The therapeutic dilemma: Treating subtle seizures or indulging in electroencephalogram cosmetics?

The Therapeutic Dilemma: Treating Subtle Seizures or Indulging in Electroencephalogram Cosmetics? Frank M.C. Besag The treatment of epileptiform abnormalities in the absence of obvious seizures has, in the past, been dismissed as "EEG cosmetics." The work on transitory cognitive impairment has highlighted the importance of asking the question: "What is a seizure?" The extent to which epileptiform discharges cause temporary or permanent impairment, profoundly influences decisions on whether to treat with antiepileptic medication or surgery. Copyright 9 1995 by W.B. Saunders Company

EN IT BECAME possible to record the ectrical activity from brains of people W~el with epilepsy, Berger in 19331 recognized that 3-Hz ele6troencephalogram (EEG) activity accompanied absence seizures. The article by Kasteleijn-Nolst Trenit6 on transient cognitive impairment (TCI) in this issue of Seminars in Pediatric Neurology has reviewed in detail the effects on cognition of epileptiform discharges that are not accompanied by obvious clinical change. This subject has also been reviewed extensively by Binnie and Marston) The concept of TCI is that epileptiform discharges that are not manifested by obvious seizures may result in transitory cognitive deficits that are detectable by suitable testing. Relatively infrequent discharges of this type may also have effects on psychosocial function, as will be discussed. The importance of frequent epileptiform discharges both on the function of the child at the time and with regard to long-term effects will also be considered in this report. DEFINITIONS

Several investigators, have discussed the diffic u l t i e s arising from terminology in this context. 26 Besag6 has commented on The International League Against Epilepsy definitions of absence seizures (Commission on Classification and Terminology of the International League Against Epilepsy, 1981). "Typical absence seizures may be manifested as impairment of consciousness only, or may occur with automatisms, myoclonic movements, tonic components or autonomic components." If absence seizures can present with "impairment of consciousness only" they may not be easy to observe. If they are not easy to observe they may not be easy to count. Furthermore, because the definition of a seizure depends on its clinical manifestation, there is a semantic problem about what constitutes "clinical" in

this context because there is no easy test for brief impairment of consciousness. These conceptual problems have also been discussed in detail by Binnie et al. 3 Aarts et al4 distinguished EEG discharges with overt absence seizures, that is, "clinical" absence seizures in the normal understanding of the term, from subtle cognitive changes associated with epileptiform discharges detectable with appropriate tests. They have defined "subclinical" EEG discharges as being those during which no clinical change can be detected by close observation. The term "subclinical" according to this operational criterion does not imply that there is no clinical change but merely that the clinical change is not obvious by the usual means of close observation; it may be detected by appropriate testing. In contrast, the term "subclinical seizure" is self-contradictory. If there is no clinical manifestation then the episode cannot be a seizure. An EEG discharge that is associated with subtle change, even if this change is only detectable with appropriate specialized testing, should in the opinion of many investigators including Besag,6 be classified as a seizure; it is a subtle seizure. Marston et al 7 have commented: "TCI itself calls into question the definition of an epileptic seizure: a discharge which is accompanied by a brief impairment of cognition is not strictly subclinical." In the earlier publication of Aarts et aP it was stated that "although any attempt to equate epileptiform activity with epilepsy in general is to be deplored, the occurrence of a paroxysmal change in cerebral electrical activity simultaneously

From St Piers Lingfield, Lingfield, Surrey, England. Address reprint requests to Frank M.C. Besag, MD, ChB, PhD, FRCP, FRCPsych, DCH, Medical Director, St Piers Lingfield, Lingfield, Surrey, RH7 6PW, England. Copyright 9 1995 by W.B. Saunders Company 1071-9091/95/0204-000555.00/0

Seminars in Pediatric Neurology, Vol 2, No 4 (December), 1995: pp 261-268

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accompanied by cognitive impairment meets generally accepted definitions of an epileptic seizure." This raises the question: Are generalized spike-wave discharges always accompanied by impaired performance? There is disagreement in the literature on this point. In the extensive work on TCI, not every patient showed a detectable change with every discharge, even when specialized testing was used. Does this imply that some discharges are truly subclinical or does it merely imply that the testing required to detect the clinical change was not sufficiently sensitive? What types of test should be used? These concepts on TCI are discussed by Kasteleijn-Nolst Trenit6 in this issue and have also been reviewed by Binnie and Marston. 2 Relatively nondemanding tests such as rhythmic tapping, simple reaction time, and tracking may not necessarily detect TCI, whereas tests such as choice reaction time, signal detection, shortterm memory tasks, and language tests may be more demanding and may, consequently, be more sensitive in detecting TCI. KasteleijnNolst Trenit6 et al 8 produced some particularly interesting results with subjects monitored during reading. When discharges occurred, the speed of reading paradoxically increased but so did the rate of errors per word read, hence the task was performed more rapidly but less accurately. Binnie et al 9 raised further fundamental questions about terminology when they showed that TCI could occur with rolandic spikes in typical benign epilepsy of childhood with rolandic spikes. They also concluded that such E E G discharges could be associated with behavioral or cognitive problems, although they stated that the subjects tested may have been selected because they were referred to a tertiary center. THE PRACTICAL IMPORTANCE OF EPILEPTIFORM DISCHARGES

There now seems to be overwhelming evidence that epileptiform discharges can cause transitory cognitive impairment, but how significant is this impairment? In particular, which patients should be treated? It would be impractical to treat all patients who show epileptiform activity. Some estimates, such as the ones by Eeg-Olafsson et al, 1~ suggest that epileptiform activity might occur in about 10% of children

without epilepsy. It would clearly be impractical and almost certainly unwise to treat such a large proportion of the population. Besag 11 made the following comments in this context: "My approach is a very naive one. H e r e we have an abnormal child and an abnormal E E G . I do not know whether the two are linked but let us try to get the E E G more normal and see if the child becomes more normal as a result. Sometimes he does, and that has been a worthwhile exercise. If antiepileptic drugs do not make the child better then you withdraw them." The implication of this statement is that if a child presents with a problem and is found to have an abnormal E E G that might account for the problem then it may be reasonable to consider treatment with antiepileptic medication, although such consideration would not necessarily lead to treatment in every case. Binnie and Marston 2 made a more specific recommendation: "The presence of frequent discharges, particularly in a person with problems of social or cognitive function, should be regarded as an indication for considering appropriate testing to determine whether or not TCI is present." Marston et al 7 stated that the point at issue is not whether to "treat the E E G " but whether the seizures, so subtle as to be recognizable only by E E G and behavioral monitoring, produce disability sufficient to justify treatment. Ultimately the decision must lie with the clinician, in full consultation with the patient and, in the case of a child, the parents/caregivers. The study by Marston et al 7 was specifically designed to answer the question raised in earlier studies: Is psychosocial function affected by transitory cognitive impairment? The three hypotheses examined in this article may-be summarized as follows. 1. TCI can sometimes cause significant disability. 2. Medication can suppress epileptiform discharges and TCI. 3. The psychosocial gain from treatment outweighs adverse drug effects. Two-hundred forty E E G s from the most recent referrals to St Piers Lingfield, a special residential school for children with epilepsy, allowed the selection of 12 subjects in whom epileptiform discharges were sufficiently fre-

TREATING SUBTLE SEIZURES OR EEG COSMETICS?

quent to make testing feasible but were also sufficiently infrequent to allow reasonable "interictal" phases. Ten subjects (5 boys and 5 girls) completed the trial. This was a doubleblind crossover trial with repeated measures. Sodium valproate increases were used to treat the epileptiform discharges or, if this was not feasible, clobazam was prescribed. All subjects were tested on a video game similar to Corsi's block-tapping test, as described in the Aarts et al 4 report. The tests were videorecorded. Conners rating scales were completed by the teachers and caregivers. Alternative treatment (active drug to replace placebo and vice versa) was administered in the second phase of the study. Each phase lasted 12 to 16 weeks. Twenty-fourhour EEGs were recorded at the beginning and at the end of the baseline period and at the end of each trial period. A global assessment was performed by three blinded investigators reviewing each case, reaching consensus about whether the child functioned better overall during one phase than the other, based on the Conners ratings, verbal reports of teachers, care staff and parents, and the investigators own assessment of the reliability of the information. Eight of the ten children functioned better on active drug than on placebo (P < .05). All the subjects h a d a reduction of discharges during a 24-hour telemetry. Despite the positive outcome, this study was unusual in that the Corsi test rarely showed transitory cognitive impairment in this group of patients. On the contrary, there was a trend toward improved performance in the presence of discharges, possibly as a result of a nonspecific alerting effect. Only 1 subject had a clearly significant deterioration in association with the discharges. A further confounding factor was a 33% reduction in overt seizures in the active phase. However, this study concluded that epileptiform discharges that are not manifested by obvious clinical changes may nevertheless cause psychosocial dysfunction that can be ameliorated by the use of medication that suppresses these discharges. The original hypotheses were largely confirmed. Although the measurements of transitory cognitive impairment were inconsistent, there was no doubt that medication suppressed epileptiform discharges and that there was a significant improvement in psychosocial function that outweighed any pos-

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sible adverse drug effects. The author has recently reviewed some of the original video recordings from this study. Although there was considerable variation in the performance of each subject, it was quite clear that TCI was present in most of them during at least some of the tests. Furthermore, there were occasions when the frustration resulting from the incorrect response was all too evident. The uncertainty of not knowing whether they would perform well or badly when demands were made on them might have had a considerable influence on self-confidence and psychosocial function. It is also possible that the subject could perform reasonably well during discharges when these occurred during a pleasurable game but might perform poorly when such discharges occurred in demanding social situations. The additional demands of the social situation might, in effect, be a more sensitive test of TCI. Anxiety arising from such a situation might also increase the number of discharges, making the situation even worse for the individual. THE EFFECT OF FREQUENT EPILEPTIFORM DISCHARGES

The discussion to this point has considered the phenomenon of relatively infrequent discharges. However, it has become clear from recent work performed at St Piers Lingfield6 that some children may have subtle seizures that are so frequent that they affect both social interaction and educational performance to a marked degree. Prolonged monitoring of spikeand-wave events in the author's patients has quite clearly shown that parents, teachers, and caregivers generally underestimate the number of epileptiform events by a factor of 10 to 100. Besag 6 has stated that it is of little value to try t o count the number of absence seizures because this is simply not practicable. Instead, the Lingfield studies have depended on using an automatic spike-and-wave detector that gives a measure of the number of spike-and-wave events and also measures the total duration of the number of seconds of spike-and-wave activity. This device has been validated in a study performed by Besag et al. 12 This device has shown that some children may have thousands of spike-and-wave episodes daily, with a total duration lasting several hours per day. Some ex-

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amples of the results and the response to treatment are shown in Fig 1. Parents and caregivers reported that these children became brighter, happier, more alert, and more in control of their lives as a result of the treatment. It is interesting to note that there have been a number of reports of people feeling better as a result of antiepileptic medication, in contrast to the well-known reports of antiepileptic drugs resulting in adverse effects. In particular, Smith et a113 performed a double-blind placebocontrolled trial of lamotrigine in adult subjects who were rated on a number of scales. They found that there was a significant improvement on measures of happiness and mastery. In discussion with these investigators it has become clear that they were not of the opinion that their subjects had frequent epileptiform abnormalities. However, the appropriate monitoring was not performed. Even if overt epilepti-

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form discharges were not observed on the scalp EEG, one might raise the provocative question: could deep-seated epileptiform discharges, suppressed by the antiepileptic medication, have been responsible for the mood changes? The alternative explanation is that the antiepileptic medication was exerting a direct favorable psychotropic effect, through a mechanism that has yet to be identified. PERMANENT AND STATE-DEPENDENT COGNITIVE DYSFUNCTION

The subject of more obvious cognitive dysfunction in children with epilepsy is worthy of further examination. Besag14 has distinguished between permanent cognitive dysfunction on the one hand and state-dependent dysfunction on the other. Although permanent cognitive dysfunction may appear too obvious to warrant further discussion, confusion arises when these two types of cognitive dysfunction occur together. Permanent cognitive dysfunction may arise, for example, from prenatal or perinatal brain damage, nonaccidental injury, or accidental brain trauma. It may also arise from other causes, including metabolic conditions. The epilepsy itself may cause permanent brain damage through prolonged status epilepticus. The most obvious example of state-dependent cognitive dysfunction is the impairment resulting from antiepileptic drugs. In children, phenobarbitone, benzodiazepines, and vigabatrin can all cause gross attention deficit and behavioral disturbance. However, the epilepsy itself may cause state-dependent cognitive dysfunction. The peri-ictal phenomena of prodrome, aura, ictal changes, and postictal changes may all contribute to state-dependent cognitive dysfunction, as discussed in detail by Besag. 14 There are some interesting examples of reversible state-dependent cognitive impairment and behavioral change. The obvious adverse behavioral and cognitive effects of the storm of abnormal discharges observed in some children with unilateral brain damage, (for example, as a consequence of Rasmussen's ei~ephalitis), can be reversed dramatically by hemispherectomy,is It would be difficult to attribute the improvement in behavior observed in these children simply to the elimination of the obvious seizures, although the latter is also likely to have a beneficial effect.

TREATING SUBTLE SEIZURES OR EEG COSMETICS?

Some young people with frequent frontal lobe epileptiform discharges present with grossly disinhibited and disturbed behavior. The author has had two young people under his care who very clearly fell into this category. Although the following account is anecdotal it illustrates the point very well. After a normal early development a boy developed afebrile seizures at 2 years of age. The seizures were resistant to antiepileptic medication. His behavior deteriorated markedly. EEGs consistently showed a very active left frontal lobe focus. A sphenoidal EEG at 13 years of age was reported as follows: "A very active polyspike or sharp wave focus was seen continuously throughout the recording.., maximal activity was over the left prefrontal area." A computerized tomography scan was reported as normal but a magnetic resonance imaging scan showed evidence of a migrational defect in the left frontal lobe and he underwent a resection of the focus when he was 15 years of age. His parents literally thanked the doctors for giving their son back to them. Although they had not known the reason, they recognized that, some years before the operation, their son's personality underwent an unpleasant change into something that was quite foreign to him. At that stage he had very frequent frontal epileptiform discharges. When the focus of the discharges was removed surgically his brain was released from the very frequent discharges and was allowed to function more normally, returning his personality to the one his parents recognized as belonging to their son. In this case there seems little doubt about the value of treating the epileptiform abnormality. It is particularly interesting to note that the seizures were not controlled by the surgery, although the frontal focus was removed, an active left temporal focus was noted on subsequent EEGs. However, his behavior remained good without the storm of very frequent discharges impinging on the remainder of the frontal lobe. It is not surprising that the location of the frequent epileptiform may be an important factor in determining the effect, not only on cognition, as discussed in the article by Kasteleijn-Nolst Trenit6, but also on behavior. Of particular relevance to the current discussion is an important question. Can the state-

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dependent cognitive dysfunction of frequent epileptiform discharges lead to permanent dysfunction after a period of time? It is especially important to answer this question because some drugs may treat subtle seizures without necessarily treating overt seizures adequately. For example, the two cases shown in Fig 2 and Fig 3 illustrate this point. In Fig 2 the overt seizures and the six-hourly spike-and-wave counts have been reduced with drug treatment. However, in Fig 3 the overt seizures have not been affected by treatment. One might conclude that the antiepileptic drug should be stopped. However, the 24-hour spike-and-wave counts show a reduction of more than 2,000 per day. The teenager became bright, happy, and alert. His parents were delighted with the dramatic change in his day-to-day performance. Stopping the drug on the basis that it had not treated the overt seizures would have been a major therapeutic blunder in this case. Results such as these have led Besag6 to conclude, in agreement with Smith et al, 13 that failure to control overt

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most of these children continues to increase it is alarming to note that it is not doing so at the expected rate, In a previous study by Besag} 6 no significant association between age of onset, total number of seizures, seizure type, antiepileptic medication, or other factors was found. In the most recent study (Besag FMC et al, unpublished observations, 1994) a significant association was found between the decrease in IQ and the combined group of children with gross overnight EEG abnormality and those Who had very frequent epileptiform events, as recorded by the St. Piers Lingfield monolog spike-and-

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Fig 3. This lad had no reduction in overt seizures (A) with the addition of another antiepileptic drug but had a marked reduction in spike-and-wave events(B). He was much more alert as a result, despite failure of the drug to control the overt seizures.

seizures does not mean failure to help the patient. However, this author has proceeded from the statement to add that failure to control overt seizures does not mean failure to control seizures. Controlling subtle seizures may be very important in this context.

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THE CAUSES OF DECREASING IQ IN CHILDREN WITH EPILEPSY

Returning to the question of permanent cognitive dysfunction, reference Should be made to that small subgroup of children with epilepsy who have a decreasing IQ. Studies at St. Piers Lingfield a4 have documented such a group of children in detail, it was shown that most of these children did not deteriorate in absolute terms. Their mental age increased more slowly than expected and because IQ is a quotient of mental age divided by chronological age, the IQ decreased. This point is illustrated in Fig 4, which shows both the IQ and the mental age plotted against chronological age in the same group of children. Although the mental age in

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TREATING SUBTLE SEIZURES OR EEG COSMETICS.'?

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wave monitor. This association was significant (P < .05). These results may have important implications for the treatment of frequent epileptiform abnormalities. It should be noted that these epileptiform abnormalities, although frequent, did not generally amount to electrical status epilepticus of slow wave sleep, to which reference is made below. Before discussing this matter further it may be of interest to examine existing models. In infantile spasms, gross epileptiform abnormalities are associated with a very poor prognosis for intellectual outcome. The new drugs vigabatrin and lamotrigine (used together with valproate) can be very effective in treating infantile spasms. It will be of great interest to follow successfully treated children to determine whether the intellectual outcome is much improved by this treatment. The Landau-Kleffner syndrome of acquired aphasia is characterized by focal spikes that may be either left-sided, right-sided, or bilateral. These focal spikes strongly resemble the EEG abnormality observed in benign epilepsy of childhood with rolandic spikes. However, many of the children with the Landau-Kleffner syndrome have electrical status epilepticus of slowwave sleep, in which 85% or more of slow-wave sleep is occupied by spike-and-wave discharges. If the child with Landau-Kleffner is treated early, energetically, and effectively, language skills can be saved in at least some cases. The older text books presumably reported cases that were treated too late and, as a consequence, past investigators concluded, quite incorrectly, that antiepileptic treatment had no role to play in preventing language deterioration. This is quite untrue. Early treatment may prevent the language deterioration and may even allow return of language. The author has experience both of medical and surgical treatment resulting in a good response. The interesting operation of multiple subpial transections, pioneered by Mor-

rell, 17 offers promise in cases for whom medical treatment has failed. It is also interesting to speculate on the unusual pattern of deterioration observed in Rett syndrome. In this syndrome the girls lose skills in early childhood, but girls do not continue to lose skills. Instead, they reach a plateau. These changes might conceivably occur because of frequent epileptiform discharges at the time when state-dependent deterioration is noted, leading to permanent impairment, but not to further loss of absolute skills. These examples emphasize the author's strong view that absolute loss of skills in a child with epilepsy should always be investigated thoroughly because a cause can usually be found. Sometimes this cause will be treatable, for example, the state-dependent impairment of frequent epileptiform discharges or drug toxicity, If frequent epileptiform discharges are allowed to continue for very long periods they may lead to permanent impairment. This hypothesis is supported by existing models and also by the most recent results from the St Piers Lingfield studies (Besag FMC, unpublished observations, 1994). CONCLUSION

There appear to be strong reasons for assessing the importance of epileptiform abnormalities in children who are not functioning as well as expected and particularly in those who have lost skills. Not only is this situation potentially treatable but, in cases in which frequent epileptiform abnormalities exist, either during the daytime or solely at night, treatment may prevent permanent cognitive impairment. ACKNOWLEDGM ENT I would like to thank Professor Thierry Deonna for his invitation and encouragement to write this article. I would also like to thank my close colleague and sometime coauthor Dr Colin Binnie for his invaluable expert advice and help.

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Long-Term Monitoring in Epilepsy. Amsterdam, The Netherlands, Elsevier, 1983, pp 341-355 4. Aarts JHP, Binnie CD, Smit AM, et al: Selective cognitive impairment during focal and generalised EEG activity. Brain 107:293-308, 1984 5. Binnie CD: Transitory cognitive impairment (TCI) during subclinical EEG discharges, in Besag F (ed): Proceedings of Symposium Epilepsy, Learning and Behaviour.

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Leicester, England, British Psychological Society. Educ Child Psychol 6:33-36, 1989 6. Besag FMC: Lamotrigine in the management of subtle seizures. Rev Contemp Pharmacother 5:123-131, 1994 7. Marston D, Besag FMC, Binnie CD, et al: Effects of transitory cognitive impairment on psychosocial functioning of children with epilepsy: A therapeutic trial. Dev Med Child Neurol 35:574-581, 1993 8. Kasteleijn-Nolst Trenit6 DGA, Bakker DJ, Binnie CD, et ah Psychological effects of sub-clinical epileptiform discharges: Scholastic skills. Epilepsy Res 2:111-116, 1988 9. Binnie CD, de Silva M, Hurst A: Rolandic spikes and cognitive function, in Degen R, Dreifuss FE (eds): Benign Localized and Generalized Epilepsies of Early Childhood. Epilepsy Res 71-73, 1992 (suppl 6) 10. Eeg-Olafsson O, Peters6n I, Selld6n U: The development of the electroencephalogram in normal children from the age of 1 through 15 years: Paroxysmal activity. Neuropadiatrie 2:375-404, 1971 11. Besag FMC: Discussion, in Trimble MR, Reynolds EH (eds): Proceedings of Symposium on Epilepsy, Behaviour and Cognitive Function. Chichester, England, Wiley, 1988, pp 201-202

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12. Besag FMC, Mills M, Wardale F, et ah The validation of a new spike and wave monitor. Electroeucephalogr Clin Neurophysio173:157-161, 1989 13. Smith D, Chadwick D, Baker G, et al: Quality of life and reduction in seizure severity produced by lamotrigine, in Richens A (ed): Clinical Update on Lamotrigine: A new Antiepileptic Agent. Royal Tunbridge Wells, England, Wells Medical, 1992, pp 43-50 14. Besag FMC: Epilepsy education and the role of mental handicap, in Ross EM, Woody RC (eds): Epilepsy. BailliSre's Clinical Paediatrics International Practice and Research, vol 2, no 3. Royal Tunbridge Wells, England, Wells Medical, 1994, pp 561-583 15. Lindsay J, Ounsted C, Adams CB: Hemispherectomy for childhood epilepsy: A 36-year study. Dev Med Child Neuro129:592-600, 1987 16. Besag FMC: Cognitive deterioration in children with epilepsy, in Trimble MR, Reynolds EH (eds): Proceedings of Symposium on Epilepsy, Behaviour and Cognitive Function. Chichester, England, Wiley, 1988, pp 113-127 17. Morrell F, Whisler WW, Bleck TP: Multiple subpial transection: A new approach to the surgical treatment of focal epilepsy. J Neurosurg 70:231-239, 1989