Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability.

OBJECTIVE: Leucine-rich glioma-inactivated 1 (LGI1) encephalitis is the second most common antibody-mediated encephalopathy, but insight into the intrathecal B-cell autoimmune response, including clonal relationships, isotype distribution, frequency, and pathogenic effects of single LGI1 antibodies, has remained limited. METHODS: We cloned, expressed, and tested antibodies from 90 antibody-secreting cells (ASCs) and B cells from the cerebrospinal fluid (CSF) of several patients with LGI1 encephalitis. RESULTS: Eighty-four percent of the ASCs and 21% of the memory B cells encoded LGI1-reactive antibodies, whereas reactivities to other brain epitopes were rare. All LGI1 antibodies were of IgG1, IgG2, or IgG4 isotype and had undergone affinity maturation. Seven of the overall 26 LGI1 antibodies efficiently blocked the interaction of LGI1 with its receptor ADAM22 in vitro, and their mean LGI1 signal on mouse brain sections was weak compared to the remaining, non-ADAM22-competing antibodies. Nevertheless, both types of LGI1 antibodies increased the intrinsic cellular excitability and glutamatergic synaptic transmission of hippocampal CA3 neurons in slice cultures. INTERPRETATION: Our data show that the patients' intrathecal B-cell autoimmune response is dominated by LGI1 antibodies and that LGI1 antibodies alone are sufficient to promote neuronal excitability, a basis of seizure generation. Fundamental differences in target specificity and antibody hypermutations compared to the CSF autoantibody repertoire in N-methyl-D-aspartate receptor encephalitis underline the clinical concept that autoimmune encephalitides are very distinct entities. Ann Neurol 2020;87:405-418.

Etiology-specific response to antiseizure medication in focal epilepsy.

OBJECTIVE: In focal epilepsy, data on the etiology-specific response to antiseizure medication (ASM) are surprisingly sparse. In this study, we sought to reappraise whether seizure outcome of pharmacological treatment is linked to the underlying etiology. Furthermore, we assessed ASM load with respect to the cause of epilepsy. METHODS: Data were retrospectively obtained from the electronic database of the three sites of an academic adult epilepsy outpatient clinic. For each patient, presumed cause of epilepsy was categorized into one of nine etiological groups. Individual drug loads were calculated according to the 2020 World Health Organization Center for Drug Statistics Methodology ATC/DDD Index. Univariate and multivariate analyses were conducted to explore the association between different etiologies and outcome regarding 12-month seizure freedom as well as ASM load. RESULTS: A total of 591 patients with focal epilepsy were included in the final analysis. Ischemic stroke was the etiology with the highest rate of 12-month terminal seizure freedom (71.2%, 95% confidence interval [CI] = 57.9-82.2) and, considering all etiological groups, was an independent predictor of seizure freedom (odds ratio = 2.093, 95% CI = 1.039-4.216). The lowest rates of seizure freedom were observed in patients with hippocampal sclerosis (28.2%, 95% CI = 15.0-44.9) and malformation of cortical development (16.7%, 95% CI = 2.1-48.4). In patients with ischemic stroke, median ASM load (1.0, interquartile range [IQR] = .5-1.8) was significantly lower compared to that in patients with hippocampal sclerosis (median = 1.8, IQR = 1.2-3.0, p = .008) and brain tumors (median = 1.7, IQR = .7-3.2, p = .049). SIGNIFICANCE: Response to treatment with ASM is highly etiology-specific and best in patients with epilepsy due to ischemic stroke. Interestingly, this most favorable treatment outcome can be achieved by the lowest ASM load considering all etiological groups. In focal epilepsy, etiology should be taken into account when counseling patients about their expected seizure outcome with pharmacological treatment and when tailoring initial ASM doses.

Valproic acid use in fertile women with genetic generalized epilepsies.

OBJECTIVES: In genetic generalized epilepsies (GGE), valproic acid (VPA) is the most efficacious compound. However, due to teratogenicity and increased risk for impaired cognitive development after intrauterine exposure, its use in women of fertile age is strictly regulated but sometimes unavoidable. METHODS: All patients with GGE treated at the outpatient clinic of a tertiary epilepsy center with at least one visit between January 2015 and April 2020 were included in this retrospective study. The rate of women aged 18 to 49 years taking VPA was compared to that of men of the same age group and to women > 49 years. Furthermore, in each group, clinical variables associated with VPA use were sought. RESULTS: Twenty-eight out of 125 women of fertile age (22%) were treated with VPA, compared to 28 out of 56 men ≤ 49 years (50%; p = .002) and to 22 out of 40 female patients > 49 years (55%; p < .001). VPA dose was lower in fertile women compared to men, with no difference in seizure freedom rates. In women ≤ 49 years, multivariate analysis demonstrated age as the only variable independently associated with VPA use (OR 1.095; 95% CI 1.036-1.159). In the other two groups, no associated variables were identified. CONCLUSIONS: Despite warnings with respect to teratogenicity and impaired cognitive development with VPA, from 2015 to 2020, almost every fourth women of fertile age with GGE received this compound. Inevitably lower VPA doses in these women seem sufficient for favorable seizure freedom rates.

Surgery in intractable epilepsy-physicians' recommendations and patients' decisions.

OBJECTIVES: To identify demographic and clinical variables independently associated with patients' decisions against their physicians' recommendations for resective epilepsy surgery or further scalp video-EEG monitoring (sca-VEM), semi-invasive (sem-)VEM with foramen ovale and/or peg electrodes, and invasive (in-)VEM. METHODS: Consecutive patients, who underwent presurgical assessment with at least one sca-VEM between 2010 and 2014, were included into this retrospective analysis. Multivariate analysis was used to identify independent variables associated with patients' decisions. RESULTS: Within the study period, 352 patients underwent 544 VEM sessions comprising 451 sca-, 36 sem-, and 57 in-VEMs. Eventually, 96 patients were recommended resective surgery, and 106 were ineligible candidates; 149 patients denied further necessary VEMs; thus, no decision could be made. After sca- or additional sem-VEM, nine out of 51 eligible patients (17.6%) rejected resection. One hundred and ten patients were recommended in-VEM, 52 of those (47.2%) declined. Variables independently associated with rejection of in-VEM comprised intellectual disability (OR 4.721, 95% CI 1.047-21.284), extratemporal focal aware non-motor seizures ("aura") vs. no "aura" (OR 0.338, 95% CI 0.124-0.923), and unilateral or bilateral vs. no MRI lesion (OR 0.248, 95% CI 0.100-0.614 and 0.149, 95% CI 0.027-0.829, respectively). CONCLUSIONS: During and after presurgical evaluation, patients with intractable focal epilepsy declined resections and intracranial EEGs, as recommended by their epileptologists, in almost 20% and 50% of cases. This calls for early and thorough counseling of patients on risks and benefits of epilepsy surgery. Future prospective studies should ask patients in depth for specific reasons why they decline their physicians' recommendations.

Referral to evaluation for epilepsy surgery: Reluctance by epileptologists and patients.

OBJECTIVE: Despite the obvious advantages of resective surgery in patients with drug-resistant focal epilepsy, namely high probability of seizure freedom, decreased mortality, and increased quality of life, referral rates from physicians and approval rates by patients for presurgical assessment remain constantly low. METHODS: In the outpatient clinics of a tertiary epilepsy center, checklists were implemented asking treating epileptologists whether they recommended presurgical evaluation with noninvasive video-electroencephalographic monitoring to adult patients with drug-resistant focal epilepsy and asking respective patients whether they followed this recommendation. RESULTS: Of 185 eligible patients, 80 (43%) were recommended presurgical evaluation by their epileptologists, and 24 (30%) of these patients consented. Nineteen of all patients (10%) actually underwent noninvasive presurgical assessment, and nine of these eventually proceeded to resection. The most frequent reason for nonreferral by epileptologists was their subjective appraisal of seizure frequency as low (31%), whereas patients declined most often due to overall fear of brain surgery (50%). Variables independently associated with nonreferral by epileptologists comprised older age of patients at questioning (odds ratio [OR] = 1.03), no previous evaluation for epilepsy surgery (OR = 4.04), the presence of legal guardianship (OR = 4.29), and ≥11 years of professional experience by the treating epileptologist (OR = 4.62). Independent predictors for patients' rejection of presurgical evaluation were older age at questioning (OR = 1.08), lifetime number of antiepileptic drugs ≥ 5 (OR = 4.47), presence of focal aware seizures (OR = 4.37), and absence of focal seizures with impaired awareness (OR = 11.24). SIGNIFICANCE: In both epileptologists and patients with difficult-to-treat epilepsy, we found high decision rates against presurgical assessment. Some reasons given by physicians for not recommending presurgical evaluation to patients may be understandable; others need further exploration. On the patients' side, early and thorough counseling on risks and benefits of epilepsy surgery is necessary to increase understanding and acceptance.

Absence epilepsy beyond adolescence: an outcome analysis after 45 years of follow-up.

OBJECTIVES: Depending on patient age at onset, absence epilepsy is subdivided into childhood and juvenile forms. Absence seizures can occur several times per day (pyknoleptic course) or less frequently than daily (non-pyknoleptic course). Seizures typically terminate before adulthood, but a quarter of patients need ongoing treatment beyond adolescence. Little is known about their long-term seizure and psychosocial outcome. METHODS: Files of 135 outpatients with absence epilepsy (76 females; 123 had additional generalised tonic-clonic seizures) were retrospectively analysed after a median follow-up of 45.4 years (IQR: 31.9-56.2). Eighty-two subjects completed an additional interview. Patients were dichotomised according to age at epilepsy onset (childhood: n=82; juvenile: n=53) and course of absence seizures (pyknoleptic: n=80; non-pyknoleptic: n=55). RESULTS: Among all patients, 53% achieved 5-year terminal seizure remission, 16% without antiepileptic medication. Median age at last seizure was lower in patients with childhood onset of absence epilepsy (37.7 years) versus juvenile onset (44.4 years; P≤0.01). However, rates and duration of terminal seizure remission were similar. Pyknoleptic versus non-pyknoleptic course of absence seizures made no difference for long-term seizure outcome. Multivariate analysis identified only higher age at investigation to be associated with terminal 5-year seizure remission. Regarding aspects of psychosocial outcome, there were no significant differences between the respective subgroups. CONCLUSIONS: These data indicate that if absence epilepsy persists beyond adolescence, long-term seizure and psychosocial outcome do not differ between childhood and juvenile onset or between pyknoleptic and non-pyknoleptic course of absence epilepsy. However, higher patient age increases the chance of terminal seizure remission.

Long-term outcome in adolescent-onset generalized genetic epilepsies.

OBJECTIVE: Until now, it has been unclear if the three subsyndromes of adolescent-onset generalized genetic epilepsy (GGE) differ in long-term prognosis. Therefore, this study aimed to compare long-term seizure outcome in juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with generalized tonic-clonic seizures alone (EGTCS). METHODS: This retrospective study is based on the archive of an institutional tertiary care outpatient clinic for adult patients with epilepsy. Charts of 870 epilepsy outpatients were reviewed among whom 176 had adolescent-onset GGE (53 JAE, 66 JME, 57 EGTCS). Median patient age at investigation was 60 years; median follow-up time was 42.5 years. If possible, GGE patients were additionally interviewed on psychosocial and clinical variables. RESULTS: Age at first seizure was significantly higher in EGTCS patients (median 18 years) than in patients with JAE or JME (14 years each; p ≤ 0.001). Long-term seizure outcome hardly differed between the three subsyndromes. At the end of follow-up, 60% of all patients were in 5-year terminal seizure remission, and in 14%, epilepsy even had resolved (>10 years without seizures, >5 years without pharmacotherapy). Twenty percent of patients had persistent seizures during the last year of follow-up. Across all patients, 23% reported a psychiatric comorbidity, 87% had married, and 57% had achieved university entrance qualification. SIGNIFICANCE: Long-term outcome was shown to be highly similar across all subsyndromes of adolescent-onset GGE. Even in a selection of difficult-to-treat epilepsy patients still attending an adult epilepsy clinic, most become seizure-free. To confirm these findings, prospective studies are needed.

Specific adverse effects of antiepileptic drugs--A true-to-life monotherapy study.

BACKGROUND: In patients taking antiepileptic drugs (AEDs) for epilepsy, adverse effects (AEs) often lead to unfavorable quality of life, impaired adherence, and, eventually, discontinuation of pharmacological treatment. In a true-to-life sample of subjects from our academic epilepsy outpatient clinic, we aimed to identify predictors for overall high AE burden and for specific AEs focusing on patients on monotherapy. METHODS: All patients ≥16years of age with epilepsy for ≥12months were routinely asked to complete the Liverpool Adverse Event Profile (LAEP) just before their appointment. Demographic, epilepsy, and treatment variables were derived from our comprehensive outpatient database. RESULTS: Out of 841 patients, 438 (61% female, mean age: 44.7±17.1years) on monotherapy were included in this study. Levetiracetam (n=151), lamotrigine (n=167), valproic acid (n=73), or controlled-release carbamazepine (n=47) were the most commonly used antiepileptic drugs (AEDs). Independent predictors for general high AE burden (LAEP score≥45) were duration of epilepsy, lack of 12-month seizure freedom, and partial epilepsy, but none of the four individual AEDs. The most frequent LAEP-defined specific AEs were sleepiness, difficulty concentrating, tiredness, and memory problems. The three most frequent independent predictors for each of the 19 AEs were lack of 12-month seizure freedom (13/19 AEs), individual AED (7/19 AEs), and partial epilepsy (6/19 AEs). Levetiracetam was independently associated with anger/aggression, nervousness/agitation, upset stomach, depression, and sleep disturbance; lamotrigine with nervousness/agitation, upset stomach, and difficulty concentrating; and valproic acid with upset stomach and shaky hands. CONCLUSION: Individual AEDs independently predicted some specific AEs, but not overall high AE burden. Our findings may help to characterize patients with epilepsy who are at high risk for specific AEs. Dose reduction or change to another AED may reduce LAEP score and potential nonadherence.

No unified reward prediction error in local field potentials from the human nucleus accumbens: evidence from epilepsy patients.

Functional magnetic resonance imaging (fMRI), cyclic voltammetry, and single-unit electrophysiology studies suggest that signals measured in the nucleus accumbens (Nacc) during value-based decision making represent reward prediction errors (RPEs), the difference between actual and predicted rewards. Here, we studied the precise temporal and spectral pattern of reward-related signals in the human Nacc. We recorded local field potentials (LFPs) from the Nacc of six epilepsy patients during an economic decision-making task. On each trial, patients decided whether to accept or reject a gamble with equal probabilities of a monetary gain or loss. The behavior of four patients was consistent with choices being guided by value expectations. Expected value signals before outcome onset were observed in three of those patients, at varying latencies and with nonoverlapping spectral patterns. Signals after outcome onset were correlated with RPE regressors in all subjects. However, further analysis revealed that these signals were better explained as outcome valence rather than RPE signals, with gamble gains and losses differing in the power of beta oscillations and in evoked response amplitudes. Taken together, our results do not support the idea that postsynaptic potentials in the Nacc represent a RPE that unifies outcome magnitude and prior value expectation. We discuss the generalizability of our findings to healthy individuals and the relation of our results to measurements of RPE signals obtained from the Nacc with other methods.

Long-term outcome in epilepsy with grand mal on awakening: forty years of follow-up.

Epilepsy with grand mal on awakening (EGMA) is a well-defined subtype of idiopathic generalized epilepsy. Patients with follow-up of at least 20 years were assessed retrospectively regarding 5-year terminal seizure remission. Forty-two patients were included (mean age=60 ± 13 years). After follow-up of 40 ± 13 years, 26 patients (62%) were in remission, 5 without antiepileptic drugs. Age at investigation (odds ratio=0.939, 95% confidence interval=0.887-0.994, p=0.029) independently predicted lacking remission. Nineteen patients (45.2%) had withdrawn from antiepileptic drugs at least once; 12 of those (63.2%) had seizure relapse. EGMA has a favorable long-term prognosis. With increasing age and treatment duration, antiepileptic drug withdrawal may be justified.

Nucleus accumbens stimulation in partial epilepsy--a randomized controlled case series.

Neuromodulative treatment options are warranted in patients with difficult-to-treat epilepsy. However, acquisition of controlled data on deep brain stimulation has so far been achieved only for the centromedian and anterior thalamic nucleus. In a case series of four patients with intractable partial epilepsy, a randomized controlled cross-over protocol was used to get insight into efficacy and safety of 3-month nucleus accumbens stimulation. Seizure frequency, neurocognitive testing, "Liverpool Seizure Severity Score," "Quality of Life in Epilepsy Inventory," "Beck Depression Inventory," and "Mini International Neuropsychiatric Interview" were obtained at every visit. In a subsequent open-label phase, nucleus accumbens stimulation responders underwent concomitant anterior thalamic nucleus stimulation, whereas nonresponders received solely thalamic stimulation. Under nucleus accumbens stimulation, three of four patients had ≥ 50% reduction in frequency of disabling seizures without further improvement with additional anterior thalamic nucleus stimulation. Patient-reported outcome and neurocognitive testing remained unchanged. Accumbens stimulation is safe and seems to be a suitable option in intractable partial epilepsy. The current findings require substantiation by an adequately powered multicenter study.

The First Neuropalliative Care Unit in Germany-Characteristics of Patients.

A unique structure of care for neurological inpatients with significant palliative care (PC) needs was established in the Department of Neurology at the Charité-Universitätsmedizin Berlin in 2021: a specialized neuropalliative care (NPC) unit. After one year, we provide an overview of the concept and the patients' characteristics. METHODS: We retrospectively analyzed the characteristics of patients treated in our NPC unit between February 2021-February 2022. Data were extracted from medical records and PC assessment including diagnosis, mode of admission and discharge, length of stay, and palliative symptoms. Data are presented as averages with a 95% confidence interval [lower limit; upper limit] or percentage (absolute number). RESULTS: We included 143 patients (52% (75) female, 67.9 years [65.6; 70.2]). Patients were admitted from general wards (48%; 68), their homes (22%; 32), intensive care units (16%; 23) or emergency departments (14%; 20). The main diagnoses were tumors of the nervous system (39%; 56), neurodegenerative diseases (30%; 43), neurologic complications (13%; 19) and cerebrovascular diseases (12%; 17). Complaints most frequently rated as severely to overwhelmingly burdensome were motor- or fatigue-associated problems, problems communicating, dysphagia and pain. The average length of stay was 13.7 days [12.2; 15.2]. Forty-five percent (64) of patients were discharged without further PC, 17% (24) were referred to a hospice and 13% (18) were discharged with outpatient PC. Five percent (7) were referred to neurorehabilitation and 21% (30) of patients died. CONCLUSIONS: Our NPC unit is a new model of care for neurological patients with substantial PC needs especially within the structures of a highly specialized and individualized medicine.

Acute symptomatic seizures in the emergency room: predictors and characteristics.

BACKGROUND: When treating patients with epileptic seizures in the emergency room (ER), it is of paramount importance to rapidly assess whether the seizure was acute symptomatic or unprovoked as the former points to a potentially life-threatening underlying condition. In this study, we seek to identify predictors and analyze characteristics of acute symptomatic seizures (ASS). METHODS: Data from patients presenting with seizures to highly frequented ERs of two sites of a university hospital were analyzed retrospectively. Seizures were classified as acute symptomatic or unprovoked according to definitions of the International League Against Epilepsy. Univariate and multivariate analysis were conducted to identify predictors; furthermore, characteristics of ASS were assessed. RESULTS: Finally, 695 patients were included, 24.5% presented with ASS. Variables independently associated with ASS comprised male sex (OR 3.173, 95% CI 1.972-5.104), no prior diagnosis of epilepsy (OR 11.235, 95% CI 7.195-17.537), and bilateral/generalized tonic-clonic seizure semiology (OR 2.982, 95% CI 1.172-7.588). Alcohol withdrawal was the most common cause of ASS (74.1%), with hemorrhagic stroke being the second most prevalent etiology. Neuroimaging was performed more often in patients with the final diagnosis of ASS than in those with unprovoked seizures (82.9% vs. 67.2%, p < 0.001). Patients with ASS were more likely to receive acute antiseizure medication in the ER (55.9% vs. 30.3%, p < 0.001). CONCLUSIONS: In one quarter of patients presenting to the ER after an epileptic fit, the seizure had an acute symptomatic genesis. The independently associated variables may help to early identify ASS and initiate management of the underlying condition.

Causes for Emergency Hospitalization of Neurological Patients With Palliative Care Needs.

Background: Acute and unexpected hospitalization can cause serious distress, particularly in patients with palliative care needs. Nevertheless, the majority of neurological inpatients receiving palliative care are admitted via an emergency department. Objective: Identification of potentially avoidable causes leading to acute hospitalization of patients with neurological disorders or neurological symptoms requiring palliative care. Methods: Retrospective analysis of medical records of all patients who were admitted via the emergency department and received palliative care in a neurological ward later on (n = 130). Results: The main reasons for acute admission were epileptic seizures (22%), gait disorders (22%), disturbance of consciousness (20%), pain (17%), nutritional problems (17%), or paresis (14%). Possible therapy limitations, (non)existence of a patient decree, or healthcare proxy was documented in only 31%. Primary diagnoses were neoplastic (49%), neurodegenerative (30%), or cerebrovascular (18%) diseases. Fifty-nine percent were directly admitted to a neurological ward; 25% needed intensive care. On average, it took 24 h until the palliative care team was involved. In contrast to initially documented problems, key challenges identified by palliative care assessment were psychosocial problems. For 40% of all cases, a specialized palliative care could be organized. Conclusion: Admissions were mainly triggered by acute events. Documentation of the palliative situation and treatment limitations may help to prevent unnecessary hospitalization. Although patients present with a complex symptom burden, emergency department assessment is not able to fully address multidimensionality, especially concerning psychosocial problems. Prospective investigations should develop short screening tools to identify palliative care needs of neurological patients already in the emergency department.

Prognostic value of 'late' electroencephalography recordings in patients with cardiopulmonal resuscitation after cardiac arrest.

BACKGROUND: Electroencephalography (EEG) significantly contributes to the neuroprognostication after resuscitation from cardiac arrest. Recent studies suggest that the prognostic value of EEG is highest for continuous recording within the first days after cardiac arrest. Early continuous EEG, however, is not available in all hospitals. In this observational study, we sought to evaluate the predictive value of a 'late' EEG recording 5-14 days after cardiac arrest without sedatives. METHODS: We retrospectively analyzed EEG data in consecutive adult patients treated at the medical intensive care units (ICU) of the Charité-Universitätsmedizin Berlin. Outcome was assessed as cerebral performance category (CPC) at discharge from ICU, with an unfavorable outcome being defined as CPC 4 and 5. RESULTS: In 187 patients, a 'late' EEG recording was performed. Of these patients, 127 were without continuous administration of sedative agents for at least 24 h before the EEG recording. In this patient group, a continuously suppressed background activity < 10 µV predicted an unfavorable outcome with a sensitivity of 31% (95% confidence interval (CI) 20-45) and a specificity of 99% (95% CI 91-100). In patients with suppressed background activity and generalized periodic discharges, sensitivity was 15% (95% CI 7-27) and specificity was 100% (95% CI 94-100). GPDs on unsuppressed background activity were associated with a sensitivity of 42% (95% CI 29-46) and a specificity of 92% (95% CI 82-97). CONCLUSIONS: A 'late' EEG performed 5 to 14 days after resuscitation from cardiac arrest can aide in prognosticating functional outcome. A suppressed EEG background activity in this time period indicates poor outcome.

Electrically induced limbic seizures: preliminary findings in a rodent model.

In epilepsy, novel pharmacological and nonpharmacological treatment approaches are commonly assessed in model systems of acute motor and often generalized seizures. We developed a rodent model with short-term electrical stimulation of the perforant path resulting in stereotyped limbic seizures. Limbic structures play a major role in human intractable epilepsy. In 10 rats, single electrical 5-second and 20-Hz stimuli to the perforant path reliably produced limbic seizures characterized by resting behavior and subtle motor signs. Electrophysiological recordings from the dentate gyrus demonstrated a seizure pattern with 4-Hz to 5-Hz discharges. Multiple inductions of seizures within 72 hours did not alter behavioral and electrophysiological seizure characteristics. Electrophysiological excitatory and inhibitory parameters assessed by evoked single and paired pulses did not change with increasing number of seizures. We present preliminary findings on a new model of electrically induced limbic seizures of mesiotemporal origin. This model may represent a reliable screening tool for new treatment approaches such as deep brain stimulation.

Hypothermia did not prevent epilepsy following experimental status epilepticus.

In epilepsy research, one of the major challenges is to prevent or at least mitigate development of epilepsy following acquired brain insult by early therapeutic interventions. So far, all pharmacological antiepileptogenic treatment approaches were largely unsuccessful in clinical trials and in experimental animal studies. In a well-established rat model of chronic epilepsy following self-sustaining status epilepticus (SSSE), we assessed the antiepileptogenic properties of 3-h-cooling induced directly after the end of SSSE. Occurrence of spontaneous seizures and seizure severity up to 8 weeks after SSSE were compared with normothermic SSSE controls. Furthermore, electrophysiological parameters assessing inhibition and excitation in the dentate gyrus were assessed at multiple time points. Post SSSE hypothermia did not prevent the occurrence of seizures in any animal. Eight weeks after SSSE, Racine motor seizures trended to be less severe following cooling (4.0±0.6) compared with normothermic controls (4.8±0.2) but the difference was not significant when testing for multiple comparisons. Early loss of inhibition that is typically seen following SSSE was somewhat attenuated in cooled animals 3h after SSSE as expressed by smaller paired-pulse ratios (PPR; 0.16±0.21) compared with normothermic controls (0.54±0.21) but difference was not significant either. Latency between stimulus artefact and excitatory post-synaptic potential 3h after SSSE, reciprocally reflecting neuronal excitation, was higher in animals that underwent hypothermia (8.29±2.45 ms) compared with controls (4.82±0.66 ms), difference was not significant after correction for multiple comparisons. In summary, the current experiments were not able to demonstrate prevention or mitigation of epileptogenesis with immediate short-term cooling following SSSE.

Safety and feasibility of nucleus accumbens stimulation in five patients with epilepsy.

In five adult patients with intractable partial epilepsy, safety and feasibility of chronic bilateral electrical stimulation of the nucleus accumbens (NAC) were assessed, also providing initial indications of therapeutic efficacy. Concurrent medication remained unchanged. In this phase 1 trial, clinical outcome parameters of interest were Quality of Life in Epilepsy questionnaire (QOLIE-31-P), Beck Depression Inventory, Mini International Neuropsychiatric Interview, neuropsychological testing, and Liverpool Seizure Severity Scale. Those data were obtained after 6 months of NAC stimulation and compared to the equivalent assessments made directly before implantation of electrodes. Additionally, monthly frequencies of simple partial seizures, complex partial seizures (CPS), and generalised tonic-clonic seizures (GTCS) were assessed during 3 months before electrode implantation and at the end of 6-month NAC stimulation. Proportion of responders, i.e. ≥50 % reduction in frequency of disabling seizures (sum of CPS and GTCS), was calculated. Main findings were unchanged psychiatric and neuropsychological assessment and a significant decrease in seizure severity (p = 0.043). QOLIE-31-P total score trended towards improvement (p = 0.068). Two out of five participants were responders. The median reduction in frequency of disabling seizures was 37.5 %. In summary, we provide initial evidence for safety and feasibility of chronic electrical stimulation of the NAC in patients with intractable partial epilepsy, as indicated by largely unchanged neurocognitive function and psychiatric comorbidity. Even though our data are underpowered to reliably assess efficacy, the significant decrease in seizure severity provides an initial indication of antiictal efficacy of NAC stimulation. This calls for larger and at best randomised trials to further elucidate efficacy of NAC stimulation in patients with pharmacologically intractable epilepsy.

Deep hypothermia terminates status epilepticus--an experimental study.

In search for novel treatment approaches in status epilepticus, the anticonvulsant effect of moderate and deep hypothermia was assessed in a rodent model. Self-sustaining status epilepticus (SSSE) characterized by spontaneous high-amplitude discharges recorded from the dentate gyrus was induced in male adult rats by electrical stimulation of the perforant path. After the end of stimulation, rats underwent cooling to 30 °C (n=7) and 20 °C (n=10) for 120 min and rewarming to 37 °C for another 60 min. Control SSSE animals (n=6) remained untreated for 180 min. Frequency of epileptiform discharges was assessed every 10 min. At the target temperature of 20 °C, SSSE was completely suppressed in four rats, this effect was not observed in any animal of the other two groups (p=0.043). On rewarming, seizure activity did not reoccur. Discharge frequency was significantly lower in the 20 °C group at most time points after 60 min of cooling. Following deep hypothermia, eight animals were rewarmed, all survived and moved spontaneously at 37 °C. These experimental data indicate the strong and enduring anticonvulsant and obviously safe properties of cooling down to 20 °C. Patients with status epilepticus refractory to first- and second-line anticonvulsants may benefit from deep cooling as an effective non-pharmacological adjunct to anesthetic anticonvulsants.