Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy.

OBJECTIVE: To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years. METHODS: Adults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory. RESULTS: Of 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04-9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed χ2). CONCLUSIONS: Adjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low. CLINICALTRIALSGOV IDENTIFIER: NCT00572195. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.

Neurofeedback impacts cognition and quality of life in pediatric focal epilepsy: An exploratory randomized double-blinded sham-controlled trial.

OBJECTIVE: Children with epilepsy experience cognitive deficits and well-being issues that have detrimental effects on their development. Pharmacotherapy is the standard of care in epilepsy; however, few interventions exist to promote cognitive development and to mitigate disease burden. We aimed to examine the impact of two different modalities of neurofeedback (NFB) on cognitive functioning and quality-of-life (QOL) measurements in children and adolescents with controlled focal epilepsy. The study also explored the effects of NFB on clinical outcomes and electroencephalography (EEG) quantitative analysis. METHODS: Participants (n = 44) with controlled focal epilepsy were randomized to one of three arms: sensorimotor rhythm (SMR) NFB (n = 15), slow cortical potentials (SCP) NFB (n = 16), or sham NFB (n = 13). All participants received 25 sessions of intervention. The attention switching task (AST), Liverpool Seizure Severity Scale (LSSS), seizure frequency (SF), EEG power spectrum, and coherence were measured at baseline, postintervention, and at 3-month follow-up. RESULTS: In children and adolescents with controlled focal epilepsy, SMR training significantly reduced reaction time in the AST (p = 0.006), and this was correlated with the difference of change for theta power on EEG (p = 0.03); only the SMR group showed a significant decrease in beta coherence (p = 0.03). All groups exhibited improvement in QOL (p = <0.05). CONCLUSIONS: This study provides the first data on two NFB modalities (SMR and SCP) including cognitive, neurophysiological, and clinical outcomes in pediatric epilepsy. Sensorimotor rhythm NFB improved cognitive functioning, while all the interventions showed improvements in QOL, demonstrating a powerful placebo effect in the sham group.

Inappropriate Laughter and Behaviours: How, What, and Why? Case of an Adult with Undiagnosed Gelastic Seizure with Hypothalamic Hamartoma.

Gelastic seizures (GS) are a rare form of epilepsy characterized by inappropriate, uncontrolled laughter. They are highly associated with abnormal cognitive development and behavioral problems in patients. Research has shown that GS can originate from hypothalamic hamartomas (HH), non- neoplastic masses consisting of gray matter with large and small neurons interspersed with glial nuclei. GS have also been observed in patients with frontal and temporal lobe lesions. The patient in this case report is a 40-year-old man with a past medical history significant for brain tumor, diabetes mellitus, and schizophrenia who presented with a long standing history of sudden, involuntary laughter occurring 2-3 times a week since 8 years old. Since the onset of these laughing spells the patient has displayed gradual cognitive impairment and increasing behavioral problems. Subsequent EEG (21-channel electroencephalogram) showed focal epileptiform activity in the right frontotemporal region and MRI studies revealed a mass arising from the hypothalamus suggestive of a HH. Other conditions should be considered in the differential diagnosis for laughing spells and distinguishing different causes can be challenging. As demonstrated by this case report, in patients with behavioral issues, especially those with inappropriate uncontrolled laughter, gelastic seizures need to be included in the differential diagnosis. Thus, a thorough workup should include neuroimaging with attention to the suprasellar region and EEG. Accurate, early diagnosis and patient education are critical in avoiding excessive and unnecessary treatments. This condition may be pharmacoresistant and is often associated with progressive cognitive and behavioral issues. Studies have shown a surgical treatment approach may be effective.

How Can We Enhance the Sense of Self-Efficacy in Epilepsy Individual Responses from 2 Qualitative Case Reports.

BACKGROUND: Epilepsy is a serious, common and chronic neurological condition characterized by an increased disposition to suffer occasional seizures. Psychological interventions may enhance the well-being of individuals with epilepsy. So far, no qualitative study has investigated the complex effects of psychotherapeutic interventions in epilepsy. METHODS: This study examined the questions as to if and how the participation in a patient-centered 6-month resource-oriented mindfulness-based intervention would enhance an individual's well-being and sense of self-efficacy. Pre- and post-intervention semi-structured interviews were conducted with a total of 9 participants. Qualitative data analysis (Mayring) in an inter-professional group was combined with the evaluation of the Quality of Life in Epilepsy Inventory-31. The case reports follow the CAse REport Guidelines for Anthroposophic Art Therapies (CARE-AAT). To show the diverse nature of individual intervention objectives, we chose the single case study format, contrasting 2 participants with diagnosed focal epilepsy. RESULTS: Pre-intervention deductive and inductive outcome categories revealed high levels of stress regarding personal seizure experience and loss of autonomy, for both participants. Post-intervention interviews consist of increased seizure-related self-efficacy and self-awareness: while minimizing the debilitating impact of the seizures on her life was relevant to Iris, Carl developed a personalized aura interruption technique. CONCLUSIONS: These qualitative case analyses suggest that enhanced psychological well-being and even positive medical results may be achieved when epilepsy care focuses on the wishes that are most meaningful to the individual. The possibility of improving the quantitative evaluation of the effects of psychotherapeutic interventions needs to be explored.

Comparing neurostimulation technologies in refractory focal-onset epilepsy.

For patients with pharmacoresistant focal epilepsy in whom surgical resection of the epileptogenic focus fails or was not feasible in the first place, there were few therapeutic options. Increasingly, neurostimulation provides an alternative treatment strategy for these patients. Vagal nerve stimulation (VNS) is well established. Deep brain stimulation (DBS) and cortical responsive stimulation (CRS) are newer neurostimulation therapies with recently published long-term efficacy and safety data. In this literature review, we introduce these therapies to a non-specialist audience. Furthermore, we compare and contrast long-term (5-year) outcomes of newer neurostimulation techniques with the more established VNS. A search to identify all studies reporting long-term efficacy (>5 years) of VNS, CRS and DBS in patients with refractory focal/partial epilepsy was conducted using PubMed and Cochrane databases. The outcomes compared were responder rate, percentage seizure frequency reduction, seizure freedom, adverse events, neuropsychological outcome and quality of life. We identified 1 study for DBS, 1 study for CRS and 4 studies for VNS. All neurostimulation technologies showed long-term efficacy, with progressively better seizure control over time. Sustained improvement in quality of life measures was demonstrated in all modalities. Intracranial neurostimulation had a greater side effect profile compared with extracranial stimulation, though all forms of stimulation are safe. Methodological differences between the studies mean that direct comparisons are not straightforward. We have synthesised the findings of this review into a pragmatic decision tree, to guide the further management of the individual patient with pharmacoresistant focal-onset epilepsy.

[Vagus nerve stimulation in patients with migraine]. / Estimulacion del nervio vago en pacientes migrañosos.

INTRODUCTION: Vagus nerve stimulation (VNS) has been approved for the treatment of refractory epilepsy when resective surgery is not possible, and has proved to be highly effective. Series published in the literature suggest a beneficial effect of VNS in the treatment of migraine. AIMS: To determine the degree to which headaches improve in patients with migraine after the placement of VNS to treat refractory epilepsy, and to evaluate what variables are associated with an increased chance of success with this measure. PATIENTS AND METHODS: An observation-based retrospective study was conducted from 1st January 1999 until 31st December 2010. Patients with VNS for refractory epilepsy were contacted by telephone, after selecting those who fulfilled International Headache Society criteria for migraine. Data collected included age, gender, year of placement, age at onset of epilepsy and migraine, improvement of seizures and migraine, presence of migraine with aura and coexistence of anxious-depressive syndrome. Ninety-four patients with VNS were contacted and 13 patients with migraine were selected. RESULTS: Following placement of the VNS, the number of episodes of migraine was seen to decrease by at least 50% in nine patients (69%) (p = 0.004) and there was a drop in the number of episodes of migraine in those patients who had also reduced their epileptic seizures (p = 0.012). No statistically significant associations were observed as regards sex, age, length of disease history, existence of migraine with aura or coexistence of anxious-depressive syndrome. CONCLUSIONS: VNS could have beneficial effects for patients with migraine, especially in cases that are difficult to control. Due to the type of study, these conclusions must be taken with caution. Prospective clinical studies are needed before introducing the technique into daily clinical practice.

TITLE: Estimulacion del nervio vago en pacientes migrañosos.Introduccion. La estimulacion del nervio vago (ENV) esta aprobada para el tratamiento de la epilepsia refractaria cuando no es posible cirugia resectiva, con una eficacia bien establecida. Series publicadas sugieren un efecto beneficioso de la ENV en la migraña. Objetivos. Determinar el grado de mejoria de la cefalea en pacientes migrañosos a los que se les habia implantado una ENV para tratamiento de la epilepsia refractaria y evaluar que variables se asocian a mayor posibilidad de exito con esta medida. Pacientes y metodos. Estudio observacional y retrospectivo desde el 1 de enero de 1999 hasta el 31 de diciembre de 2010. Se contacto telefonicamente con los pacientes con ENV para epilepsia refractaria, seleccionando a aquellos que cumplian los criterios de la Sociedad Internacional de Cefaleas para la migraña. Se recogieron edad, genero, año de implantacion, edad de inicio de la epilepsia y la migraña, mejoria de crisis y de migraña, presencia de aura migrañosa y coexistencia de sindrome ansiosodepresivo. Se contacto con 94 pacientes con ENV y se selecciono a 13 pacientes migrañosos. Resultados. Tras la implantacion de la ENV, se observo una disminucion de al menos el 50% de los episodios de migraña en nueve pacientes (69%) (p = 0,004), asi como una disminucion del numero de episodios de migraña en aquellos pacientes que tambien habian reducido sus crisis epilepticas (p = 0,012). No se observaron asociaciones estadisticamente significativas en cuanto al sexo, edad, tiempo de evolucion, existencia de aura migrañosa o coexistencia de sindrome ansiosodepresivo. Conclusiones. La ENV podria resultar beneficiosa en pacientes con migraña, especialmente en casos de dificil control. Debido al tipo estudio, hay que tomar estas conclusiones con precaucion. Seran necesarios estudios clinicos prospectivos antes de llevarse a la practica clinica habitual.

Bright light therapy for symptoms of anxiety and depression in focal epilepsy: randomised controlled trial.

BACKGROUND: Bright light therapy is an effective treatment for seasonal affective disorder and non-seasonal depression. Depression and anxiety are common psychiatric comorbidities in epilepsy. AIMS: To examine the efficacy of bright light therapy for symptoms of anxiety and depression in adults with focal epilepsy (trial registration at ClinicalTrials.gov: NCT01028456). METHOD: We recruited 101 adults with medically intractable focal epilepsy. Participants completed the Hospital Anxiety and Depression Scale (HADS) at the beginning (T1) and end of a 12-week baseline period (T2) and again after 12 weeks of daily light therapy (T3), with 51 participants using a high-intensity light box and 50 using a low-intensity one. Seizure diaries were kept throughout the baseline and trial period. RESULTS: A total of 58 patients completed the trial. Anxiety and depression scores were significantly reduced following the light therapy at T3 in both the high- and low-intensity groups. CONCLUSIONS: Light therapy resulted in a significant reduction in symptoms of anxiety and depression but we did not find any differences between high- v. low-intensity treatment. This may, therefore, be an effective treatment for symptoms of low mood in epilepsy at lower intensities than those typically used to treat seasonal affective disorder. Further work is needed to investigate this possibility with an adequate placebo condition.

Suppressors of interictal discharges in idiopathic childhood occipital epilepsy of Gastaut.

Idiopathic childhood occipital epilepsy of Gastaut (ICOE-G) is a rare form of epilepsy, characterized by visual hallucinations, periods of blindness, motor seizures, and migraine-like symptoms. A characteristic EEG feature is fixation-off sensitivity: epileptiform discharges are suppressed by visual input. Here, we present an 11-year-old girl suffering from ICOE-G, who was studied to identify potential additional suppressors of the epileptiform discharges.

Psychogenic gelastic seizures in a patient with hypothalamic hamartoma.

Gelastic seizures are classically associated with hypothalamic hamartoma. The most effective treatment for gelastic epilepsy is surgery, although confirming that a hypothalamic hamartoma is an epileptic lesion prior to surgical intervention is challenging. Here, we report the case of a patient with a hypothalamic hamartoma who was diagnosed with psychogenic non-epileptic gelastic seizures using video-EEG monitoring. [Published with video sequences].

Responsive cortical stimulation for the treatment of medically intractable partial epilepsy.

OBJECTIVES: This multicenter, double-blind, randomized controlled trial assessed the safety and effectiveness of responsive cortical stimulation as an adjunctive therapy for partial onset seizures in adults with medically refractory epilepsy. METHODS: 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 predetermined 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). Efficacy and safety were assessed over a 12-week blinded period and a subsequent 84-week open-label period during which all subjects received responsive stimulation. RESULTS: 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. CONCLUSIONS: 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. Responsive stimulation may provide another adjunctive treatment option for adults with medically intractable partial seizures. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that responsive cortical stimulation is effective in significantly reducing seizure frequency for 12 weeks in adults who have failed 2 or more antiepileptic medication trials, 3 or more seizures per month, and 1 or 2 seizure foci.

Numinous-like auras and spirituality in persons with partial seizures.

This study investigated hyperreligiosity in persons with partial epilepsy by exploring a relationship between aura symptoms and spirituality. It was reasoned that patients with high frequencies of auras that are suggestive of metaphysical phenomena, termed numinous-like auras, would report increased spirituality of an unconventional form, both during their seizures and generally. Numinous-like auras included: dreaminess/feeling of detachment, autoscopy, derealization, depersonalization, time speed alterations, bodily distortions, and pleasure. A high-frequency aura group, low-frequency aura group, and nonseizure reference group were compared on the Expressions of Spirituality-Revised. The High group had significantly greater Experiential/Phenomenological Dimension and Paranormal Beliefs factor scores than the Low group, and significantly greater Experiential/Phenomenological Dimension factor scores than the reference group. There were no differences between the Low group and the reference group. In addition, there were no differences among the three groups on traditional measures of religiosity. The results provide preliminary evidence that epilepsy patients with frequent numinous-like auras have greater ictal and interictal spirituality of an experiential, personalized, and atypical form, which may be distinct from traditional, culturally based religiosity. This form of spirituality may be better described by the term cosmic spirituality than hyperreligiosity. It is speculated that this spirituality is due to an overactivation and subsequent potentiation of the limbic system, with frequent numinous-like auras indicating sufficient activation for this process to occur. It is likely that numinous-like experiences foster cosmic spirituality in a number of circumstances, including seizures, psychosis, near-death experiences, psychedelic drug use, high-elevation exposure, and also normal conditions.

Mid-latency auditory-evoked responses and sensory gating in focal epilepsy: a preliminary exploration.

The relationship between epilepsy and psychosis is not well defined. Sensory gating is a possible endophenotype for psychosis, and has not been fully examined in epileptic patients. The authors examined 29 patients with focal epilepsy who were on antiepileptic medications, and 29 age-matched healthy comparison subjects, using a paired-stimulus (S1-S2) paradigm. P50 and N100 amplitudes or gating did not differ between the groups. The P200 was significantly smaller and did not gate as well in epileptic patients. Though alteration of sensory gating can be demonstrated in epileptic patients, it seems to be qualitatively different from alterations reported in association with schizophrenia.

Effect of vagus nerve stimulation on creativity and cognitive flexibility.

OBJECTIVE: The purpose of this study was to determine whether vagus nerve stimulation influences cognitive flexibility and creativity. METHODS: Ten subjects, in whom vagus nerve stimulators had been implanted for the treatment of intractable seizures, performed tasks that assessed cognitive flexibility (solving anagrams), creativity (Torrance Test), and memory (Hopkins Verbal Learning Test) during actual and sham vagus nerve stimulation. RESULTS: Vagus nerve stimulation impaired cognitive flexibility and creativity, but these results could not be explained by the induction of a general encephalopathy because VNS did not impair learning and improved retention. CONCLUSIONS: The means by which vagus nerve stimulation impairs cognitive flexibility and creative thinking is probably related to increased activity of the locus coeruleus-central adrenergic system that increases the signal-to-noise ratio and improves the brain's ability to attend to sensory input, but decreases its ability to recruit large-scale networks.

The contribution of spirituality to quality of life in focal epilepsy.

People with epilepsy of comparable severity may differ widely in quality of life (QOL), suggesting a role for unexplored individual aspects. This study considered the possible role of spirituality. Thirty-two patients with focal epilepsy completed scales for QOL (World Heath Organization QOL, WHOQOL 100), spirituality (WHO Spirituality, Religiousness, and Personal Beliefs), depression, anxiety, and cognitive efficiency, as well as neuropsychological testing. The QOL and spirituality scales exhibited satisfactory internal consistency. Factor analyses of the scale and test scores yielded separate spiritual (Personal Meaning, Inner Energy, Awe and Transcendence, and Openness), affective (Mood), and cognitive (Cognition, Memory, and Perceived Cognitive Efficiency) factors. The total WHOQOL 100 score was significantly predicted by the Awe and Transcendence and Mood factors. The spiritual, Mood, and Cognition factors significantly predicted single QOL domains. These preliminary results highlight the contribution of spirituality to QOL in epilepsy, encouraging future studies. This could influence the conceptualization and assessment of QOL in these patients.

Subdural recordings of the mismatch negativity (MMN) in patients with focal epilepsy.

Mismatch negativity (MMN) is elicited by discernible changes in an otherwise regular stream of auditory stimulation and reflects a pre-attentive detection mechanism. In the current study, auditory evoked potentials were recorded intracranially and electrode contacts sensitive for stimulus deviance were selected in order to further elucidate the contribution of different brain areas to MMN generation. Data were obtained from patients with frontal and temporal lobe epilepsy undergoing a presurgical evaluation by subdural and depth electrodes. In 13 of 29 patients under investigation an intracranial MMN could be observed, while in four other patients a response recovery of the N100 was revealed, mimicking an MMN. Most electrodes with an MMN signal were located in or close to the superior temporal lobe. In two patients an MMN was observed at electrode contacts over the lateral inferior frontal cortex and in one patient at a frontal interhemispheric electrode strip, giving evidence for a participation of the frontal gyrus in MMN generation. Current findings have, however, to be interpreted with caution owing to the placement and limited extension of the used electrode arrays.

[Vagus nerve stimulation and refractory partial epilepsies]. / La stimulation du nerf vague dans le traitement des épilepsies partielles pharmaco-résistantes.

Since 1988, intermittent electric stimulation of the cervical portion of the left vagus nerve is proposed as additive treatment of epilepsy. The effects of vagus nerve stimulation (VNS) on the modulation of cerebral activity, shown in animals and confirmed by the data of functional imagery in human beings, can be apprehended by the anatomic and functional characteristics of this nerve, whereas the anti-epileptic mode of action remains unknown. Following five controlled multicentric studies, including 440 patients presenting refractory epilepsy, 20,000 patients worldwide have been treated by VNS for this indication. Proposed as additive symptomatic treatment of refractory epilepsies, VNS has proven effective and well tolerated by both children and adults with refractory partial epilepsy. After 2 years of treatment, patients achieve an overall average of 40 p. 100 reduction of seizure frequency. In 40 to 50 p. 100 of the patients, the frequency of seizure can even be decreased by 50 p. 100. Moreover, even in the absence of a significant reduction of seizure, patients subjected to this treatment have reported an improvement in their quality of life. The economic surveys also show a favorable impact of VNS on the management of refractory partial epilepsies.

Partial epilepsy with "ecstatic" seizures.

Reports focusing on auras of ecstasy or pleasure have been limited largely to single case descriptions. We examined 11 consecutive patients with such ictal symptoms. Eight had sensory hallucinations, four had erotic sensations, five described "a religious/spiritual experience," and several had symptoms that were felt to have no counterpart in human experience. Ictal EEG recordings were performed in four patients; two had seizure onset in the right temporal lobe and two in the left. In seven the onset could not be definitely localized. The diagnosis of epilepsy was often delayed. Eight patients wished to experience seizures; self-induction was possible in five and four showed treatment noncompliance. In patients with insufficient drug intake, in whom good compliance should be expected, it is relevant to consider seizures with pleasant symptomatology. According to the literature, experiential and ecstatic seizures seem to have had a substantial impact on our cultural and religious history.

Long-term outcome of nonsurgical candidates with medically refractory localization-related epilepsy.

PURPOSE: Epilepsy surgery can result in complete seizure remission rates of upto 80% in patients with mesial temporal sclerosis and unilateral seizures. The seizure-free rate after surgery for patients with extratemporal nonlesional epilepsy has ranged between 30% and 40%. Some patients with medically refractory localization-related epilepsy cannot be offered surgical resection because of inadequate localization of the epileptogenic zone, documentation of bilateral ictal onsets, or functionally important areas of cortex that prohibit resection. The short-term rate of complete remission with medications in temporal lobe epilepsy is poor. Less is known about remission rates in patients who are not surgical candidates. In this study, we evaluated the outcome of medical treatment in patients with medically refractory partial epilepsy who were evaluated for possible epilepsy surgery but deemed to be inadequate surgical candidates. METHODS: A retrospective chart review and telephone survey with a self-rating questionnaire were completed for all patients who underwent epilepsy surgery evaluation but were not ultimately offered surgical treatment at the University of Michigan from 1990 through 1998. We assessed changes in seizure frequency and type, imaging characteristics, ictal recordings, interim medication history, and subjective changes in quality of life. RESULTS: Thirty-four subjects were available for follow-up study, at an average of >4 years after surgical evaluation. A significant reduction in seizure frequency was noted at the time of follow-up compared with that at the time of surgical evaluation. Of patients, 21% achieved seizure remission and remained seizure free for an average of 2.5 years. Four of the seven seizure-free patients attributed their remission to new antiepileptic drugs (AEDs). On a global self-rating item, 15 of 34, or 44%, felt more or much more satisfied with their lives, and 41% felt their quality of life was stable. CONCLUSIONS: A surprisingly large number of patients we surveyed, with refractory partial epilepsy not eligible for surgical management, reported reduced seizure frequency at follow-up, and 21% were seizure free. Our findings suggest that the long-term prognosis in patients with refractory partial epilepsy who are not surgical candidates may be more positive than might be generally expected.