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INVITED REVIEW
Year : 2008  |  Volume : 3  |  Issue : 1  |  Page : 41-47
 

Prognosis of pediatric epilepsy


Department of Neuroepidemiology, Mumbai Hospital Institute of Medical Sciences, Mumbai, India

Correspondence Address:
Girish C Nair
Department of Neuroepidemiology, Room No.11, 15th Floor MRC., Bombay Hospital, 12 - Marine Lines, Mumbai - 400 020
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1817-1745.40589

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   Abstract 

Epilepsy is a significant and commonplace neurological disability in the pediatric population. Data from increasingly larger and more representative studies have brought about noteworthy changes in our understanding of the prognosis of epilepsy in the pediatric age-group. Prevalence rates for epilepsy in both the developing and the developed world are surprisingly similar despite distinct differences in incidence and large treatment gaps in the developing world; this strongly points towards the possibility of spontaneous remission, at least in some patients. Prognosis after an isolated first seizure is generally quite favorable, but worsens with recurring seizures, remote symptomatic etiology, and the presence of abnormalities on EEG. Presently available antiepileptic drugs (AEDs) are at best seizure suppressant in their action and have not been shown to be antiepileptic in the sense that they alter the long-term prognosis of the epilepsy for the better. Epilepsy syndromes can be considered to belong to distinct groups on the basis of their prognosis. Some have an excellent outcome in terms of seizure freedom and neurological development; yet others have a grim prognosis with respect to these variables. Factors that impact on the prognosis of treated epilepsy are being understood and include the specific etiology, age of onset of epilepsy, and EEG findings. Epileptics, especially those with remote symptomatic seizures and refractory epilepsy, suffer higher mortality as compared to the general population. While the outcomes in terms of seizure freedom in patients with epilepsy appear favorable, disturbing data on psychosocial morbidity are coming to light and are reflected in the lower rates of higher education, employment, marriage, and fertility among epileptics.


Keywords: Epilepsy, pediatric, prognosis, seizure, treatment


How to cite this article:
Nair GC, Bharucha NE. Prognosis of pediatric epilepsy. J Pediatr Neurosci 2008;3:41-7

How to cite this URL:
Nair GC, Bharucha NE. Prognosis of pediatric epilepsy. J Pediatr Neurosci [serial online] 2008 [cited 2019 Dec 16];3:41-7. Available from: http://www.pediatricneurosciences.com/text.asp?2008/3/1/41/40589



   Introduction Top


Epilepsy is the most common treatable serious neurological disorder in children and young adults and is the third most common of the serious neurological disorders of childhood, with mental retardation and cerebral palsy being the most common. [1] Epilepsy affects up to 1% of youngsters up to the age of 16 years. [2] Epilepsy is defined as two or more unprovoked seizures, more than 24 h apart, in a child of over one month of age. [3] The term prognosis generally refers to the probability of attaining seizure freedom while on treatment and after drug withdrawal. [4] Guidelines for epidemiological research, published in 1993, classify the etiology of seizures as remote symptomatic, cryptogenic, and idiopathic. [3] Remote symptomatic seizures are those without an immediate cause but with an identifiable previous brain injury; the presence of a static encephalopathy, such as mental retardation or cerebral palsy; or the presence of a clear imaging abnormality, such as cortical dysplasia. Cryptogenic seizures are those occurring in otherwise normal individuals without an identifiable disorder or abnormality associated with an increased risk of epilepsy. Idiopathic seizures are those occurring in the context of presumed genetic, age-dependant epilepsy, such as benign rolandic epilepsy or childhood absence epilepsy. The prognosis of epilepsy depends on the population characteristics, case definition, severity of the condition, duration of follow-up, and treatment. [4]


   Overall Prognosis of Epilepsy Top


The majority of patients with epilepsy have a favorable prognosis. The past three decades have witnessed a paradigm shift in the understanding of the prognosis of childhood-onset seizures and epilepsy. As late as the 1980s, it was thought that epilepsy was a progressive, rarely remitting disorder. [5] Rodin's monograph on the prognosis of epilepsy indicated a high rate of chronicity (in excess of 80%). [6] Patients seen at tertiary epilepsy centers constituted the study subjects in most of the early studies on the prognosis of epilepsy and most of them had refractory epilepsy for many years. Studies done more recently in newly diagnosed epileptics have reported a high rate (55-68%) of prolonged seizure remission. [7] These studies, which have followed patients from the onset of their seizure disorder, report seizure freedom on antiepileptic drugs (AEDs) in most patients in the early years after diagnosis, with many being able to discontinue medication.

It is worth noting that prevalence rates for epilepsy from several underdeveloped countries, where large treatment gaps exist, are broadly similar to those reported from the developed world. The prevalence rates for active epilepsy are usually between 4-10 per 1000 in both cases. [8],[9],[10],[11],[12],[13],[14],[15] The incidence of epilepsy is higher in resource-poor countries (in excess of 70 cases per 100,000) as compared to the industrialized world (30-60 cases per 100,000). [9],[16],[17],[18],[19],[20] While the increased mortality associated with epilepsy in resource-poor countries does contribute to the difference between incidence and prevalence, it does not explain all of it. The prevalence rates are similar in the two settings most likely on account of spontaneous remissions in some patients. [4]


   Prognosis after First Unprovoked Seizure Top


The International League Against Epilepsy (ILAE) guidelines for epidemiologic research in epilepsy define a first unprovoked seizure as one seizure or a flurry of seizures, all occurring within 24 h, in a person over 1 month of age with no prior history of unprovoked seizures. [3] A flurry of seizures in one day does not signify a recurrence risk that is very different from the recurrence risk following a single ictus. [21],[22] As many as 33% of children who apparently present with the first unprovoked seizure have had prior episodes. [22],[23] One-third to one-half of patients with seizures come to medical attention following the first seizure. [24],[25]

The recurrence risk following a first unprovoked seizure in children and adults has been examined by a number of studies in the past couple of decades. [21],[23],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39] The recruitment and identification techniques used in these studies varied. Some were prospective studies that identified the subject at the first seizure and excluded those with prior events, and others were retrospective reviews that included all seizure patients. The risk of recurrence after a first unprovoked seizure ranges from 23-71%. [40] The risk of recurrence at 2 years is 21-69% and at 5 years it is 34 to > 71%. When population-based studies are considered, relapse rates are 36-37% at 1 year and 43-45% at 2 years. [24],[30] When several reports are reviewed, the average overall recurrence risk emerges as 51%. [33] The 2-year recurrence risk in prospective studies was 36%, while that in retrospective studies was 47%. The relapse risk, after a first unprovoked seizure, decreases with time. The first 6 months following the unprovoked seizure witness about 50% of the recurrences. Up to 76-96% of recurrences occur within 2 years of the first seizure. [33]


   Risk Factors for Relapse after First Unprovoked Seizure Top


A number of factors are associated with the differential recurrence risk after a first unprovoked seizure. Two strikingly consistent predictors of recurrence are a documented etiology for the seizure and an abnormal EEG pattern. [33] The presence of a documented etiology for the seizure places it in the category of remote symptomatic seizure as opposed to idiopathic or cryptogenic seizures. An abnormal EEG may show either an epileptiform pattern or slowing. The etiology of seizures assumes the greatest importance in predicting multiple recurrences and decides long-term prognosis. [39] The pooled recurrence risk in patients with an idiopathic or cryptogenic first seizure is 32% compared with 57% for a remote symptomatic seizure. The recurrence risk more than doubles from 27% with a normal EEG tracing to 58% with an EEG showing epileptiform abnormalities. Epileptiform abnormalities on EEG are associated with a greater recurrence risk than are nonepileptiform abnormalities. When the pooled 2-year recurrence risk is analyzed as a composite of etiology and EEG findings, the following findings emerge: the lowest recurrence risk (24%) is for an idiopathic or cryptogenic first seizure with a normal EEG; the risk is intermediate (48%) for a remote symptomatic seizure with a normal EEG or an idiopathic/cryptogenic seizure with an abnormal EEG; and the highest risk (65%) is with a remote symptomatic seizure with an abnormal EEG. [33] Seizures occurring during sleep are associated with a higher risk of recurrence. [21],[41] Even when controlled for etiology and EEG abnormalities, partial seizures are associated with a higher risk of recurrence. [29],[30] One study [32] has confirmed a positive correlation between seizure relapse and a positive family history of seizures. At present, there is insufficient evidence to correlate risk of recurrence with gender, age at presentation, presentation with status epilepticus / prolonged duration of the initial seizure, and number of seizures in the first 24 h of presentation . [33]

The time period in which seizures recur tends to be similar across several studies, irrespective of the degree of recurrence risk. [21],[23],[26],[28],[29],[30],[32],[33],[35],[38],[39] Up to 50% of recurrences occur within 6 months of the initial seizure and over 80% within 2 years of the initial seizure. Late recurrences are decidedly unusual, but have been reported up to 10 years after the initial seizure. [21]


   Treatment of First Unprovoked Seizure Top


The First Seizure Trial Group (FIRST Group) study [35] was a large multicenter Italian trial of 397 children and adults. It assessed the effect of treatment of the first seizure on the risk of relapse and the long-term prognosis of epilepsy. The trial showed that in treated patients, the cumulative time-dependant risk of recurrence was 17% at 12 months and 25% at 24 months. In untreated patients, the recurrence risk was more than double that of treated patients at 41% and 51%, respectively. Similar results were reported by Camfield et al ., [31] in a study of 30 pediatric patients randomized to either non-treatment or treatment with carbamazepine. However, these differences became less remarkable when the chance of initiating a 2-year remission was the considered endpoint. From the second year of follow-up to the fifteenth year after randomization, the cumulative probability of long-term remission in the two treatment groups tended to be similar. [42] Confirmation for the results of the FIRST study came from the larger European trial (MESS study - MRC Multicentre Trial for Early Epilepsy and Single Seizures), where immediate and deferred treatment for early epilepsy and single seizures were compared. [43] In this trial, more than half the patients in both the immediate and deferred treatment arms had experienced a single seizure at randomization. Immediate treatment prolonged the time to the first relapse and increased the proportion (64 vs 52%) of patients achieving immediate 2-year remission. In addition, the proportion of patients achieving 2-year remission at 5 years and 8 years was similar or very nearly so. The results of the aforementioned two trials tended to support observational reports that the long-term prognosis of the first seizure is not significantly affected by immediate treatment. AEDs are effective at suppressing seizures but are not antiepileptogenic in the sense that they can change the underlying epilepsy. [44],[45] There is now, general agreement that AED therapy is not indicated following a single unprovoked seizure. [21],[29],[31],[39],[46],[47],[48],[49] Regarding therapy after a second unprovoked seizure, when the definition of epilepsy is satisfied, there is greater controversy, and the issues that need to be addressed, especially in the pediatric age group, are more complex. [4]


   Prognosis of Newly Diagnosed Epilepsy Top


The diagnosis of epilepsy is made after a minimum of two unprovoked seizures have occurred. In the industrialized countries, treatment starts at the time of diagnosis. The risk of a third seizure following a second unprovoked seizure has been estimated to be 73% and the risk of the fourth seizure following the third at 76%. [38] In a Finnish cohort of patients with childhood-onset epilepsy, over a 30-year follow-up period, 64% of patients had entered 5-year terminal remission, and of these patients 74% were off medication. [50] As many as 58-65% of patients in population-based studies on the long-term prognosis of treated epilepsy are in a cumulative 5-year remission at 10 years. [51],[52] The remission rate rises to about 70% at 20 years following seizure onset. [51] In the pediatric age group, the 3-5 year remission rate at 12 to 30 years is 74-78%. [53]


   Principal Prognostic Predictors Top


The strongest prognostic predictor for seizure recurrence in patients with epilepsy is the etiology of the epilepsy. [4] Idiopathic epilepsy enjoys a better chance of seizure remission than symptomatic or cryptogenic epilepsy.

Epilepsy studies previously used a dichotomous outcome of 'remission' or 'not in remission.' Absence of remission was equated to intractability. There are significant differences between the terms 'intractability' and 'not in remission.' Patients not in remission are essentially those who do not enjoy complete seizure freedom. Thus, occasional seizures on account of drug noncompliance and intercurrent illness satisfy the conditions for absence of remission, but it does not imply intractability. In childhood-onset epilepsy, a documented etiology has been found to be a significant predictor of intractability. [54] The Connecticut study of childhood-onset epilepsy examined early predictors of intractability. A patient was defined as having intractable epilepsy if one or more seizures had been experienced every month for 18 months or longer and if two or more appropriately selected AEDs had failed to control seizures. Specific syndrome / known etiology, high initial seizure frequency, and focal EEG slowing were noted to be early predictors of intractability. [55] In the Connecticut study, the actual number of seizures prior to treatment, and a history of status epilepticus, were not associated with a significantly increased risk of intractability. The number of seizures experienced in the first 6 months after the index seizure was an independent predictor of 1-year and 2-year remission in the UK National General Practice Study of Epilepsy (NGPSE). [52] In the first population-based studies from Rochester, Minnesota, the chance of a 5-year remission at 15 years in subjects with symptomatic epilepsy was 30%-significantly lower than the 42% possibility of remission for those with idiopathic epilepsy. [51] In patients with symptomatic epilepsy, those with neurological dysfunction at birth had a lower chance of remission. In the Finnish childhood-onset epilepsy cohort, etiology, epilepsy syndrome, seizure type, and early response to AED therapy were important factors deciding remission. [50] While status epilepticus has been associated with intractability [56] and lack of remission, [57] the multivariate analysis in the Finnish study did not support the association.


   Prognosis of Epilepsy Syndromes Top


Epileptic syndromes have fairly uniform clinical and electrographic features and shared patterns with respect to family history, age at onset, presumed etiology, and neuroimaging findings. [1] A classification of epilepsy syndromes into four prognostic groups has been suggested based on characteristic outcomes and response to treatment, especially in the pediatric age-group. [58] The four groups are as follows:

  • Excellent prognosis: These epilepsy syndromes have a high probability of spontaneous remission. They represent about 20-30% of the total. Examples include neonatal seizures, benign partial epilepsies, benign myoclonic epilepsy in infancy, and epilepsies provoked by specific modes of activation.
  • Good prognosis: These syndromes are easy to control with pharmacological measures and enjoy good chances of spontaneous remission. Examples of this type include infantile absence epilepsy, epilepsies with generalized tonic-clonic seizures secondary to specific conditions, and some partial epilepsies. These represent about 30- 40% of the total.
  • AED-dependant prognosis: These syndromes may respond to pharmacological measures, but tend to relapse when these are withdrawn. They represent about 10-20% of the total. Examples of epilepsy syndromes of this type include juvenile myoclonic epilepsy and most partial epilepsies (symptomatic or cryptogenic).
  • Guarded prognosis: These epilepsy syndromes represent about 20% of the total. Here seizures tend to recur despite treatment which is intensive and multimodal. Examples of this type include epilepsies associated with congenital neurological defects, progressive neurological disorders, and some symptomatic or cryptogenic partial epilepsies.



   Prognosis of Epilepsy after Treatment Withdrawal Top


Across studies of recurrence risk after a first seizure, the reported recurrence varies rather widely, but the risk factors for recurrence tend to remain consistent. In contrast, studies of antiepileptic drug withdrawal agree on the actual risk of recurrence but do not throw up consistent risk factors for recurrence of seizures on discontinuation of therapy. [59] After a 2-4 year period of seizure freedom on medication, 60-75% of children and adults with epilepsy remain seizure free following discontinuation of therapy. [60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73],[74],[75],[76],[77] The duration of the seizure-free period (2 years vs 4 years) prior to drug withdrawal did not affect the prognosis following medication withdrawal. A pooled relapse risk of 25% at 1 year and 29% at 2 years following AED withdrawal was reported by a meta-analysis of data available up to 1994. [74]


   Factors Predicting Seizure Relapse after Treatment Withdrawal Top


Etiology, age of onset of epilepsy, and EEG findings are factors consistently associated with seizure recurrence risk after withdrawal of medication. Duration of epilepsy, number of seizures, seizure type, and the specific medication used have not shown a consistent association with a differential risk of relapse following discontinuation of medication. [59] In the pediatric age-group, in patients harboring no major risk factors for recurrence (i.e., cryptogenic / idiopathic etiology, a normal EEG prior to discontinuation, age of onset < 12 years), the rate of recurrence after drug withdrawal is < 15%. [73]

The prognosis is worse after cessation of drug therapy in pediatric patients with remote symptomatic epilepsy, as compared to those with idiopathic or cryptogenic epilepsy. This guarded prognosis applies both to the probability of attaining remission [50],[51] and the probability of seizure freedom once medications are withdrawn. [66],[69],[74] The relative risk of seizure recurrence following cessation of drug therapy in patients with remote symptomatic seizures, compared to those with idiopathic or cryptogenic seizures, was found to be 1.55 on meta-analysis. [74] In spite of the comparatively worse prognosis, as many as 50% of patients with remote symptomatic epilepsy who are in remission on drug therapy remain so after medication withdrawal. [74],[75]

The age of onset of epilepsy plays an important role in the prognosis of the condition after withdrawal of medication. Adolescent age of onset (> 12 years) is consistently associated with a higher risk of recurrence after drug withdrawal. [66],[67],[74],[75] Recurrence risk is more influenced by the age at onset of epilepsy than by age at withdrawal of medication and is higher for adolescent-onset epilepsy than for either childhood-onset or adult-onset epilepsy. [74] In patients with remote symptomatic epilepsy, a younger age of epilepsy onset has been associated with a higher recurrence risk following drug withdrawal. [75]

The presence of abnormalities on the EEG prior to drug withdrawal represents an increased risk of seizure recurrence after medication withdrawal. [65],[66],[70],[74],[75] A meta-analysis reported a relative risk of 1.45 for seizure recurrence when there are EEG abnormalities prior to drug withdrawal. [74] This increased risk was noted to exist even for abnormalities that were not frankly epileptiform. It is worth noting that a composite of etiology, age of onset, EEG abnormalities, and epilepsy syndrome (if any) must be considered before prognostication in any individual patient. For example, benign rolandic epilepsy has a favorable prognosis for remission and seizure freedom after drug withdrawal, even when the EEG is abnormal. [75]

Data from a randomized, prospective clinical trial demonstrated no need to prolong the period of medication taper once the decision to stop drug therapy has been taken. The 2-year recurrence risk was no different amongst groups randomized to a rapid 6-week taper and a gradual 9-month taper. [64] The majority of relapses occur early after cessation of drug therapy. Almost 50% of relapses are reported in the first 6 months and 60-80% within 1 year after medication withdrawal. [74] Seizures occurring 2 years or longer after discontinuation of medication are more likely attributable to the underlying epilepsy syndrome than to the discontinuation of medication. [59],[71]


   Psychosocial Outcomes Top


While the gloomy outcomes for patients with epilepsy in terms of seizure freedom seem very much a thing of the past, there is disturbing evidence that epilepsy, even when well controlled or in remission, has significant social and psychological morbidity. The occurrence of seizures in childhood appears to have a long-term adverse impact on education, employment, marriage, and fertility. [59]

In the Finnish population-based childhood-onset epilepsy cohort, which compared the educational and social outcomes in a cohort of patients of uncomplicated epilepsy with normal controls, it was found that while all epileptics successfully acquired a primary education, further academic achievement was impaired in this group as compared to normal controls. [50] Uncomplicated epilepsy was defined as epilepsy without other neurological impairment. The factors contributing to academic underachievement remained unclear and were thought to be numerous and diverse. Learning disabilities and cognitive dysfunction commonly reported in children with epilepsy contribute to a lower intellectual level, which seems the most likely explanation for academic underachievement. [78] While epilepsy and use of AEDs are factors associated with academic underperformance, the strongest independent predictors of poor school performance include early onset of seizures and the cumulative number of seizures. [79]

In the Finnish cohort, in spite of the differences in educational outcome, subjects with uncomplicated epilepsy had similar socioeconomic status as controls. [50] This was attributed to the socioeconomic status of the entire family and the prevalent social system in Finland, a rather benevolent welfare state. Epilepsy was noted, however, to have an adverse effect on long-term employment outcomes, even in patients with benign epilepsies. Studies show that adults with active epilepsy have lower employment rates than the general population. [80],[81]

Lower rates of marriage and fertility reported among patients with epilepsy raise concerns of social maladjustment. Adults with active temporal lobe epilepsy have been reported to have lower marriage and fertility rates, though the cause for this remains unclear. [59]

In view of the episodic, unpredictable, and sometimes catastrophic phenomenology of seizures and epilepsy, there is an intuitive association of the condition with accidents and trauma. In a European multicenter cohort study, [82] patients with epilepsy were noted to experience a higher rate of accidents as compared to normal controls (21 vs 13%). However, in patients experiencing seizure freedom (on or off medication), the risk of accidental injury was clearly lower than that of patients with ongoing seizures and was very nearly the same as in the control population. About one-quarter of accidents in patients with epilepsy were seizure related. Most accidents occurred at home and nearly a half of domestic accidents were seizure related. About a third of school accidents and a quarter of traffic accidents in patients with epilepsy were seizure related.


   Mortality Top


There is an increased mortality rate associated with childhood-onset epilepsy. [59] The greatest risk is associated with remote symptomatic seizures and refractory epilepsy. Remote symptomatic epilepsy is a major risk factor for refractory epilepsy and the two conditions tend to coexist. [50],[55],[56] The mortality rate in neurologically normal children with idiopathic or cryptogenic epilepsy in remission (on or off medication) is not substantially increased as compared to the general population. [50]


   Conclusions Top


In a gratifying departure from the gloomy predictions on the outcome of pediatric epilepsy that were made as recently as the early eighties, we now know that the majority of patients have a favorable prognosis in terms of attaining seizure freedom on or off medication. Predictors of seizure relapse risk in patients after an isolated first seizure and in those patients being taken off medication have come to light. Our expanding knowledge of the neurobiology of epilepsy continues to shed further light on the variables that influence outcomes in pediatric epilepsy. Epilepsy is more than just seizures. It is a disease with huge psychosocial consequences. As the treatment of epilepsy improves and a greater number of patients achieve seizure freedom, these patients are expected to shoulder responsibilities that they were being exempt from. This process of coping with increased demands from society produces profound psychosocial morbidity. The distressing psychosocial consequences of this inability of epileptics to cope are evident in the lower rates of education, employment, marriage, and fertility among epileptics as compared to normal controls. This area represents a possibly neglected area of epilepsy research; greater understanding would contribute immensely to better outcomes in pediatric patients diagnosed with epilepsy.

 
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    Abstract
    Introduction
    Overall Prognosi...
    Prognosis after ...
    Risk Factors for...
    Treatment of Fir...
    Prognosis of New...
    Principal Progno...
    Prognosis of Epi...
    Prognosis of Epi...
    Factors Predicti...
    Psychosocial Out...
    Mortality
    Conclusions
    References

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