits that promote neuronal synchronization and epileptogenesis. Relatively less attention has been paid to how seizures can produce subtle alterations in neural circuits that may cumulatively result in 'systems level' dysfunction. Relatively subtle but cumulative long-term alterations may be extremely important in regard to the consequences of uncontrolled or repeated seizures, and may account for the remarkable observation that brief seizures, which typically last only seconds to minutes, can produce prolonged disruption of normal functions persisting beyond the seizures and disproportionate long-term disability. Are 'systems level' neural functions and cognitive/behavioral functions gradually compromised by subtle cumulative long-term alterations in neural circuits when seizures are repeated or poorly controlled? Neuropsychological studies are addressing this question in people with epilepsy, and some of the issues that are encountered in attempting to answer this question are addressed in this section. A substantial subset of people with epilepsy show evidence of neurobehavioral dysfunction, which has a significant impact on their daily functioning and quality of life. There are undoubtedly marked individual variations in the effects of seizures, probably as a result of genetic background (Chapter 12), that are likely to influence relationships between seizure frequency and cognitive dysfunction. Multiple cross-sectional studies have provided evidence that the severity of cognitive impairment increases as a function of the life-time number of generalized tonic-clonic seizures (Chapter 35), but the possibility that the primary etiology and other factors may play a role in this effect cannot be excluded in cross-sectional studies. In the relatively more limited number of longitudinal studies that are available, mild but definite relationships between seizures and cognitive decline have been observed (Chapter 35). These relationships were noted only for generalized tonic-clonic seizures, which is of interest given evidence in experimental models of a causal relationship between number of secondary generalized seizures and memory dysfunction (Chapter 8) and the MR spectroscopy evidence in humans of a
relationship between neuronal loss/dysfunction and generalized tonic-clonic seizures (Chapter 25). In studies of cognitive and memory function in patients with intractable temporal lobe epilepsy, cross-sectional studies have suggested that there is an adverse generalized neurodevelopmental impact of childhood onset temporal lobe epilepsy (Chapter 38) and continuing slowly progressive cognitive decline involving memory but also some other measures of general intellectual ability that becomes evident with long duration of epilepsy ('-~20-30 years; Chapters 38-40). This neuropsychological observation is reminiscent of the phenomenon of initial precipitating injury and slowly progressive cellular changes in intractable human temporal lobe epilepsy (Chapter 21). Patients with shorter durations of epilepsy show less cognitive decline, and there is evidence that 'cerebral reserve' or the effects of prior level of functioning and prior educational experience may forestall or delay the cognitive decline associated with duration of temporal lobe epilepsy (Chapter 40). The indications that there may be a phenomenon of 'cerebral reserve' or a threshold for observation of cognitive decline in chronic epilepsy is of interest, as the phenomenon of 'cerebral reserve' has been noted in aging and dementia (Chapter 40), and a threshold for seizureinduced memory dysfunction has also been observed in experimental animal models (Chapter 8). Prospective studies with long duration of observation are necessary to address the cumulative longterm effects of poorly controlled epilepsy. In the relatively limited number of prospective studies, there is accumulating evidence that implicates seizures in the long-term cognitive declines (Chapter 39). Prospective studies using rating of behavioral problems in children with new onset seizures have indicated that children with multiple untreated seizures occurring prior to the rating measure have worse behavior problems than those whose initial rating measure was obtained at the time of the first seizure (Chapter 37). While the possible contribution of anticonvulsant drugs to adverse cognitive performance is a concern in cross-sectional studies, prospective studies have also indicated that the effects of antiepileptic drugs on cognitive and behavior problems appear to be negligible (Chapter 37). Neuropsychological studies are critical for understanding the long-term consequences of poorly
467 controlled seizures. The increasing appreciation of long-term adverse cognitive and behavioral effects of seizures in experimental models (Chapters 8, 32) and in human studies (Chapters 35-40) makes attention to this issue a necessary and compelling priority for epilepsy research. In human studies, prospective designs and long durations of observation are neces-
sary to address the issues of possible adverse cognitive effects of repeated brief seizures. This is likely to be challenging for both investigators and funding agencies, but such studies are ultimately critical for both clinical decision-making and understanding of the personal and social impact of epilepsy.