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Neurology 2002;59:S1-S2
© 2002 American Academy of
Neurology
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Neuroprotection and antiepileptogenesis
Overview, definitions, and context
Andrew J. Cole,
MD FRCP(C) and Marc Dichter, MD PhD
From the MGH Epilepsy Service, Massachusetts General Hospital,
and the Department of Neurology, Harvard Medical School, Boston, MA (Dr. Cole),
and the Departments of Neurology and Pharmacology, University of Pennsylvania
School of Medicine, and the David Mahoney Institute of Neurological Sciences and
Penn Epilepsy Center, Philadelphia, PA (Dr. Dichter).
Address correspondence and reprint requests to Dr. Andrew J.
Cole, Director, MGH Epilepsy Service, VBK-830, Massachusetts General Hospital,
Fruit Street, Boston, MA 02114; e-mail: cole.andrew@mgh.harvard.edu
 |
Introduction |
The stated
goal of the community of physicians and scientists who treat and
study epilepsy, as articulated at an NIH-sponsored consensus
conference in 2000, is "no seizures, no side effects." The conference
report, however, makes clear that suppression of the symptoms of
epilepsy, i.e., seizures per se, is not sufficient. Additional
efforts must focus on preventing the development of epilepsy in
individuals at risk and preventing the negative consequences of
seizures when they occur (see
http://www.ninds.nih.gov/about_ninds/epilepsybenchmarks.htm). This
holistic approach to epilepsy, which emphasizes disease modification
in addition to symptomatic relief, represents nothing less than a
paradigm shift for the discoverers, developers, prescribers, and
users of epilepsy therapeutics.
Gowers recognized that "seizures beget seizures" over a century
ago. Using the tools of clinical observation alone, however, it
was impossible to determine whether seizures were epileptogenic or
whether both the initial seizure and subsequent seizures a patient
experienced were the result of a common pathology or genetic
predisposition. Recent studies using animal models strongly support
the notion that an otherwise normal individual can develop epilepsy
as the result of an initial seizure.1,2
These studies used chemoconvulsants to induce status epilepticus
and then documented the occurrence or spontaneous recurrent
seizures weeks to months later. It remains unclear whether a
single seizure or nonconvulsive seizures have the same potential
to induce epilepsy in otherwise normal individuals.
As early as 1825, Bouchet and Cazauvielh3
noted loss of neurons in the hippocampus of patients with seizures.
Subsequent studies of autopsy material and surgical specimens have
amply supported the notion that there is a specific topography of
neuronal loss in patients with certain types of epilepsy and that
there are additional pathological markers of brain injury in these
patients, including atrophy, gliosis, reactive astrocytes, and
microglial proliferation. Despite the overwhelming evidence for
anatomic injury in patients with epilepsy, it has been much more
difficult to establish whether seizures are the cause or the
consequence, or perhaps both. Here, too, animal models have improved
our understanding of the relationship between seizures and
injury. Normal animals exposed to status epilepticus develop a
stereotyped pattern of cell loss and gliosis,4–6
supporting the notion that seizures cause injury. By contrast,
animals with focal lesions, such as cortical dysplasia or migrational
abnormalities, manifest clinical seizures infrequently,7,8
making the notion that injury causes seizures more difficult to
prove. Moreover, it appears likely that some kinds of seizures, such
as absence and benign rolandic seizures, may occur repeatedly without
causing overt injury.
The preceding discussion highlights the two important concepts
that form the subject matter of this supplement, seizure-induced
injury and epileptogenesis. With the recent development of a
host of new antiepileptic drugs, considerable interest has focused
around the question of whether any or all of these compounds
might have disease-modifying activities. An important limitation
of work in this field is that most studies have addressed the
neuroprotective and antiepileptogenic activities of existing
antiepileptic drugs rather than taking a broader approach to
examining drugs from other classes for neuroprotective or
antiepileptogenic activity. Therefore, this supplement specifically
considers the question of whether we have drugs with neuroprotective
or anti-epileptogenic properties, in addition to their
demonstrated antiepileptic properties.
|
Definitions. |
Antiepileptic.
An antiepileptic compound prevents or reduces epileptic seizures.
Because not all seizures are convulsive, this term is preferred to
anticonvulsant.
Neuroprotective.
A compound with neuroprotective activity
prevents neuronal injury. An antiepileptic may be neuroprotective if
seizures are injurious or if the compound has an additional
protective activity independent of its antiepileptic activity.
Antiepileptogenic.
An antiepileptogenic compound prevents
or slows the process of developing epilepsy. An antiepileptic might
be antiepileptogenic if the seizures it blocks are themselves
epileptogenic. A neuroprotective compound might be antiepileptogenic
if injury leads to epilepsy. Alternatively, some compounds might have
antiepileptogenic activity without either blocking seizures or
preventing injury.
|
Context. |
Behavioral,
anatomic, biochemical, and molecular techniques have revealed an
extraordinary range of responses of the previously normal brain to
brief episodes of abnormal activity such as that seen during
epileptic seizures. Calcium ion influx, gene activation and
expression, kinase activation, cell loss, synaptic remodeling,
neurogenesis, behavioral change, and enhanced susceptibility to
additional seizures have all been described (see Cole9
for review). These events occur on a timescale from milliseconds
to months. If one hypothesizes that seizures are either epileptogenic
or injurious, it appears likely that some of the short-term
consequences of seizures act to transduce brief episodes of
abnormal neuronal activity into long-term functional and anatomic
changes in the CNS. This process, which is temporally dispersed,
offers a therapeutic target for agents that are antiepileptogenic
or neuroprotective. It remains unclear whether the transduction
process is arranged in a linear series fashion or whether multiple
short-term processes lead in parallel to the same long-term
result. An answer to this question has obvious implications for
the development of neuroprotective and antiepileptic therapeutics.
This supplement has been developed to address the issues surrounding
neuroprotection and antiepileptogenesis. It is organized to
consider and review data from animal and human studies addressing
the following questions:
- Do seizures cause neuronal injury? Dr. Holmes reviews animal
data supporting the idea that seizures cause injury. Dr. Duncan,
using mainly neuroimaging data, addresses the issue of whether
seizures cause injury in humans.
- Are seizures epileptogenic? Dr. White reviews animal
models and data addressing the issue of whether seizures
are epileptogenic. Dr. Hermann, using mainly
epidemiologic data, then considers the question of whether
seizures are epileptogenic in humans.
- Do we have neuroprotective or antiepileptogenic drugs? Dr.
Pitkanen reviews the experimental data from animal
studies concerning neuroprotective and antiepileptogenic
activity of existing compounds. Dr. Schachter then
examines the data, or lack of same, in human studies and
outlines strategies for testing the hypothesis that some
compounds are neuroprotective or antiepileptogenic in humans.
Although the notions of neuroprotection and antiepileptogenesis
are frequently discussed, only recently have investigators taken
on the issues in a focused and formal manner. We hope that this
supplement will clarify the issues and the terminology in the
field, present the best data available, and highlight future
directions in the field that will ultimately lead to the stated
goal of a cure for epilepsy, i.e., "no seizures, no side effects."
|
Footnotes |
Publication of this supplement was supported by an
educational grant from GlaxoSmithKline. The sponsor has provided
A.J.C. with honorarium during his professional career.
|
References |
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- Bouchet C, Cazauvielh Y. De l’épilepsie considérée dans ses
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