Opinion

EDITORIAL

The Prevention of Epilepsy

Mark Agostini, MD

Almost 21 years ago, Dreifuss1 reviewed the state of epilepsy

prevention in this journal. He anticipated a quarter century of
advances in the understanding of the neurobiological mechanisms and prevention of epileptogenesis. He also identified theoretically preventive
strategies such as immunizaRelated article page 390
tions, optimizing maternal
health, preventing early teenage pregnancies with their increased risk for premature and low-weight infants, increasing
the use of helmets for sports and transportation, preventing falls
among elderly individuals, and ending boxing in high schools.
The focus on prevention is critical given the approximately 30% rate of pharmacoresistance among patients with
epilepsy. This is despite at least 16 new antiseizure medications since 1993, some with novel mechanisms of action.2 Failure to control epileptic seizures leads to increased mortality
and reduced quality of life.3 From the Presidential Commission for the Control of Epilepsy and its Consequences in 1976
to the 2012 publication of the Institute of Medicine report, Epilepsy Across The Spectrum: Promoting Health and Understanding, there has been consistent recognition of the vital
importance of acquiring epidemiologic data addressing progress in the prevention of epilepsy. 4-6 Neuroscientific advances in the mechanisms of and potential treatments for epileptogenesis have exploded within the last few decades.7,8
Public health measures to prevent head injuries, from car air
bags to bicycle helmets, have become commonplace. There has
been an understandable sense of optimism that these basic and
clinical research advances together with public health safety
initiatives would translate to a decline in the rate of epilepsy.
We only needed the data to prove this. It is within this
atmosphere of great optimism that the article by Sillanp et al9
comes as a disappointment.
Sillanp and his colleagues9 analyzed the incidence rate
of new-onset epilepsy (patients with epilepsy per 100 000 person-years) in Finland from 1973 to 2013.9 They took advantage of a national hospital registry that identifies all patients
discharged with a diagnosis of epilepsy. They also benefitted
from a national standard of care to hospitalize all patients with
epileptic seizures who presented to a hospital emergency department. Coding systems (International Classification of Diseases, Eighth Revision; International Classification of Diseases,
Ninth Revision; and International Classification of Diseases,
Tenth Revision) as well as the individual codes (345.3-9, 345.4-7,
and G40.0-2) changed during this study but the application of
an epilepsy diagnosis was consistent for each time interval.
The authors major finding was that the yearly incidence
for new-onset epilepsy was constant for all age groups until
2000, when there was a significant increase. This increase was
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entirely accounted for by a nearly 5-fold increase in patients

older than 65 years. Subgroups, such as children younger than
1 year of age and patients with symptomatic focal epilepsy, also
showed an increased incidence over the observation period.
For patients with focal epilepsy, the incidence densities increased from 7 per 100 000 person-years in 1978 to 39 per
100 000 person-years in 2013.
The strengths of this study included a very long observational period and a strong, consistent method to systematically capture all patients with new-onset epilepsy. However,
they noted that in the last 15 years of their study, unpublished data suggested that the diagnoses of new-onset epilepsy doubled if outpatient care was included. It is not clear
whether inpatient and outpatient diagnoses represent different types of epilepsy. The latter perhaps might show a different response to 40 years of epilepsy prevention. The authors
also raised the concern of an increasingly lower threshold to
diagnose epilepsy or perhaps better tools (eg, magnetic resonance imaging and video electroencephalogram) to make a secure diagnosis. This seems unlikely given that the diagnosis
of epilepsy remains a predominantly clinical diagnosis, which
probably has not changed over the years. The study also used
the most conservative definition of epilepsy.10
The authors concluded that not only have we failed to reduce the occurrence of epilepsy over the last 40 years, but there
has been a significant 5-fold increase in new-onset epilepsy
among the elderly population. The authors discussed the balance of 2 forces that would affect the change in the incidence
of new-onset epilepsy. On one hand, over the last 40 years,
there have been tremendous and steady advances in neonatal and critical illness care. This has led to enhanced survival
of patients with brain injuries likely to precipitate epileptogenesis. Increased survival of those who have had gunshot
wounds to the head, military or civilian, or the increased survival of premature infants would be just 2 examples of factors that will contribute to more epilepsy diagnoses. In a sense,
an increase in epilepsy is the price paid for the dramatic advances of critical care medicine. Moreover, along with Finland, many nations are experiencing a demographic shift, with
a marked increase in the longevity of elderly individuals and
their anticipated higher burden of epilepsy risk factors. The
forces of public safety measures to prevent brain injuries along
with the very few documented medical interventions to prevent epileptogenesis among high-risk patients apparently have
not been a sufficient counterbalance.7,8,11
This article has several important implications for the prevention of epilepsy. The first is the importance of welldesigned, long-term, epidemiologic studies to ensure that we
have adequate feedback with respect to progress or the lack
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Opinion Editorial

thereof. While it is likely that Finlands epidemiologic data are

representative of many developed countries, this may not apply to less well-developed nations. The challenge is for every
country to initiate epidemiologic surveillance for patients with
new-onset and chronic epilepsy. Second, efforts toward identifying patients at high risk for developing epilepsy and initiating clinical treatments to prevent epileptogenesis have never
been more important if we are ever to balance the increasing
survival of brain-injured patients and aging populations. For
ARTICLE INFORMATION
Author Affiliation: Department of Neurology and
Neurotherapeutics, The University of Texas
Southwestern Medical Center, Dallas.
Corresponding Author: Mark Agostini, MD,
Department of Neurology and Neurotherapeutics,
The University of Texas Southwestern Medical
Center, 5323 Harry Hines Blvd, Dallas, TX 753908508 (mark.agostini@utsouthwestern.edu).
Published Online: February 15, 2016.
doi:10.1001/jamaneurol.2015.4780.
Conflict of Interest Disclosures: None reported.
REFERENCES
1. Dreifuss FE. Prevention as it pertains to epilepsy.
Arch Neurol. 1995;52(4):363-366.
2. Kwan P, Schachter SC, Brodie MJ. Drug-resistant
epilepsy. N Engl J Med. 2011;365(10):919-926.
3. Theodore WH, Spencer SS, Wiebe S, et al.
Epilepsy in North America: a report prepared under

example, the European Forum on Epilepsy research proposed a specific roadmap for translational research, including a recommendation to establish both preclinical and clinical European consortiums for antiepileptogenesis studies.12
Finally, there may still be public health measures that could
further reduce the incidence of severe brain injuries (eg, reductions in gun violence and in sports- and traffic-related head
trauma). Sillanp and colleagues9 have provided essential
feedback that more work has to be done.

the auspices of the global campaign against

epilepsy, the International Bureau for Epilepsy, the
International League Against Epilepsy, and the
World Health Organization. Epilepsia. 2006;47(10):
1700-1722.
4. Hesdorffer DC, Beck V, Begley CE, et al.
Research implications of the Institute of Medicine
report, Epilepsy Across the Spectrum: Promoting
Health and Understanding. Epilepsia. 2013;54(2):
207-216.
5. Hesdorffer DC, Begley CE. Surveillance of
epilepsy and prevention of epilepsy and its
sequelae: lessons from the Institute of Medicine
report. Curr Opin Neurol. 2013;26(2):168-173.
6. Institute of Medicine. Epilepsy Across the
Spectrum: Promoting Health and Understanding.
Washington, DC: The National Academics Press; 2012.
7. Giblin KA, Blumenfeld H. Is epilepsy a
preventable disorder? new evidence from animal
models. Neuroscientist. 2010;16(3):253-275.

8. Pitknen A, Engel J Jr. Past and present

definitions of epileptogenesis and its biomarkers.
Neurotherapeutics. 2014;11(2):231-241.
9. Sillanp M, Gissler M, Schmidt D. Efforts in
epilepsy prevention in the last 40 years: lessons
from a large nationwide study [published online
February 15, 2016]. JAMA Neurol. doi:10.1001
/jamaneurol.2015.4515.
10. Fisher RS, Acevedo C, Arzimanoglou A, et al.
ILAE official report: a practical clinical definition of
epilepsy. Epilepsia. 2014;55(4):475-482.
11. Guo J, Guo J, Li J, et al. Statin treatment reduces
the risk of poststroke seizures. Neurology. 2015;85
(8):701-707.
12. Baulac M, de Boer H, Elger C, et al. Epilepsy
priorities in Europe: a report of the ILAE-IBE
Epilepsy Advocacy Europe Task Force. Epilepsia.
2015;56(11):1687-1695.

Predicting Early Recurrent Stroke

With the Recurrence Risk Estimator
Graeme J. Hankey, MD, FRACP, FRCP, FAHA; Chee-Keong Wee, MBBS, MRCP

Acute ischemic stroke is a medical emergency. Early reperfusion therapy can reduce functional disability, and early
secondary prevention therapy can reduce early recurrent
stroke. The rate of recurrent
stroke in the first month is
Related article page 396
approximately 9.4% (95%
CI, 6%-14%) among patients with ischemic stroke caused by
large-artery atherosclerosis and approximately 1.2% (95% CI,
0.4%-3.0%) among patients with ischemic stroke caused by
intracranial small vessel disease.1 Because some effective
early prevention therapies may be risky or costly (eg, carotid
revascularization or dual antiplatelet therapy) and some
patients have a low risk of recurrent stroke, targeting risky or
costly treatments to patients at high risk of recurrent stroke
who are most likely to benefit is desirable. However, experienced physicians are unable to accurately discriminate or
separate patients with ischemic stroke at high and low risk of
recurrent stroke.2 Clinical prediction models, also known as
prognostic scores, which combine multiple risk factors to
estimate the absolute risk of future stroke, might improve
risk prediction. Recent evidence indicates that the ABCD2
376

score, calculated from 5 clinical features (age, blood pressure, clinical features, duration of transient ischemic attack,
and presence of diabetes mellitus), does not reliably discriminate patients at low and high risk,3 and the predictive
power of several other prognostic tools is modest.4 More
promising are prognostic scores that incorporate information about the nature and activity of the vascular disease
causing the index stroke, such as the ABCD3I score and the
Recurrence Risk Estimator (RRE).5-10
The RRE was developed from a derivation cohort of 1257
patients with ischemic stroke at a single US tertiary care center.7
It discriminated between patients who had a recurrent stroke
at 90 days from those who did not with 80% (95% CI, 73%86%) probability.7 These estimates are significantly better than
chance (50% probability) but not perfect (100% probability).
Nevertheless, the clinical utility of the RRE should not be
judged by how well it performed in the cohort from which it
was derived (internal validity) but by how well it performs in
other patient cohorts (external validity).11
In this issue of JAMA Neurology, Arsava et al12 report the
performance of the RRE in predicting 90-day recurrent stroke

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