Epilepsy, defined as more than 1 unprovoked

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1 TREATING EPILEPSY: DOES PRESENTATION MATTER? * Lionel Carmant, MD, FRCP (C) ABSTRACT The evidence supporting the use of antiepileptic drugs (AEDs) immediately after a first seizure is ambivalent. A Practice Parameter issued by the American Academy of Neurology concludes that treatment with [an] AED is not indicated for the prevention of the development of epilepsy. 1 However, there is increasing evidence that some patient subsets (developmentally delayed, initial remote symptomatic seizure, abnormal electroencephalogram) are at higher risk for developing recurrent seizure activity following an initial seizure. Furthermore, some individuals with underlying pathologies may be at risk for developing seizures following other precipitating events, such as perinatal anoxia or febrile seizures. Studies using animal models add weight to surgical observations that benign lesions may in fact predispose individuals to recurrent seizure activity. These individuals may derive short-term benefit from the use of AEDs before epilepsy develops. The development of better animal models is expected to provide a platform for more effective study of drugs with antiepileptogenic properties. Refinement of imaging and genetic techniques will assist in early identification of those patients at high risk of recurrent seizure activity. The decision to treat early should be made with reference to the wishes of both patient and family following counseling. (Adv Stud Med. 2004;4(7C):S593-S598) *Based on a presentation given by Dr Carmant at the 2003 Annual Meeting of the American Epilepsy Society. Director, Epilepsy Research Unit, Clinical Assistant Professor of Pediatrics, Department of Pediatrics, Neurology Division, Ste-Justine Hospital, University of Montreal, Quebec, Canada. Address correspondence to: Lionel Carmant, MD, FRCP (C), Department of Pediatrics, Neurology Division, Ste- Justine Hospital, 3175 Cote Ste-Catherine, University of Montreal, Montreal, Quebec H3T 1C5, Canada. lionel.carmant@umontreal.ca. Epilepsy, defined as more than 1 unprovoked seizure, often warrants the use of antiseizure medication to prevent recurrence. Recent experimental and clinical data have reinforced the possibility that epilepsy can be a progressive disorder. This rekindles the debate on whether earlier treatment should be implemented after the first unprovoked seizure to improve long-term outcome. The first unprovoked seizure may represent an isolated event or herald the beginning of epilepsy. Despite several longitudinal studies on outcomes following a first unprovoked epileptic seizure, there is still no consensus on treatment after the first seizure. 2-5 Doubt persists in the minds of clinicians and investigators because of the variable results reported. The American Academy of Neurology (AAN) and the Child Neurology Society (CNS) wrote a consensus statement in 2003 for children and adolescents experiencing a first seizure. 1 The subcommittees concluded that early treatment is not indicated for preventing the development of epilepsy but may be considered in circumstances in which the benefits of treatment outweigh the risks of pharmacologic and psychosocial side effects. The first goal of this article is to review the basis of this consensus statement. The decision not to treat is relatively easy to make in patients with an idiopathic epileptic syndrome. Therefore, the focus is on early therapy in patients at high risk based on a history of acute symptomatic seizures, abnormal neurologic status, abnormal electroencephalogram (EEG) patterns, or a severe initial presentation, namely status epilepticus. The second goal is to examine the impact of early treatment on long-term outcome. This is especially relevant for patients who present with an episode of status epilepticus. Could early treatment prevent seizure-induced brain damage/epileptogenesis? Advanced Studies in Medicine S593

2 The third and final goal of the article is to discuss the future clinical challenge of the early recognition of individuals at high risk for a poor outcome based on electroclinical, genetic, and neuroimaging techniques, as well as the use of these tests to provide early information on long-term outcome. Another group of studies in the late 1980s and early 1990s examined mixed populations of adults and children (Table 2). In this group of studies, Hart et al showed a high recurrence rate (78%). However, the HISTORICAL PERSPECTIVE The progressive nature of epilepsy was recognized as long ago as 1881, when Gowers wrote, The tendency of the disease is to self-perpetuation; each attack facilitates the occurrence of another, by increasing the instability of the nerve elements. 6 Consequently, for many years, antiseizure treatment was often initiated after the patient presented with a first seizure. Attitudes toward early treatment changed in the 1980s following the publication of several studies that drew conflicting conclusions about the probability of subsequent seizures following an initial unprovoked seizure in adult patients. Recurrence rates reported in these studies varied from 23% to 71%, and a meta-analysis of 1930 patients calculated an overall risk of recurrence of 42% and 46% after 2 and 4 years, respectively. 4 Concerns about the side effects of antiseizure medications, together with inconclusive data about the predictive value of an initial seizure, cast doubt on the value of early treatment. Table 1 summarizes the key data from some of these studies. The difficulty of making direct comparisons is evident. For instance, it seems that the study by Elwes et al, in which no patients were treated, demonstrates a high risk of recurrence. 7 However, this study was not truly prospective; retrospectively, it included participants that had already had a second seizure and were therefore at high risk for recurrence. Conversely, Hauser et al excluded 40% of the patients because they had already experienced a second seizure (interestingly, Hauser has since presented data indicating that with recurrent seizures, the risk of subsequent seizures does indeed increase, and the interval between seizures can be expected to decrease). 2,8 One risk factor that emerged as carrying a high risk of recurrence was remote symptomatic seizures (RS). Table 1. Seizure Recurrence in Adult Patients Hauser et al 2 Annegers et al 3 Elwes et al 7 (1982) (1986) (1985) Recruitment Prospective Prospective Prospective? Delay NA NA 1 day Follow-up 3 yrs 5 yrs 4 yrs % treated % recurrence % 2-year recurrence Risk factors RS-SW-FH RS-CP NA Site Hospital Community Clinic Specifics 40% excluded Subgroup RF Retrospective No effect Trt-SE-O/E PS vs EEG-O/E NA NA = not applicable; RS = remote symptomatic; SW = spike and wave discharges; FH = family history; CP = cerebral palsy; RF = risk factor; Trt = tail retraction time; SE = status epilepticus; O/E = abnormal neurologic examination; PS = partial seizure; EEG = electroencephalogram. Table 2. Seizure Recurrence in Adults and Children Hopkins et al 9 Hart et al 10 van Donselaar et al 11 (1988) (1990) (1991) Recruitment Prospective Prospective Prospective Delay <2 months Variable <3 months Follow-up 3 years 3 years 2 years % treated % recurrence (46) 40 % 2-year recurrence (37) 40 Risk factors Sleep-CT CP-PS Youth-Sleep-EEG Site Clinic Community Hospital Specifics FH trend Index # 1st Idiop-No SE No effect Trt-EEG-PS-16 yrs+ AS follow-up, cluster of seizures was considered as a recurrence CT= computed tomography; CP = cerebral palsy; PS = partial seizures; EEG = electroencephalogram; FH = family history; SE = status epilepticus; Trt = tail retraction time; AS = afebrile seizure. S594 Vol. 4 (7C) August 2004

3 first seizure counted in this study (termed the index seizure ) was the first seizure to lead to medical management. 10 When the data are reassessed so that patients are counted only if their index seizure is also their first seizure, the recurrence rate decreases to 46%, which is comparable with the other studies. Once again, RS seizures were a risk factor for recurrence (particularly with cerebral palsy), as were nocturnal seizures. Berg and Shinnar conducted a meta-analysis of 16 studies, which helped to shed more light on the risk factors associated with recurrence. 4 Overall, the rate of recurrence varied from 23% to 71%. However, they found that 3 factors predicted the risk of recurrence: RS, abnormal EEG, and etiology. Idiopathic unprovoked seizures with normal EEG have a very low recurrence rate (24%), RS unprovoked seizures with abnormal EEG have a higher rate of recurrence (65%), and idiopathic unprovoked seizures with abnormal EEG and RS unprovoked seizures with normal EEG have similar recurrence rates (48%). Additional risk factors for the RS group are partial seizures and status epilepticus. The authors of this study did not advocate treatment; however, they did suggest that this decision must be individualized. THE AAN/CNS PRACTICE PARAMETER: TREATMENT OF THE CHILD WITH A FIRST UNPROVOKED SEIZURE In preparation for the AAN/CNS Practice Parameter, a review of the literature from 1980 to 2001, including a total of 948 titles and 66 references, was undertaken to analyze risk of recurrence, risk factors, and impact of treatment on the risk of recurrence. 1 Interestingly, the review revealed that the risk of recurrence falls within a relatively narrow range of 36% to 54% and that EEG was identified as a predictor of recurrence in most of the studies. Etiology was also identified as an important predictor. The review also revealed that the risk of recurrence is maximal in the first 6 months, after which it declines. After 5 years without recurrence, the risk is very low. Only 10% to 15% of patients develop intractable epilepsy. Early intervention initially reduces the risk of recurrence but has no long-term effect on outcome. The study concluded that treatment with AEDs is not indicated for the prevention of the development of epilepsy. However, the study also concluded, treatment with AEDs may be considered in circumstances where the benefits of reducing the risk of a second seizure outweigh the risks of pharmacologic and psychosocial side effects. The latter statement emphasizes the need to individualize care when making treatment decisions. APPROACHING THE NEW-ONSET PATIENT The Practice Parameter allows the development of a systematic approach to a patient who presents with a history of a single seizure. 1 First, it should be ascertained that the event was in fact a seizure. Disorders that mimic seizures include: Sleep myoclonus Jitteriness of newborn Gastroesophageal reflux Pallid infantile syncope Night terrors Migraine and syncope Benign paroxysmal vertigo Tics and Tourette syndrome It should then be established that this was in fact the first seizure. A study by King et al showed that 45% of patients presenting with what they reported as a first seizure had actually had previous seizures, so these patients were actually already epileptic on their initial visit. 12 The presence of strong predictors of recurrence should be determined, particularly RS, an abnormal EEG, or abnormal developmental components. Before a final decision is made about treatment, it is important to counsel the patient so that the family, physician, and patient are all satisfied with the therapeutic decision. This is consistent with a statement by Fromm: We really do not have accurate information regarding chances of further seizures after a single seizure. Therefore the fairest and most ethical way to treat such patients is to share our uncertainty with them. 13 CASE STUDY This patient is a boy aged 5 years with a history of neonatal encephalopathy with early seizures, and his paternal grandmother had a history of epilepsy. He was discharged home from the hospital on no medications. He has spastic quadriplegia with global delay; magnetic resonance imaging (MRI) shows atrophy. He suffered an unprovoked nocturnal tonic-clonic seizure 75 minutes in duration. Control of the seizure required Advanced Studies in Medicine S595

4 lorazepam, diazepam, phenytoin, and phenobarbital. A workup with lumbar puncture was negative. Cerebral palsy is a strong risk factor; studies by Annegers et al and Hart et al found risk of recurrence to be 92% and 100%, respectively. 3,10 If a child presents with a first seizure and developmental regression, the diagnosis of acquired encephalopathy should be ruled out. In this case, after counseling, the parents chose to initiate treatment, clearly the best course of action for the child. Other risk factors that should be considered are: EEG. There is evidence that abnormal EEG within 48 hours following a first seizure may predict subsequent seizures. 14 Status epilepticus, which did not seem to increase the risk of recurrence except in the RS group of the Hauser study with prolonged follow-up of about 8 years. 2 Modern imaging, which has potential for prediction but has not been systematically studied. Hopkins et al reported higher risk with tumor as determined by computed tomography (CT). 9 King et al found that MRI was a better predictor than CT, although data are lacking. 12 Pohlmann- Eden et al described a subgroup of patients who were at high risk of recurrence after cerebrovascular accident. 15 IMPROVING THE LONG-TERM PROSPECTS The second objective of this article is to examine whether the findings of Shinnar et al 16,17 and Hauser et al 2,18 are still valid. They are clearly still relevant for counseling patients and family on the risk of recurrence. However, early EEG and imaging data could improve our knowledge. Ultimately, the most important question is whether early treatment has a positive effect on long-term outcome. The goals of antiepileptic therapy are prevention of recurrence, improvement of the rate of long-term remission, and prevention of the various changes that can be involved in epileptogenesis: neuronal loss, sprouting, neurogenesis, receptor expression, and glianeuron interaction. The Nova Scotia group and the Italian First Seizure Trial Group (FIRST Group) clearly showed that the short-term risk of recurrence decreases if patients are treated appropriately after a seizure. 19,20 However, there was no difference after 2 years (Table 3). Camfield et al also showed similar rates of recurrence after 15 years of follow-up. 19 It would appear, therefore, that there is no long-term benefit to AED treatment after a first seizure. For some patients, however, perhaps the onset of therapy needs to be even sooner. A study of neonates with encephalopathy resulting from severe hypoxia showed that long-term neurologic and developmental outcome was improved if they were given prophylactic phenobarbital rather than waiting for seizures to develop. 21 Outcomes may therefore be improved by initiating treatment after the initial event, whether or not the event was a seizure. The goals of therapy, then, are to prevent damage after the initial event, whether or not the event was a seizure. If damage cannot be prevented, then the goal should be to prevent the neuronal network changes that lead to epileptogenesis; if that is not possible, then the clinical expression of these changes must be prevented, which is what is achieved with antiseizure medication. Clinically oriented models, such as posttraumatic, postanoxia, and postfebrile seizure models, are needed to study this issue further. Work by Germano et al indicates that certain brain malformations increase sensitivity to hyperthermic episodes, with the possibility of leading to spontaneous recurrent seizures. 22 An association has been noted between focal cortical dysplasia along with mesial temporal sclerosis and refractory temporal lobe epilepsy in children undergoing surgery. Temporal lobe epilepsy is also known to be associated with atypical febrile seizures. To study this association further, Scantlebury et al used a rat model. 23 At 1 day postnatal, a focal cortical lesion was induced using a freeze technique. At 10 days postnatal, hyperthermic seizures Table 3. Risk of Short-term Seizure Recurrence and Recurrence after 2 Years with Early Treatment Recurrence (Treated vs 2-Year Treated (%) Untreated) Follow-up Camfield et al % vs 53% 80% vs 88% FIRST Group % vs 38% 68% vs 60% FIRST = Italian First Seizure Trial. S596 Vol. 4 (7C) August 2004

5 were induced by exposing the rats to air heated to 45 C to 50 C. The lesioned rats demonstrated atypical seizures, with such features as a prolonged nonresponsive period after the convulsion (posthyperthermia depression), as well as brief ictal episodes during recovery. This period had characteristics of epilepsy on EEG. These hyperthermic convulsions were prolonged, and their onset had shorter latency and occurred at a lower temperature than in the control rats. The seizures produced ipsilateral brain damage with reduced brain volume, and the lesioned rats subsequently developed limbic seizures. This research provides a model to test new drugs for both antiseizure and antiepileptogenic properties. It also suggests the possibility that, in the presence of an underlying and possibly undetected susceptibility, which could be a genetic or anatomical problem, recurrent seizures could be triggered by a first event such as hyperthermia or anoxia. Detailed EEG studies using a 128-channel geodesic system are under way to find potential markers of underlying abnormalities. It is suspected that genetic abnormalities in gammaaminobutyric acid (GABA) receptors may also lead to susceptibility to recurrent seizures, and studies of abnormal GABA receptor genes are in progress. Improved imaging also promises to assist in identifying susceptible patients. Anatomical and functional MRI should be useful in this regard. CONCLUSIONS More than 120 years after Gowers s observations, 6 definitive information about the benefits of early treatment after a first seizure is still lacking. The AAN has concluded that the available data do not support antiepileptic treatment with AEDs after a single seizure. 1 However, there are some identifiable circumstances in which there is at least a short-term benefit to early use of AEDs, and research is now suggesting that treatment prior to seizure activity in some high-risk situations may have long-term benefits to the patient. Improvements in modeling may lead to drugs with long-term antiepileptic effects, whereas better imaging and pharmacogenomic tools promise to improve the ability to predict which patients stand to benefit from early AED treatment. For the present, whether to give early antiseizure medication should rest on the decision of the patient and family after counseling. A wide variety of AEDs is now available, and the choice of drug should be individualized based on efficacy and side-effect profile. The development of effective antiepileptogenic treatment will require multicenter studies with strict patient selection. REFERENCES 1. Hirtz D, Berg A, Bettis D, et al. Practice parameter: treatment of the child with a first unprovoked seizure: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2003;60(2): Hauser WA, Anderson VE, Loewenson RB, McRoberts SM. Seizure recurrence after a first unprovoked seizure. N Engl J Med. 1982;307(9): Annegers JF, Shirts SB, Hauser WA, Kurland LT. Risk of recurrence after an initial unprovoked seizure. Epilepsia. 1986;27(1): Berg AT, Shinnar S. The risk of seizure recurrence following a first unprovoked seizure: a quantitative review. Neurology. 1991;41(7): Hesdorffer DC, Logroscino G, Cascino D, Annegers JF, Hauser WA. Risk of unprovoked seizure after acute symptomatic seizure: effect of status epilepticus. Ann Neurol. 1998;44(6): Gowers WR. Epilepsy and Other Chronic Convulsive Diseases: Their Causes, Symptoms, and Treatment; The Border-land of Epilepsy: Faints, Vagal Attacks, Vertigo, Migraine, Sleep Symptoms, and Their Treatment. London: J & A Churchill;1881: Elwes RD, Chesterman P, Reynolds EH. Prognosis after a first untreated tonic-clonic seizure. Lancet. 1985; 2(8458): Hauser WA, Lee JR. Do seizures beget seizures? Prog Brain Res. 2002;135: Hopkins A, Garman A, Clarke C. The first seizure in adult life: value of clinical features, electroencephalography, and computerised tomographic scanning in prediction of seizure recurrence. Lancet. 1988;1(8588): Hart YM, Sander JW, Johnson AL, Shorvon SD. National General Practice Study of Epilepsy: recurrence after a first seizure. Lancet. 1990;336(8726): van Donselaar CA, Geerts AT, Schimsheimer RJ. Idiopathic first seizure in adult life: who should be treated? BMJ. 1991;302(6777): King MA, Newton MR, Jackson GD, et al. Epileptology of the first-seizure presentation: a clinical, electroencephalographic, and magnetic resonance imaging study of 300 consecutive patients. Lancet. 1998;352(9133): Fromm GH. First seizure management reconsidered. Response I. Arch Neurol. 1987;44(11): Schreiner A, Pohlmann-Eden B. Value of the early electroencephalogram after a first unprovoked seizure. Clin Electroencephalogr. 2003;34(3): Pohlmann-Eden B, Fatar M, Hennerici M. The preserved Advanced Studies in Medicine S597

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