Interictal Epileptiform EEG-discharges in Children with Temporal Lobe Epilepsy

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Interictal epileptiform EEG-discharges in children with temporal lobe epilepsy: Clinical relevance for transient or permanent neuropsychological deficits?

F. Haverkamp, Zentrum für Kinderheilkunde der Universität Bonn


Abstract: Therapeutical refractory epilepsy, underlying brain damage and drug side effects have to be considered among major effect sizes for neuropsychological deficits in epilepsy. This review addresses the question whether interictal epileptiform EEG discharges per se (without epileptic symptomatology) may contribute significantly to the neuropsychological risks in affected children. For clinical practice some guidelines on how to proceed with children with interictal epileptiform EEG discharges will be given.Keywords: epilepsy in childhood, cognitive impairment, Abbreviations: EED: epileptiform EEG discharges, TCI: transient cognitive impairment


Introduction:

The majority of children with epilepsy can expect normal neurodevelopment and academic achievement comparable to normal population.1, 2

However there is a considerable subgroup of about 30% of affected children with low average intelligence and inferior academic achievement.3-5 Vulnerable neuropsychological areas predominantly affect attention, short term memory 5, 6 and cognitive information processing.7-9

The interindividually varying cognitive deficits are attributed to the type of epilepsy, to the frequency of seizures, kind and dosage of medication, the extent and the quality of underlying cns affection as well as to the age at onset.9 A general increased risk for cognition is predominantly seen in those patients suffering either from symptomatic epilepsy, as it is the case in the majority of patients with complex-partial epilepsy, and/or from various types of seizures occurring simultaneously.8, 9

This review is to discuss whether interictal epileptiform EEG discharges (EED) in children with epilepsy may represent an additional risk for cognitive development. This assumption is based on the observation that EED may be simultaneously accompanied by transient cognitive impairment (TCI) which itself may contribute to the general longterm risk for cognitive development in epilepsy. 10


The concept of "Transient cognitive impairment"

Negative effects on cognition may be due to either focal or generalized EEG discharges, a status epilepticus or a nonconvulsic status epilepticus during awakening or during sleep.10-14 Gibbs et al.15 and Schwab16 first described that epileptiform EEG discharges may occur without epileptic symptomatology but may be simultaneously accompanied by transient impairment of cognitive abilities. Paroxysmal EED, which occur without epileptic symptomatology but simultaneously with transient cognitive impairment is described in literature as "Transient Cognitive Impairment" (TCI). 10

With respect to clinical practice and care, this TCI-concept implies a potential risk for the cognitive development in children with epilepsy. One question that has been discussed in this vein is whether the higher rate of learning problems in those 30% of children with epilepsy needing specific education, may also be the result of interictal EED (e.g. spike- and sharp-waves with/without slow waves) occurring simultaneously with TCI‘s.10, 13, 14

Focal and generalized EED could also be found in children without epilepsy but with neuropsychological deficits (e.g. regressive speech development).17 It has thus been discussed whether interictal EED are generally associated with an impairment of cognitive cns functions (e.g. speech, attention) irrespective of whether epilepsy is present simultaneously. 10-14 Thus the question arises if these patients without epilepsy may even benefit from antiepileptic treatment.


Effect sizes for the detection of TCI

If interictal EED is present in children with epilepsy, the simultaneous existence of TCI could not be expected a priori. There is empirical evidence that the detection of TCI is related to the kind, duration and number of interictal EED but also to the particular examined neuropsychological functions in question. 12,13

Some studies find TCI only in association with interictal focal EED while others report TCI to be linked only with interictal generalized EED. Other studies point out that in correspondence with the respective neuroanatomic localization of EED either the visuo-spatial capabilities (EED on the right cerebral hemisphere) or verbal functions are affected (left hemisphere localized EED).18,19 In contrast interindividual varying cognitive impairment in patients with identical locus of EED was found. These contrasting observations have led some researchers to criticize in principal the existence of TCI.12

With respect to the minimal duration of EED necessary to detect TCI, one study found that there is TCI if EED lasted one second 13 while other studies found TCI only if EDD duration was at least three seconds.10,14,22

The detection of TCI is also related to the type of neuropsychological function to be examined. Items demanding the solution of complex cognitive abilities such as writing on dictation 21 or computer games are seen to be effective in provoking TCI. 18,22

For the detection of TCI it has thus been recommended to use test items requiring complex cognitive abilities such as reaction response, cognitive information processing and short term memory.10,14,22


TCI or subtle epileptic seizures? The relevance of EEG-video monitoring

Further methodological problems to detect TCI are related to a) the possible (but still unclear) association between neuropsychological dysfunction and interictal EED on the one hand and the individual severity of the underlying epilepsy on the other hand or b) whether the neuropsychological dysfunctions during interictal EED may be the result of a subclinical epileptic seizure.22

Subtle epileptic seizures are difficult to detect if a) the ictal motor movements fall within the normal spectrum of spontaneous movements or b) the epileptic symptomatology occurs imperceptibly to the respective child and the environment.22,23

Since the introduction of EEG-video monitoring more subtle epileptic seizures could be identified. EEG-video monitoring thus makes it possible to differentiate between TCI and subtle epileptic seizures.24

From epilepsy surgery it is also known that subdural EEG recording may facilitate detection of "subclinical" seizures. Simultaneously the patients may be not impaired and may not notice any epileptic symptomatology.25,26

In a neuropsychological study using EEG-video monitoring Aldenkamp et al.12 analyzed if focal, bilateral respective generalized EED are accompanied by either a clinical epileptic symptomatology and/or by a transient cognitive impairment. Neither in patients with seizures under treatment nor in patients being seizure free but with simultaneous EED could any TCI be detected. EEG-Video monitoring demonstrated in 50% of patients who were not seizure free short-term seizures (3-10 seconds).

Furthermore it was shown that patients with stable cognitive deficits were not additionally influenced by interictal EED. The authors concluded that in case of less extensive EEG-video monitoring much more TCI instead of subtle epileptic seizures would have been diagnosed. A further study of the same group confirmed these results.22 Aldenkamp et al.12,22 thus assume that the incidence of TCI among the population of epilepsy could be estimated as rather low (under 5 %)13.

In contrast an incidence of TCI in about 36% of children with epilepsy has been reported recently.27 In this study only EEG and neuropsychological testing but not EEG-video monitoring was used. This procedure should be criticized due to methodological reasons because the various studies of Aldenkamp and coworkers clearly indicate that the risk to mistake TCI for subtle seizures is largely increased if EEG-video monitoring is not applied.

Therapeutical trials to treat TCI with antiepileptic medication are known.13 So far there is no sufficient evidence of general improvement in the cognitive development, even if normalization of the EEG can be achieved. A general recommendation for anti-convulsic treatment thus could not be given based on contrary empirical findings in this context.13,23


The differentiation between postictal mental slowing down and transient/permanent cognitive impairments (TCI)

The detection of TCI may be also complicated due to ictal or postictal effects on cognition. Single seizure events alone may have longterm postictal effects in the individual cognitive performance. Dodrill28 found that the occurrence of a single tonic-clonic Grand Mal may have a 30 day lasting negative effect on attention.

On the other hand the well known associated attention deficits in children with epilepsy may also contribute to an increase of variable cognitive performance in every day life which itself may simulate TCI.22


Cognitive risks in persisting focal EED and in EED during sleep

Persisting focal interictal ETP but also status bioelectricus in sleep (ESES) have been seen as relevant risk factors especially as far as speech development is concerned, e.g. in Landau-Kleffner-Syndrome.29-33 This is characterized by focal or bilateral interictal spikes or spike-waves in the temporoparietal region, which are activated during sleep.31

Recent studies provide evidence that speech deficits may benefit from anticonvulsic treatment only in a part of patients with Landau-Kleffner-Syndrome.17,29,32,33

Even a normalization of the EEG records under anticonvulsic treatment does not guarantee a recovery of disturbed speech development.33 The question has been adressed, whether the underlying neuropathophysiology in these patients represents a complex neuropathoanatomic disorder which goes beyond a pure epileptogenic cns disturbance.17


Epilepsy surgery perspectives on interictal EED in focal epilepsy

A subgroup of focal epilepsies may benefit from epilepsy surgery. The chance of being seizure free post surgery is directly related to the question, whether the epileptogenic area could be identified during the presurgical diagnostic process . This area is not necessarily identical with the neuroanatomic zone of functional deficits.34

Lendt et al.35 found evidence that the previous existing behavior and cognitive problems may recover postoperatively in 50% of epileptic children treated with surgery. This holds true especially in those patients, in whom a complete suppression of interictal EED during neurosurgical intervention can be revealed. However the preoperative EEG findings, including interictal EED, of these patients did not predict the surgical (behavioral) benefit.


Consequences with specific reference to focal epilepsy

Concerning the complex differential diagnostic process with respect to the cognitive effects of ictal and interictal EED in patients with focal epilepsy a series of various effect sizes such as the etiology and neuropathoanatomic extent of the underlying disease, the localization, number and duration of EED as well as the specific neuropsychological deficits should be evaluated (see graphic 1).

First should be clarified whether these persistent interictal either focal or generalized EED are associated with a subtle epileptic symptomatology. EEG-video monitoring appears as the necessary prerequisite to exclude subtle epileptic seizures.24 With respect to the overall significance concerning the number and duration of interictal EED, EEG recording during a longer period (e.g. 24 hours) as well as during sleep should be undertaken.

If subtle epileptic seizures could be excluded then consecutive neuropsychological examinations simultaneously with EEG-video monitoring are needed to clarify the existence of TCI. In case of coexisting cognitive deficits a differentiation must be made between stable and transient cognitive deficits. In case of stable cognitive deficits prolonged postictal from longterm interictal effects on cognition should be taken into account.

If the neuropsychological examination revealed more transient cognitive deficits indicating TCI, prior to this final diagnosis, it should be analyzed if they are actually related to the corresponding locus of EED (e.g. decreased verbal functions with EED-Focus on the left cerebral temporal region).11,14 Afterall if there is no evidence for neither subtle epileptic seizure nor for TCI, the EED could be then interpreted as an epiphenomenon for the underlying brain damage36, which can be frequently found in patients with focal epilepsy.37 In these patients EED per se seem to be without serious neuropsychological relevance.

There is no official guideline on how to treat TCI in case of focal or generalized EED. Empirical knowledge about therapeutical effectiveness is limited and disappointing11,12. Frequently benzodiazepines, but also other drugs (e.g. ethosuximide) have been reported to reduce interictal EED38,39. In case of coexisting epilepsy the specific treatment procedure should probably be adopted to the underlying specific type of this associated epilepsy.

Generally the decision making process for the antiepileptic treatment in TCI is complicated by the fact that antiepileptic drugs themselves may have a) negative neuropsychological effects (e.g. phenobarbital, at least in higher dosages) or b) other severe side effects (e.g. corticosteroids) and c) the potential risk for seizure-inducing effects including interictal EED (e.g. carbamazepine)40.

In any case one should be aware that there is a general lack of empirical predictors regarding the individual antiepileptic therapeutical response and the individual occurrence of the various potential side effects. Therefore it has been recommended to assess each person individually with respect to these factors41. As far as the individual treatment decision making process is concerned as regards TCI one should be aware that in case of treatment decisions a careful individual monitoring regarding therapeutical effectiveness of TCI and EED on the one hand and regarding potential negative neuropsychological and other known side effects of antiepileptic treatment on the other hand is necessary. If there is a decision not to treat, the same monitoring regarding EED and TCI (including neuropsychological examinations) are necessary to exclude potential longterm cognitive impairment. This procedure seems to be necessary in order to reevaluate the potential neuropsychological benefit as well as the risks of the treatment- and correspondingly of the "non-treatment" -decision.


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