Medline ® Abstracts for References 5-13

BACKGROUND: More than 30 percent of patients with epilepsy have inadequate control of seizures with drug therapy, but why this happens and whether it can be predicted are unknown. We studied the response to antiepileptic drugs in patients with newly diagnosed epilepsy to identify factors associated with subsequent poor control of seizures.

METHODS: We prospectively studied 525 patients (age, 9 to 93 years) who were given a diagnosis, treated, and followed up at a single center between 1984 and 1997. Epilepsy was classified as idiopathic (with a presumed genetic basis), symptomatic (resulting from a structural abnormality), or cryptogenic (resulting from an unknown underlying cause). Patients were considered to be seizure-free if they had not had any seizures for at least one year.

RESULTS: Among the 525 patients, 333 (63 percent) remained seizure-free during antiepileptic-drug treatment or after treatment was stopped. The prevalence of persistent seizures was higher in patients with symptomatic or cryptogenic epilepsy than in those with idiopathic epilepsy (40 percent vs. 26 percent, P=0.004) and in patients who had had more than 20 seizures before starting treatment than in those who had had fewer (51 percent vs. 29 percent, P<0.001). The seizure-free rate was similar in patients who were treated with a single established drug (67 percent) and patients who were treated with a single new drug (69 percent). Among 470 previously untreated patients, 222 (47 percent) became seizure-free during treatment with their first antiepileptic drug and 67 (14 percent) became seizure-free during treatment with a second or third drug. In 12 patients (3 percent) epilepsy was controlled by treatment with two drugs. Among patients who had no response to the first drug, the percentage who subsequently became seizure-free was smaller (11 percent) when treatment failure was due to lack of efficacy than when it was due to intolerable side effects (41 percent) or an idiosyncratic reaction (55 percent).

CONCLUSIONS: Patients who have many seizures before therapy or who have an inadequate response to initial treatment with antiepileptic drugs are likely to have refractory epilepsy.

OBJECTIVE: To construct a clinical prediction model for the early identification of children destined to develop refractory temporal lobe epilepsy (TLE) 2 years after epilepsy onset.

METHODS: Patients with TLE between 1 and 18 years old seen in the Division of Neurology at Children's Hospital of Philadelphia during 1999 were identified through billing records and chart review. Data were abstracted independently on 5 candidate predictor variables for refractory TLE and on seizure frequency outcome at 2 years after epilepsy onset.

RESULTS: One hundred twenty patients met inclusion criteria and had at least 2 years of follow-up. Forty-five of 120 patients (37.5%) had refractory TLE at 2 years after onset, and 75 of 120 (62.5%) were seizure free. Three significant predictors of refractory TLE were found on bivariate analysis: an early risk factor for epilepsy (risk ratio = 3.5 [95% CI 2.2, 5.6]), temporal lobe abnormality on MRI scan (2.9 [95% CI 1.9, 4.6]), and failure of the first antiepileptic drug (AED) trial (16.5 [95% CI 6.3, 43.9]). Logistic regression indicated that the best model to predict refractory TLE contained only the variable "failure of first AED trial," with a positive predictive value of 0.89 (95% CI 0.76, 0.96) and negative predictive value of 0.95 (95% CI 0.87, 0.99) to predict "refractory TLE" at 2 years.

CONCLUSIONS: Failure of first AED trial accurately predicts refractory TLE at 2 years after onset, based on retrospective cohort data in children. If verified prospectively and with longer follow-up, this finding should support earlier consideration of surgical options.

BACKGROUND: Little is known about early prediction of intractable epilepsy (IE) in children. Such information could help guide the early use of new therapies in selected patients.

METHODS: Children with newly diagnosed epilepsy (n = 613) were prospectively identified from child neurology practices in Connecticut (1993--1997) and followed-up for the occurrence of IE (failure of>or = 2 drugs,>or = 1 seizure/month, over 18 months) [corrected]. Etiology and epilepsy syndromes were classified per International League Against Epilepsy guidelines.

RESULTS: The median follow-up is 4.8 years, and 599 (97.7%) have been followed for more than 18 months. Sixty children (10.0%) have met the criteria for IE, including 34.6% with cryptogenic/symptomatic generalized, 2.7% with idiopathic, 10.7% with other localization-related, and 8.2% with unclassified epilepsy (p<0.0001). After multivariable adjustment for epilepsy syndrome, initial seizure frequency (p<0.0001), focal EEG slowing (p = 0.02), and acute symptomatic or neonatal status epilepticus (p = 0.001) were associated with an increased risk of IE, and age at onset between 5 and 9 years was associated with a lowered risk (p = 0.03). The absolute number of seizures and unprovoked or febrile status epilepticus were not associated substantially with IE.

CONCLUSIONS: Approximately 10% of children meet criteria for IE early in the course of their epilepsy. Cryptogenic/symptomatic generalized syndromes carry the highest risk and idiopathic syndromes the lowest. Half of IE occurs in children with nonidiopathic localization-related syndromes. Initial seizure frequency is highly predictive of IE. By contrast, absolute number of seizures and unprovoked or febrile status epilepticus are not.

The effectiveness of resective surgery for the treatment of carefully selected patients with medically intractable, localization-related epilepsy is clear. Seizure-free rates following temporal lobectomy are consistently 65% to 70% in adults and 68% to 78% in children. Extratemporal resections less commonly lead to a seizure-free outcome, although one recent childhood series reported a seizure-free rate of 62% following extratemporal epilepsy surgery. With both temporal and extratemporal resections, additional patients have a reduction in seizures following surgery but are not completely seizure free. The identification of favorable surgical candidates has been the subject of extensive research, and many investigators have examined predictors of outcome following epilepsy surgery. However, the early identification of the potential epilepsy surgery candidate and the optimal timing of surgery have only occasionally been addressed in the literature. This issue is methodologically challenging to study since studies require large numbers of patients with new-onset partial epilepsy who are followed over time. The purpose of this article is to review the current ability for early prediction of medical intractability in patients with surgically remediable epilepsy. Emphasis will be placed on the early prediction of intractable temporal lobe epilepsy in children and adolescents, since temporal lobectomy remains the prototype epilepsy surgery, and early surgery may improve psychosocial outcome in younger patients.

BACKGROUND: Much remains unknown about the natural history of intractable localization-related epilepsy, including how long it typically takes before intractability becomes evident. This information could guide the design of future studies, resolve certain discrepancies in the literature, and provide more accurate information about long-term prognosis.

METHODS: Individuals evaluated for resective surgery for refractory localization-related epilepsy were prospectively identified at the time of initial surgical evaluation at seven surgical centers (between 1996 and 2001). The latency time between onset of epilepsy and failure of second medication and history of remission (>/=1 year seizure-free) before surgical evaluation were examined with respect to age at onset, hippocampal atrophy, febrile seizures, and surgical site.

RESULTS: In the 333 patients included in the analysis, latency time was 9.1 years (range 0 to 48) and 26% reported a prior remission before surgery. A prior remission of>/=5 years was reported by 8.5% of study participants. Younger age at onset was strongly associated with longer latency time (p<0.0001) and higher probability of past remission (p<0.0001). In multivariable analyses, age at onset remained as the most important explanatory variable of both latency time and prior remission.

CONCLUSIONS: A substantial proportion of localization-related epilepsy may not become clearly intractable for many years after onset. This is especially true of epilepsy of childhood and early adolescent onset. If prospective studies confirm these findings and the underlying mechanisms behind these associations become understood, this raises the possibility of considering interventions that might interrupt such a process and some day prevent some forms of epilepsy from becoming intractable.

The natural history of treated epilepsy has substantial relevance to its pharmacologic and surgical management. In our center, 525 unselected, untreated patients were given a diagnosis of epilepsy, started on antiepileptic drug (AED) therapy, and followed for a median of 5 years. Sixty-three percent of patients had been seizure-free for at least the previous year. Forty-seven percent of 470 previously drug-naïve patients responded to their first AED. Thirteen percent were seizure-free on the second AED, and 1% on the third monotherapy choice. Only 3% were controlled with two AEDs and none with three. The prognosis for patients whose epilepsy did not respond to the first AED was strongly associated with the reason for failure. Only 11% of patients with inadequate control on the first AED later became seizure-free. These results suggest that patients with newly diagnosed epilepsy comprise two distinct populations. Around 60% will be controlled on monotherapy, usually with the first or second AED chosen. The remaining 30 to 40% will be difficult to control from the outset. A management plan should be formulated for each patient when treatment is started. Strategies for combining drugs should involve individual assessment of patient-related factors, including seizure type and epilepsy syndrome classification, combined with an understanding of the mechanisms of action, side effects, and interactions of the AEDs. Epilepsy surgery should be considered after failure of two well-tolerated treatment regimens, whether as monotherapy or with one monotherapy and the first combination. Prevention of refractory epilepsy should be the goal of treatment when the first AED is prescribed. A staged approach to the pharmacologic management and, when appropriate, surgical work-up for each epilepsy syndrome will optimize the chance of perfect seizure control and help more patients achieve a fulfilling life.

To improve patient care and facilitate clinical research, the International League Against Epilepsy (ILAE) appointed a Task Force to formulate a consensus definition of drug resistant epilepsy. The overall framework of the definition has two "hierarchical" levels: Level 1 provides a general scheme to categorize response to each therapeutic intervention, including a minimum dataset of knowledge about the intervention that would be needed; Level 2 provides a core definition of drug resistant epilepsy using a set of essential criteria based on the categorization of response (from Level 1) to trials of antiepileptic drugs. It is proposed as a testable hypothesis that drug resistant epilepsy is defined as failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom. This definition can be further refined when new evidence emerges. The rationale behind the definition and the principles governing its proper use are discussed, and examples to illustrate its application in clinical practice are provided.

OBJECTIVE: To delineate the temporal patterns of outcome and to determine the probability of seizure freedom with successive antiepileptic drug regimens in newly diagnosed epilepsy.

METHODS: Patients in whom epilepsy was diagnosed and the first antiepileptic drug prescribed between July 1, 1982, and April 1, 2006, were followed up until March 31, 2008. Outcomes were categorized into 4 patterns: (A) early and sustained seizure freedom; (B) delayed but sustained seizure freedom; (C) fluctuation between periods of seizure freedom and relapse; and (D) seizure freedom never attained. Probability of seizure freedom with successive drug regimens was compared. Seizure freedom was defined as no seizures for≥1 year.

RESULTS: A total of 1,098 patients were included (median age 32 years, range 9-93). At the last clinic visit, 749 (68%) patients were seizure-free, 678 (62%) on monotherapy. Outcome pattern A was observed in 408 (37%), pattern B in 246 (22%), pattern C in 172 (16%), and pattern D in 272 (25%) patients. There was a higher probability of seizure freedom in patients receiving 1 compared to 2 drug regimens, and 2 compared to 3 regimens (p<0.001). The difference was greater among patients with symptomaticor cryptogenic than with idiopathic epilepsy. Less than 2% of patients became seizure-free on subsequent regimens but a few did so on their sixth or seventh regimen.

CONCLUSIONS: Most patients with newly diagnosed epilepsy had a constant course which could usually be predicted early. The chance of seizure freedom declined with successive drug regimens, most markedly from the first to the third and among patients with localization-related epilepsies.