Advances in epilepsy: new perspectives on new-onset epilepsy, comorbidities, and pharmacotherapy.

Abstract

The purpose of this brief article is to review old concepts of the significance of acute symptomatic seizures, the impact of psychiatric comorbidities on the response of pharmacologic and surgical treatments of the seizure disorder, and the importance of factoring comorbid medical comorbidities into the choice of antiepileptic drugs (AEDs). In addition, this article provides an update on the latest data on the teratogenic effects of AEDs and reviews the most relevant results of a recent practice guideline on pregnancy issues in women with epilepsy. The article closes with a review of the latest advances in the therapeutic effects of first- and second-generation AEDs.

Full text

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Advances in epilepsy: new perspectives on new-onset epilepsy,
comorbidities, and pharmacotherapy
Andres M Kanner
Addresses: Rush Medical College at Rush University; Laboratory of Electroencephalography and Video-EEG-Telemetry; and Section of Epilepsy and
Rush Epilepsy Center, Rush University Medical Center, 1653 West Congress Parkway, Chicago, IL 60612, USA
Email: akanner@rush.edu
F1000 Medicine Reports 2010, 2:51 (doi:10.3410/M2-51)
The electronic version of this article is the complete one and can be found at: http://f1000.com/reports/medicine/content/2/51
Abstract
The purpose of this brief article is to review old concepts of the significance of acute symptomatic
seizures, the impact of psychiatric comorbidities on the response of pharmacologic and surgical
treatments of the seizure disorder, and the importance of factoring comorbid medical comorbidities
into the choice of antiepileptic drugs (AEDs). In addition, this article provides an update on the latest
data on the teratogenic effects of AEDs and reviews the most relevant results of a recent practice
guideline on pregnancy issues in women with epilepsy. The article closes with a review of the latest
advances in the therapeutic effects of first- and second-generation AEDs.
Introduction and context
The approach to the evaluation and management of
epilepsy has continued to evolve in the last two years.
The purpose of this article is to highlight some of the
more relevant advances with respect to the significance of
a first seizure, the need to incorporate medical and
psychiatric comorbidities, and advances in first- and
second-generation antiepileptic drugs (AEDs).
Recent advances
Reassessing old assumptions
a) The good and bad news of a first acute symptomatic seizure
In 2005, Fisher and colleagues [1] suggested a redefini-
tion of epilepsy as having experienced at least one
seizure associated with an enduring alteration of the
brain that increases the likelihood of future seizures
and neurobiologic, cognitive, and social disturbances.
Four years later, Hesdorffer et al. [2] questioned the
significance of a first acute symptomatic seizure in a
study that compared the mortality and risk of seizure
recurrence between 262 patients with acute sympto-
matic seizures caused by acute stroke, central nervous
system (CNS) infection, or trauma and 148 patients
with a first unprovoked seizure caused by static brain
lesions. While patients with acute symptomatic seizures
had an almost ninefold higher risk of dying within the
first 30 days after the seizure, they were 80% less likely
to have subsequent unprovoked seizures over the
following 10 years compared with patients with a first
unprovoked seizure.
b) Are cognitive deficits identified in patients with epilepsy
the result of recurrent seizures?
The long-held belief that cognitive deterioration in
patients with idiopathic/cryptogenic epilepsy is a con-
sequence of recurrent seizures was revised in a recent
population-based study of 155 newly diagnosed epi-
lepsy patients in whom no CNS pathology could be
identified. All patients underwent a neuropsychological
evaluation before the start of AED therapy. Compared
with 87 healthy volunteers from the general population
who were matched for age and sex, patients with
epilepsy (PWEs) performed significantly worse than
healthy volunteers on 6 of 14 cognitive measures after
adjustments for age, sex, and education. Of note,
cognitive performance was not related to the number
of seizures, type of epilepsy, or mood [3]. Thus, this
study suggests that cognitive deficits in many patients
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with idiopathic/cryptogenic epilepsy are related to the
CNS disturbances that resulted in the seizure disorder.
Reassessing the significance of comorbidities:
the treatment of epilepsy is not restricted to
the remission of seizures
In the last decade, epileptologists have recognized the
importance of recognizing and managing comorbid
medical and psychiatric disorders. Publications in the
last two years reflect the increased interest in these
problems.
a) Psychiatric comorbidities
Recent population-based studies have identified a high
lifetime prevalence of depressive and anxiety disorders of
up to 35% [4]. The negative impact of comorbid mood
disorders on the quality of life in PWEs had already been
recognized by several independent investigators in the
last decade. In the last two years, the negative impact of
comorbid mood disorders on the suicidal risk of PWEs
has been recognized. In a population-based study,
Christensen et al. [5] demonstrated that the risk to
achieve completed suicide increases by 32-fold in the
presence of comorbid mood disorder compared with a
twofold increased risk in the absence of any psychiatric
comorbidity.
The negative impact of comorbid mood disorders on the
response of pharmacologic and surgical treatment of
seizures was reported in two recent studies. Hitiris et al.
[6] found that a history of depression preceding the
onset of epilepsy increased the risk of pharmaco-resistant
epilepsy by twofold, and Kanner et al. [7] found that a
lifetime history of depression was an independent
predictor against achieving seizure freedom following
an antero-temporal lobectomy.
Yet despite the relatively high prevalence of mood
disorders in PWEs and the significant negative impact
on their lives, no randomized controlled study had been
conducted on its treatment in the last 30 years until
recently, when Gilliam and colleagues [8] conducted a
randomized controlled study comparing the efficacy of
sertraline (up to 200 mg/day) and cognitive behavior
therapy in the treatment of major depressive episodes in
140 consecutive patients. The results presented at the
2009 annual meeting of the American Academy of
Neurology (AAN) revealed symptom remission in 60%
of patients randomly assigned to each treatment arm.
Furthermore, patients assigned to sertraline did not have
a worsening of seizures. Thus, these data demonstrate the
efficacy of these two treatment modalities, which are
comparable to those seen in people with primary major
depressive episodes.
InJanuary of2008, the US Foodand Drug Administration
(FDA) issued an alert regarding the association between
suicidality (defined as suicidal ideation, behavior, and
completed suicides) and AEDs [9]. The alert was based on
results of a meta-analysis that included data from 199
randomized clinical trials of 11 AEDs (carbamazepine,
felbamate, gabapentin, lamotrigine, levetiracetam, oxcar-
bazepine, pregabalin, tiagabine, topiramate, valproate,
and zonisamide). Suicidality occurred in 4.3 per 1000
patients treated withAEDsin the active arm and in 2.2per
1000 patients in the comparison arm. Of all of the
suicidality reported, suicidal ideation accounted for
67.6%, preparatory acts for 2.8%, attempts for 26.8%,
and completed suicide for 2.8%. AEDs were found to be
associated with a greater risk for suicidality with epilepsy
(odds ratio [OR] 3.53, 95% confidence interval [CI] 1.28-
12.10) than with psychiatric disorders (OR 1.51, 95%
CI 0.95-2.45) or other disorders (OR 1.87; 95% CI 0.81-
4.76). The FDA concluded that there was a statistically
significant 1.80-fold increased risk of suicidality with
exposure toAEDs. Since its publication, this meta-analysis
has been viewed as a source of great controversy and the
validity of its results has been questioned by professional
societies, including the American Epilepsy Society and the
AmericanNeurologicAssociation.Infact,adetailedreview
of the data of this meta-analysis demonstrated several
seriousmethodologicalproblems[10].Theseincludedthe
following: (a) The assessment of suicidality was based on
‘spontaneous’reportsofpatientsandwasnotgatheredina
systematic prospective manner. (b) The FDA associated
the increased risk of suicide with all AEDs, despite the fact
that statistical significance was found in only 2 (i.e.,
topiramate and lamotrigine) of the 11 AEDs studied.
Furthermore, inclusion of three additional studies of
lamotrigine resulted in the loss of statistical significance
for this AED. Two other AEDs, valproic acid and
carbamazepine, actually yielded a ‘small protective effect’.
The FDA’s decision to present the risk as involving all
AEDs stemmed from a concern that singling out specific
AEDs might only change prescribing practices rather than
emphasize the suicide risk. (c) Most epilepsy trials (92%)
included patients on adjunctive therapy (compared with
14% of psychiatric trials and 15% of other medical trials).
It is unclear whether the higher suicidality rates in the
epilepsytrialswereduetodruginteractions,giventhehigh
proportionofepilepsytrialsdesignedwithpolytherapy,or
whether they potentially were due to the low suicidality
risk associated with carbamazepine and valproate – both
drugs were protective for suicidality and were the most
common comparison drugs in these trials. (d) Suicidal
behavior was greater in certain geographic regions. For
example, the ORs of suicidality were 1.38 (95% CI
0.9-2.13) in North American studies and 4.53 (95% CI
1.86-13.18) in studies conducted elsewhere.
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While there is no question that several AEDs can cause
psychiatric adverse events, including suicidal ideation
and behavior, the FDA’s conclusions must be interpreted
with great caution at this time. Only a study in which
suicidality data are collected in a systematic and
prospective manner can help determine whether a
specific AED increases or decreases the risk. Yet because
the FDA has decided to insert suicide warnings in the
package inserts of all AEDs, these data cannot be
disregarded; thus, physicians will need to identify
patients with increased risks of suicide.
b) Medical comorbidities
Because they may have a negative impact, comorbid
medical conditions must be considered in the choice of
AEDs. For example, in 34 PWEs taking two of the most
frequently prescribed enzyme-inducing AEDs (pheny-
toin and carbamazepine), hyperlipidemia and high
C-reactive protein decreased significantly when switched
to AEDs without enzyme-inducing properties (lamotri-
gine and levetiracetam) [11].
Osteoporosis and osteopenia have been recognized for a
long time in patients treated with enzyme-inducing
AEDs. A recent study, however, shows that significant
decrease in bone mineral density can be identified after
only 1 year of therapy. In a study of 93 premenopausal
women who had been taking phenytoin monotherapy
for 1 year, a significant decrease in bone mineral density
in the head of the femur was found in women treated
with phenytoin, but not in those on carbamazepine or
lamotrigine [12]. Thus, while enzyme-inducing AEDs are
the most widely prescribed drugs in the treatment of
epilepsy, they should be used with great caution and
avoided in patients at risk for cardiovascular disease and
osteoporosis.
c) Pregnancy in women with epilepsy
Teratogenic impact of antiepileptic drugs
Teratogenic effects of valproic acid have been recognized
for the last 10 years. However, this AED can negatively
affect the cognitive development of children exposed to
it in utero. In a recent study, Meador et al. [13]
demonstrated that children exposed to valproic acid in
utero had significantly lower IQ scores at 3 years of age
than those who had been exposed to phenytoin,
carbamazepine, and lamotrigine. Of note, in a practice
guideline on pregnancy in women with epilepsy, the
AAN recommended that AED serum concentrations be
monitored (see below) [14].
Contradictory data on the risk of lamotrigine to cause
cleft lip or cleft palate by two different pregnancy
registries were published in 2008. While neither registry
found an overall risk of major malformations, the North
American AED Pregnancy Registry found that an
increased risk of orofacial clefts was 11.2-fold higher
compared with their control group of 221,746 unex-
posed infants born at a Boston hospital [15]. On the
other hand, the EUROCAT (European Registration of
Congenital Anomalies) registry, which is a population-
based case control study that includes over one-quarter
of births in Europe, did not find an increased risk of
orofacial clefts for children exposed to lamotrigine
monotherapy. Thus, this problem remains unsolved at
this time [16].
In a practice guideline on the use of AEDs in pregnant
women with epilepsy, the AAN made the following
suggestions: (a) monotherapy should be used whenever
possible, and any reductions of AED doses or conversion
to monotherapy should be carried out before pregnancy.
(b) Lowest doses should be used whenever possible,
allowing for non-disabling simple partial seizures.
(c) Avoid phenobarbital and valproic acid as much as
possible [17].
By the same token, the AAN guidelines put into question
the following long-held beliefs: (a) There is possibly a
modestly increased risk of delivery by cesarean section
and probably no substantially increased risk of late
pregnancy bleeding. (b) There is probably no moderately
increased risk of premature labor and delivery except for
women who smoke [17].
Pharmacokinetic changes of antiepileptic drugs
during pregnancy
The clearance of lamotrigine and levetiracetam, particu-
larly that of lamotrigine, which doubles by the end of the
third trimester, has been found to increase during the
course of pregnancy [18,19]. Accordingly, monthly
serum concentrations need to be obtained and doses
adjusted to prevent a drop in their serum concentration
from resulting in breakthrough seizures.
What’s new about the efficacy of old antiepileptic drugs?
The use ofethosuximide, valproic acid,and lamotriginein
childhood absence epilepsy had been taken for granted,
but no head-to-head comparison had ever been con-
ducted. Glauser et al. [20] recently reported the results of a
National Institutes of Health-sponsored multicenter
randomized double-blind trial in 453 children with
childhood absence epilepsy. After 4 months of treatment,
53% and 58% of the children randomly assigned to
ethosuximide and valproic acid, respectively, remained
seizure-free compared with only 29% of children
randomlyassignedtolamotrigine[20].However,children
randomly assigned to valproic acid experienced a greater
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number of adverse events, suggesting that ethosuximide
appears to be the drug of choice. This observation,
however, is restricted to children who have not had
generalizedtonic-clonicseizuresasethosuximidedoesnot
have a therapeutic effect in these seizures.
What’s new about the efficacy of second-generation
antiepileptic drugs?
In a double-blind placebo-controlled study, levetirace-
tam monotherapy was found to be effective in juvenile
myoclonic epilepsy [21]. In addition, in a double-blind
multicenter randomized study, levetiracetam and
controlled-release carbamazepine in monotherapy were
found to be equally effective in the treatment of new-
onset partial or primary generalized tonic-clonic seizures;
furthermore, more than 90% of responders remained
seizure-free at low daily doses (400 mg/day of carbama-
zepine and 1000 mg/day of levetiracetam) [22].
In a large population-based study (Standard and New
Antiepileptic Drugs, or SANAD), the efficacies of
lamotrigine, topiramate, oxcarbazepine, gabapentin,
and carbamazepine were compared in the treatment of
new-onset partial epilepsy; lamotrigine was considered
to be significantly better than carbamazepine, gabapen-
tin, and topiramate and had a non-significant advantage
compared with oxcarbazepine. The authors concluded
that ‘lamotrigine is clinically better than carbamazepine,
the standard drug treatment, for time to treatment failure
outcomes and is therefore a cost-effective alternative for
patients diagnosed with partial-onset seizures’ [23].
In a separate study, valproic acid, topiramate, and
lamotrigine were compared in the treatment of new-
onset idiopathic generalized epilepsy. Valproic acid and
topiramate yielded comparable efficacies, which were
superior to that of lamotrigine but valproic acid was
better tolerated than topiramate. The authors concluded
that ‘valproic acid should remain the drug of first choice
for many patients with generalized and unclassified
epilepsies. However, because of known potential adverse
effects of valproate during pregnancy, the benefits for
seizure control in women of childbearing years should
be considered’ [24].
Implications for clinical practice
This article focuses on revised old concepts of epilepsy
and established treatments as these are very relevant to
the general neurologist and clinician who treats PWEs.
A separate article is necessary to review the third
generation of AEDs that have become available as well
as non-pharmacologic therapies, including deep brain
stimulation of thalamic nuclei and responsive
neurostimulation systems, as well as the role of new
diagnostic modalities used in the presurgical evaluation
of patients with pharmaco-resistant epilepsy.
To summarize, in terms of reassessing old assumptions,
there is now evidence to suggest that acute symptomatic
seizures should not always be considered an expression
of epilepsy and that cognitive deficits in many patients
with idiopathic/cryptogenic epilepsy are related to the
CNS disturbances that resulted in the seizure disorder.
When the significance of comorbidities is reassessed,
psychiatric and medical conditions must always be
considered in the choice of AEDs as they may have a
negative impact. Enzyme-inducing AEDs should be
avoided as much as possible in patients at risk for
cardiovascular disease and osteoporosis, whereas lipid
profiles should be obtained in patients taking these
AEDs. Furthermore, when these AEDs are used, calcium
and vitamin D supplements should be recommended to
minimize the risk of osteopenia and osteoporosis, which
should be monitored every year with DEXA (dual-energy
X-ray absorptiometry) scans.
In pregnant women with epilepsy, new guidelines
published by the AAN and the American Epilepsy Society
have recommended that AED serum concentrations be
monitored; in addition, monotherapy should be used
whenever possible and any reductions of AED doses or
conversion to monotherapy should be carried out before
pregnancy. Furthermore, low doses should be used
whenever possible, allowing for non-disabling simple
partial seizures. Finally, phenobarbital and valproic acid
should be avoided as much as possible.
Among the second-generation AEDs, studies have shown
that lamotrigine is a cost-effective alternative for patients
diagnosed with partial-onset seizures [21], whereas levetir-
acetamcanbeagoodalternativefornew-onsetgeneralized
tonic-clonic seizures and juvenile myoclonic epilepsy.
One recent study looking into old AEDs suggests that
ethosuximide is the drug of choice for the treatment of
childhood absence epilepsy; however, other options
should be considered in children who also experience
generalized tonic-clonic seizures as ethosuximide does
prevent their occurrence. In addition, valproic acid
remains the drug of first choice for men with idiopathic
generalized epilepsies.
Abbreviations
AAN, American Academy of Neurology; AED, antiepi-
leptic drug; CI, confidence interval; CNS, central nervous
system; FDA, US Food and Drug Administration; OR,
odds ratio; PWE, patient with epilepsy.
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Competing interests
The author has received research grants from Novartis,
GlaxoSmithKline and Pfizer.
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