Evaluation and management of drug-resistant epilepsy

INTRODUCTION — 

Patients with epilepsy whose seizures do not successfully respond to antiseizure medication (ASM) 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. 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".)

●(See "Evaluation and management of the first seizure in adults".)

●(See "Initial treatment of epilepsy in adults".)

●(See "Epilepsy surgery: Presurgical evaluation".)

●(See "Resective and ablative surgical treatment of epilepsy in adults".)

●(See "Vagus nerve stimulation therapy for the treatment of epilepsy".)

DEFINITION — 

The International League Against Epilepsy (ILAE) has defined drug-resistant epilepsy (DRE) as the failure of adequate trials of two tolerated, appropriately chosen and administered antiseizure medications (ASMs), whether as monotherapy or in combination, to achieve seizure freedom [1].

This definition of DRE is based on evidence showing that a high likelihood of medical drug resistance can be identified after two unsuccessful ASM trials; with each ASM failure, the likelihood of successful treatment with ASMs diminishes [1-5]. As an example, in one study, 1098 adolescent and adult patients with a diagnosis of epilepsy were started de novo on ASM treatment and followed up to 25 years (median of 7.5 years) [2]. With the first ASM 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 ASM responsiveness largely persisted over time.

Frequency and severity of seizures are not included in the ILAE definition of DRE [6,7]. These factors 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 [8]. Even infrequent seizures can have a substantial effect. (See 'Health and psychosocial consequences' below.)

Less often considered, but also important, is the burden of adverse effects of ASMs 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.

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 (ASMs) used for treatment (figure 1) [9,10].

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 [6,11-16]. 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 [13,17-19]. 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) [13,20]. 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 [21,22]. Longitudinal neuroimaging studies also support a progressive process [23,24]. Alterations in neural circuitry conceivably may lead to an epileptic network that becomes drug resistant over time [25]. (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 ASM targets, as well as morphologic alterations in the hippocampus [26,27].

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 [28], 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 ASMs. A systematic review reported that six of nine studies found a significant association of ABCB1 polymorphisms with DRE [28]. An alternative hypothesis is that overexpression of these multidrug transporters is induced by recurrent seizures, potentially providing an impetus for early aggressive seizure treatment [26,29].

Other potential causes of pharmacoresistance include alterations, acquired or inherited, of ASM absorption, metabolism, receptor-binding, and blood brain barrier permeability, as well as neuroinflammation and maladaptive changes in the neuronal network [5,9,30].

EPIDEMIOLOGY — 

Because of unstandardized definitions as well as misdiagnoses, the incidence and prevalence of drug-resistant epilepsy (DRE) are somewhat uncertain [31].

Incidence and prevalence — 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 [28]. The prevalence of DRE among patients with an epilepsy diagnosis in population- and community-based studies was approximately 14 percent, while the prevalence 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 — Many 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 adults, children, or both. 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 [32,33].

●Lack of response to first ASM – The response to the first antiseizure medication (ASM) 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 [2,32,34]. While more than half of patients respond to the first ASM prescribed, less than 20 percent are likely to respond to subsequent drug trials. ASM failure due to lack of efficacy is a stronger predictor of DRE than failure due to intolerance or side effects [21]. With each number of failed ASM trials, the risk of DRE increases [21,26,35,36]. One analysis found that a seizure occurrence since the previous clinic visit or a change in ASM regimen at the previous clinic visit were important factors predicting DRE [33].

●High seizure frequency – A high number of seizures prior to diagnosis and treatment is another consistently identified risk factor for DRE [3,11,12,24,32,33,37,38]. As an example, a post hoc analysis of patients enrolled in a randomized trial of ASM treatment found that the risk of DRE was somewhat increased for patients with 4 to 11 seizures versus ≤2 seizures prior to randomization (hazard ratio [HR] 1.08, 95% CI 1.05-1.11) [32].

●Epilepsy syndromes – Genetic or inherited syndromes for both generalized and localization-related epilepsy have a better prognosis than symptomatic or cryptogenic epilepsy in both adult and pediatric populations [28,31,33].

Certain pediatric-onset epilepsy syndromes are almost invariably drug-resistant. These include early infantile developmental and epileptic encephalopathies, Lennox-Gastaut syndrome, and Rasmussen encephalitis, among others. Localization-related epilepsy underlies more than half of the cases of DRE in children [39].

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 [32,40-42]. Individuals with MTS have some of the highest rates of DRE, 40 to 80 percent [43,44].

●Neurologic deficit – The presence of a neurologic deficit was one of the most frequently reported predictors of DRE in a 2021 systematic review [28].

●Abnormal electroencephalography (EEG) findings – The presence of epileptiform and other abnormalities on EEG has been identified as a risk factor for DRE in meta-analyses [28,31] and in a post hoc analysis of patients starting ASM monotherapy in a large randomized trial [32].

●Younger age at epilepsy onset – Evidence from systematic reviews and other studies suggests that younger age at epilepsy onset is a factor in the development of DRE [24,28,31-33]. Individuals who develop epilepsy later in life (>65 years) appear to be less likely to develop DRE than younger adults [45,46]. The varying risk of DRE by age group likely relates to the underlying pathogenesis of epilepsy that also varies by age.

●Other variables – Other findings associated with the risk of DRE include the following:

•Presentation with status epilepticus [28,31]

•Multiple seizure types [28,47,48]

•Longer duration of epilepsy [28,49]

•Family history of epilepsy [3,11,33,38]

•History of febrile convulsions [31,38]

•Developmental delay or intellectual disability [28,31]

•Female sex [28]

•Previous recreational drug use [3,50]

•Abnormal neuroimaging findings [31]

Onset of drug resistance — The studies cited above have generally been performed by examining a patient's response to initial ASM 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 [13,19,51,52]. This phenomenon of delayed intractability is most often described in the setting of MTS. Factors that predict a later development of DRE are not well defined. (See 'Pathogenesis' above.)

HEALTH AND PSYCHOSOCIAL CONSEQUENCES

●Increased risk of injury and death – Individuals with drug-resistant epilepsy (DRE) have an increased rate of premature mortality [34,53]. The standardized mortality ratio for patients with DRE ranges from 3.3 to 3.6 [54,55]. Provided they survive the underlying cause of their seizures, individuals who become seizure-free do not appear to have increased mortality [56].

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. One study found that sudden unexpected death in epilepsy (SUDEP) was 40 times more likely among patients who continued to have seizures than in those who were seizure-free [57]. (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 [58].

●Diminished quality of life – DRE is also associated with disability and diminished quality of life [59,60]. 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 [61]. These complications of DRE result from the combined effects of recurrent seizures, antiseizure medication (ASM) toxicity, comorbid depression and anxiety, as well as psychosocial factors such as excessive dependency [21,59,62]. (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 (ASM) therapy, the clinician should reconsider the seizure classification and the appropriateness of the ASM regimens that have been employed.

Clinicians should also reconsider the diagnosis of epilepsy.

Apparent intractability — It is important to differentiate true drug-resistant epilepsy (DRE) versus apparent DRE (pseudoresistance). Reasons for apparent treatment failure that do not reflect drug resistance include:

●Incorrect drug choice – An incorrect diagnosis of seizure classification can lead to an incorrect drug choice [63,64]. It is not uncommon for idiopathic generalized epilepsy syndromes to be unrecognized and inappropriately treated with ASMs that are more appropriate to localization-related epilepsy (table 1) [65]. In some instances, a narrow-spectrum ASM can worsen seizure frequency in individuals with generalized epilepsy. One example is when carbamazepine is prescribed for juvenile myoclonic epilepsy [66-68].

●Inappropriate dose – Inadequate dosing or frequency of ASM dosing has led to apparent intractability [66]. By contrast, seizures can also occur with ASM toxicity. This has been described in rare cases in association with phenytoin, carbamazepine, tiagabine, and valproate [68].

●Nonadherence – Rates of ASM nonadherence are high among people with epilepsy. The potential consequences include an increased risk of seizures, hospitalization, fractures, head injuries, and mortality. Patient education and the use of calendars, medication alarms, and medication dosette boxes may help improve adherence. (See "Antiseizure medication maintenance therapy and drug monitoring", section on 'Nonadherence with ASM therapy'.)

●Lifestyle factors – Examples of lifestyle factors that can increase seizure frequency include recreational drug or alcohol use disorder and sleep deprivation [5,38,69].

Patients with ASM failure due to these factors may respond to adjustments in their ASM regimen. (See 'Optimize antiseizure medication regimen' below.)

Misdiagnosis of epilepsy — Misdiagnosis of epilepsy is common [70]; in one series, as many as 26 percent of individuals thought to have DRE were incorrectly diagnosed, most often as a result of incomplete history-taking and/or EEG misinterpretation [66].

●Psychogenic nonepileptic seizures – Psychogenic nonepileptic seizure (PNES) can mimic epileptic seizures. In contrast to epileptic seizures, PNES are not associated with physiologic central nervous system dysfunction but are instead psychogenically determined. PNES typically do not respond to ASM 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, a substantial number are diagnosed instead with PNES. The clinical features, diagnosis, and treatment of PNES are discussed separately. (See "Functional 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). (See "Nonepileptic paroxysmal disorders in adolescents and adults".)

EVALUATION

Referral to an epilepsy specialist — When possible, patients with apparent drug-resistant epilepsy (DRE) should be referred for evaluation by an epilepsy specialist, ideally at a comprehensive epilepsy center [5,30]. The evaluation may require further testing (video-EEG monitoring, interictal EEG, and brain imaging) to exclude seizure mimics, confirm the diagnosis of epilepsy, and better define the epilepsy syndrome and underlying classification, which is important for directing treatment (algorithm 1). (See 'Video-EEG monitoring' below and 'Neuroimaging' below.)

A comprehensive evaluation is not necessary in every case; based on the patient's history, previous tests, and medication trials, it may be obvious why seizures are continuing, and the initial strategy may be to optimize the antiseizure medication (ASM) regimen rather than perform a lengthy and expensive evaluation. (See 'Optimize antiseizure medication regimen' below.)

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 [66]. 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, 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, a follow-up MRI will reveal an etiology for epilepsy (eg, cerebral neoplasm, autoimmune encephalitis) that was not seen on the initial study and requires specific therapies in addition to ASMs [71]. 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 "Epilepsy surgery: Presurgical evaluation", 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 "Resective and ablative surgical treatment of epilepsy in adults" and "Epilepsy surgery: Presurgical evaluation", section on 'MRI epilepsy protocol'.)

Seizure diary — In some patients, it may be helpful to have them carefully record seizures each day, along with other relevant information, including dietary changes, timing of medication intake of both ASMs 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 "Antiseizure medication maintenance therapy and drug monitoring", section on 'Seizure calendar'.)

TREATMENT OPTIONS — 

Resective epilepsy surgery is the treatment of choice for drug-resistant lesional focal epilepsy, as this has the most likely chance of producing remission [72]. (See "Epilepsy surgery: Presurgical evaluation" and "Resective and ablative surgical treatment of epilepsy in adults".)

Further antiseizure medication (ASM) trials, vagus nerve stimulation (VNS), 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 [8,73].

Optimize antiseizure medication regimen — For patients with apparent ASM treatment failure that does not reflect true drug resistance (see 'Apparent intractability' above), several strategies may be helpful:

●Addressing pseudoresistance – In some cases, ASM failure may be due to one of the following factors (see 'Apparent intractability' above):

•Poor adherence

•Intolerance of adverse effects rather than lack of efficacy

•Inappropriate ASM dose

•Inappropriate ASM selection

The appropriateness of past ASM regimens to the individual's seizure type (table 1) should be specifically evaluated, as should any potential causes of nonadherence.

Useful strategies to improve adherence include patient education with review of adverse ASM effects, use of a seizure calendar, medication alarms, medication dosette boxes, regular follow-up visits, and ASM level monitoring. (See "Antiseizure medication maintenance therapy and drug monitoring", section on 'Nonadherence with ASM therapy' and "Antiseizure medication maintenance therapy and drug monitoring", section on 'ASM levels'.)

It is also important to mitigate seizure-precipitating factors and avoid seizure triggers (eg, sleep deprivation, alcohol intake, and stress) [74].

●Alternative or add-on ASMs – Alternative ASM monotherapy or polytherapy may benefit some individuals with epilepsy, especially if one suspects that prior trials of ASMs 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.

Sequential drug trials have a low likelihood of inducing remission in patients who have already failed two or more ASM regimens. This approach produces remission rates estimated at 4 to 6 percent per year, or a cumulative rate of 14 to 20 percent [17,35-37,40,41,75]. Nevertheless, 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 [36,37,40,76]. Reduction in seizure severity may also improve patients' quality of life [77]. In addition, treatment with an adjunctive ASM is associated with a reduced risk of sudden unexpected death in epilepsy (SUDEP) [78]. (See "Sudden unexpected death in epilepsy", section on 'Optimize treatment of drug-resistant epilepsy'.)

However, studies with long-term follow-up find that the benefit of successive drug trials is not sustained in one-quarter or more [17,18,76].

Choosing an ASM with a different mechanism of action than one not previously efficacious may maximize the benefit from subsequent drug trials (table 3 and table 4). Drug combinations employing ASMs 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 ASMs administered as add-on therapy in patients with refractory focal epilepsy found that differences in efficacy were of too small a magnitude to allow conclusions about which ASM is more effective in this setting [79]. The approach to successive drug trials is discussed in more detail separately. (See "Overview of the management of epilepsy in adults", section on 'Failure of initial therapy'.)

Investigational trials of ASMs may also be available; epilepsy centers and other neurologic centers often have several active ongoing research protocols.

Epilepsy surgery — All patients with drug-resistant epilepsy (DRE) should be assessed for epilepsy surgery referral. (See "Epilepsy surgery: Presurgical evaluation", section on 'Referral to a comprehensive epilepsy center'.)

●Who and when to refer – Our approach is concordant with 2022 expert consensus recommendations from the International League Against Epilepsy (ILAE) [80]:

•We recommend surgical evaluation for every patient with confirmed 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 use, if patients are cooperative with management [80].

•We discuss surgical referral with older patients (age >70 years) with DRE who have no surgical contraindication [80].

•We discuss surgical referral with adults who are seizure-free on one or two ASMs (ie, before DRE is established) but have a brain lesion in noneloquent cortex [80]. This approach may be best suited for patients with epilepsy associated with lesions at higher risk for causing DRE, including hippocampal sclerosis, cavernous malformations, glioneuronal tumors, and focal cortical dysplasia type II [5,80,81].

•Surgical referral should not be offered to patients with active substance use disorders who are nonadherent with management [80].

Epilepsy surgery is particularly appropriate for patients with DRE when seizures are disabling or reduce quality of life because of any of the following [82,83]:

•Impairment of consciousness

•Causing injury

•High seizure frequency

•Increased risk of mortality (eg, generalized tonic-clonic seizures, especially if three or more per year)

These considerations are necessarily individualized.

●Surgically remediable epilepsy syndromes – In well-selected patients with DRE, epilepsy surgery is superior to medical therapy [5,84]. Mesial temporal lobe epilepsy is the most frequently encountered surgically remediable epilepsy syndrome in adults. Neocortical nonlesional focal epilepsy and epilepsy due to focal brain lesions may also respond to surgery. (See "Resective and ablative surgical treatment of epilepsy in adults", section on 'Surgically remediable epilepsy syndromes'.)

●Factors that may preclude epilepsy surgery – These include bilateral or multifocal areas of seizure onset, generalized seizure onset, eloquent cortex as the site of seizure onset, or significant medical comorbidities. (See "Epilepsy surgery: Presurgical evaluation", section on 'Identify factors that may preclude surgery'.)

Such patients may be offered treatment with neurostimulation methods or dietary therapy. (See 'Neurostimulation' below and 'Ketogenic diet' below.)

Neurostimulation — Neurostimulation techniques should be considered for patients with DRE who are not considered candidates for focal resective epilepsy surgery [85,86]. While the chance of complete seizure remission with these treatments is not high, reductions in seizure frequency and with improved quality of life and reduced risk for SUDEP are often possible. However, surgery for appropriate candidates is preferred over neurostimulation techniques because of the substantially greater potential for complete seizure remission.

Approach to choosing — The choice among neurostimulation techniques must be individualized, based upon patient preferences and clinician experience; the evidence base for guidance is limited since head-to-head randomized trials are lacking.

●In general, patients who have a discrete focus in an eloquent area or discrete foci in two or fewer locations may respond well to responsive cortical stimulation, assuming that the EEG electrodes are able to target those foci. Responsive cortical stimulation also allows for ongoing assessment of seizure burden in patients with two seizure foci; determining that seizures largely or exclusively arise from one of the foci during real-life circumstances may allow for a definitive resection. (See 'Responsive cortical stimulation' below.)

●In general, patients with nonfocal or generalized epilepsy may be better suited for deep brain stimulation or VNS. (See 'Vagus nerve stimulation' below and 'Deep brain stimulation' below.)

Vagus nerve stimulation — VNS is a valid treatment option for adults with documented DRE who are opposed to intracranial surgery, or who are not candidates for intracranial surgery, or whose seizures were not substantially improved by prior intracranial epilepsy surgery. (See "Vagus nerve stimulation therapy for the treatment of epilepsy", section on 'Patient selection'.)

VNS is approved for adjunctive (to ASM) treatment of drug-resistant focal seizures in adults and children over 12 years of age.

The efficacy and other aspects of VNS treatment are reviewed 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. Patients with more than one seizure focus or with epilepsy originating from eloquent cortex may be particularly good candidates for this device.

Responsive cortical stimulation devices employ a closed-loop cortical stimulation unit with implanted electrodes that are coupled to a seizure-detection system [87-90].

Observational studies have found that responsive cortical stimulation may be associated with a substantial reduction in seizure number, intensity, and duration in patients with focal-onset seizures [91], but randomized trial data are sparse. In a controlled clinical trial, 191 adults with medically intractable focal epilepsy were randomly assigned in a 1:1 ratio to sham or active stimulation in response to seizure detection; approximately one-half of patients in each group had mesial temporal seizure onset [92,93]. 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; odds ratio [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 but without permanent neurologic sequelae in seven of the nine.

Similar to VNS, responsive cortical stimulation appears to have sustained, or even improving, antiseizure effects over time [86,91,93]. In addition, there is indirect evidence that responsive cortical stimulation may reduce the risk of SUDEP among patients with DRE [94].

Deep brain stimulation — Deep brain stimulation is another invasive option for treating patients with DRE who are not candidates for resective epilepsy surgery.

Subcortical deep brain stimulation paradigms have targeted the anterior and centromedian thalamic nuclei, the subthalamic nucleus, the caudate, hippocampus, and the cerebellum [95]. 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 [91,95-99], although not by statistically or clinically significant amounts with short-term follow-up [97].

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 [100]. Focal seizures with impaired awareness (complex partial seizures) 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 [101]. 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 with expected rates in the general refractory epilepsy population [101,102].

Other stimulation approaches — Noninvasive therapeutic devices under investigation for refractory epilepsy include [103]:

●Transcranial magnetic stimulation – Low frequency transcranial magnetic stimulation also reduces cortical excitability [104,105]. Uncontrolled trials and case reports have suggested that this may reduce seizure frequency [106,107]. However, small controlled trials have had mixed results [108-111].

●Trigeminal nerve stimulation – Low-frequency (120 Hz) trigeminal nerve stimulation applied externally may reduce seizures in patients with drug-resistant focal-onset epilepsy [112,113]. This approach was investigated in a randomized, double-blind trial in 50 patients with two or more partial onset seizures per month [112]. 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".)

PROGNOSIS — 

Approximately one third of patients with drug-resistant epilepsy (DRE) subsequently achieve prolonged (12 months or more) periods of seizure remission [43,75,114]. However, the risk of seizure relapse in these individuals remains high, greater than 70 percent in one series [114].

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

●Definition – Drug-resistant epilepsy (DRE) is defined as the failure of adequate trials of two tolerated, appropriately chosen and administered antiseizure medications (ASMs), whether as monotherapy or in combination, to achieve seizure freedom. (See 'Definition' above.)

●Prevalence and risk factors – Between 14 and 36 percent of patients with epilepsy will not have complete seizure control with ASM therapy alone. Predictors of DRE include lack of response to a first ASM trial, a high number of seizures prior to treatment, and a symptomatic or cryptogenic rather than idiopathic epilepsy syndrome. (See 'Epidemiology' above.)

●Adverse consequences – 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 'Health and psychosocial consequences' above.)

●Evaluation – When possible, patients with apparent or true DRE should be referred for evaluation by an epilepsy specialist, ideally at a comprehensive epilepsy center. The evaluation may require further testing (video-EEG monitoring, interictal EEG, and brain imaging) to exclude seizure mimics, confirm the diagnosis of epilepsy, and better define the epilepsy syndrome and underlying classification, which are all important for directing treatment (algorithm 1). (See 'Evaluation' above.)

●Management

•Adjusting ASM therapy – For patients with apparent ASM treatment failure that does not reflect true drug resistance, strategies include addressing and rectifying possible reasons (poor adherence, intolerance of adverse effects rather than lack of efficacy, inappropriate ASM dose, or inappropriate ASM selection), and using alternative or add-on ASM. (See 'Optimize antiseizure medication regimen' above.)

•Surgical evaluation – We recommend surgical evaluation for every patient with confirmed DRE up to 70 years of age as soon as drug resistance is ascertained if patients are cooperative with management. Surgical referral should also be considered for older patients with DRE who have no surgical contraindication and for adults who are seizure-free on one or two ASMs but have a brain lesion in noneloquent cortex. Surgical referral should not be offered to patients with active substance use disorders who are nonadherent with management.

Epilepsy surgery is particularly appropriate for patients with DRE when seizures are disabling or reduce quality of life due to impairment of consciousness, injury, high seizure frequency, or increased risk of mortality. (See 'Epilepsy surgery' above.)

•Other options – For patients in whom epilepsy surgery is not an option or whose seizures persist after surgery, treatment options include empiric trials with other ASMs appropriate for their epilepsy syndrome, neurostimulation (eg, vagus nerve stimulation), or ketogenic dietary therapy. While the chance of complete seizure remission with these treatments is not high, reductions in seizure frequency with improved quality of life and reduced risk for sudden unexpected death in epilepsy (SUDEP) are often possible. (See 'Optimize antiseizure medication regimen' above and 'Neurostimulation' above and 'Ketogenic diet' above.)