Evaluation and Management of Drug-Resistant Epilepsy

13.07.
2015 Evaluation and management of drugresistant epilepsy
Official reprint from UpToDate®
www.uptodate.com ©2015 UpToDate®
Evaluation and management of drugresistant epilepsy
Author Section Editor Deputy Editor

Joseph I Sirven, MD Timothy A Pedley, MD April F Eichler, MD, MPH
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jun 2015. | This topic last updated: Mar 17, 2015.
INTRODUCTION — Patients with epilepsy whose seizures do not successfully respond to antiepileptic drug
(AED) therapy are considered to have drugresistant epilepsy (DRE). This condition is also referred to as
intractable, medically refractory, or pharmacoresistant epilepsy. As many as 20 to 40 percent of patients with
epilepsy (roughly 400,000 Americans) are likely to have refractory epilepsy. The annual cost for patients with
epilepsy in the United States is estimated to be approximately 12.5 billion dollars (based on a 1995 survey);
DRE contributes a substantive proportion of this cost [1,2]. People with DRE have the greatest burden of
epilepsyrelated disabilities, further contributing to the scope of this problem.
Because of the need to individualize therapy, no rigid set of guidelines can be applied to determine medical
intractability, however, populationbased studies have provided information regarding the prognosis of DRE that
are helpful in making treatment decisions. Resective surgical therapy for epilepsy has the potential to eliminate
seizures in many patients with localizationrelated DRE.
This topic discusses the evaluation and approach to the management of individuals with DRE. Other issues
regarding the evaluation and treatment of individuals with seizures and epilepsy are presented separately. (See
"Overview of the management of epilepsy in adults" and "Evaluation of the first seizure in adults" and "Initial
treatment of epilepsy in adults" and "Surgical treatment of epilepsy in adults" and "Vagus nerve stimulation
therapy for the treatment of epilepsy".)
DEFINITION — Traditionally, therapeutic failure of three antiepileptic drugs (AEDs) defined intractability [311].
With many new AEDs available in recent years, it might have been expected that more, rather than fewer, drug
trials would be recommended before determining intractability. However, several prospective case series have
shown that a high likelihood of medical intractability can be identified after two unsuccessful trials, as with
each AED failure, the likelihood of successful treatment with other drugs diminishes [513]. As an example, in
one study, 1098 adolescent and adult patients with a diagnosis of epilepsy were started de novo on AED
treatment and followed up to 25 years (median of 7.5 years). With the first drug trial, 49 percent became
seizurefree. A second medication trial produced remission in an additional 13 percent, while only a further 4
percent became seizurefree on a third medication regimen [13]. In this cohort, these patterns of AED
responsiveness largely persisted over time.
A task force of the International League against Epilepsy proposed that drugresistant be defined as the failure
of adequate trials of two tolerated, appropriately chosen and administered antiepileptic drugs (whether as
monotherapy or in combination) to achieve seizure freedom [12]. They also recommended replacing the term
“intractable” with “drugresistant” epilepsy (DRE).
Some patients who meet this definition of DRE subsequently achieve prolonged (12 months or more) periods of
seizure remission [14,15]. However, the risk of seizure relapse in these individuals remains high, greater than
70 percent in one series.
Frequency and severity of seizures are less commonly included in a definition of DRE [4,16]. These can vary
among individuals with DRE and are important considerations when weighing treatment options. Similarly, it is
important to understand the impact of seizures in the context of the individual's life, job, and other psychosocial
circumstances [17]. Even infrequent seizures can have a large impact.
Less often considered, but also important, is the burden of adverse effects of AEDs that a patient experiences.
If seizures can be controlled but only at medication doses that produce disabling side effects, then it may also
be reasonable to consider that such a person has DRE.
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13.07.2015 Evaluation and management of drugresistant epilepsy
EPIDEMIOLOGY — Because of unstandardized definitions as well as misdiagnoses, the incidence and
prevalence of DRE are somewhat uncertain [18]. Estimates of the proportion of epilepsy cases that are or
become medically resistant vary between 20 and 40 percent [3,11,1922].
Risk factors — A number of prospective studies have attempted to identify factors that predict the risk of
DRE. These studies have varied somewhat in their sampling (populationbased versus hospitalbased) and
whether they included children, adults, or both [5]. No single factor has been found to be uniquely useful in
making accurate predictions. A combination of one or several of these factors may help to define those who
are not likely to respond to medical treatment. [23]
● The response to the first AED trial is the most important and consistently cited predictive factor among
both populationbased and hospitalbased studies and in both adult and pediatric populations [5,6,13,23
26]. While more than half of patients respond to the first AED prescribed, less than 20 percent are likely
to respond to subsequent drug trials. AED failure due to lack of efficacy is a stronger predictor of DRE
than failure due to intolerance or side effects [11]. With each number of failed AED trials, the risk of DRE
increases [11,25,2729].
● A high number of seizures prior to diagnosis and treatment is another consistently identified risk factor for
DRE [57,11,19,23,24,3035].
● The underlying etiology and seizure classification are also important. Idiopathic syndromes, for both
generalized and localizationrelated epilepsy, have a better prognosis than symptomatic/cryptogenic
epilepsy in both pediatric and adult populations [7,11,13,15,19,24,28,30,3640].
Certain pediatric epilepsy syndromes are almost invariably medically intractable. These include early
(neonatal) myoclonic encephalopathy, early infantile epileptic encephalopathy, Lennox Gastaut syndrome,
and Rasmussen encephalitis among others.
Nonidiopathic localizationrelated epilepsy underlies more than half of the cases of DRE in adults [7].
Among the localizationrelated epilepsies, those associated with vascular lesions may be more treatment
responsive than those with mesial temporal sclerosis (MTS), cortical dysgenesis, or dual pathology
[6,23,3638,41]. Individuals with MTS have some of the highest rates of medical intractability, 40 to 80
percent [3,6,8,37].
● Other findings more variably associated with the risk of DRE include a presentation with status
epilepticus [7,24,27,36,39], a longer duration of epilepsy [28,30], a family history of epilepsy [11,19,32], a
history of febrile convulsions [32], and abnormal EEG findings [7,11,23]. An abnormal neurologic
examination and/or developmental delay are also identified as risk factors for DRE in some studies
[19,27,31,36].
● Some studies, but not all, suggest that age at presentation may be a factor in the development of DRE
[6,11,23,27,35,36]. Some pediatric studies have found that seizure onset in later childhood or
adolescence appears to be more likely to be associated with DRE than seizures with onset between the
ages of 5 and 10 years [7,31,39]. Onset in the neonatal time period has been associated with DRE in at
least one series [31]. Individuals who develop epilepsy later in life (>65 years) appear to be less likely to
develop DRE than younger adults [22,42]. The varying risk of DRE by age group likely relates to the
underlying pathogenesis of epilepsy that also varies by age.
The studies cited above have generally been performed in studies examining a patient's response to initial AED
trials. However, a smaller percentage of patients with epilepsy enter remission early in their course and
develop DRE later, after a period of remission that in some cases is a long as several years [9,22]. Factors
that predict a later development of DRE are not well defined. However, this phenomenon of delayed
intractability is most commonly described in the setting of mesial temporal sclerosis. (See 'Pathogenesis'
below.)
PATHOGENESIS — It is uncertain why seizures are or become medically resistant in any given individual.
Medical intractability may be a feature of epilepsy at the time of presentation or may evolve over time.
Prospective studies with a long duration of followup suggest that 70 to 80 percent of patients retain their
status as intractable versus in remission [4,9,19,22,24,34,40,4345]. This means that a minority of patients
with apparent DRE are subsequently able to achieve remission and also that some patients whose seizures
are initially controlled will later relapse. In the latter group, medical control can be regained with subsequent
drug trials in some patients, while in others, medical intractability is then permanent [40,4648]. These different
clinical courses may represent different mechanisms of medical intractability or pharmacoresistance.
A delayed development of intractability is most often described with epilepsy onset in childhood, particularly
with epilepsy associated with mesial temporal sclerosis (MTS) [9,40,49,50]. Accumulating evidence suggests
that in some individuals, MTS is a progressive condition. Pathologic studies demonstrate an evolving process
involving glial proliferation and dendritic sprouting with synaptic reorganization [11,51]. Longitudinal
neuroimaging studies also support a progressive process [35,52]. Alterations in neural circuitry conceivably
may lead to an epileptic network that becomes drug resistant over time [53]. (See "Localizationrelated (focal)
epilepsy: Causes and clinical features" and "Pathophysiology of seizures and epilepsy", section on
'Consequences of repeated seizures'.)
Studies in animal models comparing drugresistant and drugsensitive temporal lobe epilepsy have found that
the former is associated with altered expression of multidrug transporters, altered expression of AED targets,
as well as morphologic alterations in the hippocampus [29]. Similarly in humans, one study used invivo
positron emission tomograph (PET) with the Pglycoprotein substrate (R)[11C] verapamil to demonstrate
increased Pglycoprotein activity in various brain regions in 16 patients with drug resistant temporal lobe
epilepsy compared with health controls and patients with wellcontrolled epilepsy [54]. Distinguishing which of
these findings is the cause versus the effect of intractable epilepsy, and whether they have clinical relevance
in humans, are the subjects of ongoing investigations. As an example, one study found an association with a
polymorphism in the drug transporter gene (ABCB1 or MDR1) and drugresistant epilepsy [55], although this
was not corroborated in followup studies [5658].
An alternative hypothesis is that overexpression of these multidrug transporters is induced by recurrent
seizures, potentially providing an impetus for early aggressive seizure treatment [29,59]. Other alterations,
acquired or inherited, of AED absorption, metabolism, receptorbinding, and blood brain barrier permeability are
also potential causes of pharmacoresistance [60,61].
COMPLICATIONS OF INTRACTABLE EPILEPSY — Individuals with DRE have an increased mortality rate,
estimated at 1.37 per 100 personyears [26,6264]. The standardized mortality ratio for patients with recurrent
seizures is 4.69 [63]. Individuals who become seizure free have no increased mortality [65]. Some deaths are
related to the underlying cause of epilepsy (eg, cerebral neoplasm, neurodegenerative disease); other deaths
are directly seizurerelated, such as those that occur in the context of status epilepticus and in seizurerelated
accidents. Sudden unexplained death in epilepsy patients (SUDEP) is 40 times more likely among patients
who continue to have seizures than in those who are seizure free [62]. (See "Sudden unexpected death in
epilepsy" and "Overview of the management of epilepsy in adults", section on 'Mortality'.)
Nonfatal injuries are also common in those with DRE. These include head injury, burns, and fractures, among
others; most are seizurerelated [66].
DRE is also associated with disability and diminished quality of life [8,11,67]. Examples include poor academic
achievement, unemployment, and social isolation. Most patients with DRE cannot drive. In one community
based survey of people with epilepsy, those with selfreported incomplete seizure control were more likely to
express concerns about the feelings of fear, their quality of life, work, adverse effects of therapy, and the
stigma associated with their condition, even when their seizures were relatively infrequent [68]. These
complications of DRE result from the combined effects of recurrent seizures, AED toxicity, comorbid
depression, as well as psychosocial factors such as excessive dependency [8,11,67]. (See "Overview of the
management of epilepsy in adults", section on 'Psychosocial issues'.)
DIFFERENTIAL DIAGNOSIS — When a patient's seizures do not appear to respond to AED therapy, the
clinician should reconsider the seizure classification and the appropriateness of the AED regimens that have
been employed. Clinicians should also reconsider the diagnosis of epilepsy. Misdiagnosis is common; in one
series, as many as 26 percent of individuals thought to have DRE were incorrectly diagnosed most often as a
result of incomplete historytaking and/or EEG misinterpretation [69].
Apparent intractability — It is important to differentiate true versus apparent medical intractability. Reasons
for apparent treatment failure that do not reflect intractability include:
● An incorrect diagnosis of seizure classification leading to incorrect drug choice. It is not uncommon for
idiopathic generalized epilepsy syndromes to be unrecognized and inappropriately treated with AEDs that
are more appropriate to localizationrelated epilepsy (table 1) [3]. In some instances, a narrowspectrum
AED can worsen seizure frequency in individuals with generalized epilepsy. One example is when
carbamazepine is prescribed for juvenile myoclonic epilepsy [6971].
● Inappropriate dose. In other cases, inadequate dosing or frequency of AED dosing has led to apparent
intractability [69]. In contrast, seizures can also occur with AED toxicity. This has been described in rare
cases in association with phenytoin, carbamazepine, tiagabine, and valproate [71].
● Noncompliance. Compliance with AED is frequently imperfect. In one case series, 71 percent of patients
reported at least occasional dose omissions, and 45 percent reported a seizure after a missed dose [72].
Providing a nonjudgmental setting in which to elicit this history is important. Support from family members
and physicians increases medical compliance [3,73,74]. (See "Overview of the management of epilepsy
in adults", section on 'Nonadherence with AED therapy'.)
● Lifestyle factors. Examples of lifestyle factors that can increase seizure frequency include recreational
drug or alcohol abuse and sleep deprivation [3,32,74].
Psychogenic nonepileptic seizures — Psychogenic nonepileptic seizure (PNES) can mimic epileptic
seizures. In contrast to epileptic seizures, PNES are not associated with physiological central nervous system
dysfunction but are instead psychogenically determined. PNES typically do not respond to AED therapy. While
not without limitations, videoEEG monitoring is the gold standard test for the diagnosis of PNES.
Among patients referred to epilepsy monitoring units for apparent IE, 25 to 40 percent are diagnosed with
PNES [75,76]. The clinical features, diagnosis, and treatment of PNES are discussed separately. (See
"Psychogenic nonepileptic seizures".)
Other nonepileptic paroxysmal disorders — In addition to PNES, other nonepileptic paroxysmal events,
especially syncope but also certain sleep and movement disorders, can be mistaken for epilepsy (table 2)
[69,77]. (See "Nonepileptic paroxysmal disorders in adolescents and adults".)
EVALUATION — Patients with DRE should have further testing to confirm the diagnosis of epilepsy and also
to better define the epilepsy syndrome and underlying classification in order to best direct treatment [17,78]. In
most cases, the evaluation of DRE will include videoEEG monitoring and magnetic resonance imaging [74].
Video EEG monitoring — Inpatient videoEEG monitoring combines both a video and EEG recording of
clinical events. This test is used primarily to determine whether epilepsy is the cause of recurrent seizurelike
events. In some series, more than 25 percent of individuals referred for monitoring for refractory epilepsy are
found to have nonepileptic events, usually psychogenic nonepileptic seizures [69]. EEG monitoring can also
aid in seizure classification and is used for presurgical evaluation of epilepsy patients. (See "Video and
ambulatory EEG monitoring in the diagnosis of seizures and epilepsy".)
Neuroimaging — By the time a patient is considered to have IE, a magnetic resonance imaging (MRI) study
will usually have been performed. In many cases, this should be repeated, particularly if the original study was
unrevealing. In some cases, followup MRI reveals an etiology for epilepsy (such as cerebral neoplasm,
autoimmune encephalitis) that was not seen on the initial study and requires specific therapies in addition to
AEDs [79]. The sensitivity of MRI for an underlying cause of epilepsy (socalled lesional epilepsy) can be
substantially improved by using an epilepsy protocol; these are not routinely used outside of subspecialty
epilepsy centers. (See "Neuroimaging in the evaluation of seizures and epilepsy", section on 'Sensitivity'.)
Not all MRI findings are relevant; isolated findings of diffuse atrophy, punctate foci of T2 signal abnormalities in
the white matter, and other nonspecific findings are not known to be epileptogenic. MRI findings should be
correlated with the patient's seizure semiology and EEG findings; some potentially epileptogenic lesions may
be incidental.
In the absence of a causative lesion on MRI, an epileptogenic focus can sometimes be defined in patients with
localizationrelated epilepsy using advanced neuroimaging techniques including positron emission tomography
(PET), single photon emission computed tomography (SPECT), and magnetic source imaging (MSI). The
choice of study often depends upon the availability and expertise at a particular center. The use of these tests
is discussed in detail separately. (See "Neuroimaging in the evaluation of seizures and epilepsy" and "Surgical
treatment of epilepsy in adults".)
Seizure diaries — In some patients, it may be helpful to have them carefully record seizures, along with other
relevant information, including dietary changes, timing of medication intake of both AEDs and other drugs,
amount and quality of sleep, and menstrual cycle changes. This may serve to improve compliance and may
also help in identifying precipitants, such as hormonal changes associated with the menstrual cycle. (See
"Catamenial epilepsy".)
TREATMENT OPTIONS — Resective epilepsy surgery is the treatment of choice for medically resistant
lesional partial epilepsy as this has the most likely chance of producing remission. Further AED trials, vagal
nerve stimulation, and the ketogenic diet can reduce seizure frequency and improve quality of life but are more
likely to be palliative, rather than curative, treatment options [17].
Antiepileptic drugs — Further medications trials of AEDs in mono or polytherapy can be of benefit in
individuals with epilepsy. It is important to review past treatment trials with the patient to assess whether the
dose or frequency of dosing was adequate. The appropriateness of past AED trials to the individual’s seizure
type (table 1) should also be specifically evaluated, as should compliance and any potential barriers to
compliance. (See "Overview of the management of epilepsy in adults", section on 'Antiepileptic drug therapy'.)
Sequential drug trials have a small likelihood of inducing remission in patients who have already failed two or
more AED regimens. This approach can produce remission rates estimated at 4 to 6 percent per year, or a
cumulative rate of 14 to 20 percent [15,27,28,30,36,38,46]. Among those who do not become seizurefree, a
substantial reduction in seizure frequency is possible; in different series, 21 to 70 percent of patients achieve a
50 percent or greater reduction in seizure frequency [28,30,36,80]. Reduction in seizure severity may also
improve patients’ quality of life [81]. However, studies with longterm followup find that the benefit of
successive drug trials is not sustained in onefourth or more [46,47,80].
Choosing an AED with a different mechanism of action than one not previously efficacious may maximize the
benefit from subsequent drug trials (table 3). Some suggest that drug combinations employing AEDs with
different mechanisms of action may also be fruitful, although neither of these approaches has been
systematically evaluated. An analysis of 70 randomized controlled trials of AEDs administered as addon
therapy in patients with refractory partial epilepsy found that differences in efficacy were of two small a
magnitude to allow conclusions about which AED is more effective in this setting [82]. The approach to
successive drug trials is discussed in more detail separately. (See "Overview of the management of epilepsy in
adults", section on 'Subsequent drug trials'.)
Enrollment in clinical drug trials for investigational AEDs is a treatment option for patients who do not wish to
proceed with current therapy, are not surgical candidates, or whose preference is to continue with medical
management. Epilepsy centers and other neurologic centers often have several active ongoing research
protocols.
Epilepsy surgery — Epilepsy surgery should be considered in appropriate patients with DRE when seizures
are sufficiently frequent or severe as to significantly disrupt the patient's quality of life. These considerations
are necessarily individualized, but in general include those seizures that impair consciousness, cause injury,
and occur sufficiently frequently as to be disabling [83,84].
Resective epilepsy surgery has the bestestablished efficacy for individuals with lesional temporal lobe
epilepsy [85]. Patients with concordant abnormalities in one temporal lobe on MRI and EEG have a rate of
seizure remission as high as 90 percent [86,87]. Patients with nonlesional temporal lobe epilepsy also have a
high remission rate with surgical therapy. The efficacy is highest in patients in whom EEG and another imaging
modality (eg, SPECT, PET, or MSI) reveal a consistent location of the epileptic focus.
Neocortical focal epilepsy also responds to resective surgery. As with mesial temporal lobe epilepsy, rates of
seizure remission are highest in patients who have MRI lesions that are concordant with the anatomic focus of
seizure activity on EEG. However, localization using SPECT, PET, and/or MSI, can also define a seizure
focus that when surgically removed leads to seizure remission rates that exceed 50 percent.
Other surgical treatments (lobar and multilobar resections, hemispherectomy, corpus callosotomy, multiple
subpial transections) are sometimes employed for palliative treatment in children and sometimes adults with
catastrophic epilepsy syndromes.
Epilepsy surgery appears to be underutilized in patients with uncontrolled epilepsy [8891]. Epilepsy surgery is
discussed in more detail separately. (See "Surgical treatment of epilepsy in adults" and "Seizures and epilepsy
in children: Refractory seizures and prognosis", section on 'Epilepsy surgery'.)
Vagus nerve stimulation — Vagus nerve stimulation (VNS) has been approved for adjunctive treatment of
medically intractable partial onset seizures in adults and children over 12 years of age. Approximately 30 to 40
percent of patients achieve a greater than 50 percent reduction in seizure frequency, a benefit that is sustained
over time [9295]. Serious adverse events are rare.
VNS is a valid treatment option for patients with welldocumented IE, who are either opposed to intracranial
surgery, or who are not candidates for intracranial surgery, or whose seizures were not substantially improved
by prior intracranial epilepsy surgery [9698]. Resective surgery for appropriate candidates is preferred over
VNS because of the substantially greater potential for complete seizure remission.
VNS is discussed in detail separately. (See "Vagus nerve stimulation therapy for the treatment of epilepsy".)
Cortical stimulation — Responsive cortical stimulation is a valid treatment option for patients with refractory
focal epilepsy and a well delineated seizure focus. Although resective surgery is still preferred in such patients
because it offers a substantially greater potential for complete seizure remission, cortical stimulation may be
useful when surgery is not possible. Patients with bitemporal lobe epilepsy or epilepsy originating from eloquent
cortex may be particularly good candidates for this device.
Responsive cortical stimulation devices employ a closedloop cortical stimulation unit coupled to a seizure
detection system [99102]. Openlabel studies have found that this treatment may be associated with a
substantial reduction in seizure number, intensity, and duration in patients with focalonset seizures.
In a clinical trial, 191 adults with medically intractable focal epilepsy were randomly assigned to sham or active
stimulation in response to seizure detection [103,104]. After 12 weeks of therapy, the reduction in seizure
frequency was greater in the active compared to the sham treatment arm (37.9 versus 17.3 percent), but the
proportion of patients achieving ≥50 percent reduction in seizure frequency was similar (29 versus 27 percent;
OR 1.1, 95% CI 0.62.1). Both active and sham treatments were associated with modest improvements in
quality of life; neither mood nor cognition was negatively impacted. Electrode implantation was associated with
intracranial hemorrhage in nine patients (5 percent), rated as serious in seven but without permanent neurologic
sequelae. Based on these results, the US Food and Drug Administration approved the device in 2013 for use in
patients with DRE.
Similar to VNS, responsive cortical stimulation appears to have sustained, if not increasing, antiseizure effects
over time [104,105].
Several small controlled trials, as well as other open label studies, have found that stimulation of the
hippocampus appears to reduce seizure frequency in patients with mesial temporal lobe epilepsy [106109], but
more data are needed to establish safety and efficacy of this method [110].
Other stimulation approaches — Other therapeutic devices under investigation for refractory epilepsy include
[111]:
● Deep brain stimulation — Subcortical stimulation paradigms have targeted the anterior and centromedian
thalamic nuclei, the subthalamic nucleus, the caudate, and the cerebellum [99,100]. Openlabel and some
small controlled studies have found that stimulation in these sites appears to reduce seizure frequency by
50 percent or more in some patients [99,100,112,113], although not by statistically or clinically significant
amounts with shortterm follow up [110].
In a randomized clinical trial of stimulation in the anterior nucleus of the thalamus (SANTE trial) in 110
patients with drugresistant epilepsy, stimulation therapy was associated with a 29 percent reduction in
seizure frequency compared with sham stimulation at three months; 54 percent of patients had a seizure
reduction of at least 50 percent by two years in the unblinded phase [114]. Complex partial and “most
severe” seizures were most significantly reduced by stimulation. Participants in the stimulated group were
more likely to report depression and memory problems as adverse affects. There were five asymptomatic
hemorrhages (5 percent) and 14 implant site infections (13 percent).
In a longterm follow up study of the same trial, the responder rate was 68 percent at five years in 59
surviving patients with complete seizure diary information [115]. Measures of seizure severity and quality
of life also improved over time. There were no unanticipated adverse events with extended follow up, and
rates of depression, suicidality, and SUDEP were comparable to expected rates in the general refractory
epilepsy population.
The device did not gain approval by the US Food and Drug Administration when the application was
reviewed in 2010, although it has been approved for refractory epilepsy elsewhere, including in Europe,
Canada, and Australia.
● Transcranial magnetic stimulation — Low frequency transcranial magnetic stimulation also reduces
cortical excitability [116,117]. Uncontrolled trials and case reports have suggested that this may reduce
seizure frequency [118,119]. However, small controlled trials have had mixed results [120,121].
● Trigeminal nerve stimulation — Low frequency (120 Hz) trigeminal nerve stimulation applied externally
may reduce seizures in patients with drug resistant focal onset epilepsy [122,123]. This approach was
investigated in a randomized, doubleblind trial in 50 patients with two or more partial onset seizures per
month [122]. Over an 18 week treatment period, external trigeminal nerve stimulation was associated with
a greater response rate (>50 percent decrease in seizure frequency) compared with active control
stimulation (30 versus 21 percent). External trigeminal nerve stimulation was also associated with
improvements in mood as measured by the Beck depression inventory. The device has been approved for
use in the European Union and is still being investigated in the United States.
Ketogenic diet — The ketogenic diet (highfat, low protein) diet has demonstrated efficacy in children with IE,
with more than onethird experiencing a 50 percent or greater reduction in seizures
In two small case series of adult patients, the traditional ketogenic diet and a modified Atkins diet reduced
seizure frequency by 50 percent or more in half of patients with DRE [124,125].
The ketogenic diet is discussed in detail separately. (See "The ketogenic diet".)
Catamenial seizures — Women with catamenial epilepsy may benefit from specific interventions to lower
seizure frequency. (See "Catamenial epilepsy".)
Cannabinoids — At the present time, there are no data from controlled clinical trials to indicate that
cannabinoids have any efficacy in the treatment of epilepsy.
Animal studies and anecdotal reports suggest that cannabinoids have anticonvulsant properties [126128],
although proconvulsant effects have also been described [129]. Despite limited safety and efficacy data in
humans, marijuana use is not uncommon in patients with chronic epilepsy. In a 2004 telephone survey of 136
adults with epilepsy followed at a tertiary care epilepsy clinic in Canada, 21 percent of patients reported active
marijuana use; of these, twothirds believed that marijuana improved their seizure severity [130]. In a
multivariable analysis, significant predictors of marijuana use included seizure frequency (≥1 seizure per
month), longer disease duration, and other illicit drug use.
Data in humans are extremely limited. A 2014 systematic review found four randomized trial reports that
included a total of 48 patients [131]. The treatment agent was cannabidiol in all reports. One report was an
abstract and another was a letter to the editor. No adverse effects were reported for the dose of 200 to 300 mg
of cannabidiol with short term treatment; safety of long term treatment could not be assessed. The authors
concluded that no reliable conclusions could be drawn regarding the efficacy of cannabinoids as a treatment for
epilepsy from the available data. A review by the American Academy of Neurology also concluded that there is
insufficient evidence to prescribe cannabidiol or recommend selftreatment with smoked marijuana in patients
with epilepsy [132].
SUMMARY AND RECOMMENDATIONS — It is estimated that between 20 to 40 percent of patients with
epilepsy will not have complete seizure control with antiepileptic drug (AED) therapy alone.
● Prospective studies indicate that most patients with drugresistant epilepsy (DRE) can be identified early
in their presentation, after a failure of two AED trials. (See 'Definition' above.)
● Predictors of DRE include lack of efficacy of a first AED trial, a high number of seizures prior to
treatment, and a symptomatic/cryptogenic rather than idiopathic epilepsy syndrome. (See 'Risk factors'
above.)
● Individuals with DRE have an increased risk of mortality as well as other disabilities including poor
academic performance, unemployment, and other lifestyle restrictions. This provides an impetus for
aggressive treatment. (See 'Complications of intractable epilepsy' above.)
● Patients with DRE should undergo evaluation (usually video EEG monitoring) to confirm the diagnosis of
epilepsy; as many as 20 percent of patients with apparent DRE will have a nonepileptic paroxysmal
disorder, usually psychogenic nonepileptic seizures. EEG monitoring can also aid in seizure
classification; findings should be correlated with the clinical history. (See 'Evaluation' above.)
● Patients with localizationrelated DRE should have a magnetic resonance imaging study (MRI) to identify
a potential surgical lesion. The sensitivity of MRI can be enhanced by the use of an epilepsy MRI
protocol. Other neuroimaging studies (eg, SPECT, PET) can be employed in individuals in whom MRI
does not show a lesion, in whom the MRI lesion does not correspond to the EEG localization, or who
have dual pathology. (See 'Neuroimaging' above.)
● We recommend surgical evaluation for patients with localizationrelated or partial epilepsy (Grade 1A).
Magnetic resonance imaging (MRI) scan performed using an epilepsy protocol will often identify a lesion
(eg, mesial temporal sclerosis, cortical dysplasia) amenable to surgical resection. The best efficacy for
surgery is achieved in individuals with concordant localization of MRI and EEG abnormalities. For
patients without a MRI lesion, an MRI lesion that is discordant with EEG findings, or with dual pathology,
further neuroimaging studies can help identify an epileptic focus that might respond to surgical therapy.
(See "Surgical treatment of epilepsy in adults".)
● For patients in whom epilepsy surgery is not an option or whose seizures persist after surgery, we
suggest treatment trials with other AEDs appropriate for their epilepsy syndrome and/or vagus nerve
stimulation or responsive cortical stimulation (Grade 2C). While the chance of seizure remission with
these treatments is not high, reductions in seizure frequency and improved quality of life are possible in
most. (See "Vagus nerve stimulation therapy for the treatment of epilepsy" and 'Antiepileptic drugs'
above.)
● There are no data from controlled clinical trials to indicate that cannabinoids have any efficacy in the
treatment of epilepsy. (See 'Cannabinoids' above.)
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Topic 2214 Version 23.0
GRAPHICS
Antiepileptic medications and seizure types
Seizure type Antiepileptic drug
Broad spectrum: all seizure types Clobazam, felbamate, lamotrigine,
(generalized from onset and focal onset levetiracetam, rufinamide, topiramate,
seizures) valproate, zonisamide
Narrow spectrum: focal with or without Carbamazepine, eslicarbazepine, ezogabine,
alteration in consciousness or awareness and gabapentin, lacosamide, oxcarbazepine,
focal evolving to bilateral convulsive seizure perampanel, phenobarbital, phenytoin,
pregabalin, primidone, tiagabine, vigabatrin
Absence seizure (a type of generalized Ethosuximide
seizure)
Note that although there is evidence to support the use of these medications for these
seizure types, the medication may not be indicated for this use by the United States Food
and Drug Administration.
Graphic 78021 Version 6.0
Imitators of epilepsy: Nonepileptic paroxysmal disorders
Neonates
Apnea
Jitteriness
Benign neonatal sleep myoclonus
Hyperkplexia
Infants
Breathholding spells
Benign myoclonus of infancy
Shuddering attacks
Sandifer syndrome
Benign torticollis in infancy
Abnormal eye movements (eg, spasmus nutans, opsoclonusmyoclonus)
Rhythmic movement disorder (head banging)
Children
Breathholding spells
Vasovagal syncope
Migraine
Benign paroxysmal vertigo
Staring spells
Tic disorders and stereotypies
Rhythmic movement disorder
Parasomnias
Adolescents and young adults
Vasovagal syncope
Narcolepsy
Periodic limb movements of sleep
Sleep starts
Paroxysmal dyskinesia
Tic disorders
Hemifacial spasm
Stiff person syndrome
Migraine
Psychogenic nonepileptic pseudoseizures
Hallucinations
Older adults
Cardiogenic syncope
Transient ischemic attack
Drop attacks
Transient global amnesia
Delirium or toxicmetabolic encephalopathy
Rapid eye movement sleep behavior disorder
Common mechanisms of antiepileptic drug action
Na+ Ca+ K+ Inhibitory Excitatory

Drug
channels channels channels transmission transmission
Benzodiazepines +++
Carbamazepine +++ +
Clobazam +++
Ethosuximide +++
Ezogabine ++
Felbamate ++ + ++ ++
Gabapentin + + ++
Lacosamide +++
Lamotrigine +++ +
Levetiracetam + + + +
Oxcarbazepine +++ + +
Perampanel +++
Phenobarbital + +++ +
Phenytoin +++ +
Rufinamide +++
Tiagabine +++
Topiramate ++ ++ ++ ++
Valproate + + ++ +
Vigabatrin +++
Zonisamide ++ ++
+++: primary action; ++: probable action; +: possible action.
Adapted with permission from: Brodie MJ, Kwan P. Staged approach to epilepsy management.
Neurology 2002; 58:S2. Copyright © 2002 Lippincott Williams & Wilkins.
Disclosures
Disclosures: Joseph I Sirven, MD Nothing to disclose. Timothy A Pedley, MD Nothing to disclose.
April F Eichler, MD, MPH Equity Ownership/Stock Options: Johnson & Johnson [Dementia
(galantamine), Epilepsy (topiramate)].
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multilevel review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
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