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The Early Identification of Candidates for Epilepsy Surgery
Dennis J. Dlugos, MD
Arch Neurol. 2001;58:1543-1546.
ABSTRACT
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The effectiveness of resective surgery for the treatment of carefully
selected patients with medically intractable, localization-related epilepsy
is clear. Seizure-free rates following temporal lobectomy are consistently
65% to 70% in adults1, 2 and 68%
to 78% in children.3, 4 Extratemporal
resections less commonly lead to a seizure-free outcome, although one recent
childhood series reported a seizure-free rate of 62% following extratemporal
epilepsy surgery.5 With both temporal and extratemporal
resections, additional patients have a reduction in seizures following surgery
but are not completely seizure free. The identification of favorable surgical
candidates has been the subject of extensive research, and many investigators
have examined predictors of outcome following epilepsy surgery. However, the
early identification of the potential epilepsy surgery candidate and the optimal
timing of surgery have only occasionally been addressed in the literature.
This issue is methodologically challenging to study since studies require
large numbers of patients with new-onset partial epilepsy who are followed
over time. The purpose of this article is to review the current ability for
early prediction of medical intractability in patients with surgically remediable
epilepsy. Emphasis will be placed on the early prediction of intractable temporal
lobe epilepsy in children and adolescents, since temporal lobectomy remains
the prototype epilepsy surgery, and early surgery may improve psychosocial
outcome in younger patients.6, 7
THE PROGNOSIS OF EPILEPSY IN ADULTS AND CHILDREN
Population-based studies of epilepsy patients of all ages have shown
a mixed prognosis with 70% to 80% of patients becoming seizure free for 3
to 5 years,8, 9 although adults
with complex partial seizures have the poorest prognosis for complete seizure
control.10 Studies of pediatric patients with
various seizure types (not limited to partial epilepsy) indicate a 90% chance
of achieving a 1-year remission11 and a 76%
chance of being seizure free for 5 years.12
Such data are helpful to provide a broad overview but have limited applicability
to individual patients. Studies on the prognosis of particular epilepsy syndromes
(such as temporal lobe epilepsy [TLE]) would be more clinically useful but
are limited. The best available evidence on the prognosis of adult TLE is
found in a hospital-based cohort study from France13
in which 80% of 500 adults with TLE had ongoing seizures with medical therapy,
making TLE the most refractory form of adult partial epilepsy.
The prognosis of childhood TLE is more uncertain. Older hospital-based
studies of childhood TLE suggest a poor prognosis. Lindsay et al14
studied a series of 100 children with TLE, beginning in 1948. When followed
into adulthood, only 33% were seizure-free and living independently. Another
series found only 10% of 63 children with TLE to be seizure free after 6 years
of medical treatment.15 Patients in these studies
were diagnosed before the use of magnetic resonance imaging (MRI) scans and
video electroencephalogram (EEG), and some of the patients had evidence of
brain disease outside of the temporal lobe,16
so the contemporary relevance of these studies is uncertain. Childhood TLE
is almost certainly a more heterogeneous entity than these studies suggest,
and small series have proposed benign variants of TLE in childhood.17 Studies limited to children with newly diagnosed
complex partial seizures (many of whom have TLE) indicate remission rates
of 59% to 63%.18, 19 It has been
suggested that children with cryptogenic TLE likely have a more favorable
prognosis than children with temporal lobe lesions on MRI,20
but this important point has not been demonstrated in a prospective study.
MEDICAL INTRACTABILITY
An issue inextricably linked to prognosis is medical intractability,
where additional medical therapy is unlikely to completely control seizures
and alternate treatment is considered. Hospital-based studies of adults with
partial seizures indicate that patients who have persistent seizures despite
an initial antiepileptic drug (AED) trial have only a 12% to 14% chance of
complete seizure control with alternate AED monotherapy21, 22
and a 3% to 11% chance with AED polytherapy.21, 23
Consequently, many adult epilepsy centers define medical intractability as
persistent seizures despite 2 years and 2 maximally tolerated AED trials.24
Medical intractability is more challenging to define in children because
of the tendency of many forms of pediatric epilepsy to remit with time. For
example, a population-based study in Nova Scotia of children with generalized
tonic-clonic, partial, and secondarily generalized seizures found that remission
of seizures occurred in 42% of children who failed their first AED trial,25 a vastly different conclusion than from hospital-based
data in adults. The Nova Scotia study, however, was not limited to TLE, and
no specific information is available on the impact of initial AED failure
in children with TLE.
DELAY IN EPILEPSY SURGERY
Because of the irreversible nature of surgery and uncertainties surrounding
prognosis (especially in children), it is not surprising that patient referral
for epilepsy surgery is delayed. A recent adult temporal lobectomy series
of 89 patients reported a mean age of epilepsy onset of 13.1 years but a mean
age at surgery of 31.9 years, resulting in a mean duration of epilepsy of
18.8 years prior to surgery.1 The delay occurred
despite a median seizure frequency of 8 per month. In a childhood series,
patients were referred for temporal lobectomy after receiving an average of
7 to 8 AED trials and 9 years after the onset of epilepsy.26
Causes for such delay include lack of timely referral to epilepsy surgery
centers from primary care physicians and community neurologists, multiple
AED trials in patients with little chance of remission, lack of appreciation
that even occasional complex partial seizures can be disabling, and patient
reluctance to undergo irreversible surgery. Although surgery must clearly
be avoided in patients destined to enter remission within a reasonable period
of time, excessive delay in pursuing effective surgical therapy may risk serious
psychosocial and physical disability.
BENEFITS AND RISKS OF EARLY SURGERY
It has been postulated that the early use of successful epilepsy surgery,
especially in children and adolescents, could minimize the long-term physical
and psychosocial consequences of intractable epilepsy.6, 7
Children and adolescents with epilepsy are clearly at increased risk for considerable
psychosocial, vocational, and cognitive dysfunction, which persists into adulthood.27 A population-based study of 337 children and young
adults with normal intelligence and epilepsy found the following: school failure
in 34% of patients, special education utilization in 34%, mental health consultation
in 22%, unemployment in 20%, social isolation in 27%, and inadvertent pregnancy
in 12%.28 Causes of such dysfunction are complex
and difficult to study but may include underlying brain abnormalities, effects
of recurrent seizures, AED toxicity, and psychosocial factors such as excessive
dependency and overprotection.28 If ongoing
seizures or the psychosocial consequences of the seizures are largely responsible
for this dysfunction, then earlier use of effective surgical therapy could
reduce these long-term problems.
However, the ability of early surgery to actually improve long-term
outcome has not been demonstrated and is particularly challenging to study.
One series that supports this contention included 50 adolescents who underwent
temporal lobectomy at a mean age of 15.8 years.6
Mean age at epilepsy onset was 7.5 years, with the time between epilepsy onset
and surgery averaging 8.3 years. Postoperatively, 78% were seizure free or
experienced auras only. No changes were seen in Wechsler Intelligence Scale
scores after surgery, but there was a greater likelihood of improvement in
verbal and perceptual intelligence quotients with a shorter time between seizure
onset and surgery.
The obvious risk of early surgery is performing an invasive and irreversible
procedure in a patient who ultimately would have become seizure free within
a reasonable period of time, before irreversible psychosocial consequences
ensued. The elusive goal of optimizing the timing of epilepsy surgery can
be summarized and oversimplified as this: Not too early, but not too late.
The current rule of thumb regarding timing of epilepsy surgery—at least
2 years and 2 AED trials—is likely not adequate for all types of surgically
remediable epilepsy, especially in children. Regardless, the available evidence
clearly suggests that most patients undergo epilepsy surgery well beyond 2
years and 2 AED trials.
A randomized clinical trial of early surgical intervention for mesial
TLE has been proposed in the United States but has not yet begun.29 Patients aged 12 years and older with refractory
TLE of less than 2 years' duration would be randomized to surgery or an additional
2 years of medication. The challenges of successfully completing such a study
are huge. Recruiting adequate numbers of patients willing to agree to randomization
will be difficult. Another complex issue is whether patients willing to agree
to such a randomization are generalizable.30
The only randomized trial comparing epilepsy surgery to medical therapy was
recently completed in Ontario, Canada,31 but
randomization was accommodated via an existing 1-year waiting list for epilepsy
surgical evaluations, and the study did not address the issue of early surgical
intervention. The proposed US trial will not be able to rely on a long waiting
list to make randomization more attractive to potential study subjects. If
randomized trials are not practical, other study designs such as cohort studies
(retrospective or prospective) should be considered to answer questions regarding
early surgery.
PREDICTING OUTCOME IN CHILDHOOD EPILEPSY
Because of the uniquely complicated issues surrounding prognosis in
childhood epilepsy, several cohort studies have attempted to identify predictors
of outcome for childhood epilepsy, although not necessarily with an eye on
early surgery. One study looked at predictors of remission, and 3 studies
examined predictors of intractability. A population study of 504 patients
in Nova Scotia found that age younger than 12 years at onset, normal intelligence,
no prior neonatal seizures, and fewer than 21 seizures before treatment were
"reasonably accurate" predictors of remission.32
A population study of 178 patients in Finland found that poor short-term outcome
of AED therapy, occurrence of status epilepticus, high initial seizure frequency,
and remote cause were independent predictors of intractability.33
A hospital-based study of 172 patients in the United States found a history
of infantile spasms, early age of onset, remote symptomatic cause, and history
of status epilepticus were independent predictors of intractability.34 Lastly, a hospital-based study of 466 children in
the Netherlands developed a regression model to predict outcome in newly diagnosed
epilepsy. Variables such as number of seizures prior to treatment, seizure
type, cause, and initial response to therapy were used in the model. The predictive
model was correct in 66% of children in whom a "poor" outcome was predicted
and 79% of children in whom a "not poor" outcome was predicted. Sensitivity
of the model was only 47% and specificity 89%.35
It is important to note that none of these studies were "syndrome specific"
and thus were limited by the great heterogeneity of childhood epilepsy.
SYNDROME-SPECIFIC CLINICAL PREDICTION MODELS
A potential solution to the unanswered questions regarding optimal timing
of epilepsy surgery lies in the development of clinical prediction models
tailored to specific epilepsy syndromes. A clinical prediction model36, 37, 38 is a decision-making
tool that includes a set of variables obtained from the history, physical
examination, or simple diagnostic tests and provides the probability of an
outcome or suggests a diagnostic or therapeutic course of action.37 Predictor variables must be well specified, clinically
appropriate, reliably measured between observers, reproducible between centers,
and dependably available via medical record review; outcomes must be clearly
defined and clinically important. Prediction models have been developed for
several acute and chronic medical conditions, such as myocardial infarction,
pneumonia, meningitis, chronic renal disease, lymphoma, and prostate cancer.37, 38 Prediction models are usually constructed
using retrospective cohort data and then subsequently validated in a prospective
cohort study.
A clinical prediction model designed to predict outcome in patients
with TLE could include variables such as age of epilepsy onset, presence of
early risk factors for epilepsy (such as a history of febrile seizures, central
nervous infection, or serious head trauma), MRI results, family history of
epilepsy, and response to the initial AED trial. Other variables such as suspected
cause of epilepsy, number of seizures prior to treatment, presence of developmental
delay or mental retardation, abnormalities in the neurological examination,
and EEG findings could also be included if the information is available, accurate,
and reproducible between examiners and centers. A reasonable outcome variable
could be as simple as a dichotomous seizure frequency classification (seizure
free: yes/no), a continuous variable such as number of seizures per month,
or a score on a health-related quality of life instrument. For models initially
developed using retrospective data, the available data in the medical records
may limit the choice of the outcome variable to a dichotomous seizure frequency
classification.
At The Children's Hospital of Philadelphia, we are constructing a clinical
prediction model designed for the early identification of children with TLE
destined to have refractory seizures at 2 years after epilepsy onset. The
accuracy of a 2-year outcome in identifying longer-term outcomes will also
be examined. Preliminary data39 have suggested
that the presence of an early risk factor for epilepsy or a temporal lobe
MRI abnormality is linked to a poor response to initial AED trials, with only
16% of children becoming seizure free. Conversely, absence of early risk factors
and normal findings on MRI scan were linked to a better outcome, with 62%
of children becoming seizure free. These and other variables are being studied
to identify accurate predictors of outcome at 2 years after epilepsy onset.
If the 2-year outcome can be predicted early, and if the 2-year outcome reflects
the longer-term outcome, then perhaps temporal lobectomy could be considered
even earlier than 2 years after epilepsy onset in some patients.
Prediction models can be evaluated like diagnostic tests, using sensitivity,
specificity, positive predictive value (PPV), and negative predictive value
(NPV). For example, the PPV of a model to identify patients destined to develop
refractory TLE is the percentage of patients predicted to develop refractory
TLE who actually do so (PPV = true positives/[true positives + false positives]).
In contrast, the NPV is the percentage of patients predicted to be seizure
free who actually are (NPV = true negatives/[true negatives + false negatives]).
Clearly, any prediction model with the intent of identifying candidates for
epilepsy surgery must have a high PPV (ie, very few false positives) so that
patients are not unnecessarily subjected to surgery.
Another considerable challenge in the construction of a prediction model
is the inclusion of patients with an appropriate mixture of disease severity.
Models constructed based on data from epilepsy surgery referral centers will
clearly be biased toward patients with poor outcomes and thus will have limited
generalizability. It is easy to imagine an epilepsy surgery referral center
constructing a model which demonstrates that the presence of a temporal lobe
lesion on MRI scan and failure of the first AED trial predicts a poor outcome
with a very high PPV. Of course, missing from such a study are an unknown
number of patients with abnormalities on MRI and first AED trial failures
who became seizure free while receiving alternative AED therapy and thus were
never referred to the tertiary care center. Multicenter data from epilepsy
surgery centers would not address this potentially serious bias.
As challenging as it is to obtain, there is no substitute for population-based
data in the study of epilepsy prognosis. As epilepsy surgery (especially temporal
lobectomy) becomes more readily available, investigators who promulgate treatment
recommendations must work diligently to ensure that recommendations generated
at tertiary care centers are generalizable to the broader population. The
effectiveness of epilepsy surgery is clear, but challenging work remains to
be done to clarify and optimize the timing of epilepsy surgery, especially
in children and adolescents.
AUTHOR INFORMATION
Accepted for publication June 7, 2001.
From the Pediatric Regional Epilepsy Program, Division of Neurology,
The Children's Hospital of Philadelphia, University of Pennsylvania School
of Medicine.
Corresponding author: Dennis J. Dlugos, MD, Division of Neurology,
The Children's Hospital of Philadelphia, 6th Floor, Wood Building, 34th Street
and Civic Center Boulevard, Philadelphia, PA 19014 (e-mail: dlugos{at}email.chop.edu).
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