J Neurol (2007) 254:268–270 DOI 10.1007/s00415-007-0527-6
Medical and surgical treatment of epilepsy
JON 2527
Over the last twenty years considerable progress has been made in the treatment of different forms of epilepsy: new drugs have been established and surgical intervention has been shown to be effective. Several topics, however, still need further evaluation. Progress in three of them will be reported in this month’s Journal Club. The first article reports on a head-tohead comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. This state-of-the-art trial demonstrates similar efficacy with lower withdrawal rates for adverse events in patients treated with levetiracetam. The second study evaluated a very important clinical question: how effective are treatment changes in patients with apparently drug-resistant chronic epilepsy. The authors concluded that ‘‘the rather nihilistic view that intractability is inevitable if seizure control is not obtained within a few years of the onset of therapy is incorrect’’. The third article deals with the efficacy of temporal lobectomy in patients with medically refractory non-lesional temporal lobe epilepsy. It clearly demonstrates that the extent of resection of the region of hypometabolism on the preoperative FDG-PET is predictive of outcome and that strategies that tailor resection extent to regional hypometabolism are very promising.
Prof. Dr. med. M. Strupp (&) Dept. of Neurology Ludwig-Maximilians University Klinikum Großhadern Marchioninistr. 15 81366 Munich, Germany E-Mail:
[email protected]
JOURNAL CLUB Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy In the last ten years several new anti-epileptic drugs (AEDs) have been developed which have proved to be efficient in different forms of epilepsy. Further, some of the newer AEDs are better tolerated than the older agents. There had been, however, no direct head-to-head comparative study that had demonstrated higher efficacy for any of these newer AEDs over standard agents such as carbamazepine, phenotoin or valproic acid. Such studies are highly warranted because so far more than thirty percent of patients with epilepsy are refractory to existing treatments (for references see Brodie et al. 2007). One of the new promising AEDs is levetiracetam. This agent has a novel mode of action: it binds to synaptic vesicle protein 2A (for reference see Brodie et al. 2007). Since preliminary studies had demonstrated that levetiracetam may also be effective as a monotherapy, Brodie and coworkers from Glasgow performed a prospective randomised doubleblind trial to compare the effects of levetiracetam with controlled release carbamazepine in newly diagnosed epilepsy. According to current European regulations for the evaluation of new AEDs they designed a non-inferiority trial with the aim that the new AED should show at least a similar benefit-risk balance compared with an acknowledged standard at individually optimised dosages using clinically relevant endpoints. According to these guidelines, the primary outcome measure should be the proportion of patients remaining seizure-free for at least six months on either drug during the evaluation period with main-
tenance of efficacy for at least a year. During the patient recruitment period from 2002 to 2005, 288 adults with at least two partial or generalised tonic-clonic seizures in the previous year were randomly assigned to levetiracetam and 291 to controlled-release carbamazepine. For levetiracetam the initial dose was 500mg twice daily, if a seizure occurred within 26 weeks of stabilisation, dosage was increased incrementally to a maximum of 1500mg twice daily; for carbamazepine the initial dosage was 200mg twice daily which could be increased to 600mg twice daily. The major findings of this study were as follows: 73% of patients randomised to levetiracetam and 72.8% of those receiving controlled-release carbamazepine were seizure-free at the last evaluated dose. Regarding adverse events, a similar proportion of patients from both groups (about 80%) experienced at least one adverse effect during the treatment period, with most events being mild or moderate. The patients reported (with a rate between 10 and 25%) headache, fatigue, somnolence and dizziness in both groups. The withdrawal rates for adverse events were 14.4% in the levetiracetam group and 19.2% in the carbamazepine group (difference not statistically significant). Conclusions and Comments. The authors pointed out in their discussion that more patients treated with controlled-release carbamazepine discontinued treatment because of adverse events; however, patients treated with levetiracetam were more likely to report depression and insomnia. The authors also mention at the end of their article that ‘‘the fast and sustained efficacy and good tolerability of levetiracetam in adults and children with partial-onset seizures,
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together with its favourable pharmacokinetic profile, lack of enzyme-inducing properties, and low potential for pharmacokinetic interactions, make it a promising AED for use as initial monotherapy in newly diagnosed epilepsy’’. All in all, this very carefully performed study clearly demonstrates the efficacy of levetiracetam as a monotherapy in partial or generalised tonic-clonic seizures. Brodie MJ et al. (2007) Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology 68: 402–408 (E-mail:
[email protected]).
Results of treatment changes in patients with apparently drug-resistant chronic epilepsy It is well known that the temporal stage of epilepsy is one of the best clinical prognostic indicators for the efficacy of medical treatment: newly diagnosed epilepsy is much easier to treat than chronic epilepsy. Therefore, a rather nihilistic view developed. Anna Luciano and Simon Shorvon from the National
Hospital for Neurology and Neurosurgery in London questioned this view. They performed a prospective study and evaluated the result of adding a previously unused AED to the treatment regimen in adults with so-far uncontrolled chronic epilepsy which had been resistant to previous AED therapy. One hundred and fifty-five adult patients with chronic epilepsy, i.e. epilepsy active at least five years after initiation of therapy, were included. In these patients a total of 265 drug additions were performed. The follow-up in the clinic was at least 12 months after the drug introduction and the response to treatment had to be quantified. AEDs that were added (see Table 1) were levetiracetam in 101, clobazam in 26, topiramate in 24, lamotrigine in 18, tiagabine, carbamazepine, pregabalin, phenytoin and oxcarbamazepine in 10 to 15 patients and gabapentin, valproic acid, acetazolamide, vigabatrin, primidone, clonazepam and zonisamide in 1 to 9 patients. The major findings of this study were as follows: 16% of all drug introductions caused seizure
freedom, i.e. no seizure at last follow-up for 12 months or longer; a 50–99% seizure reduction could be achieved. All in all, of the 155 patients 28% were rendered seizure-free by a drug addition. Factors that correlated with a good response were fewer previously used AEDs, shorter duration of epilepsy and idiopathic epilepsy. Conclusions and Comments: Although the design of this study is not state-of-the-art, it gives a quantitative estimate of the value of adding a previously unused AED to the treatment regimen in apparently pharmaco-resistant patients. In the end the authors pointed out that the rather nihilistic view that intractability is inevitable if seizure control is not obtained within a few years of the onset of therapy is incorrect. This should change our attitude to the treatment of these patients: after a careful evaluation of the drugs and the dosages that have been given previously, we should add so-far unused drugs which have a remarkably and unexpectedly positive effect. Luciano AL & Shorvon SD (2007) Results of treatment changes in patients with apparently
Table 1 Target dosing regimens used in the treatment protocols in this study (from Luciano and Shorvon (2007)
a
Drug
Initial Dose (mg/day)
Drug Initiation: Usual Dosage Increment (mg/day) Stepped up Every 2 Weeks
Usual Maintenance Dosage (mg/day)
Dosing Intervals (per day)
Drug Reduction: Usual Dosage Decrement (mg/day) Stepped Down Every 2–4 Weeks
Acetazolamide Carbamazepinea Clobazam Clonazepam Gabapentin Lamotrigine Levetiracetam Oxcarbazepine Phenytoin Pregabalin Primidone Tiagabine Topiramate Valproate Zonisamide
250 100 10 0.25 300–400 12.5–25 125–250 300 200 150 62.5–125 4–5 25–50 200–500 50
250 100–200 10 0.25–0.5 300–400 25–100 250–500 300 25–100 50–100 125–250 4–15 50–100 200–500 50
250–750 400–1,600 10–30 0.5–2.0 1,200–3,600 200–500 1,000–4,000 900–2,100 100–400 200–600 500–1,250 30–60 50–500 500–2,000 200–600
1–2 2 1–2 1–2 2–3 2 2 2 1–2 2 1–2 2–3 2 2–3 1–2
250 200 10 1 300–400 100 250 300 50 150 125 4–5 50 200 100
Values are for the slow-release formulation, which is the formulation of choice, particularly at high doses.
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drug-resistant chronic epilepsy. Ann Neurol (in press) (E-mail:
[email protected])
The extent of resection of FDG-PET hypometabolism relates to outcome of temporal lobectomy Surgical treatment of certain forms of epilepsy has been proven to be efficient and is now used in more and more specialised centres all over the world, especially in temporal lobe epilepsy. The efficacy rate regarding a good outcome varies between 33 and 93% with an average of about 70% of patients for temporal lobectomy (for reference see Vinton et al. 2007). The reasons for the large variability are not well understood and therefore preoperative prognostic indicators which allow a more appropriate selection of patients for surgery and improved surgical strategies to optimise postoperative outcomes are necessary. One of these parameters may be the hypometabolism demonstrated by FDG-PET which is found in a majority of patients with non-lesional temporal lobe epilepsy even in the absence of hippocampal atrophy. Therefore,
Vinton and co-workers from Melbourne evaluated whether the extent of resection of the area of FDG-PET hypometabolism has an influence on the outcome following surgery for non-lesional temporal lobe epilepsy. The authors included 26 patients who had temporal lobectomy for medically refractory temporal lobe epilepsy. The follow-up time was at least 12 months. Preoperatively they performed an FDG-PET to identify regions of significant hypometabolism. From these data they calculated the volume of FDG-PET hypometabolism within the area of the resected temporal lobe. In addition, the total volume of temporal lobe resected was also measured. The major findings of this study were as follows: 1) The total volume resected did not have a significant influence on the clinical outcome. 2) The greater the proportion of the total FDG-PET hypometabolism volume resected the better the outcome (p = 0.86). 3) This was independent of the presence of hippocampal sclerosis and total brain volume of hypometabolism.
Conclusions and Comments: Vinton and co-workers concluded from this state-of-the-art study with careful measurements of volume and statistical analysis that the percentage of total volume of the region of cerebral hypometabolism on a preoperative FDGPET image is significantly correlated with a good post-surgical outcome. This is a clear message to all surgeons performing temporal lobectomy: in all patients with temporal lobe epilepsy an FDG-PET should be performed and, based on these findings, as much as possible of the volume with hypometabolism should be resected to get a good postoperative outcome. In other words, this will require an intensive cooperation between neurologists, neurosurgeons and doctors in nuclear medicine in highly specialised dedicated centres with all the necessary facilities. Vinton AB et al. (2007) The extent of resection of FDG-PET hypometabolism relates to outcome of temporal lobectomy. Brain 130: 548–560 (E-mail:
[email protected])
