Version May 2024
INTRODUCTION — Patients with epilepsy whose seizures do not successfully respond to antiseizure medication therapy are considered to have drug-resistant 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 people living in the United States) 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 epilepsy-related 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, population-based 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 localization-related 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 and management 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 — A task force of the International League Against Epilepsy (ILAE) recommended replacing the term "intractable" with "drug-resistant" epilepsy (DRE) and proposed that "drug-resistant" be defined as the failure of adequate trials of two tolerated, appropriately chosen and administered antiseizure medications (whether as monotherapy or in combination) to achieve seizure freedom [3].
Traditionally, therapeutic failure of three antiseizure medications defined intractability (drug resistance) [4-12]. With many newer antiseizure medications available since the 1990s, it might have been expected that more, rather than fewer, drug trials would be recommended before determining drug resistance. However, several prospective case series have shown that a high likelihood of medical drug resistance can be identified after two unsuccessful trials, as with each antiseizure medication failure, the likelihood of successful treatment with other drugs diminishes [3,6-14]. As an example, in one study, 1098 adolescent and adult patients with a diagnosis of epilepsy were started de novo on antiseizure medication treatment and followed up to 25 years (median of 7.5 years) [13]. With the first antiseizure medication trial, 49 percent became seizure free. A second medication trial produced remission in an additional 13 percent, while only a further 4 percent became seizure-free on a third medication regimen. In this cohort, these patterns of antiseizure medication responsiveness largely persisted over time.
Approximately one third of patients who meet this definition of DRE subsequently achieve prolonged (12 months or more) periods of seizure remission [15-17]. However, the risk of seizure relapse in these individuals remains high, greater than 70 percent in one series [15].
Frequency and severity of seizures are less commonly included in a definition of DRE [5,18]. 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 [19]. Even infrequent seizures can have a large impact.
Less often considered, but also important, is the burden of adverse effects of antiseizure medications that a patient experiences. If seizures can be controlled only at medication doses that produce disabling side effects, it may be reasonable to consider that such a person has DRE.
EPIDEMIOLOGY — Because of unstandardized definitions as well as misdiagnoses, the incidence and prevalence of drug-resistant epilepsy (DRE) are somewhat uncertain [20]. In a systematic review of 35 observational studies that included over 13,000 patients with epilepsy and 3900 patients with DRE, the pooled prevalence of DRE was 30 percent, and the pooled incidence proportion was 15 percent [20]. Notably, only 12 percent of the studies met the requirements of the International League Against Epilepsy (ILAE) definition of DRE. (See 'Definition' above.)
A 2021 systematic review and meta-analysis, which included 103 observational studies, found that the cumulative incidence of DRE among people with epilepsy was 15 percent in adult and mixed-age studies and 25 percent in pediatric studies [21]. The prevalence of DRE among patients with an epilepsy diagnosis in population- and community-based studies was approximately 14 percent and in clinic-based studies was approximately 36 percent. There was a high level of heterogeneity and risk of bias among the included studies.
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 (population-based versus hospital-based) and whether they included children, adults, or both [6]. No single factor has been found to be uniquely useful in making accurate predictions. A combination of two or more of these factors may help to define those who are not likely to respond to medical treatment [22,23].
●Response to first antiseizure medication – The response to the first antiseizure medication trial is the most important and consistently cited predictive factor among both population-based and hospital-based studies and in both adult and pediatric populations [6,7,13,22,24-26]. While more than half of patients respond to the first antiseizure medication prescribed, less than 20 percent are likely to respond to subsequent drug trials. Antiseizure medication failure due to lack of efficacy is a stronger predictor of DRE than failure due to intolerance or side effects [12]. With each number of failed antiseizure medication trials, the risk of DRE increases [12,25,27-29]. One analysis found that a seizure occurrence since the previous clinic visit or a change in antiseizure medication regimen at the previous clinic visit were important factors predicting DRE [23].
●Seizure frequency – A high number of seizures prior to diagnosis and treatment is another consistently identified risk factor for DRE [6-8,12,14,22-24,30-36].
●Epilepsy etiology and pathology – The underlying etiology and seizure classification are also important. Genetic or inherited syndromes, for both generalized and localization-related epilepsy, have a better prognosis than symptomatic/cryptogenic epilepsy in both pediatric and adult populations [8,12,13,16,20,21,23,28,30,31,37-39].
Certain pediatric epilepsy syndromes are almost invariably drug resistant. These include early infantile developmental and epileptic encephalopathy, Lennox-Gastaut syndrome, and Rasmussen encephalitis, among others. Localization-related epilepsy underlies more than half of the cases of DRE in children [8].
Among the localization-related epilepsies, those associated with vascular lesions may be more treatment responsive than those with mesial temporal sclerosis (MTS), cortical dysgenesis, or dual pathology [7,22,37,38,40,41]. Individuals with MTS have some of the highest rates of DRE, 40 to 80 percent [4,7,9,17,40].
●Other demographic variables – Other findings more variably associated with the risk of DRE include a presentation with status epilepticus [8,20,27,37], a longer duration of epilepsy [28,31], a family history of epilepsy [12,14,23,30,33], a history of febrile convulsions [20,33], abnormal electroencephalography (EEG) findings [8,12,20-22], and previous recreational drug use [14]. An abnormal neurologic examination and/or developmental delay are also identified as risk factors for DRE in some studies [21,27,30,32,37].
●Age at presentation – Some studies, but not all, suggest that age at presentation may be a factor in the development of DRE [7,12,20,22,23,27,36,37]. 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 [8,32,42]. Onset in the neonatal time period has been associated with DRE in at least one series [32]. Individuals who develop epilepsy later in life (>65 years) appear to be less likely to develop DRE than younger adults [43,44]. 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 antiseizure medication 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 as long as several years [10,43]. 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. Mechanisms may vary according to the underlying disease, type of epilepsy, and antiseizure medications used for treatment (figure 1) [45,46].
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 follow-up suggest that 70 to 80 percent of patients retain their status as intractable versus in remission [5,10,24,30,35,39,43,47-49]. This means that a minority of patients with apparent drug-resistant epilepsy (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 persists [39,50-52]. 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) [10,39,53,54]. 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 [12,55]. Longitudinal neuroimaging studies also support a progressive process [36,56]. Alterations in neural circuitry conceivably may lead to an epileptic network that becomes drug resistant over time [57]. (See "Focal epilepsy: Causes and clinical features".)
Studies in animal models and patients comparing drug-resistant and drug-sensitive temporal lobe epilepsy have found that the former is associated with altered expression of multidrug transporters, altered expression of antiseizure medication targets, as well as morphologic alterations in the hippocampus [29,58].
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, some evidence supports an association between DRE and the ABCB1 gene, which encodes an adenosine triphosphate (ATP)-dependent transporter p-glycoprotein that pumps out xenobiotic compounds from cells; overexpression of the transporter might reduce the response to antiseizure medications. A systematic review reported that six of nine studies found a significant association of ABCB1 polymorphisms with DRE [21]. 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 antiseizure medication absorption, metabolism, receptor-binding, and blood brain barrier permeability are also potential causes of pharmacoresistance [60,61].
COMPLICATIONS — Individuals with drug-resistant epilepsy (DRE) have an increased mortality rate, estimated at 1.37 per 100 person-years [26,62-64]. The standardized mortality ratio for patients with recurrent seizures is 4.69 [63]. Provided they survive the underlying cause of their seizures, individuals who become seizure free do not appear to have increased mortality [65].
Some deaths are related to the underlying cause of epilepsy (eg, cerebral neoplasm, neurodegenerative disease); other deaths are directly seizure-related, such as those that occur in the context of status epilepticus and in seizure-related 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 "Comorbidities and complications of epilepsy in adults", section on 'Premature mortality'.)
Nonfatal injuries are also common in those with DRE. These include head injury, burns, and fractures, among others; most are seizure-related [66].
DRE is also associated with disability and diminished quality of life [9,12,67,68]. 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 self-reported 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 [69]. These complications of DRE result from the combined effects of recurrent seizures, antiseizure medication toxicity, comorbid depression, as well as psychosocial factors such as excessive dependency [9,12,67]. (See "Comorbidities and complications of epilepsy in adults", section on 'Psychosocial issues'.)
DIFFERENTIAL DIAGNOSIS — When a patient's seizures do not appear to respond to antiseizure medication therapy, the clinician should reconsider the seizure classification and the appropriateness of the antiseizure medication 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 drug-resistant epilepsy (DRE) were incorrectly diagnosed most often as a result of incomplete history-taking and/or EEG misinterpretation [70].
Apparent intractability — It is important to differentiate true versus apparent DRE. Reasons for apparent treatment failure that do not reflect drug resistance include:
●Misdiagnosis – An incorrect diagnosis of seizure classification can lead to an incorrect drug choice [71]. It is not uncommon for idiopathic generalized epilepsy syndromes to be unrecognized and inappropriately treated with antiseizure medications that are more appropriate to localization-related epilepsy (table 1) [4]. In some instances, a narrow-spectrum antiseizure medication can worsen seizure frequency in individuals with generalized epilepsy. One example is when carbamazepine is prescribed for juvenile myoclonic epilepsy [70,72,73].
●Inappropriate dose – Inadequate dosing or frequency of antiseizure medication dosing has led to apparent intractability [70]. By contrast, seizures can also occur with antiseizure medication toxicity. This has been described in rare cases in association with phenytoin, carbamazepine, tiagabine, and valproate [73].
●Nonadherence – Antiseizure medication adherence 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 [74]. Providing a nonjudgmental setting in which to elicit this history is important. Support from family members and clinicians increases medical adherence [4,75,76]. (See "Overview of the management of epilepsy in adults", section on 'Nonadherence with antiseizure medication therapy'.)
●Lifestyle factors – Examples of lifestyle factors that can increase seizure frequency include recreational drug or alcohol use disorder and sleep deprivation [4,33,76].
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 antiseizure medication therapy. While not without limitations, video-EEG monitoring is the gold standard test for the diagnosis of PNES.
Among patients referred to epilepsy monitoring units for apparent DRE, 25 to 40 percent are diagnosed with PNES [77,78]. The clinical features, diagnosis, and treatment of PNES are discussed separately. (See "Psychogenic nonepileptic seizures: Etiology, clinical features, and diagnosis".)
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) [70,79]. (See "Nonepileptic paroxysmal disorders in adolescents and adults".)
EVALUATION — Patients with drug-resistant epilepsy (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 (algorithm 1) [19,80]. In most cases, the evaluation of DRE will include video-EEG monitoring and magnetic resonance imaging (MRI) [76].
Video EEG monitoring — Inpatient video-EEG 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 seizure-like 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 [70]. 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 DRE, an MRI study will usually have been performed. In many cases, this should be repeated, particularly if the original study was unrevealing. In some cases, follow-up 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 antiseizure medications [81]. The sensitivity of MRI for an underlying cause of epilepsy (so-called 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 localization-related 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 antiseizure medications 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 "Initial treatment of epilepsy in adults".)
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 [82].
Further antiseizure medication trials, vagus nerve stimulation, deep brain stimulation, responsive cortical 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 [19,83].
Antiseizure medications — Further trials of antiseizure medications in mono- or polytherapy can be of benefit in individuals with epilepsy, especially if one suspects that prior trials of antiseizure medications did not work because of adverse effects or nonadherence. 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 antiseizure medication 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 'Antiseizure medication therapy'.)
Sequential drug trials have a small likelihood of inducing remission in patients who have already failed two or more antiseizure medication regimens. This approach can produce remission rates estimated at 4 to 6 percent per year, or a cumulative rate of 14 to 20 percent [16,27,28,31,37,38,50]. Among those who do not become seizure-free, 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 [28,31,37,84]. Reduction in seizure severity may also improve patients' quality of life [85]. However, studies with long-term follow-up find that the benefit of successive drug trials is not sustained in one-fourth or more [50,51,84].
Choosing an antiseizure medication with a different mechanism of action than one not previously efficacious may maximize the benefit from subsequent drug trials (table 3 and table 4). Some suggest that drug combinations employing antiseizure medications 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 antiseizure medications administered as add-on therapy in patients with refractory partial epilepsy found that differences in efficacy were of too small a magnitude to allow conclusions about which antiseizure medication is more effective in this setting [86]. 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 antiseizure medications 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 drug-resistant epilepsy (DRE) when seizures are sufficiently frequent or severe as to significantly increase the mortality risk or 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 [87,88]. There are no contraindications to epilepsy surgery. Thus, all patients with drug-resistant epilepsy should be assessed as to whether they are a surgical candidate as early as the failure of the first antiseizure medication. (See "Surgical treatment of epilepsy in adults", section on 'Surgical evaluation'.)
Early referral for epilepsy surgery is supported by 2022 expert consensus recommendations from the International League Against Epilepsy (ILAE) [89]:
●Referral for a surgical evaluation should be offered to every patient with DRE up to 70 years of age as soon as drug resistance is ascertained, regardless of epilepsy duration, sex, socioeconomic status, seizure type, epilepsy type (including epileptic encephalopathies), localization, and comorbidities, including severe psychiatric comorbidity like psychogenic nonepileptic seizures (PNES) or substance abuse, if patients are cooperative with management.
●Surgical referral should be considered for older patients with DRE who have no surgical contraindication and for adults and children who are seizure-free on one or two antiseizure medications but have a brain lesion in noneloquent cortex.
●Surgical referral should not be offered to patients with active substance abuse who are noncooperative with management.
Resective epilepsy surgery has the best-established efficacy for individuals with lesional temporal lobe epilepsy [90]. Patients with concordant abnormalities in one temporal lobe on MRI and EEG have a rate of seizure remission as high as 90 percent [91,92]. 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, single photon emission computed tomography [SPECT], positron emission tomography [PET], or magnetic source imaging [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. If noninvasive evaluations (inclusive of EEG, MRI, magnetoencephalography [MEG], and PET scans) are discordant in regard to location of a seizure generator, invasive monitoring with intracranial electrodes is often performed to determine whether a patient is a candidate for surgical resection. Invasive monitoring is useful to localize the epileptogenic focus, to assess whether cortical tissue can be resected, and to establish cortical targets for neuromodulation [93]. Stereo-EEG electrodes are increasingly used for intracranial monitoring to determine if a patient is a candidate for surgery [94].
Other surgical treatments (lobar and multi-lobar 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 [90,95,96]. Epilepsy surgery is discussed in more detail separately. (See "Surgical treatment of epilepsy in adults" and "Seizures and epilepsy in children: Refractory seizures", section on 'Epilepsy surgery'.)
Neurostimulation — Neurostimulation techniques should be considered for patients with drug-resistant epilepsy who are not considered candidates for focal resective epilepsy surgery [97,98]. Factors that may preclude epilepsy surgery include bilateral or multifocal areas of seizure onset, generalized seizure onset, eloquent cortex as the site of seizure onset, or significant medical comorbidities.
Vagus nerve stimulation — Vagus nerve stimulation (VNS) is approved for adjunctive (to antiseizure medications) treatment of drug-resistant focal 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 [98-102]. In a 2022 systematic review and meta-analysis of five observational studies for VNS with a mean follow-up of 1.3 years, the pooled mean decrease in seizure frequency was 34.7 percent (95% CI -5.1 to 74.5 percent) [103]. Serious adverse events are rare.
VNS is a valid treatment option for patients with well-documented DRE, 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 [104-106]. 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".)
Responsive 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 resective surgery is not possible, such as an epilepsy focus in an area of eloquent cortex or individuals with multiple seizure foci. Patients with more than one seizure focus or epilepsy originating from eloquent cortex may be particularly good candidates for this device.
Responsive cortical stimulation devices employ a closed-loop cortical stimulation unit coupled to a seizure-detection system [107-110]. Open-label studies have found that this treatment may be associated with a substantial reduction in seizure number, intensity, and duration in patients with focal-onset seizures [103].
In a controlled clinical trial, 191 adults with medically intractable focal epilepsy were randomly assigned to sham or active stimulation in response to seizure detection [111,112]. After 12 weeks of therapy, the reduction in seizure frequency was greater in the active compared with 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 0.6-2.1). 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, or even improving, antiseizure effects over time [98,112,113]. In addition, there is indirect evidence that responsive cortical stimulation may reduce the risk of sudden unexpected death in epilepsy (SUDEP) among patients with treatment-resistant epilepsy [114].
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 [115-118], but more data are needed to establish safety and efficacy of this method [119].
A novel type of cortical stimulation is currently being evaluated by using chronic subthreshold stimulation. Early results have been promising [120-122]. A larger trial is underway.
Deep brain stimulation — Subcortical deep brain stimulation paradigms have targeted the anterior and centromedian thalamic nuclei, the subthalamic nucleus, the caudate, hippocampus, and the cerebellum [123]. Short-term open-label and small sham-controlled studies have found that stimulation in these sites reduces seizure frequency by 50 percent or more in some patients [103,123-127], although not by statistically or clinically significant amounts with short-term follow up [125].
In a randomized clinical trial of deep brain stimulation in the anterior nucleus of the thalamus (SANTE trial) in 110 patients with DRE, 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 [128]. Complex partial and "most severe" seizures were most significantly reduced by stimulation. Participants in the stimulated group were more likely to report depression (15 versus 2 percent) and memory problems (13 versus 2 percent) as adverse effects. There were five asymptomatic hemorrhages (5 percent) and 14 implant site infections (13 percent).
In a long-term follow-up study of the same trial, the responder rate was 68 percent at five years in 59 continuing patients with complete seizure diary information [129]. 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 [129,130].
Other stimulation approaches — Other therapeutic devices under investigation for refractory epilepsy include [131]:
●Transcranial magnetic stimulation – Low frequency transcranial magnetic stimulation also reduces cortical excitability [132,133]. Uncontrolled trials and case reports have suggested that this may reduce seizure frequency [134,135]. However, small controlled trials have had mixed results [136-139].
●Trigeminal nerve stimulation – Low frequency (120 Hz) trigeminal nerve stimulation applied externally may reduce seizures in patients with drug resistant focal onset epilepsy [140,141]. This approach was investigated in a randomized, double-blind trial in 50 patients with two or more partial onset seizures per month [140]. 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 — Ketogenic dietary therapy (high-fat, low carbohydrate) is an effective treatment for all patients with epilepsy, regardless of age or seizure type. A greater than 50 percent seizure reduction occurs in 38 to 60 percent of patients. The ketogenic diet is discussed in detail separately. (See "Ketogenic dietary therapies for the treatment of epilepsy".)
Catamenial seizures — Women with catamenial epilepsy may benefit from specific interventions to lower seizure frequency. (See "Initial treatment of epilepsy in adults", section on 'Catamenial epilepsy'.)
Cannabinoids — Several randomized trials have demonstrated modest efficacy of a standardized preparation of cannabidiol oil in specific patient groups (eg, Dravet syndrome, Lennox-Gastaut syndrome) [142-144]. These data are reviewed separately. (See "Seizures and epilepsy in children: Refractory seizures", section on 'Cannabinoids' and "Dravet syndrome: Management and prognosis", section on 'Cannabidiol' and "Lennox-Gastaut syndrome", section on 'Cannabidiol'.)
Aside from Dravet syndrome and Lennox-Gastaut syndrome, high-quality data in humans are limited [145-147]. In 2018, a consortium of 25 epilepsy centers from the United States reported results from an expanded-access program supplying adjunctive cannabidiol to 607 children and adults with treatment-resistant epilepsies [148]. The median reduction in seizures at 12 and 96 weeks was approximately 50 percent. The withdrawal rate was 24 percent, mainly due to lack of efficacy and adverse events, the most common of which were diarrhea and somnolence.
Despite limited safety and efficacy data, marijuana use is common in patients with chronic epilepsy [149]. In a 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, two-thirds believed that marijuana improved their seizure severity [150]. In a multivariable analysis, significant predictors of marijuana use included seizure frequency (≥1 seizure per month), longer disease duration, and other illicit drug use.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Seizures and epilepsy in adults".)
SUMMARY AND RECOMMENDATIONS — It is estimated that between 20 to 40 percent of patients with epilepsy will not have complete seizure control with antiseizure medication therapy alone.
●Prospective studies indicate that most patients with drug-resistant epilepsy (DRE) can be identified early in their presentation, after a failure of two antiseizure medication trials. (See 'Definition' above.)
●Predictors of DRE include lack of efficacy of a first antiseizure medication 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' 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 (algorithm 1). EEG monitoring can also aid in seizure classification; findings should be correlated with the clinical history. (See 'Evaluation' above.)
●Patients with localization-related DRE should have an MRI study 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, single photon emission computed tomography [SPECT], positron emission tomography [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 localization-related or partial epilepsy (Grade 1A). 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 an 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 antiseizure medications 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 'Antiseizure medications' above.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
