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Summary: Purpose: To investigate the interaction among efficacy, tolerability, and overall effectiveness of the first antiepileptic drug (AED) in patients with newly diagnosed epilepsy.
Methods: The 470 patients were diagnosed, treated and followed up from January 1984 at a single center. Outcome was classified as seizure freedom for at least the last year or failure of initial treatment because of inadequate seizure control, adverse events, or for other reasons.
Results: Overall, 47% of patients became seizure-free with the first prescribed AED. A higher proportion (p = 0.025) of patients with symptomatic or cryptogenic epilepsy changed treatment because of intolerable side effects (17%), and a lower proportion (p = 0.007) became seizure-free (43.5%) compared with those with idiopathic epilepsy (8.5% and 58%, respectively). Most patients (83%) received carbamazepine (CBZ; n = 212), sodium valproate (VPA; n = 101), or lamotrigine (LTG; n = 78). The majority of seizure-free patients required only a moderate daily AED dose (93.1% with ≤800 mg CBZ, 91.3% with ≤1,500 mg VPA, 93.8% with ≤300 mg LTG), with commonest dose ranges being 400–600 mg for CBZ, 600–1,000 mg for VPA, and 125–200 mg for LTG. Most withdrawals due to poor tolerability also occurred at or below these dose levels (CBZ: 98%; VPA: 100%; LTG: 75%). Patients taking CBZ (27%) had a higher incidence of adverse events necessitating a change of treatment than did those treated with VPA (13%) or LTG (10%), resulting in fewer becoming seizure-free (CBZ vs. VPA, p = 0.02; CBZ vs. LTG, p = 0.002).
Conclusions: Nearly 50% of newly diagnosed patients became seizure-free on the first-ever AED, with >90% doing so at moderate or even modest dosing. Tolerability was as important as efficacy in determining overall effectiveness.
The “natural history” of newly diagnosed epilepsy in response to treatment has not been well documented. Long-term outcome studies (1) and randomized comparative trials (2–5) have suggested that <50% of patients become seizure-free with the first antiepileptic drug (AED). Failure due to lack of efficacy is associated with poor subsequent outcome (1). Effectiveness encompasses both efficacy and tolerability (6), but the importance of the latter is often inadequately assessed in randomized, particularly regulatory, studies that are not designed to address the everyday practical use of the drug (7). In patients with persistent seizures, it is unclear at what dose an AED should be deemed nonefficacious and when alternative treatment, such as with a second drug or a combination of two AEDs, should be considered. The usual recommendation of escalating the dose to near-toxic levels in patients with persisting seizures (8) assumes an appropriate dose–response relationship.
Although randomized controlled trials are essential to establish the efficacy of a new AED, whether these results can be extrapolated to clinical practice has been questioned (9). Observational studies may assist the translation of trial data into everyday use (10–12). We studied the interaction among efficacy, tolerability, and overall effectiveness in response to the first AED in patients with newly diagnosed epilepsy followed up at a single center.
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This study aimed to assess the response to treatment in a cohort of patients with newly diagnosed epilepsy followed up at a single center over a 15-year period. Nearly 50% became seizure-free with the first prescribed AED across a wide range of doses. Patients with symptomatic/cryptogenic epilepsy were more likely to change treatment because of side effects compared with those with idiopathic epilepsy. This reduction in the ability of patients with localization-related epilepsy to tolerate AED therapy contributed substantially to their lower seizure-free rate compared with patients with idiopathic epilepsy.
Tolerability also appeared to be a contributing factor in determining overall effectiveness of individual AEDs. VPA and LTG were better tolerated than CBZ. Comparisons between drugs in observational studies inevitably suffer from potential confounding factors, including bias in selection of AEDs for individual patients. It is possible, for instance, that CBZ was prescribed for a few patients with absence or myoclonic seizures, which it may exacerbate (18) and which might not have been apparent at initial presentation. This could have contributed to its lower seizure-control rate compared with VPA and LTG, which have a wider spectrum of activity (18,19). Similar findings, however, have been reported in randomized trials comparing CBZ with VPA and LTG, also involving previously untreated patients (3,4,21–23). CBZ was reported to be more effective than VPA in controlling partial seizures in the Veterans Administration study (2). This trial, however, had different patient and treatment characteristics, including enrollment of previously treated and mainly older men and use of high VPA doses (24). A randomized study in newly diagnosed epilepsy is required to confirm the differences reported here in overall seizure-free rates among these three AEDs.
Because AED doses are usually progressively increased in patients with uncontrolled seizures, it is not surprising that they received a higher average dose compared with the seizure-free patients. Those intolerant of AED treatment took a lower average dose than the responding patients, as the majority of withdrawals due to adverse events occurred at relatively low dosage for all three AEDs. The reasons for such marked differences in outcome in individual patients (i.e., seizure freedom or intolerability at low AED dosage) is poorly understood. This may reflect the diversity of underlying neuropathologies (25,26) and possible pharmacogenetic factors influencing drug response (27). These data also support the suggestion of two distinct populations of patients with newly diagnosed epilepsy [i.e., those responding to monotherapy and those requiring treatment with more than one AED (1)].
Examination of response to AEDs at different dose levels in newly diagnosed epilepsy has not been explored in randomized studies with flexible dosing schedules (3,4,21–23). A similar pattern emerged for CBZ, VPA, and LTG, the three most commonly prescribed AEDs in our cohort. Successful dosing in seizure-free patients appeared to be normally distributed, with the majority receiving middle-of-the-range amounts. More than 90% of seizure-free patients were taking ≤800 mg CBZ, 1,500 mg VPA, or 300 mg LTG per day. However, the commonest dosage ranges were more modest (i.e., 400–600 mg for CBZ, 600–1,000 mg for VPA, and 125–200 mg for LTG).
These observations support the widely held view that many patients with newly diagnosed epilepsy respond well to moderate doses of AED therapy (18). This perhaps explains why randomized monotherapy trials using fixed doses of AEDs in newly diagnosed epilepsy failed to demonstrate positive dose–response relationships (28,29). These data also suggest that in patients unresponsive to moderate AED doses, the chance of achieving seizure freedom with higher amounts is likely to be small. Alternative or combination therapy should, perhaps, be introduced earlier in the treatment paradigm than is currently recommended (8). Undoubtedly, other factors need to be considered before making this decision for the individual patient, including the extent of the response and the presence or absence of side effects. More prospective studies are required to determine what factors influence the likelihood of success with AED monotherapy, and at what stage combination therapy should be introduced.
In conclusion, ∼50% of patients with newly diagnosed epilepsy became seizure-free with the first prescribed AED. More than 90% did so at modest or moderate doses of CBZ (≤800 mg/day), VPA (≤1,500 mg/day), or LTG (≤300 mg/day). As has been shown in a number of randomized comparative monotherapy trials (4,21,30), tolerability was as important as efficacy in determining overall effectiveness. A better understanding of the natural history of treated epilepsy would allow more accurate assessment of the factors influencing prognosis and help formulate a strategic approach to management in patients in whom monotherapy with the first-choice AED fails.