epi˙01060 EPI-xml.
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LETTERS/COMMENTARY
HOW TO GET THE ANSWER TO NEARLY
EVERYTHING: USING THE INTERNET
FOR EPILEPSY RESEARCH
It is surprising how little we know regarding the optimal
treatment for patients with epilepsy. This lack of infor-
mation has been highlighted recently in this journal with
respect to management of patients with newly diagnosed
epilepsy (Glauser et al., 2006). There is probably even less
evidence regarding the optimal management of patients
who have failed the first drug tried (Kwan and Brodie,
2000). In this article, we propose a new approach to deter-
mining how patients with epilepsy should be managed.
OVERVIEW
We propose that the epilepsy community establish an
Internet-based research program. This would be a multi-
center program, open to any neurologist anywhere in the
world who has sufficient expertise and interest in epilepsy.
A series of prospective, pragmatic, randomized research
protocols would run in parallel. Recruitment, randomiza-
tion and subsequent data collection would be via the In-
ternet. Although patients would be randomized, neither
they nor the treating doctors would be blinded. Recruit-
ment would be simple and would take just a few minutes.
Doctors would not be paid to enroll subjects.
THE PROBLEM
Most of us who treat people with epilepsy see patients
whose management is difficult. Often, we do not know
which of the several treatment options offers the best
prospect of seizure control. In some circumstances, we
know that several drugs may be effective. However, we
may not know which drug has the best chance of render-
ing the patient seizure-free with the lowest likelihood of
side effects. If a patient has failed to respond to a first
or second treatment, we often have very little evidence to
guide our subsequent therapeutic choices. In practice, we
usually have to rely on the recommendation of experts and
our own previous experience (Karceski et al., 2005).
Relatively few studies have been performed in which
different drugs have been directly compared. Pharmaceu-
tical companies appear to have little interest in comparing
their drug with an antiepileptic drug produced by another
company; why would they want to take the risk of showing
that their drug is less effective than a rival’s product?
There is also very little data comparing specific combi-
nations of drugs. At present, there are over 100 possible
1415
combinations of two different drugs that could be pre-
scribed in most Western countries. Again, we have remark-
ably little information to guide us when trying to choose
a specific combination. There is some information from
animal studies suggesting that particular combinations are
likely to be synergistic (Borowicz et al., 2002; Luszczki
and Czuczwar, 2004) but little controlled data from hu-
mans. We do not even know whether we should be treat-
ing patients who have failed a first drug with alternative
monotherapy, or a combination of two drugs (Kwan and
Brodie, 2000; Deckers, 2002). The conventional approach
is to try a second drug as monotherapy before combining
drugs (Karceski et al., 2005), but there is limited data to
suggest that, at least in some circumstances, combinations
may be more effective (Deckers et al., 2001; Kwan and
Brodie, 2006).
Most studies have grouped together patients according
to seizure type, rather than the underlying pathology. In
particular, patients with partial seizures tend to be grouped
together while it is possible (and in our opinion likely) that
patients with different etiologies may respond differently
to particular antiepileptic drugs or drug combinations. Is
it reasonable to assume that a patient who has seizures
secondary to a cavernous hemangioma, where there is
hemosiderin staining of the brain, will necessarily respond
in the same way as a patient whose seizures are due to a
malformation of cortical development or mesial temporal
sclerosis?
THE SOLUTION
An Internet-based research program, open to neurolo-
gists throughout the world, could answer many of these
questions. We are aware that Internet-based programs are
underway to prospectively collect data on patients with
epilepsy; we are suggesting that this approach be devel-
oped further and used for conducting randomized con-
trolled trials. Eucare, for instance, intends following pa-
tients with newly diagnosed epilepsy who are being treated
throughout Europe (Brodie, 2003). We are proposing a
complementary program in which the epilepsy commu-
nity uses the Internet to randomize patients to different
treatment arms, and thus also obtain prospective random-
ized efficacy data.
In the scheme we are proposing, doctors would log onto
a website whenever they are unsure of the optimal man-
agement for a patient. The doctor would answer questions
regarding the seizure type, seizure syndrome, and etiol-
ogy. Information would be sought regarding previous drug
epi˙01060 EPI-xml.cls June 21, 2007 5:6
1416 GRAY MATTERS
use and intercurrent illnesses. This information would be
entered into a database, and a computer algorithm would
determine immediately if the particular patient’s charac-
teristics matched those required for any of the controlled
trials being undertaken. If an appropriate trial was under-
way, randomization would be offered.
If enough neurologists chose to participate, it would
be possible to enroll a large number of patients relatively
rapidly. This approach would enable epileptologists to or-
ganize trials that would be focused on patients with spe-
cific syndromes or etiologies, as well as those with partic-
ular seizure types.
We propose that the project belong to the entire com-
munity of epileptologists, so that anybody could propose
a research protocol; obviously, he or she would have to
provide some justification for the proposal. Equally ob-
viously, it would not be practical to conduct all possible
trials simultaneously. We would envisage that a panel of
experts in a particular syndrome would decide on the op-
timal research protocol.
Protocols would be published on the Internet with ex-
plicit instructions regarding the introduction of the ap-
propriate drugs. Introduction of drugs would be flexible,
reflecting what is done in real life, and would not be ex-
cessively regimented. Doctors would download and print
information sheets regarding the protocols and the drugs
for their patients. Subsequent data collection would also
be online.
It would not be necessary to establish protocols for
all epilepsy syndromes at the outset. Initially, there may
be protocols established for the more common problems,
and other protocols could be added as the need became
apparent. If it became clear (or if we already have the
evidence) that a particular treatment is the optimal treat-
ment in a given condition, then this information could be
made available to the doctor when he or she logs onto the
website.
The whole approach would need to be flexible, so that it
could adapt to ongoing developments. We are aware that
we do not yet have definitive classification systems for
either seizures or epileptic syndromes (Engel, 2006). At
the outset, we intend using the currently accepted ILAE
classifications, but it would be possible to alter these cat-
egories if new classifications are adopted. Similarly, it
would be possible to set up new study protocols when
new information becomes available. For instance, if a ge-
netic mutation was discovered that is common in a par-
ticular syndrome, then it would be possible to subdivide
patients depending on whether or not they have had the
appropriate test, and if so, whether the test was positive or
negative.
It would also be possible to collect data regarding out-
comes of patients even if there was no study protocol suit-
able for them. In this way, observational studies could
be included in the project. It would be possible to collect
Epilepsia, Vol. 48, No. 7, 2007
other valuable information about patients, including infor-
mation on sudden death in epilepsy and outcomes of preg-
nancy. Because of the potential to enroll a large number
of subjects relatively rapidly, this project could provide an
excellent opportunity to coordinate large prospective stud-
ies when there is a low likelihood of a particular outcome.
For instance, it would be possible to use this network of
epileptologists to undertake prospective studies of possi-
ble strategies to prevent sudden death in epilepsy.
POTENTIAL DIFFICULTIES
There are potential difficulties with this proposal. How-
ever, we do not think any of them are insurmountable.
Funding
In the project we are proposing, epileptologists would
not be paid to enroll patients, but they would do so because
they could see the potential of this research. Obviously, the
process would have to be simple and rapid if this were to
succeed. The drugs themselves would not be funded by
the project, but patients would be randomized to drugs
that are already available in the particular country. We
think it is important that the project remain independent
of pharmaceutical companies, and we would not envisage
that they would provide the drugs free of charge.
The website and associated database that we are envis-
aging would be complex, and would need ongoing refine-
ments. There would be a cost in establishing and maintain-
ing these. A large amount of data would be collected, and
there would be costs involved in analyzing it. A funding
source would need to be identified for these costs.
Encouraging participation
For the project to succeed, it would require that doctors
actually enroll subjects. In the fullest development of this
idea, doctors would be able to enroll (almost) any patient
about whose management they are uncertain. It would take
some time before this stage could be reached. Initially, it
would require a concerted effort to bring the project to
doctors’ attention and to remind them of the studies that
are being undertaken. However, once the project had ob-
tained a certain level of momentum, we would hope that
this project would remain at the forefront of epileptolo-
gists’ minds. In addition, of course, the projects would
start providing all of us with important and clinically rel-
evant information. Doctors could check the website to see
what the current best evidence is for the treatment of a
patient with a particular syndrome.
Accuracy of data collected
It is essential that all data collected are accurate. It would
also be critical that follow-up data be entered reliably. It
would, therefore, be necessary that the data entry be kept as
simple as possible. We envisage that regular e-mails would
be issued to update participants on the studies’ progress
and to remind them of the need to provide data at the
epi˙01060 EPI-xml.cls June 21, 2007 5:6
GRAY MATTERS
appropriate times. This could be done automatically by
the computer software.
To ensure that appropriate patients were recruited into
the various studies, protocols would contain checklists to
ensure that a “pure culture” of subjects was recruited. A
doctor would have to review a checklist for each specific
patient before that patient could be recruited. Clearly, it
would be necessary that the doctors are knowledgeable
about epilepsy. For example, it may be that doctors would
need to be members of the International League Against
Epilepsy, or their national neurological association, before
they could recruit patients to a study.
The studies we are proposing would not be blinded,
although patients would be randomized. For nonblinded
studies to be worthwhile, there needs to be a robust and
reliable end point that is not subjective. In the current
context, we envisage that the end point would be seizure
freedom. Information would also be collected regarding
seizure frequency and drug side effects, but these would
be secondary analyses.
Ethics committee approvals
In most centers, there would be separate ethics com-
mittees that would need to give approval before patients
could be recruited. It is likely that each separate random-
ization procedure would require separate approval. This
could significantly slow the uptake of the project. How-
ever, it is not necessary that all centers or countries start
simultaneously. Centers could join as soon as the ethics
committees give approval. Some countries have national
ethics committees that could give approval for doctors
throughout the country to enter patients into a particular
study; this is now the case in New Zealand. We are en-
visaging that all the medication used would have proven
effective and have been approved for use in epilepsy. The
studies we are envisaging would be designed to determine
whether one drug or combination of drugs is superior to
another in a particular condition.
Personal security
The website would be secure, using the same mecha-
nisms used for conducting business transactions.
Moving forward
There may be other problems that we have not consid-
ered. Some of these problems may not become apparent
until the approach is tested. The New Zealand chapter
of the International League Against Epilepsy is therefore
planning to undertake a pilot study to look at the feasibil-
ity of Internet-based recruitment. In the first instance, we
will be looking at the management of patients who have
failed to respond to the first drug that has been prescribed.
However, New Zealand is not a sufficiently large coun-
try to answer many questions, so the pilot study will aim
1417
to test the concept of Internet-based recruitment and data
collection.
We believe that the approach outlined here has the po-
tential to systematically answer a number of questions
regarding the management of patients with epilepsy. We
are proposing the idea in this forum to gauge how much
enthusiasm there is among the wider epilepsy community.
It seems appropriate that the International League Against
Epilepsy would coordinate and promote the project, but
this role could be undertaken by some other international
organization. We would like to determine how much in-
terest there is throughout the world, and we would invite
readers to contact us with their responses and ideas.
Acknowledgment: We thank Greg Gamble, Statistician,
Auckland Medical School, Auckland University for his help.
∗
Peter Bergin
∗
pbergin@adhb.govt.nz
∗
Richard Frith
∗
Elizabeth Walker, and
† Paul Timmings
∗
Department of Neurology, Auckland City Hospital
Auckland, New Zealand
and †Department of Neurology
Waikato Hospital, Hamilton, New Zealand
REFERENCES
Borowicz KK, Swiader M, Luszczki J, Czuczwar SJ. (2002) Effect
of gabapentin on the anticonvulsant activity of antiepileptic drugs
against electroconvulsions in mice: an isobolographic analysis.
Epilepsia 43:956–963.
Brodie MJ. (2003) EUCARE–past, present, and future. Lancet Neurology
2:269.
Deckers CL, Hekster YA, Keyser A, van Lier HJ, Meinardi H, Re-
nier WO. (2001) Monotherapy versus polytherapy for epilepsy:
a multicenter double-blind randomized study. Epilepsia 42:1387–
1394.
Deckers CL. (2002) Place of polytherapy in the early treatment of
epilepsy. CNS Drugs 16:155–163.
Engel J Jr. (2006) Report of the ILAE classification core group. Epilepsia
47:1558–1568.
Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Chadwick
D, Guerreiro C, Kalviainen R, Mattson R, Perucca E, Tomson
T. (2006) ILAE treatment guidelines: evidence-based analysis of
antiepileptic drug efficacy and effectiveness as initial monother-
apy for epileptic seizures and syndromes. Epilepsia 47:1094–
1120.
Karceski S, Morrell MJ, Carpenter D. (2005) Treatment of epilepsy in
adults: expert opinion, 2005. Epilepsy & Behavior 7(suppl 1):S1–
S64; quiz S65–S67.
Kwan P, Brodie MJ. (2000) Epilepsy after the first drug fails: substitution
or add-on? Seizure 9:464–468.
Kwan P, Brodie MJ. (2006) Combination therapy in epilepsy: when and
what to use. Drugs 66:1817–1829.
Luszczki JJ, Czuczwar SJ. (2004) Preclinical profile of combinations
of some second-generation antiepileptic drugs: an isobolographic
analysis. Epilepsia 45:895–907.
Epilepsia, Vol. 48, No. 7, 2007
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1418 GRAY MATTERS
To the Editors:
I am a young clinical investigator using the internet
hourly on a daily basis. I believe that the Internet will
play a major role in the establishment of a large network
among epileptologists as well as recruitment of research
participants in the future. The advantage of Internet-based
research includes speedy data collection from geographi-
cally dispersed subjects with a small cost (Asano, 2007).
One may assume that prospective data collection can be
done online using self-report by participants, if “seizure-
freedom” is the outcome of interest as suggested by Bergin
et al. Such online self-report can potentially reduce the
running cost of study and allow more frequent outcome
measurements. A repeated measurement approach will be
useful to study epilepsy syndromes of which sample size
is limited.
Here, I will propose a hypothetical study to compare the
efficacies of two treatments in children with focal epilepsy
associated with tuberous sclerosis complex. Comparisons
will be made between two medical treatments or between
surgical and further medical treatments. Participants who
meet the study criteria will be randomized to each treat-
ment group (Wiebe et al., 2001). Each guardian of a patient
will report whether the patient is free from seizures or not.
If a single binary outcome measurement is applied, the re-
quired sample size will be 93 in each group to detect a 20%
difference in efficacy at a two-tailed significance level of
0.05 and a power of 0.80, supposing that the chance of
seizure-freedom is expected to be 50% in one treatment
and 30% in the alternative treatment. If a repeated mea-
surement analysis is employed to the outcome measures
reported four times per patient, the required sample size
will be as small as 52 to 80 in each group, depending on
the degree of clustering among observations within pa-
tient (Leon, 2004). It would take five years or more for a
single institute to recruit more than 100 new patients with
tuberous sclerosis complex. I believe that a multicenter
program with a repeated measurement approach will in-
crease the chance of successful recruitment of participants
enough to complete the study.
Is online data collection dependent on repeated self-
reports feasible? I agree with the authors that some of the
problems may not be apparent until somebody begins to
test the approach. To explore what internet users think
about the research program with health data collected via
the Internet, I have recently conducted a small survey in
Japanese on my personal blog (http://blogs.yahoo.co.jp/
eishi asano md phd/44835508.html). Concerns describ-
ed by responders in this survey include a threat to confi-
dential data and uncertain validity of self-reports. Non-
response bias will be another concern in a web-based
research as reported previously (Harewood et al., 2003;
Partridge et al., 2004; Brod et al., 2006; Asano , 2007).
I would like to introduce some of the potential solutions
proposed by internet users. For example, it was proposed
Epilepsia, Vol. 48, No. 7, 2007
that a participant should be able to choose not only online-
but also offline-data-entry according to her/his preference,
offline-data can be saved on her/his ID card or cellular
phone, and offline-data will be transferred to the main
computer when she/he sees the reporting physician in
hospital. It was also proposed that participants should
not enter any identifiable personal data onto the research
database, and that such personal data should be separately
saved. It was also suggested that some forms of rewards
and feedback may motivate patients to participate in the
program for a long period.
Regardless of the method of data collection, I hope that
the web-based multicenter research program will be es-
tablished by the epilepsy community. I am willing to par-
ticipate in the program.
Eishi Asano, MD, PhD, MS
Departments of Pediatrics and Neurology
Wayne State University
Detroit, Michigan, USA, 48201
Eishi@pet.wayne.edu
REFERENCES
Asano E. (2007) A public outreach in epilepsy surgery using a serial
novel on BLOG: a preliminary report. Brain Dev 29:102–104.
Brod M, Skovlund SE, Wittrup-Jensen KU. (2006) Measuring the impact
of diabetes through patient report of treatment satisfaction, produc-
tivity and symptom experience. Qual Life Res 15:481–491.
Harewood GC, Wiersema MJ, de Groen PC. (2003) Utility of web-based
assessment of patient satisfaction with endoscopy. Am J Gastroen-
terol 98:1016–1021.
Leon AC. (2004) Sample-size requirements for comparisons of two
groups on repeated observations of a binary outcome. Eval Health
Prof 27:34–44.
Partridge AH, Gelber S, Peppercorn J, Sampson E, Knudsen K, Laufer
M, Rosenberg R, Przypyszny M, Rein A, Winer EP. (2004) Web-
based survey of fertility issues in young women with breast cancer.
J Clin Oncol 22:4174–4183.
Wiebe S, Blume WT, Girvin JP, Eliasziw M; Effectiveness and Effi-
ciency of Surgery for Temporal Lobe Epilepsy Study Group. (2001)
A randomized, controlled trial of surgery for temporal-lobe epilepsy.
N Engl J Med 345:311–318.
To the Editors:
Dr. Peter Bergin and coworkers made an interesting pro-
posal consisting in the establishment of an internet-based
research program to address the unsolved question on the
best drug(s) to use in patients with epileptic seizures and
syndromes for whom the clinician has a genuine uncer-
tainty. The authors clearly explained the advantages of this
proposal, which can be summarized in the possibility of
running pragmatic trials of adequate size following spe-
cific clinical questions and independent of pharmaceutical
companies. The idea of Internet-driven independent stud-
ies is appealing because several questions posed by the
clinician in clinical practice may find an answer outside
the past and ongoing regulatory trials. However, a num-
ber of problems must be addressed (and solved) before a
epi˙01060 EPI-xml.cls June 21, 2007 5:6
GRAY MATTERS
correct implementation of such studies is put in act. First
of all, the investigator should be strongly committed to
the study and not just merely enthusiastic, without being
knowledgeable of the problems related to the participation
in a randomized trial. Second, the investigators should be
properly trained prior to being accepted in the trial. Train-
ing should include the delivery of a solid background in the
conduction of a randomized trial. If this cannot be pursued,
the correctness of data recording would be endangered.
Third, a web database should be devised to have a struc-
ture including an automatic control of several indicators
of the quality and completeness of data collection. A mon-
itoring unit should be also activated to complement the
potentialities of the database. Fourth, priorities should be
set up, which could help putting the idea to investigate a
new treatment strategy in a widely accepted perspective,
to limit the flourishing of initiatives devoid of any signifi-
cance for clinical practice. In that sense, the International
League Against Epilepsy should take the lead and cre-
ate an ad hoc commission to evaluate the feasibility of
each project. Fifth, clear rules should be set to define data
property and to attribute an authorship to the participating
investigator, provided that he/she gave a valuable contri-
bution to the study. Sixth, the final evaluation of such
projects by the regulatory authorities (EMEA and FDA)
should be more flexible than that of the industry-driven tri-
als, in respect of good clinical practice. Last, the European
Union and the U.S. Government should give access to ad-
equate funds to support the infrastructure of these studies.
With this in mind, I support the implementation of such
projects, which should be also strongly encouraged by the
scientific community.
Ettore Beghi, MD
Laboratory of Neurological Disorders
Istituto di Ricerche Farmacologiche “Mario Negri”
Milano, Italy
beghi@marionegri.it
To the Editors:
The Internet is an accessible medium for information
transfer, which makes the World Wide Web (www) com-
ponent of the internet a very powerful vehicle for provid-
ing educational materials to the public. Although most of
the so-called medical websites are not standardized, pa-
tients and physicians are increasingly using the internet
as a source of medical information (Burneo, 2006). This
is a reflection of the overall availability of computers and
access to the www. The Internet is a resource that can
rapidly reach a wide geographic population. This would
include patients and physicians that otherwise may not
have access to clinical trials information.
The idea of using internet for clinical research is not
new. But, its use in research has been basically limited
to matching services mainly for oncology and HIV trials
1419
(Ohno-Machado et al., 1993; Wei et al., 2004; Metz et al.,
2005). These have been shown to be effective capturing
those patients interested in a specific trial, and from the
investigator’s perspective, as they have seen prescreened
patients based on the inclusion and exclusion criteria of the
trial. This bypasses some of the major roadblocks that have
been identified in the problem of clinical trials recruitment
(Metz et al., 2005).
But from my point of view, that would be it. Bergin
et al. also suggest randomization but without blinding,
something of major concern. This idea would not work
as randomization does not always succeed in its goal of
achieving groups with similar prognosis. Neurologists in
charge of the process may make mistakes that compromise
randomization or they may encounter bad luck. Random-
ization does not provide the guarantees that the two groups
(treatment and control groups) will remain prognostically
balanced.
Differences in patient care other than the intervention
under study can also bias the results. Clinicians gain great-
est confidence in study results when investigators docu-
ment that all co-interventions that may plausibly impact on
the outcome are administered more or less equally in treat-
ment and control groups. The absence of such documen-
tation is a much less serious problem if the neurologists
are blind to whether patients are receiving active treatment
or are part of the control group. Blinding eliminates the
possibility of either conscious or unconscious differen-
tial administration of effective interventions to treatment
and control groups. Furthermore, the lack of concealment
would be another major problem with what Bergin et al.
suggest. If those making the decision about patient eli-
gibility are aware of the arm of the study to which the
patient will be allocated, they may systematically enroll
sicker (patients with prolonged seizures and/or patients
with high frequency of seizures) or less sick patients to
either treatment or control groups. This behavior will de-
feat the purpose of randomization and the study will yield
a biased result (Schulz et al., 1995).
The idea remains a great one, but only I believe appli-
cable to the initial process of recruitment for clinical trials
or for follow up purposes.
Jorge G. Burneo, MD, MSPH
Epilepsy Programme
University of Western Ontario
London, Canada
jorge.burneo@lhsc.on.ca
REFERENCES
Burneo JG. (2006) An evaluation of the quality of epilepsy education on
the Canadian World Wide Web. Epilepsy Behav 8(1):299–302.
Metz JM, Coyle C, Hudson C, Hampshire M. (2005) An internet-based
cancer clinical trials matching resource. J Med Internet Res 7(3):e24.
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1420 GRAY MATTERS
Schulz KF, Chalmers I, Hayes RJ, Altman DG. (1995) Empirical evi-
dence of bias. Dimensions of methodological quality associated with
estimates of treatment effects in controlled trials. JAMA 273(5):408–
412.
Wei SJ, Metz JM, Coyle C, Hampshire M, Jones HA, Markowitz S,
Rustgi AK. (2004) Recruitment of patients into an internet-based
clinical trials database: the experience of OncoLink and the National
Colorectal Cancer Research Alliance. J Clin Oncol 22(23): 4730–
4736.
To the Editors:
Peter Bergin and colleagues have identified two im-
portant questions, at present unanswered in the published
literature.
The first question is that of “when should a new drug be-
come a first line monotherapy?” This is particularly signif-
icant because of the financial pressures involved. Pharma
companies invest millions of dollars in bringing a new
drug to market, and amounts not much less in trying to
persuade neurologists to use it. These new drugs then cost
orders of magnitude more than the established drugs, but
the industry regulatory studies address efficacy, not supe-
riority, use short-term and surrogate end points, and may
miss clinically important comparisons. Crucially there is
no cost/benefit analysis, and we are left not knowing if the
new drug is a worthwhile advance on the older ones. The
U.K. SANAD study (Marson et al., 2007) goes some way
toward addressing this, but does not include at least one
important new drug.
The second question, one of particular significance to
neurologists with specialist epilepsy practice, is what to do
in the patient who fails to respond to first line monother-
apy. Again industry studies fail to address this, with lack of
any meaningful comparisons between drugs, and attempts
to address this with retrospective statistical analysis have
failed.
These are both important questions, and it is an indict-
ment of our practice that it is only now that one is being
(partially) answered, and the other is the subject of largely
evidence free conjecture. Contrast this with for instance
the management of in particular haematological, but also
other, malignancies, where, certainly in the U.K., all pa-
tients have now for many years been entered in sequen-
tially designed studies: as a result of which many of these
once fatal disorders are now largely curable.
The questions Bergin and colleagues pose are undoubt-
edly important ones, but this does not mean that the mech-
anism they propose is workable, or even appropriate. The
SANAD group in the U.K. has shown that large pragmatic
epilepsy studies are feasible, but in fact this only depended
on recruitment from a small number of clinics in the U.K.
This ensured consistency of practice and therefore mean-
ingful results: attempting to replicate this internationally
would potentially introduce complications, and is unnec-
essary. The study worked because of the close network of
committed collaborators, hard to replicate with a website.
Epilepsia, Vol. 48, No. 7, 2007
These new drugs are expensive and even if they have
superior efficacy, and/or better tolerability to the standard
drugs, an equally important question is that of cost effec-
tiveness, and this can only be addressed with comparisons
within similar health care systems, an international study
would miss this essential issue.
I think therefore that the first question can be adequately
addressed using existing mechanisms, with the added ad-
vantage of health economics data.
When used in refractory patients what the industry stud-
ies have shown us is that it is difficult to establish differ-
ences in efficacy between the newer drugs: the differences
appear to be those of tolerability. These differences proba-
bly represent genetically determined pharmacokinetic fac-
tors, so-called pharmacogenomics; this requires not only
a physical sample, but also more complex ethics and con-
sent, and I doubt would be practicable within the internet
based system proposed. The important question of which
drug is best suited to a refractory patient probably more
reflects that individual’s drug metabolism than the nature
of the epileptogenic process, and the key variable would
be then missing from the suggested web-based approach.
I believe that although the authors have identified im-
portant questions, these can either be answered with exist-
ing mechanisms, or are not appropriate for the proposed
system.
Paul Cooper, DM FRCP
Department of Neurology
Greater Manchester Centre for Clinical Neurosciences
Hope Hospital, Salford
Manchester, U.K.
paul.cooper@manchester.ac.uk
REFERENCE
Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chad-
wick DW, Cramp C, Cockerell OC, Cooper PN, Doughty J, Eaton B,
Gamble C, Goulding PJ, Howell SJ, Hughes A, Jackson M, Jacoby A,
Kellett M, Lawson GR, Leach JP, Nicolaides P, Roberts R, Shackley
P, Shen J, Smith DF, Smith PE, Smith CT, Vanoli A, Williamson PR
(SANAD Study group). (2007) Carbamazepine, gabapentin, lamot-
rigine, oxcarbazepine or topiramate for epilepsy: results from arm A
of the SANAD trial. Lancet 369:1000–1015.
To the Editors:
Bergin and colleagues challenge the academic epilepsy
community to move outside our box of how we do clin-
ical studies to help address common, important clinical
problems for which we lack data: go to the net. It is an
awesome idea. The nemesis, the devil, lies in the detail.
No one can doubt the power of the Internet: its reach,
its exponential capacities, its speed, its potential to answer
questions. Academic medicine must embrace it. But how?
Bergin and colleagues suggest that randomized
prospective research protocols could be successfully
executed to study problems such as the comparative
epi˙01060 EPI-xml.cls June 21, 2007 5:6
GRAY MATTERS
efficacy and toxicity of different two antiepileptic drug
therapies as well as different therapies for specific etiolo-
gies of epilepsy.
As a resident (OD), I was struck by a distinguished
epileptologist, a basic scientist, who lectured on “Ratio-
nal Polytherapy.” This doctor published articles in leading
scientific journals and understood the burden of scientific
proof, yet gave an hour lecture on the wonderful merits
of some antiepileptic drug combinations and trashed oth-
ers as toxic and illogical. To summarize, if the presumed
mechanisms of action were different, he liked the com-
bos. If they were the same, he disliked them. What about
clinically proven breakthroughs in cancer therapy that tar-
geted multiple sites in a specific pathway, all acted by the
same general “mechanism of action.” That was 1986 – two
decades later and the evidence for “rational polytherapy”
remains a cacophony of experts opining in the dark.
The Internet could waken us from our sleep, not only by
giving us a new tool, but by allowing us to ask new
questions, and by providing new partners. Not only
academicians, but patients. Sites such as http://www.
patientslikeme.com allow patients and families with ALS
to partner in information, and look at subtypes, progres-
sion, mainstream and alternative therapies, etc. Databases
and tracking devices can be mined by patients to help them
make decisions. Discussions are underway to bring this to
epilepsy.
It is time for doctors and patients to work together to
advance knowledge. For both professional and lay efforts,
one challenge will be the quality of the data (who checks
that it was entered correctly?, who checks that it is cor-
rect?). There are endless questions of methodology— ac-
curacy of classification of seizures and seizure counts,
inclusion of nonepileptic patients, compliance, classifica-
tion of lesions, heterogeneity of lesions (cavernomas may
be more grey or white matter based, may have bled mini-
mally or moderately, occur in sensory or limbic or frontal
or temporal regions, be single or multiple, occur with or
without other structural problems, etc.).
Large numbers may address these issues of data qual-
ity. As noted in a Wikipedia entry on signal noise, “In
science. . . noise is fluctuations in (and the addition of ex-
ternal factors to) the stream of target information (signal)
being received at a detector.” As the number of data points
increases, the probability of discerning signals through
noise increases. The opportunity to gather large numbers
is a core strength of the Internet.
Still, only random noise eliminates itself with numbers.
Accuracy and consistency of data and classification will
still matter if errors show consistent bias. Large numbers
will help address small sample size and loss of power with
subgroup analyses, but they will not address all problems
with the accuracy and consistency of the data that is en-
tered. And therein lies the rub, the challenge to making
this work.
1421
Bergin and colleagues’ suggestion should be pursued.
However, a central oversight and monitoring committee
that guides evolution will be critical to success in this
endeavor as they have been in the success of Wikipedia
itself. We must start with version 1.0 although the fruits
will likely lie in subsequent versions.
Orrin Devinsky, M.D.
NYU School of Medicine
od4@nyu.edu
Warren Lammert
Founder, epilepsy.com & Epilepsy
Therapy Development Project
warren@granitepoint.com
To the Editors:
Dr. Bergin and colleagues have recognized that the an-
swers to nearly everything can now or someday will be
found on the Internet, including best treatment practices
for epilepsy. Can collaborative “grass roots” research on
the Internet derive these best practices? The authors’ pro-
posal is to establish a structure by which any interested
physician could post a study protocol under a common
framework. Participating clinicians later could log on and
enter a patient into the protocol, which would then spec-
ify a randomized treatment option. Treatment would be
open-label. Once enough patients accrued to permit an
answer to a study question, then the results would become
available to all.
The concept of using the Internet to harness collabo-
rative investigative power of epileptologists around the
world is very attractive. Would physicians participate? As
noted by the proposers, randomization of treatment op-
tions requires approval of human subjects consent boards
at most academic institutions, and for many private prac-
tices. In the United States, and perhaps elsewhere, ques-
tions of indemnification will be paramount in the eyes of
academic administrators; namely, who pays if something
goes wrong and someone gets sued. Time spent on this
research is not likely to be reimbursed, as it typically is by
industry or granting agencies, so such participation would
have to be a labor of love. Without a committed body of
investigators to nag and motivate, patient accrual could be
slow.
These problems might be obviated by a less ambitious
proposal, namely to provide a framework for creating reg-
istries. Examples exist in the form of several antiepilep-
tic medications pregnancy registries. In this circumstance,
there is no randomization. Physicians could provide best
practice according to their own beliefs, as they would in the
usual clinical circumstance. Privacy considerations would
still require careful consideration. There are problems in-
herent to any proposal for open-ended Web-based clinical
trials, but not too many years from now we probably will
Epilepsia, Vol. 48, No. 7, 2007
epi˙01060 EPI-xml.cls June 21, 2007 5:6
1422 GRAY MATTERS
be trying to remember how we ever did research any other
way.
Robert S. Fisher, M.D., Ph.D.
Department of Neurology
Stanford University School of Medicine
Stanford, CA 94305
rfisher@stanford.edu
To the Editors:
Each patient with epilepsy wants their doctor to pre-
scribe the medicine that is best for them. While this ex-
pectation is quite reasonable and consistent with today’s
emphasis on personalized and evidenced-based medicine,
physicians treating patients with epilepsy currently have
neither the tools nor the knowledge to systematically in-
dividualize therapeutic decisions in order to maximize ef-
ficacy and minimize toxicity. As pointed out by Bergin
and colleagues, we rely on anecdotal experience, expert
consensus, pragmatic and controlled trials, meta-analyses,
and medical society guidelines, which while helpful, are
limited in their application and cannot precisely tell us
which therapies will be best for particular persons at par-
ticular times in their lives. Physicians do their best to match
patients with therapies, but when these efforts are unsuc-
cessful, patients call it for what it is: trial and error.
Bergin and colleagues outline a way forward. They pro-
pose developing a global, large-scale, clinical research
consortium for conducting investigator-initiated studies,
using the internet for site coordination and data cap-
ture/sharing. Randomized and observational studies could
be conducted and managed by physician committees. In-
terventions would consist of approved therapies. Stud-
ies would be structured to identify patient- and epilepsy-
specific variables that predict seizure-free outcomes with
specific therapies either alone or in combinations. Their
proposal has attractive features and deserves serious con-
sideration, if we are prepared to test the unproven hy-
pothesis that best therapies for specific patient phenotypes
(and, possibly, genotypes) could be identified by studying
enough patients and tracking enough variables. Patient ad-
vocacy groups believe this to be true—see, for example,
http://www.patientslikeme.com/.
As with any project, the devil is in the details. How do
we keep the process simple and yet obtain informative re-
sults? Is the Internet the best tool to bridge investigators
and gather data? What can we learn from existing epilepsy
clinical trial consortiums? Should all patients be enrolled
or only those whose management is uncertain, as sug-
gested by the authors? Identifying qualified investigators
and research subjects, verifying the accuracy and com-
pleteness of data, defining the variables to track, agreeing
on outcome measures, powering studies, selecting statis-
tical analyses, and maintaining subject confidentiality are
but a few of the many other challenges and hurdles to over-
Epilepsia, Vol. 48, No. 7, 2007
come. Designing and implementing a standard epilepsy
data collection form for clinical use and for data capture
in clinical research studies would itself represent a major
step forward.
Can the Internet get us the answer to nearly every-
thing, as suggested by Bergin and colleagues? Let us
put it to the test by further exploring their proposal via
the web-based ILAE Discussion Group (http://www.ilae-
epilepsy.org/Visitors/Centre/discussion.cfm).
Steven C. Schachter, M.D.
Department of Neurology
Beth Israel Deaconess Medical Center
Boston, MA 02215
sschacht@bidmc.harvard.edu
Response to Commentaries
To the Editors:
We are delighted with the generally positive responses
to our proposal, and grateful for the opportunity to re-
spond to these commentaries. We acknowledge that there
are difficulties with the proposal we have put forward; it is
possible that some of these will prove insurmountable, but
we do not think this is likely. Our view is that with enthu-
siasm, ingenuity, and hard work, all the problems outlined
by the various commentators can be overcome. We do not
have all the answers at present, and we agree with Devin-
sky that the fruits of success are likely to lie in subsequent
versions of the project. It will be a challenge to get the
project up and running and giving us useful information,
but we will certainly not succeed if we do not make an
attempt. We believe that it is worth the attempt, because
this approach gives the opportunity to answer questions
that are very unlikely to be answered in any other way.
We are not proposing that all epilepsy research should
be conducted in the manner we have outlined here. We ac-
cept that a double-blind randomized controlled trial is the
optimal way of comparing two or more alternative treat-
ments. We encourage researchers who are able to organize
such trials to address specific questions to do so. We ac-
cept, as Cooper asserts, that many questions may be able
to be answered via alternative approaches. However, if a
condition is relatively uncommon, and one needs to re-
cruit, say, 500 patients, then it is surely easier and quicker
to have 500 doctors who recruit one patient each than 10
doctors who have to recruit 50 patients each. The approach
we propose would enable researchers to select quite spe-
cific patient groups. We think it may well be possible to
perform pharmacogenetic studies in the future using the
approach we outline here, though we do not ourselves have
any plans to organize such a study.
We disagree with Burneo’s assertion that, because the
doctors and patients are not blinded, randomization may
not succeed in its goal of achieving groups with similar
epi˙01060 EPI-xml.cls June 21, 2007 5:6
GRAY MATTERS
prognosis. Randomization cannot be guaranteed to pro-
duce groups with similar prognosis, but this is the case
even when the patients and doctors are blinded. It is the
randomization, rather than the blinding, that gives prog-
nostically balanced groups. If enough patients are random-
ized, then it is statistically very unlikely that the groups
will differ in any substantial way at the outset. Doctors will
not know before randomization which arm of the study
patients are going to be allocated to. Some doctors might
recruit only sicker or less sick patients than those recruited
by other doctors (referral bias), but these patients will still
be allocated to the different arms in a random manner;
this same referral bias may also be present in conventional
double-blind randomized controlled trials. We accept that
if patients in one treatment arm were more likely to drop
out than those in another arm, then the groups who finish
the study may no longer be comparable. However, this
will be clear to everybody, since the patients have been
recruited and their participation has been recorded. There
would not be any attempt to hide this information; indeed,
the rate of dropping out would be one of the end points
being monitored, and one of the analyses would be on an
intention-to-treat basis. There is the possibility of bias, if
doctors are less likely to record a particular end point in
patients who receive one form of treatment than another,
but we cannot see why this should actually happen, and
could envisage methods to prevent or document this (such
as monitoring of randomly chosen patients, or indepen-
dent endpoint adjudicators). It is also worth emphasizing
that we are not suggesting that this approach be used to
conduct placebo-controlled trials. We suggest that it is
used to compare different active treatments. If a doctor
believes one treatment is certainly better than another, or
if a patient is only prepared to use one of the proposed
alternatives, then the patient should not be recruited for a
trial; indeed, we believe it would be unethical to do so.
We have emphasized these points because we believe
that the major benefit of the proposal we have made is
precisely that it would enable the epilepsy community to
rapidly perform randomized controlled trials. We note that
the recently published SANAD trial (Marson et al., 2007),
which compared various drugs in the management of pa-
tients with newly diagnosed epilepsy, was conducted in
precisely the manner that we are proposing, except that
the study was limited to predetermined researchers, and
the internet was not used as a tool. We think this is a very
impressive study, which has answered one of the many
questions that needed to be addressed. However, we note
that it took the SANAD investigators 4.5 years to recruit
the required number of patients. It is also apparent that the
researchers analyzed patients as if they were a homoge-
nous group. One of the advantages of the project we are
proposing is that it would be possible to compare drugs in
highly selected patient groups; we do not know whether
patients with complex partial seizures due to cerebrovas-
1423
cular disease will respond to different drugs compared
with patients who have post-traumatic epilepsy or epilepsy
following meningitis, but we think this possibility should
be considered.
We agree with Fisher and Burneo that the internet
could be used to create registries of patients with dif-
ferent epilepsy syndromes. These would be suitable for
patients when they or their doctors were not happy with
the idea of randomization, and when no suitable trial ex-
ists. Review of these registries would help guide future
trial development. However, we would envisage that the
registries would run in parallel with the randomized con-
trolled trials, within the major project.
We agree that it is essential to ensure that the data en-
tered are accurate. We accept, as Beghi states, that en-
thusiasm alone may not be sufficient to ensure this. We
think that his recommendations have a great deal of merit,
and we would enthusiastically support the proposal that
the ILAE establish an ad hoc commission to oversee the
project. Perhaps neurologists will need to be credentialed
in some way; our initial proposal was that doctors would
need to be members of the ILAE before they could recruit
patients, but some other form of credentialing might also
be required. Perhaps the recruiting doctors should have
to satisfy their local ILAE committee that they have the
appropriate expertise to undertake this form of research.
Perhaps there should be different levels of access; for ex-
ample, general pediatricians with an interest in epilepsy
may be able to recruit patients to a study of childhood ab-
sence epilepsy, but only registered pediatric neurologists
might be able to recruit children with (say) Ohtahara syn-
drome or Dravet syndrome. If one wanted to perform a
study on a highly specified group, then there may be a
diagnostic test that needs to be met (e.g., confirmation of
a ring chromosome 20). The details need to be considered
carefully, but we remain optimistic that these problems
can be overcome.
Asano raises the possibility that patients themselves en-
ter data via the internet regarding their outcomes. This is
something that we have considered, but it is not an ap-
proach that we have adopted for the pilot study we are
currently undertaking in New Zealand. However, we can
foresee that this approach may be appropriate for some
patient groups.
Fisher has expressed concern that patient accrual might
be slow, since participation will be a labor of love. This
may turn out to be correct, but we have been delighted
with the enthusiasm of the New Zealand neurologists and
pediatric neurologists to the invitation to participate in
the pilot study we are conducting. More than one third of
the country’s neurologists have expressed a willingness
to participate. We need to see whether this enthusiasm is
maintained, and how much coercion is required to obtain
the follow-up data. However, we remain enthusiastic re-
garding this proposal, and once again invite those who are
Epilepsia, Vol. 48, No. 7, 2007
epi˙01060 EPI-xml.cls June 21, 2007 5:6
1424 GRAY MATTERS
interested in participating to contact us, or the ILAE, or
both.
Peter Bergin
Richard Frith
Department of Neurology
Auckland City Hospital
Auckland, New Zealand
Contact author: Peter Bergin
E-mail: psbergin@xtra.co.nz,
pbergin@adhb.govt.nz
REFERENCE
Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chad-
wick DW, Cramp C, Cockerell OC, Cooper PN, Doughty J, Eaton B,
Gamble C, Goulding PJ, Howell SJ, Hughes A, Jackson M, Jacoby A,
Kellett M, Lawson GR, Leach JP, Nicolaides P, Roberts R, Shackley
P, Shen J, Smith DF, Smith PE, Smith CT, Vanoli A, Williamson PR
(SANAD Study group). (2007) The SANAD study of effectiveness
of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or top-
iramate for treatment of partial epilepsy: an unblinded randomised
controlled trial. Lancet 369:1000–1015.
To the Editors:
Lack of Appropriate Treatment for People
with Comorbid HIV/AIDS and Epilepsy in
Sub-Saharan Africa
We would like to draw your readership’s attention to
an emerging problem in epilepsy care in resource poor
settings, particularly for regions heavily impacted by the
HIV/AIDS pandemic such as sub-Saharan Africa (SSA).
Through the efforts of the Global Fund, the President’s
Emergency Plan for HIV/AIDS Relief (PEPFAR), and the
World Health Organization’s three by five initiative, peo-
ple in southern Africa are now gaining access to antiretro-
viral (ART) agents. Access to ARTs for people in the SSA
region has been long-awaited and is clearly a humanitar-
ian necessity—not only to decrease the global morbidity
and mortality of HIV/AIDS, but also to facilitate social,
economic, and political stability and development in such
regions. Triomune, which contains stavudine, lamivudine,
and nevirapine (NVP), is the most common fixed-dose,
combination provided. In reality, many public ART clinics
in SSA have only Triomune routinely available. Second-
line agents are not affordable or accessible, particularly in
the rural areas.
Unfortunately, for people in resource-limited setting
with epilepsy who also require ART therapy, access to
ARTs represents a mixed blessing. Phenobarbitone is the
mainstay of treatment for people with epilepsy in SSA.
NVP’s half-life is substantially shortened by the use of
such enzyme-inducing agents. Coadministration of Tri-
omune with the older, enzyme-inducing anticonvulsants
results in suboptimal levels of NVP (L’Homme et al.,
2006), which will likely lead to NVP resistance and ART
treatment failure (Nowak et al., 1997). Development of
Epilepsia, Vol. 48, No. 7, 2007
HIV resistance to NVP has a negative impact on the health
of the person undergoing treatment as well as public health
implications for the long-term efficacy of presently afford-
able ART regimens. Newer antiepileptic drugs (AEDs)
without enzyme induction properties are at present virtu-
ally unavailable in the region.
This evolving situation places people with comorbid
epilepsy and HIV in resource-poor regions in an unten-
able situation—essentially for each of these conditions
they have one treatment available, but combining the two
treatment (Triomune + phenobarbitone) has serious po-
tential adverse outcomes for the individual as well as ma-
jor public health implications for the community at large.
Whether epilepsy care providers and/or ART clinic staff
are aware of this concerning situation is unclear. ART
provision has been largely facilitated by the development
of separate, stand-alone clinics, and exchange between
HIV/AIDS and epilepsy healthcare providers in Africa
may be quite limited despite the reality that both condi-
tions are exceedingly common in SSA relative to other
parts of the world.
We believe this is a complex, urgent, and important is-
sue that requires the consideration and attention of inter-
national groups such as the International League against
Epilepsy, the World Health Organization, and UNAIDS.
Recognized interactions between NVP and TB treatment
regimens have resulted in the development of recommen-
dations for and access to alternative ART regimens for in-
dividuals with HIV/AIDS and TB comorbidity (Moreno
et al., 2006). Similar attention and consideration is needed
for persons suffering from HIV/AIDS and epilepsy.
∗
Gretchen Birbeck
†
Elwyn Chomba
‡
Edward Ddumba
§
Felix Kauye
Jens Mielke
∗
Michigan State University
East Lansing, Michigan, U.S.A., and
Chikankata Health Services, Mazabula, Zambia
gbirbeck@zamnet.zm
†
University of Zambia, Department of
Paediatrics & Child Health, Lusaka, Zambia
‡
Consultant Neurologist, Mulago Hospital Complex,
Kampala, Uganda
§
Chief Government Psychiatrist & Director
Zomba Mental Hospital, Zomba, Malawi
Consultant Neurologist, University of
Zimbabwe College of Medicine, Harare, Zimbabwe
REFERENCES
L’Homme RF, Dijkema T, van der Ven AJ, Burger DM. (2006) Brief
report: enzyme inducers reduce elimination half-life after a single
dose of nevirapine in healthy women. Journal of Acquired Immune
Deficiency Syndromes 43:193–196.
epi˙01060 EPI-xml.cls June 21, 2007 5:6
GRAY MATTERS
Moreno S, Hernandez B, Dronda F. (2006) Antiretroviral therapy in
AIDS patients with tuberculosis. AIDS Review 8:115–124.
Nowak MA, Bonhoeffer S, Shaw GM, May RM. (1997) Anti-viral drug
treatment: dynamics of resistance in free virus and infected cell pop-
ulations. Journal of Theoretical Biology 184:203–217.
To the Editors:
Response to Birbeck et al.
With their letter, Birbeck and colleagues call the atten-
tion of the epileptologic community to the problems that
derive from the pharmacokinetic interaction between an-
tiretroviral agents (ARTs) and antiepileptic drugs (AEDs).
This issue is particularly important in sub-Saharan African
countries where AIDS prevalence is dramatically high and
epilepsy comorbidity is rather frequent due to opportunis-
tic central nervous system infections.
As stressed by the authors, no systematic studies
of ART–AED interactions have been carried out to
date, the available evidence being exclusively based on
case reports. Liedtke et al. (2004) reported that carba-
mazepine levels are increased by approximately two-
to threefold with concurrent ART ritonavir, resulting in
carbamazepine-related toxicity. The same authors found
the effect of ritonavir on phenytoin to be variable; a 30%
reduction in phenytoin serum concentration occurred in
one patient, while no apparent change was observed in
another patient. Another ART, nelfinavir, decreased the
plasma levels of phenytoin in a patient who subsequently
developed recurrent seizures. Of even more severe con-
cern is the reciprocal effect of enzyme inducer AEDs,
which significantly shorten the half-life of the ART, navi-
rapine. The resulting suboptimal levels of navirapine can
lead to drug resistance and ART failure. Thus, the enzyme
inducers carbamazepine and phenobarbital, two of the
most widely-used traditional AEDs, may have a contra-
productive effect on antiviral therapy, leading to loss of
viral suppression and the emergence of resistance. Con-
versely, the other widely used traditional AED, sodium
valproate, is an enzyme inhibitor and may therefore lead
to an unwanted increase in ARTs levels. Moreover, in vitro
studies suggest that sodium valproate may increase viral
replication (Jennings and Romanelli, 1999).
The above problems can be significantly reduced with
the use of newer AEDs whose metabolism is indepen-
dent from, or only partially dependent on the cytochrome
P450 system—and thus are less likely to interact with
coadministered ARTs. Since some newer AEDs have no
enzyme inducing properties, they have little potential for
reducing ART effect. The obvious recommendation of us-
ing newer AEDs when dealing with AIDS-epilepsy co-
morbidity clashes with the issue of economic sustainabil-
ity, which is particularly dramatic in some sub-Saharan
countries where the per capita health expenditure is only
$5/year.
1425
The International League Against Epilepsy (ILAE) and
the International Bureau for Epilepsy (IBE) have among
its priorities the epilepsy care across the world. Through
the Global Campaign Against Epilepsy (GCAE), a joint
ILAE-IBE-World Health Organization (WHO) program,
ILAE and IBE are strongly engaged in reducing the treat-
ment gap in developing countries. The problem raised in
the letter from Birbeck et al., will be brought to the atten-
tion of the GCAE with the following recommendations:
A group of experts should review the available evidence
about AED–ART interactions. Prospective studies, which
focus on systematic monitoring of plasma levels of both
AEDs and ARTs, should be carried out in more devel-
oped countries. Using these findings, the GCAE should
develop a plan that WHO can implement in Africa to face
this emergency. To find the necessary resources for im-
plementation, GCAE should seek the collaboration of the
pharmaceutical industry.
Giuliano Avanzini
Past President, International League
Against Epilepsy, Cochair
Global Campaign Against Epilepsy
Istituto C. Besta, Milan, Italy
avanzini@istitutobesta.it
REFERENCES
Jennings HR, Romanelli F. (1999) The use of valproic acid in HIV pos-
itive patients. Ann Pharmacother 33:1113–1116.
Liedtke MD, Lockhart SM, Rathbun RC. (2004) Anticonvulsant and
antiretroviral interactions Ann Pharmacother 38:482–489.
NEXT MONTH IN Epilepsia
The August issue of Epilepsia will survey a number
of different areas of current investigative interest. A set
of papers on surgical intervention will discuss surgery
for tuberous sclerosis, for posterior quadrantic epilepsy,
and for gliomatosis cerebri. Neuropathological descrip-
tions are presented from investigations of cortical dyspla-
sia in older patients, and white matter changes in mal-
formations of cortical development. Clinical and imaging
studies include considerations of inter-observer reliability
in using video recordings to diagnose nocturnal frontal
lobe seizures, and MRI evidence of temporopolar atro-
phy in temporal lobe epilepsy. Psychological investiga-
tions focus on lateralization of function following surgery
for TLE, reorganization of verbal and non-verbal memory
in TLE, postictal psychotic episodes, and serotonin-PET
receptor binding associated with depression in epilepsy.
Finally, several papers describe both clinical and ex-
perimental approaches that involve different modes and
Epilepsia, Vol. 48, No. 7, 2007
epi˙01060 EPI-xml.cls June 21, 2007 5:6
1426 GRAY MATTERS
locations of stimulation, and a consideration of networks
responsible for seizure generation and spread.
Online Early
Ashrafi et al., “A probably causative factor for an old
problem: Selenium and glutathione peroxidase appear to
play important roles in epilepsy pathogenesis”
Belcastro et al., “Antiepileptic drugs and MTHFR poly-
morphisms influence hyper-homocysteinemia recurrence
in epileptic patients”
Billiau et al., “Intravenous immunoglobulins in refrac-
tory childhood-onset epilepsy: Effects on seizure fre-
quency, EEG activity, and cerebrospinal fluid cytokine
profile”
Bragin et al., “Analysis of initial slow waves (ISWs) at
the seizure onset in patients with drug resistant temporal
lobe epilepsy”
Cantello et al., “Ketogenic diet: Electrophysiological
effects on the normal human cortex”
Dodrill and Ojemann, “Do recent seizures and recent
changes in antiepileptic drugs impact performances on
neuropsychological tests in subtle ways that might easily
be missed?”
Eadie, “Cortical epileptogenesis – Hughlings Jackson
and his predecessors”
Ferraro et al., “Analysis of a quantitative trait locus
for seizure susceptibility in mice using bacterial artificial
chromosome-mediated gene transfer”
Fogarasi et al., “Age-dependent seizure semiology in
temporal lobe epilepsy”
Hawley et al., “Initial perspectives from Midwestern
neurologists: Epilepsy patients’ barriers and motivators
for seeking treatment”
Kang et al., “The effects on cognitive function and
behavioral problems of topiramate compared to car-
bamazepine as monotherapy for children with benign
Rolandic epilepsy”
Øyen et al., “Maternal epilepsy and offsprings’ adult
intelligence: A population-based study from Norway”
Lossius et al., “Reversible effects of antiepileptic drugs
on reproductive endocrine function in men and women
with epilepsy – A prospective randomized double-blind
withdrawal study”
Marini et al., Idiopathic epilepsies with seizures precip-
itated by fever and SCN1A abnormalities”
Palma et al., “The antiepileptic drug levetiracetam sta-
bilizes the human epileptic GABAA receptors upon repet-
itive activation”
Patrylo et al., “Dentate filter function is altered in a
proepileptic fashion during aging”
Raedt et al., “Radiation of the rat brain suppresses
seizure-induced neurogenesis and transiently enhances
excitability during kindling acquisition”
Epilepsia, Vol. 48, No. 7, 2007
Ramaglia et al., “Impact of idiopathic epilepsy on moth-
ers and fathers: Strain, burden of care, worries and percep-
tion of vulnerability”
Reynolds, “Jackson, Todd, and the concept of “dis-
charge” in epilepsy”
Saemundsen et al., “Autism spectrum disorders in chil-
dren with seizures in the first year of life – A population-
based study”
Somera-Molina et al., “Glial activation links early-life
seizures and long-term neurologic dysfunction: Evidence
using a small molecule inhibitor of proinflammatory cy-
tokine upregulation”
Taylor et al., “Is photosensitive epilepsy less common
in males due to variation in X chromosome photopigment
genes?”
Ueda et al., “In vivo EPR estimation of bilateral hip-
pocampal antioxidant ability of rats with epileptogenesis
induced by amygdalar FeCl3 microinjection”
Van Paesschen et al., “Cognitive deficits during sta-
tus epilepticus and time course of recovery: A case
report”
Vesper et al., “Chronic high-frequency deep brain
stimulation of the STN/SNr for progressive myoclonic
epilepsy”
Yang et al., “Prolonged exposure to Levetiracetam re-
veals a presynaptic effect on neurotransmission”
ANNOUNCEMENTS
Morris-Coole Prize
The first Morris-Coole Prize for excellence in epilepsy
research was awarded to Dr. Zita Gajda for her paper on
“The significance of gap junction channels in the epilep-
togenicity and seizure susceptibility of juvenile rats”
(Epilepsia, 2006, 47:1009-1022). The award, consisting
of 10,000 Euros, was presented to Dr. Gajda at the recent
International Epilepsy Congress in Singapore. Dr. Gajda
also delivered the first Morris-Coole Lecture, describing
her studies.
Dr. Gajda is a young epilepsy researcher in the lab-
oratory of Professor Magdolna Szente, at the Univer-
sity of Szeged, Hungary. She received her Ph.D. in
2006 for studies on the role of gap junctions in seizure
genesis.
The Morris-Coole Prize is a new annual ILAE award,
given for an outstanding research paper—on any epilepsy-
related topic, basic or clinical - published in Epilepsia.
The paper should, in the opinion of the judges, con-
tribute significantly to our understanding and/or treat-
ment of epilepsy and seizures. Candidates for the Prize
are nominated by the Associate Editors of Epilepsia, and
the Prize-winner is chosen from this short-list by a com-
mittee composed of the Epilepsia Editors-in-Chief and the
epi˙01060 EPI-xml.cls June 21, 2007 5:6
GRAY MATTERS
President of ILAE. This year, fourteen articles were nom-
inated from the list of full-length research articles pub-
lished in Epilepsia in 2006. The Prize is the generous gift
of Mr. and Mrs. Christopher Morris-Coole, whose goal is
to encourage young researchers who have chosen to work
in epilepsy research field.
EUREPA Distance Education Programs 2007/2008
EUREPA’s schedule of educational programs for 2007-
2008 will again include a course on “Genetics of
Epilepsy.” Deadline for application is July 30, 2007. For
detailed information and application procedures, please
go to http://www.epilepsy-academy.org or contact the
EUREPA Secretariat at office@epilepsy-academy.org.
2nd Eilat International Educational Course on
Pharmacological Treatment of Epilepsy
Princess Hotel, Eilat, Israel, September 2-9, 2007.
The Course (conducted in English) will include ses-
sions on Pharmacology of AEDs, Pharmacokinetics and
TDM, Drug Interactions, Assessing Efficacy and Safety,
Optimizing Medical Management. There will also be sev-
eral tutorial sessions, training workshops, case studies, and
guided problem-solving exercises.
The Course will be held under the auspices of the ILAE
Commission on European Affairs (CEA) and the Euro-
pean Epilepsy Academy (EUREPA). It is designed for
junior scientists (45 years and younger). Suitable candi-
dates accepted to the course will receive a bursary towards
the cost of their attendance.
Course Organizers: Meir Bialer, Israel, Chairperson;
Ana Dimova, Macedonia; Alla Guekht, Russia; Svein
I. Johannessen, Norway; Anne-Mari Kantanen, Finland;
Cigdem Ozkara, Turkey; Emilio Perucca, Italy; Torbjörn
Tomson, Sweden; Federico Vigevano, Italy.
For details, see http://www.eilat-aeds.com, under Forth-
coming Conferences, or contact the Secretariat: Target
Conferences Ltd, PO Box 29041, Tel Aviv 61290, Is-
1427
rael, Tel: +972 3 5175150, Fax: +972 3 5175155, e-mail:
eilatedu@targetconf.com.
Milken Family/American Epilepsy Society Early
Career Physician Scientists Award
The Milken Family Foundation and the American
Epilepsy Society announce the opening of the Early
Career Physician Scientists awards to investigators
from around the world. This award is designed to assist
physician-scientists embarking on early academic careers
devoted to epilepsy research. Preference is given to
innovative studies leading to new treatments or other
novel translational research. $50,000 USD is awarded
for a 12-month period beginning in January 2008.
Applications are due by Friday September 14, 2007.
Eligibility requirements and application information
are available by email (ctubby@aesnet.org) or at http://
www.aesnet.org/Visitors/Research/sponsoredgrants/early
career.cfm.
American Epilepsy Society—2007 Epilepsy Re-
search Recognition Awards
The American Epilepsy Society (AES) announces the
call for nominations for the 2007 Epilepsy Research
Recognition Awards. This program honors individuals
whose history of professional excellence in epilepsy re-
search has advanced the understanding, diagnosis, and/or
treatment of epilepsy.
One Basic Scientist and one Clinical Investigator each
receive a $10,000 award and are recognized at the AES An-
nual Meeting in December. Active scientists and clinicians
around the world are eligible for these awards. Candidates
must hold a professional degree, and must be nominated
by their peers.
All nomination material must be received in the AES of-
fice by August 13, 2007. Electronic submission is encour-
aged. Detailed instructions for nomination are available on
the AES website: http://www.aesnet.org/researchaward.
Epilepsia, Vol. 48, No. 7, 2007
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1428 GRAY MATTERS

CALENDAR OF MEETINGS
2007 October 2007

July 2007 Canadian League Against Epilepsy - 30th Annivers-

ary
27th International Epilepsy Congress 2-4 October
8-12 July Vancouver, Canada
Suntec City, Singapore http://www.clae.org
http://www.epilepsysingapore2007.org

Idiopathic Generalized Epilepsy (IGE): Developmen-

6th International Course on Epilepsy: Clinical and tal Aspects, Bridging Basic Science and Clinical
Therapeutic Approaches to Childhood Epilepsy Research
23 July-3 August 3-6 October
Venice, Italy Antalya, Turkey
email: epilepsysummercourse@univiu.org http://www.ige2007.org
August 2007
2008
Baltic Sea Summer School on Epilepsy
19-23 August Venice Epilepsy Summer School, 7th International
Druskininkai, Lithuania Course: Bridging Basic with clinical epileptology – 3
http://www.epilepsy-academy.org Summer 2008
Venice, Italy
September 2007
email: epilepsysummercourse@univiu.org
2nd Eilat International Educational Course: Pharma-
cological Treatment of Epilepsy 8th European Congress on Epilepsy
2-9 September 21-25 September
Eilat, Israel Berlin, Germany
http://www.eilat-aeds.com/eilatedu2/index.asp http://www.epilepsyberlin2008.org

Epilepsia, Vol. 48, No. 7, 2007