1. Aetna considers cerebral hemispherectomy, corpus callosotomy, and temporal lobectomy medically necessary when all of the following selection criteria are met:

   1. Non-epileptic attacks such as cardiogenic syncope and psychogenic seizures have been ruled out; and
   2. The diagnosis of epilepsy has been documented, and the epileptic seizure type and syndrome has been clearly defined.  In general, appropriate candidates for epilepsy surgery are members who are incapacitated by their frequent seizures as well as the toxicity of anti-epileptic drugs. The general characteristics of individuals for each type of surgical procedure for epilepsy are as follows:  
       
      1. Cerebral hemispherectomy: Members with unilateral multi-focal epilepsy associated with infantile hemiplegia (especially in hemimegalencephaly and Sturge-Weber disease);
      2. Corpus callosotomy: Members with secondarily generalized seizures;
      3. Temporal lobectomy: Members with complex partial seizures of temporal or extra-temporal origin; and  
          
   3. Members' quality of life may significantly improve with surgery; and
   4. Seizures occur at a frequency that interferes with members' daily living and threatens their well being; and
   5. There must have been an adequate period of therapy of two or more antiepileptic drugs, namely, the correct drugs used in the correct dosage, carefully monitored for treatment effects and members' compliance. 

   Aetna considers cerebral hemispherectomy, corpus callosotomy, and temporal lobectomy experimental and investigational when selection criteria are not met.

2. Aetna considers cerebellar stimulation or deep brain stimulation for members with intractable seizures experimental and investigational because their effectiveness for this indication has not been established.

3. Aetna considers localized neocortical resections experimental and investigational for uncontrolled complex partial seizures because its effectiveness has not been established.

4. Aetna considers hippocampal electrical stimulation for the treatment of mesial temporal lobe epilepsy experimental and investigational because its effectiveness has not been established.

5. Aetna considers responsive cortical stimulation/responsive neurostimulation (e.g., the NeuroPace RNS System). medically necessary for adults with intractable partial seizures (motor or sensory) or complex partial seizures (with motor manifestations) with or without secondarily generalized seizures when the following criteria are met:

   1. Non-epileptic attacks such as cardiogenic syncope and psychogenic seizures have been ruled out; and
   2. The diagnosis of epilepsy has been documented, and the epileptic seizure type and syndrome has been clearly defined. In general, appropriate candidates for responsive cortical stimulation are members who are incapacitated by their frequent seizures as well as the toxicity of anti-epileptic drugs; and
   3. The member has been diagnosed with no more than two epileptogenic regions; and
   4. Member has one of the following indications for responsive cortical stimulation:
       
      1. Independent onset of left and right temporal lobe onset seizures in persons who are not candidates for resection due to the loss of memory and language that bilateral temporal resection is known to cause; or
      2. Left temporal lobe onset seizures where there is concern of language or memory impairment with a resection based upon WADA testing and the rest of the diagnostic work up; or
      3. More than one zone of ictal onset, either temporal lobe, neocortical, or both, clearly localized by intracranial recordings, MEG, or other suitable presurgical evaluation making surgical resection unlikely to be successful; or
      4. A well-defined neocortical focus for seizures, with or without anatomic abnormality on neuroimaging, either with or without overlap of eloquent cortex; and.
          
   5. Member has seizures that are severe enough to cause injuries or significantly impair functional ability in domains including employment, psychosocial, education and mobility; and
   6. Members' quality of life may significantly improve with responsive cortical stimulation; and
   7. There must have been an adequate period of therapy of two or more antiepileptic drugs, namely, the correct drugs used in the correct dosage, carefully monitored for treatment effects and members' compliance; and 
   8. Member does not have an implanted Vagus Nerve Stimulator (VNS) or other electronic medical device that delivers electrical energy to the head or body. Members with an inactive VNS could receive responsive cortical stimulation so long as the VNS was explanted prior to or at the same time as the responsive cortical stimulation implant; and
   9. Member's seizure onset zones are located below the level of the subthalamic nucleus (lead placement would present too high a risk).

Aetna considers responsive cortical stimulation experimental and investigational for primary generalized seizures and for all other indications.

1. Aetna considers the use of stereotactic radiosurgery including radiofrequency amygdalohippocampectomy for medial temporal lobe epilepsy and epilepsy arising in other functional cortical regions experimental and investigational because its effectiveness for these indications has not been established(see CPB 0083 - Stereotactic Radiosurgery)

2. Aetna considers stem cell therapy as well as gene therapy for the treatment of refractory epilepsy experimental and investigational because their effectiveness has not been established.

3. Aetna considers trigeminal nerve stimulation experimental and investigational for members with intractable seizures because its effectiveness has not been established.

4. Aetna considers subpial transection surgery for refractory epilepsy experimental and investigational because its effectiveness has not been established.

5. Aetna considers the use of high-frequency oscillations in epilepsy surgery planning experimental and investigational because its effectiveness has not been established.

Note: The Wada test (intra-carotid amobarbital procedure), part of the pre-surgical evaluation of members who may undergo temporal lobectomy, is considered a medically necessary service.

See also: CPB 0191 - Vagus Nerve Stimulation, CPB 0208 - Deep Brain Stimulation, CPB 0221 - Quantitative EEG (Brain Mapping), CPB 0322 - Electroencephalographic (EEG) Video Monitoring, CPB 0425 - Ambulatory Electroencephalography, and CPB 0469 - Transcranial Magnetic Stimulation and Cranial Electrical Stimulation.

For patients who have intractable seizures despite adequate treatment with appropriate antiepileptic drugs, surgery is their last hope.  The goal of epilepsy surgery is not only to decrease the frequency of seizures, but also to improve quality of life.

Temporal lobectomy has been found to be safe and effective for treating patients with complex partial seizures of temporal or extratemporal origin.  Patients who have a single identifiable focus in a restricted cortical area that can be safely excised without producing additional disability can be considered as candidates for temporal lobectomy.

Corpus callosotomy has been found to be safe and effective for treating patients with partial and secondarily generalized seizures.

There is only limited evidence that cerebral hemispherectomy is effective in managing unilateral multi-focal epilepsy associated with infantile hemiplegia (especially in hemimegalencephaly and Sturge-Weber disease).  However, it is the last hope for these patients to eliminate/alleviate their disabling epileptic seizures, and to avoid adverse irreversible psychosocial consequences that may lead to lifelong disability.

Since the advent of deep brain stimulation (DBS) for the treatment of a variety of movement disorders, studies have been performed to ascertain whether this method can reduce seizure frequency.  Evidence from experimental animal studies suggests the existence of a nigral control of the epilepsy system.  The results of animal studies are promising, but work on humans is preliminary.

In a pilot study, Boon et al (2007) assessed the effectiveness of long-term DBS in medial temporal lobe (MTL) structures in patients with MTL epilepsy.  A total of 12 consecutive patients with refractory MTL epilepsy were included in this study.  The protocol included invasive video-EEG monitoring for ictal-onset localization and evaluation for subsequent stimulation of the ictal-onset zone.  Side effects and changes in seizure frequency were carefully monitored.  Ten of 12 patients underwent long-term MTL DBS; 2 of 12 patients underwent selective amygdalo-hippocampectomy.  After mean follow-up of 31 months (range of 12 to 52 months), 1 of 10 stimulated patients was seizure-free (more than 1 year), 1 of 10 patients had a  greater than 90 % reduction in seizure frequency; 5 of 10 patients had a seizure-frequency reduction of greater than equal to 50 %; 2 of 10 patients had a seizure-frequency reduction of 30 to 49 %; and 1 of 10 patients was a non-responder.  None of the patients reported side effects.  In 1 patient, MRI showed asymptomatic intra-cranial hemorrhages along the trajectory of the DBS electrodes.  None of the patients showed changes in clinical neurological testing.  Patients who underwent selective amygdalo-hippocampectomy are seizure-free (more than 1 year), anti-epileptic drugs are unchanged, and no side effects have occurred.  The authors concluded that this open pilot study demonstrated the potential efficacy of long-term DBS in MTL structures that should now be further confirmed by multi-center randomized controlled trials (RCTs).

The Wada test (intra-carotid amytal procedure) is commonly used as a predictor of memory dysfunction following temporal lobectomy for intractable epilepsy.  Asymmetry in memory scores can provide focus lateralizing information.

The Agency for Healthcare Research and Quality's technology assessment on the management of treatment-resistant epilepsy stated that the data are inconsistent across studies and do not allow for firm evidence-based conclusions as to the exact proportion of patients who will become seizure-free or who will not benefit from multiple subpial transection.  In addition, too few studies were available to allow for an evidence-based evaluation of parietal or occipital lobe surgery (Chapell et al, 2003).  The American Academy of Neurology's practice parameter on temporal lobe and localized neocortical resections for epilepsy stated that there remains no Class I or II evidence regarding the safety and efficacy of localized neocortical resections.  Further studies are needed to determine if neocortical seizures benefit from surgery (Engel et al, 2003).

Candidates for epilepsy surgery and their family, if applicable, should receive detailed information regarding the specific surgical procedures and their possible benefits and side effects.  Candidates for epilepsy surgery should not have co-existent progressive neurological disease or major psychological or medical disorder.  Persons with progressive neurological diseases or major medical or psychological disorders are generally unsuitable candidates for epilepsy surgery because of the possibility that surgery could worsen the course of these other conditions.

In a pilot study (n = 5), Velasco and colleagues (2005) examined the safety and effectiveness of cerebellar stimulation (CS) on patients with medically refractory motor seizures, and especially generalized tonic-clonic seizures.  Bilateral modified 4-contact plate electrodes were placed on the cerebellar superomedial surface through 2 sub-occipital burr holes.  The implanted programmable, battery-operated stimulator was adjusted to 2.0 microC/cm2/phase with the stimulator case as the anode; at this level, no patient experienced the stimulation.  Patients served as their own controls, comparing their seizure frequency in pre-implant basal phase (BL) of 3 months with the post-implant phases from 10 months to 4 years (average, 8 epochs of 3 months each).  During the month after implantation, the stimulators were not activated.  The patient and the evaluator were blinded as to the next 3-month epoch, as to whether stimulation was used.  The patients were randomized into 2 groups: (i) 3 with the stimulator ON, and (ii) 2 with the stimulator OFF.  After a 4-month post-implantation period, all patients had their stimulator ON until the end of the study and beyond.  Medication was maintained unchanged throughout the study.  EEG paroxysmal discharges also were measured.  Generalized tonic-clonic seizures: in the initial 3-month double-blind phase, 2 patients were monitored with the stimulation OFF; no change was found in the mean seizure rate (patient 1, 100 %, and patient 5, 85 %; mean, 93 %), whereas the 3 patients with the stimulation initially ON had a reduction of seizures to 33 % (patient 2, 21 %; patient 3, 46 %; patient 4, 32 %) with a statistically significant difference between OFF and ON phase of p = 0.023.  All 5 patients then were stimulated and monitored.  At the end of the next 6 months of stimulation, the 5 patients had a mean seizure rate of 41 % (14  to 75 %) of the BL.  The second patient developed an infection in the implanted system, which had to be removed after 11 months of stimulation; the seizures were being reduced with stimulation to a mean of 1 per month from a mean of 4.7 per month (BL level) before stimulation.  At the end of 24 months, 3 patients were monitored with stimulation, resulting in a further reduction of seizures to 24 % (11 to 38 %).  Tonic seizures: 4 patients had these seizures, which at 24 months were reduced to 43 % (10 to 76 %).  Follow-up surgery was necessary in 4 patients because of infection in 1 patient and lead/electrode displacement needing repositioning in 3 patients.  The statistical analysis showed a significant reduction in tonic-clonic seizures (p < 0.001) and tonic seizures (p < 0.05).  These investigators concluded that the superomedial cerebellar cortex appears to be a safe and effective target for electrical stimulation for decreasing motor seizures over the long-term.  The effect shows generalized tonic-clonic seizure reduction after 1 to 2 months and continues to decrease over the first 6 months and then maintains this effectiveness over the study period of 2 years and beyond.  The results of this pilot study needed to be validated by additional trials with larger patient populations.

Fountas et al (2010) reviewed the pertinent literature to outline the role of CS in the management of medically refractory epilepsy.  The pertinent articles were categorized into 2 large groups: (i) animal experimental and (ii) human clinical studies.  Particular emphasis on the following aspects was given when reviewing the human clinical studies: their methodological characteristics, the number of participants, their seizure types, the implantation technique and its associated complications, the exact stimulation target, the stimulation technique, the seizure outcome, and the patients' psychological and social post-stimulation status.  Three clinical double-blind studies were found, with similar implantation surgical technique, stimulation target, and stimulation parameters, but quite contradictory results.  Two of these studies failed to demonstrate any significant seizure reduction, whereas the third one showed a significant post-stimulation decrease in seizure frequency.  All possible factors responsible for these differences in the findings were analyzed in the present study.  The authors concluded that CS seems to remain a stimulation target worth exploring for defining its potential in the treatment of medically intractable epilepsy, although the data from the double-blind clinical studies that were performed failed to establish a clear benefit in regard to seizure frequency.  They noted that a large-scale, double-blind clinical study is needed for accurately defining the efficacy of CS in epilepsy treatment.

Electrical stimulation of the hippocampus has been proposed as a possible treatment for mesial temporal lobe epilepsy (MTLE).  Tellez-Zenteno et al (2006) reported their findings of 4 patients with refractory MTLE (whose risk to memory contraindicated temporal lobe resection) who underwent implantation of a chronic stimulating depth electrode along the axis of the left hippocampus.  These investigators used continuous, sub-threshold electrical stimulation (90 microsec, 190 Hz) and a double-blind, multiple cross-over, randomized controlled design, consisting of 3 treatment pairs, each containing two 1-month treatment periods.  During each treatment pair, the stimulator was randomly turned ON 1 month and OFF 1 month.  Outcomes were assessed at monthly intervals in a double-blind manner, using standardized instruments and accounting for a washout period.  These researchers compared outcomes between ON, OFF, and baseline periods.  Hippocampal stimulation produced a median reduction in seizures of 15 %.  All but 1 patient's seizures improved; however, the results did not reach significance.  Effects seemed to carry over into the OFF period, and an implantation effect can not be ruled out.  These researchers found no significant differences in other outcomes.  There were no adverse effects.  One patient has been treated for 4 years and continued to experience substantial long-term seizure improvement.  The authors demonstrated important beneficial trends, some long-term benefits, and absence of adverse effects of hippocampal electrical stimulation in MTLE.  However, the effect sizes observed were smaller than those reported in non-randomized, unblinded studies.  They stated that large scale, double-blind RCTs are needed to ascertain the effectiveness of hippocampal electrical stimulation in patients with MTLE.

Velasco and colleagues (2007) evaluated the safety and effectiveness of electrical stimulation of the hippocampus in a long-term follow-up study, as well as its impact on memory performance in the treatment of patients with refractory MTLE.  A total of 9 patients were included.  All had refractory partial complex seizures, some with secondary generalizations.  All patients had a 3-month-baseline-seizure count, after which they underwent bilateral hippocampal diagnostic electrode implantation to establish focus laterality and location -- 3 patients had bilateral; 6 had unilateral foci.  Diagnostic electrodes were explanted and definitive Medtronic electrodes were implanted directed into the hippocampal foci.  Position was confirmed with MRI and afterwards, the DBS system internalized.  Patients attended a medical appointment every 3 months for seizure diary collection, DBS system checkup, and neuropsychological testing.  Follow-up ranged from 18 months to 7 years.  Patients were divided in 2 groups: (i) 5 had normal MRIs and seizure reduction of greater than 95 %, and (ii) 4 had hippocampal sclerosis and seizure reduction of 50 to 70 %.  No patient had neuropsychological deterioration, nor did any patient show side effects.  Three patients were explanted after 2 years due to skin erosion in the trajectory of the system.  The authors concluded that electrical stimulation of the hippocampus provides a non-lesional method that improves seizure outcome without memory deterioration in patients with hippocampal epileptic foci.  This is a small study; its findings need to be validated by studies with larger patient populations.

Sun and associates (2008) stated that with the success of DBS for treatment of movement disorders, brain stimulation has received renewed attention as a potential treatment option for epilepsy.  Responsive stimulation aims to suppress epileptiform activity by delivering stimulation directly in response to electrographic activity.  Animal and human data support the concept that responsive stimulation can abort epileptiform activity, and this modality may be a safe and effective treatment option for epilepsy.  Responsive stimulation has the advantage of specificity.  In contrast to the typically systemic administration of pharmacotherapy, with the concomitant possibility of side effects, electrical stimulation can be targeted to the specific brain regions involved in the seizure.  In addition, responsive stimulation provides temporal specificity.  Treatment is provided as needed, potentially reducing the likelihood of functional disruption or habituation due to continuous treatment.  The authors reviewed current animal and human research in responsive brain stimulation for epilepsy and discussed the NeuroPace RNS System, an investigational implantable responsive neurostimulator system that is being evaluated in a multi-center, randomized, double-blinded trial to assess the safety and efficacy of responsive stimulation for the treatment of medically refractory epilepsy.

Morrell et al (2011) evaluated the safety and effectiveness of responsive cortical stimulation as an adjunctive therapy for partial onset seizures in adults with medically refractory epilepsy.  A total of 191 adults with medically intractable partial epilepsy were implanted with a responsive neurostimulator connected to depth or subdural leads placed at 1 or 2 pre-determined seizure foci.  The neurostimulator was programmed to detect abnormal electrocorticographic activity.  One month after implantation, subjects were randomized 1:1 to receive stimulation in response to detections (treatment) or to receive no stimulation (sham).  Safety and effectiveness were assessed over a 12-week blinded period and a subsequent 84-week open-label period during which all subjects received responsive stimulation.  Seizures were significantly reduced in the treatment (-37.9 %, n = 97) compared to the sham group (-17.3 %, n = 94; p = 0.012) during the blinded period and there was no difference between the treatment and sham groups in adverse events.  During the open-label period, the seizure reduction was sustained in the treatment group and seizures were significantly reduced in the sham group when stimulation began.  There were significant improvements in overall quality of life (p < 0.02) and no deterioration in mood or neuropsychological function.  The authors concluded that responsive cortical stimulation reduces the frequency of disabling partial seizures, is associated with improvements in quality of life, and is well-tolerated with no mood or cognitive effects.  They noted that responsive stimulation may provide another adjunctive treatment option for adults with medically intractable partial seizures.  However, with its more invasive surgical component, this approach (responsive cortical stimulation) carries greater risks and requires careful patient selection; identification of factors prdicting good outcome prior to electrode implantation would be of great value.  Furthermore, responsive cortical stimulation has yet to be approved for use in the U.S.

Gamma knife (GK) radiosurgery has been proposed as an alternative to classic microsurgery in MTLE.  Bartolomei and colleagues (2008) reported the efficacy and tolerance of GK radiosurgery in MTLE after a follow-up of more than 5 years.  A total of 15 patients were included in this study; 8 were treated on the left side, and 7 were treated on the right.  The mean follow-up was 8 years (range of 6 to 10 years).  At the last follow-up, 9 of 16 patients (60 %) were considered seizure-free (Engel Class I) (4/16 in Class IA, 5/16 in Class IB).  Seizure cessation occurred with a mean delay of 12 months (+/- 3) after GK radiosurgery, often preceded by a period of increasing aura or seizure occurrence (6/15 patients).  The mean delay of appearance of the first neuroradiological changes was 12 months (+/- 4).  Nine patients (60 %) experienced mild headache and were placed on corticosteroid treatment for a short period.  All patients who were initially seizure-free experienced a relapse of isolated aura (10/15, 66 %) or complex partial seizures (10/15, 66 %) during anti-epileptic drug tapering.  Restoration of treatment resulted in good control of seizures.

In an editorial that accompanied the afore-mentioned paper, Spencer (2008) stated that "gamma knife treatment in mesial temporal lobe epilepsy, then, is still searching for a place.  Right now, its disadvantages (slightly lower seizure response rate, delayed response, absolute requirement for continued medications, higher mortality) compared to anterior medial temporal resection seem to outweigh its noninvasive status, which so far does not appear to carry any clear benefits in terms of neurologic or cognitive function, or seizure response.  Whether gamma knife treatment should be considered for intractable epilepsy arising in other functional cortical regions that can not be treated with resection remains unexplored.  Its efficacy, as well as morbidity, in those situations has not been examined, and the volume and definition of the tissues to be targeted are considerably less well-defined than for mesial lobe epilepsy".

In a pilot study, Barbaro et al (2009) reported the 3-year outcomes of a multi-center, study of GK radiosurgery for MTLE.  Radiosurgery was randomized to 20 or 24 Gy targeting the amygdala, hippocampus, and parahippocampal gyrus.  Seizure diaries evaluated the final seizure remission between months 24 and 36.  Verbal memory was evaluated at baseline and 24 months with the Wechsler Memory Scale-Revised (WMS-R) and California Verbal Learning Test (CVLT).  Patients were classified as having "significant improvement," "no change," and "significant impairment" based on relative change indices.  Thirteen high-dose and 17 low-dose patients were treated.  Both groups showed significant reductions in seizures by 1 year after treatment.  At the 36-month follow-up evaluation, 67 % of patients were seizure-free for the prior 12 months (high-dose: 10/13, 76.9 %; low-dose: 10/17, 58.8 %).  Use of steroids, headaches, and visual field defects did not differ by dose or seizure remission.  The prevalence of verbal memory impairment was 15 % (4/26 patients); none declined on more than 1 measure.  The prevalence of significant verbal memory improvements was 12 % (3/26).  The authors concluded that GK radiosurgery for unilateral MTLE offers seizure remission rates comparable with those reported previously for open surgery.  There were no major safety concerns with high-dose radiosurgery compared with low-dose radiosurgery.  They stated that additional research is needed to determine if GK radiosurgery may be a treatment option for some patients with MTLE.

Vojtech et al (2009) examined the effectiveness of GK radiosurgery in the treatment of MTLE due to mesial temporal sclerosis.  A total of 14 patients underwent radiosurgical entorhino-amygdalo-hippocampectomy with a marginal dose of 18-, 20-, or 25-Gy to the 50 % isodose following a standard pre-operative epilepsy evaluation.  One patient was classified as Engel Class Ib, 3 were Engel Class IIc, 1 was Engel Class IIIa, and 2 were Engel Class IVb in a subgroup of 7 patients who were unoperated 2 years prior to the last visit and at least 8 years after irradiation (average of 116 months).  The insufficient effect of irradiation led these investigators to perform epilepsy surgery on another 7 patients an average of 63.5 months after radiosurgery.  The average follow-up period was 43.5 months after the operation.  Four patients are seizure-free; 1 is Engel Class IIb and 1 is Engel Class IId.  One patient can not be classified due to the short period of follow-up.  The frequency of seizures tended to rise after irradiation in some patients.  Collateral edema was observed in 9 patients, which started earlier and was more frequent in those irradiated with higher doses.  It had a marked expansive character in 3 cases and clinical signs of intra-cranial hypertension were present in 3 cases.  Partial upper lateral quadrant anopia as a permanent side effect was observed in 2 patients.  Repeated psychotic episodes (2 patients) and status epilepticus (2 patients) were also seen after treatment.  No significant memory changes occurred in the group as a whole.  The authors concluded that radiosurgery with 25-, 20, or 18-Gy marginal dose levels did not lead to seizure control in this patient series, although subsequent epilepsy surgery could stop seizures.  Higher doses were associated with the risk of brain edema, intra-cranial hypertension, and a temporary increase in seizure frequency.

Malikova et al (2009) described MRI changes following stereotactic radiofrequency amygdalohippocampectomy (AHE) and correlated the hippocampal and amygdalar volumes reduction with the clinical seizure outcome.  A total of 18 patients were included.  Volumetry was calculated from pre-operative MRI and from MRI obtained 1 year after the operation.  The clinical outcome was examined 1 and 2 years after the treatment.  Hippocampal volume decreased by 54 +/- 19 %, and amygdalar volume decreased by 49 +/- 18 %.  One year after the procedure, 13 (72 %) patients were classified as Engel's Class I (9 as Class IA), 4 (22 %) patients as Class II and 1 (6 %) patient as Class III.  Two years after the operation, 14 patients (82 %) were classified as Class I (7 as Class IA) and 3 patients (18 %) as Class II.  There were 3 surgical complications after the procedure: 1 small subdural hematoma, and twice a small electrode tip left in operation field (these patients were excluded from the study).  In 3 patients, temporary meningeal syndrome developed.  The authors concluded that results of stereotactic radiofrequency AHE are promising.

Naegele et al (2010) stated that the potential applications of stem cell therapies for treating neurological disorders are enormous.  Many laboratories are focusing on stem cell treatments for diseases of the central nervous system, including amyotrophic lateral sclerosis, epilepsy, Huntington's disease, multiple sclerosis, Parkinson's disease, spinal cord injury, stroke, and traumatic brain injury.  Among the many stem cell types under testing for neurological treatments, the most common are fetal and adult brain stem cells, embryonic stem cells, induced pluripotent stem cells, and mesenchymal stem cells.  An expanding toolbox of molecular probes is now available to allow analyses of neural stem cell fates prior to and after transplantation.  Concomitantly, protocols are being developed to direct the fates of stem cell-derived neural progenitors, and also to screen stem cells for tumorigenicity and aneuploidy.  The rapid progress in the field suggested that novel stem cell therapy as well as gene therapy for neurological disorders are in the pipeline.

Tellez-Zenteno and Wiebe (2011) stated that hippocampal stimulation should be regarded as an experimental therapy for epilepsy, and patients considered for this intervention should do so in the context of a well-designed RCT.  The authors concluded that only well-conducted, blinded, randomized trials, followed by long-term systematic observation will yield a clear picture of the effect of this promising therapy, and will help guide its future use.

In a pilot feasibility study, Degiorgio et al (2006) evaluated the safety and preliminary effectiveness of trigeminal nerve stimulation (TNS) of the infra-orbital and supra-orbital branches of the trigeminal nerve for the treatment of epilepsy.  Trigeminal nerve stimulation was well-tolerated.  Four (57 %) of 7 subjects who completed greater than or equal to 3 months experienced a greater than or equal to 50 % reduction in seizure frequency.  The authors concluded that the results of this pilot study supported further investigation into the safety and effectiveness of TNS for epilepsy.

In a double-blind, randomized controlled trial, Degiorgio et al (2013) examined the safety and effectiveness of external TNS (eTNS) in patients with drug-resistant epilepsy (DRE), and tested the suitability of treatment and control parameters in preparation for a phase III multi-center clinical trial.  A total of 50 subjects with 2 or more partial onset seizures per month (complex partial or tonic-clonic) entered a 6-week baseline period, and then were evaluated at 6, 12, and 18 weeks during the acute treatment period.  Subjects were randomized to treatment (eTNS 120 Hz) or control (eTNS 2 Hz) parameters.  At entry, subjects were highly drug-resistant, averaging 8.7 seizures per month (treatment group) and 4.8 seizures per month (active controls).  On average, subjects failed 3.35 anti-epileptic drugs prior to enrollment, with an average duration of epilepsy of 21.5 years (treatment group) and 23.7 years (active control group), respectively.  External TNS was well-tolerated.  Side effects included anxiety (4 %), headache (4 %), and skin irritation (14 %).  The responder rate, defined as greater than 50 % reduction in seizure frequency, was 30.2 % for the treatment group versus 21.1 % for the active control group for the 18-week treatment period (not significant, p = 0.31, generalized estimating equation [GEE] model).  The treatment group experienced a significant within-group improvement in responder rate over the 18-week treatment period (from 17.8 % at 6 weeks to 40.5 % at 18 weeks, p = 0.01, GEE).  Subjects in the treatment group were more likely to respond than patients randomized to control (odds ratio 1.73, confidence interval [CI]: 0.59 to 0.51).  External TNS was associated with reductions in seizure frequency as measured by the response ratio (p = 0.04, analysis of variance [ANOVA]), and improvements in mood on the Beck Depression Inventory (p = 0.02, ANOVA).  The authors concluded that the findings of this study provided preliminary evidence that eTNS is safe and may be effective in subjects with DRE.  Side effects were primarily limited to anxiety, headache, and skin irritation.  They stated that these results will serve as a basis to inform and power a larger multi-center phase III clinical trial.

In an editorial that accompanied the afore-mentioned study by Degiorgio et al, Faught and Tatum (2013) stated that “The beneficial effect demonstrated by Degiorgio et al was modest, but is sufficient to encourage design of a more definitive study”.

Liu and associates (2013) stated that with an annual incidence of 50/100,000 people, nearly 1 % of the population suffers from epilepsy.  Treatment with anti-epileptic medication fails to achieve seizure remission in 20 to 30 % of patients.  One treatment option for refractory epilepsy patients who would not otherwise be surgical candidates is electrical stimulation of the brain, which is a rapidly evolving and reversible adjunctive therapy.  Therapeutic stimulation can involve direct stimulation of the brain nuclei or indirect stimulation of peripheral nerves.  There are 3 stimulation modalities that have class I evidence supporting their uses: (i) vagus nerve stimulation (VNS), (ii) stimulation of the anterior nuclei of the thalamus (ANT), and, (iii) the most recently developed, responsive neurostimulation (RNS).  While the other treatment modalities outlined deliver stimulation regardless of neuronal activity, the RNS administers stimulation only if triggered by seizure activity.  The lower doses of stimulation provided by such responsive devices can not only reduce power consumption, but also prevent adverse reactions caused by continuous stimulation, which include the possibility of habituation to long-term stimulation.  Responsive neurostimulation, as an investigational treatment for medically refractory epilepsy, is currently under review by the Food and Drug Administration.  

Ge and colleagues (2013) reviewed the targets of the deep brain and RNS to identify the best optimal stimulation parameters and the best mode of stimulation, whether cyclical, continuous, or smarter.  This review was based on data obtained from published articles from 1950 to 2013.  To perform the PubMed literature search, the following keywords were input: deep brain stimulation (DBS), RNS, and refractory epilepsy.  Articles containing information related to brain stimulation or RNS for the treatment of refractory epilepsy were selected.  The currently available treatment options for those patients who resist multiple anti-epileptic medications and surgical procedures include electric stimulation, both direct and indirect, of brain nuclei thought to be involved in epileptogenesis.  The number of potential targets has increased over the years to include the ANT, the centromedian nucleus of the thalamus, the hippocampus, the subthalamic nucleus, the caudate nucleus, and the cerebellum, among others.  The results of a RCT and the RNS trial were published to reveal the effectiveness.  The authors concluded that although statistically significant reductions in seizures had been observed using several different stimulation techniques, including VNS, DBS, and RNS, these effects are currently only palliative and do not approach the effectiveness comparable with that seen in resection in appropriately selected patients.  They stated that more research is needed to determine optimal stimulation targets and techniques as well as to determine which epilepsy patients will benefit most from this technology.

Krishnaiah and co-workers (2013) stated that nearly 30 % of patients with epilepsy continue to have seizures in spite of several anti-epileptic drug (AED) regimens.  In such cases they are regarded as having refractory, or uncontrolled epilepsy.  There is no universally accepted definition for uncontrolled or medically refractory epilepsy, but for the purpose of this review, these investigators considered seizures to be drug resistant if they failed to respond to a minimum of 2 AEDs.  It is believed that early surgical intervention may prevent seizures at a younger age and improve the intellectual and social status of children.  There are many types of surgery for refractory epilepsy with subpial transection being one.  In a Cochrane review, these researchers determined the benefits and adverse effects of subpial transection for partial-onset seizures and generalized tonic-clonic seizures in children and adults.  They searched the Cochrane Epilepsy Group Specialised Register (August 8, 2013), the Cochrane Central Register of Controlled Trials (CENTRAL Issue 7 of 12, The Cochrane Library July 2013), and MEDLINE (1946 to August 8, 2013).  They did not impose any language restrictions.  These investigators considered all randomized and quasi-randomized parallel group studies either blinded or non-blinded.  Two review authors independently screened the trials identified by the search.  The same 2 authors planned to independently assess the methodological quality of studies.  If studies had been identified for inclusion, 1 author would have extracted the data and the other would have verified it.  No relevant studies were found.  The authors concluded that there is no evidence to support or refute the use of subpial transection surgery for medically refractory cases of epilepsy.  Moreover, they stated that well-designed RCTs are needed to guide clinical practice.

Gloss and colleagues (2014) stated that approximately 2/3 of seizures can be controlled with anti-epileptic medications.  For some of the others, surgery can completely eliminate or significantly reduce the occurrence of disabling seizures.  Localization of epileptogenic areas for resective surgery is far from perfect, and new tools are being investigated to more accurately localize the epileptogenic zone and improve the likelihood of freedom from post-surgical seizures.  Recordings of pathological high-frequency oscillations (HFOs) may be one such tool.  In a Cochrane review, these investigators evaluated the ability of HFOs to improve the outcomes of epilepsy surgery by helping to identify more accurately the epileptogenic areas of the brain.  They searched the Cochrane Epilepsy Group Specialized Register (April 15, 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2013, Issue 3), MEDLINE (Ovid) (1946 to April 15, 2013), CINAHL (EBSCOhost) (April 15, 2013), Web of Knowledge (Thomson Reuters) (April 15, 2013), www.clinicaltrials.gov (April 15, 2013), and the World Health Organization International Clinical Trials Registry Platform (April 15, 2013).  These researchers included studies that provided information on the outcomes of epilepsy surgery at 6 months or more and which used HFOs in making decisions about epilepsy surgery.  The primary outcome of the review was the Engel Class Outcome System.  Secondary outcomes were responder rate, International League Against Epilepsy (ILAE) epilepsy surgery outcome, frequency of adverse events from any source and quality of life outcomes.  They intended to analyze outcomes via an aggregated data fixed-effect model meta-analysis.  Two studies met the inclusion criteria.  Both studies were small non-randomized trials, with no control group and no blinding.  The quality of evidence for all outcomes was very low.  The combination of these 2 studies resulted in 11 participants who prospectively used ictal HFOs for epilepsy surgery decision making.  Results of the post-surgical seizure freedom Engel class I to IV outcome were determined over a period of 12 to 38 months (average of 23.4 months) and indicated that 6 participants had an Engel class I outcome (seizure freedom), 2 had class II (rare disabling seizures), 3 had class III (worthwhile improvement).  No adverse effects were reported.  Neither study compared surgical results guided by HFOs versus surgical results guided without HFOs.  The authors concluded that no reliable conclusions can be drawn regarding the effectiveness of using HFOs in epilepsy surgery decision making at present.

The NeuroPace RNS System is a responsive cortical stimulator for the treatment of medically intractable partial epilepsy. The RNS System includes a cranially implanted programmable neurostimulator that is connected to one or two depth and/or subdural cortical strip leads that are surgically placed in or on the brain at the seizure focus. The neurostimulator continuously senses brain electrical activity through the leads. When abnormal brain electrical activity typical of the activity that precedes that patient's seizures is detected, the neurostimulator delivers pulses of stimulation through those same electrodes before an individual experiences seizures. 

Heck, et al. (2014) sought to evaluate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy to reduce the frequency of seizures in adults with medically intractable partial onset seizures arising from one or two seizure foci. The investigators conducted a randomized multicenter double-blinded controlled trial of responsive focal cortical stimulation (RNS System). Subjects with medically intractable partial onset seizures from one or two foci were implanted, and 1 month postimplant were randomized 1:1 to active or sham stimulation. After the fifth postimplant month, all subjects received responsive stimulation in an open label period (OLP) to complete 2 years of postimplant follow-up. All 191 subjects were randomized. The percent change in seizures at the end of the blinded period was −37.9% in the active and −17.3% in the sham stimulation group (p = 0.012, Generalized Estimating Equations). The median percent reduction in seizures in the OLP was 44% at 1 year and 53% at 2 years, which represents a progressive and significant improvement with time (p < 0.0001). The investigators reported that serious adverse event rate was not different between subjects receiving active and sham stimulation. Adverse events were consistent with the known risks of an implanted medical device, seizures, and of other epilepsy treatments. There were no adverse effects on neuropsychological function or mood. 

Bergey, et al. (2014) assessed the long-term efficacy and safety of responsive direct cortical stimulation in adults with medically refractory partial onset seizures. Adults with medically refractory partial onset seizures were treated with a cranially implanted responsive neurostimulator that delivers stimulation to one or two seizure foci via chronically implanted electrodes when specific electrocorticographic patterns are detected (RNS® System). Subjects had completed a 2-year primarily open label safety study (N=65) or a 2-year randomized blinded controlled safety and efficacy study (N=191); 230 subjects transitioned into an ongoing 7-year long-term study to assess safety and efficacy. The average subject was 34 years old (18 to 66) with epilepsy for 19.6 years (2 to 57). The median pre-implant frequency of disabling partial or generalized tonic clonic seizures was 10.2 seizures a month. Prior treatments included the vagus nerve stimulator (32%) and epilepsy surgery (34%). Mean post-implant follow-up was 4.7 years (5 weeks to 8.6 years) with an accumulated experience of 1199 patient implant years and 1107 patient stimulation years. The median percent seizure reduction in the randomized blinded controlled trial at 1 year was 44% and at 2 years was 53% (p<0.0001 GEE) and ranged from 55% to 60% over post-implant years 3 through 6 for patients followed in the long-term study. Significant improvements in QOL were maintained (p < 0.05). The most common serious adverse events related to the device in all studies combined were implant site infection (8.2%) and neurostimulator explantation (3.9%). 

Patients with RNS Stimulators cannot undergo magnetic resonance imaging (MRI) procedures, nor can they undergo diathermy procedures, electroconvulsive therapy (ECT) or transcranial magnetic stimulation (TMS). The energy created from these procedures can be sent through the neurostimulator and cause permanent brain damage, even if the device is turned off. The most frequent adverse events reported in clinical trials of the Neuropace were implant site infection and premature battery depletion.