Neurology -- Correspondence for French et al., 62 (8) 1261-1273

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Correspondence published:

Efficacy and tolerability of the new antiepileptic drugs: Commentary on the practice parameters: C.P. Panayiotopoulos, Selim R. Benbadis, Athanasios Covanis, Olivier Dulac, John S. Duncan, Orvar Eeg-Olofsson, Colin D. Ferrie, Richard A. Grunewald, Dorothee G.A. Kasteleijn-Nolst Trenite, Michael Koutroumanidis, Zarko Martinovic, Richard W. Newton, Alasdair P. Parker, (15 September 2004)

Reply to Panayiotopoulos et al: Jacqueline French (15 September 2004)

Efficacy and tolerability of the new antiepileptic drugs: Commentary on the practice parameters 15 September 2004

C.P. Panayiotopoulos,
Dept. of Clinical Neurophysiology and Epilepsies
St. Thomas' Hospital, London SE1 7EH,
Selim R. Benbadis, Athanasios Covanis, Olivier Dulac, John S. Duncan, Orvar Eeg-Olofsson, Colin D. Ferrie, Richard A. Grunewald, Dorothee G.A. Kasteleijn-Nolst Trenite, Michael Koutroumanidis, Zarko Martinovic, Richard W. Newton, Alasdair P. Parker,
Send Correspondence to journal:
Re: Efficacy and tolerability of the new antiepileptic drugs: Commentary on the practice parameters

tom.panayiotopoulos{at}gstt.sthames.nhs.uk C.P. Panayiotopoulos, et al.

Authors continued: Janvier Salas-Puig, JWAS Sander, Simon Shorvon, Kazuyoshi Watanabe, William P. Whitehouse, Sotirios Youroukos
We wish to alert readers to our commentary [1] on the recent practice parameters concerning new antiepileptic drugs (AEDs) published simultaneously in Neurology [2] and Epilepsia [3].
As clinical epileptologists, we assessed that the recommendations as published may mislead physicians in the appropriate use of new AEDs in epilepsies, and inadvertently perpetuate suboptimal practice in new clinical trials. In particular the practice parameters: 1. ) Are not in accordance with the established formal classification systems of epilepsies. A minimal requirement is to respect the fundamental differences between partial and idiopathic generalized epilepsies (IGE), since AEDs beneficial for focal may be detrimental for IGE. Indeed, even among IGE, an AED beneficial in one type may be ineffective or aggravate another type of the triad of IGE seizures (absences, myoclonic jerks and generalized tonic clonic seizures-GTCS). 2. ) Introduces a new term “mixed seizure disorders” as a class of epilepsy; this is particularly hazardous because of indiscriminate inclusion of generalized (any type) and partial seizures. 3.) Emphasizes “new onset epilepsy” (an incorrect term for newly identified patients with seizures) as a therapeutic category. Efficacy and safety of AEDs are not determined by how long a diagnosis has been established. 4.) Inappropriately validates some studies despite violating evidence-based clinical management: one fourth of patients with IGE, including those with juvenile myoclonic epilepsy, are inappropriately treated with carbamazepine, as a comparator drug; withdrawal of carbamazepine alone would probably benefit these patients. 5.) Ignores “the percent of patients who became seizure-free during the trials” thus introducing bias in favor of less effective AEDs. 6.) Perpetuates inappropriate confusion of epilepsy with seizure classification. GTCS are erroneously evaluated either as a type of epilepsy or as any type of generalized seizures. 7.) Recommendations favoring some AEDs are inconsistent with the documentation or contradicted within the report. 8.) Is void of recommendations regarding established documentation of harmful effects of certain AEDs. This is particularly important for “off label” uses of AEDs. 9.) Makes invalid presumptions in favor of gabapentin and applications of the recommendations in specified groups such as children.
Since these reports are likely to be influential in guiding prescribing practice beyond FDA approval limits, their review methodology must be rigorous, and they must be rigorous in the correct use of terminology, interpretation of the methodology and value of component clinical trials they review for the report. The committees responsible for making the recommendations should have adequate input from clinical epileptologists on the importance of precise diagnosis. Further, these reports should agree with established Journal requirements for publications.
In conclusion, we believe that while the endeavor was laudable, we remain concerned that such authoritative recommendations, in their current form, fail to reinforce best clinical practice parameters. This letter also addresses a plea to influential Neurology and Epilepsy committees to consider issuing recommendations regarding the conduct of AED trials and resultant publications. These should insist on precise diagnostic definition of the populations studied and appropriate use of comparator AEDs so as to avoid confusion and inappropriate generalizations as detailed in our commentary. [1]
References
1. Panayiotopoulos CP, Benbadis SR, Covanis A, Dulac O, Duncan JS, Eeg-Olofsson O et al. Efficacy and tolerability of the new antiepileptic drugs; commentary on the recently published practice parameters. Epilepsia (in press) 2004.
2. French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden CL et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2004;62:1252-60.
3. French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden CL et al. Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2004;62:1261-73.

Reply to Panayiotopoulos et al 15 September 2004

Jacqueline French,
TTA and QSS subcommittees
American Academy of Neurology, 1080 Montreal Ave., St. Paul, MN 55166
Send Correspondence to journal:
Re: Reply to Panayiotopoulos et al

kathy_pieper{at}urmc.rochester.edu Jacqueline French

We thank the authors for their careful review of our evidence based assessment of new antiepileptic drugs in Epilepsia and Neurology in 2004. [1-4] The authors have raised some concerns. We will attempt to address our methodology for this evidence based report.
1. The authors have made several points regarding the nomenclature for the types of epilepsy that are addressed in our guideline. This is quite understandable, considering that classification is an extremely important aspect of epilepsy care. This is not, however, a guideline on diagnosis and classification. When assessing the evidence in order to make evidence based conclusions, one can, essentially only "go where the money is". That is, one can only address the studies that have been performed in a controlled fashion, describe them completely, and reach conclusions. One cannot reperform the studies in the way that one might have designed them oneself. This is a frustrating aspect of evidence based medicine, but not one that is novel to this particular assessment. It is certainly the duty of the committee writing the report to try and addressed methodology where possible. More importantly, one must state the conclusions based on the evidence, not based on what one would like the evidence to be. We have made every effort to do this in our parameter, but understandably, this leads to some unusual nomenclature, mimicking the categorizations that were used in the research studies themselves.
2. A major concern of the authors is the inability to distinguish studies performed in idiopathic generalized epilepsy from those performed in partial epilepsy, in newly diagnosed epilepsy. Of course, we realize that ideal methodology would consist of studies performed in a single epilepsy syndrome. Our methodology for this evidence based review, was to assess the data that was available to us. Very few studies have been performed that were powered to assess syndromes in isolation. In fact, differences were not readily discernible within the studies themselves. For example, in the study by Brodie et al comparing carbamazepine to lamotrigine in newly diagnosed patients, no differences in outcome were found between patients with primary generalized, tonic clonic convulsions versus patients with a focal onset[5]. However, due to small numbers, we chose not to make any conclusions based on this. In our recommendations for future research, we very clearly make a plea for studies to be performed in specific syndromes. We agree that “mixed seizure disorders” is a term that could be misunderstood. We tried to clarify the meaning to the best of our ability. We also feel that physicians often find themselves in the circumstance of selecting an initial antiepileptic drug before a definitive syndromic diagnosis can be made. In an article by King et al, epilepsy syndrome was only diagnosable in 47% of patients on clinical grounds, and 77% with addition of the EEG, in the hands of experienced epileptologists, at first seizure presentation.[6] Thus, understanding the outcome in patients who are unclassified is not a clinically unimportant concept. 2. The authors go on to make the curious claim that the term "new onset epilepsy" is not of importance, and that "efficacy and safety of AEDs are not determined by how long the diagnosis has been established." In fact, there has been a great deal of recent investigation regarding the prognosis in patients with newly diagnosed epilepsy, versus those who have already failed antiepileptic drugs. The studies seem to provide evidence that in fact whether a patient is newly diagnosed may be equally as important as epilepsy syndrome in determining outcome of antiepileptic drug therapy. [7] In addition, as noted above, since this is the way patients were defined for the purposes of the studies that were performed (newly diagnosed versus refractory), we had very little choice in selection of terms.
3. The authors are concerned about a study that in their minds presents "violations of evidence based clinical management". The study in question evaluated topiramate in patients with newly diagnosed epilepsy.[8] In this blinded study, patients were randomized to topiramate versus either valproate or carbamazepine, based on the choice of the treating physician. They correctly point out that 27% of the patients randomized to treatment with carbamazepine in fact had idiopathic generalized epilepsy. Randomization to treatment based on physician preference, may be considered to be as valid a methodology as any other, since it may mimic "real life". In fact, the guideline does not specifically say that topiramate is effective in either partial or generalized epilepsy.
4. Another concern is that seizure freedom was not used as an outcome measure, and this “might bias towards less effective drugs”. In fact, as noted in the guideline, seizure freedom is rarely reported in the literature, and therefore could not consistently be used.
5. Again, the authors are concerned about imprecise and ambiguous classification with respect to GTCCs. As noted above, the recommendations are based on the populations that were included in the trial, whether they represent a precise seizure classification or not. It is unclear where the authors concerns rest. They claim that “GTCS are erroneously evaluated… as any type of generalized seizures". In fact, this is not the case. Under the category of generalized epilepsy, the data is presented for any study that would be included in that category. The only study that was identified, was one performed with topiramate in generalized tonic clonic convulsions. It is clearly stated both in the practice parameter as well as in the table that accompanies it, that the evidence specifically addresses refractory generalized tonic clonic convulsions. In addition, there is a discussion that this may not be translatable to patients with similar syndromes, but not refractory disease.
6. The authors claim that the QSS and TTA do not provide any recommendations regarding established documentation of harmful effects of certain antiepileptic drugs. We had a great deal of difficulty handling adverse events in an evidence based fashion. Of course, most adverse event data derives from case reports rather than randomized controlled trials. Dtermining attribution can be very tricky in these cases. Going beyond the adverse events that are listed in the parameter, would have been going beyond the available evidence.
7. The final, and perhaps most damning claim, is that the QSS and TTA report “make invalid presumptions in favor of gabapentin and applications of the recommendations in specified group such as children." We truly hope that this is not the case. Since no examples are provided, we cannot address this claim specifically, other than to indicate that gabapentin was evaluated in the same way as all other drugs, and the recommendations for children also followed a strict evidence-based methodology.
In summary, we totally support the author’s conclusion that clinical trials should insist on precise diagnostic definition of populations studied. However, we cannot agree that our practice parameter was in any way misleading, incorrect or biased. The authors would like to see recommendations that "reinforce best clinical practice.” However, evidence based guidelines are specifically designed not to make recommendations that go beyond the available evidence.
References
1. French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2004;62:1261-73.
2. French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2004:62;1252-60.
3. French JA, Kanner AM, Bautista J, et al.Efficacy and tolerability of the new antiepileptic drugs, II: Treatment of refractory epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society. Epilepsia 2004:45;410-23.
4. French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs, I: Treatment of new-onset epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society. Epilepsia 2004:45;401-9.
5. Brodie MJ, Richens A, Yuen AW, Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. UK Lamotrigine/Carbamazepine Monotherapy Trial Group. Lancet 1995:345;476-9.
6. King MA et al.Epileptology of the first-seizure presentation: a clinical, electroencephalographic, and magnetic resonance imaging study of 300 consecutive patients. Lancet 1998:352;1007-11.
7. Kwan P and M.J. Brodie, Effectiveness of first antiepileptic drug. Epilepsia 2001:42;1255-60.
8. Privitera M et al.Topiramate, carbamazepine and valproate monotherapy : Double-blind comparison in newly diagnosed epilepsy. Acta Neurol Scand 2002: p. in press.