Interleukin-6, interleukin-1 beta and interleukin-1 receptor antagonist levels in epileptic seizures

PurposeData are accumulating to support the involvement of inflammatory mechanisms in the pathogenesis and course of epilepsy.MethodsThe aim of this study was to examine seizure-induced changes in plasma concentrations of interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1Ra), and interleukin-1 beta (IL-1β) in 23 patients with epilepsy undergoing a video-electroencephalography (EEG) study. Patients were divided into groups based on epilepsy type as follows: temporal lobe epilepsy (TLE) (n = 6), extra-temporal lobe epilepsy (XLE) (n = 8) and idiopathic generalised epilepsy (IGE) (n = 9). Serum levels of IL-1β, IL-1Ra and IL-6 were measured at baseline, immediately after the epileptic seizure, and at 3 h, 6 h, 12 h and 24 h after the seizure.ResultsWe demonstrated a significant increase in plasma levels of IL-6 and IL-1Ra that peaked at 12 h into the post-ictal period (p < 0.05). IL-1β levels did not differ from the baseline levels. We did not observe any differences in post-ictal cytokine release patterns between the TLE, XLE and IGE groups.ConclusionThe present study confirms the findings that epileptic seizures induce the production of IL-6 and IL-1Ra.     

Interleukin-6 levels are increased in temporal lobe epilepsy but not in extra-temporal lobe epilepsy

Previous studies have reported activation of inflammatory cytokines in seizures, but clinical characteristics of epilepsy associated with cytokine activation have not been well established. In this study, serum levels of interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1RA) were measured, and clinical characteristics of epilepsy were assessed in 86 well-evaluated patients with refractory focal epilepsy and in 5 patients with controlled focal epilepsy. Epilepsy was evaluated based on patient histories, electroclinical findings, and high-resolution brain MRI scans. Sixty-three healthy blood donors served as controls. IL-6 concentrations were chronically increased in epilepsy patients (11%) compared with healthy controls (0%) (P = 0.007). Increased levels of IL-6 were more prevalent in patients with temporal lobe epilepsy (TLE) compared to patients with extra-TLE (P = 0.028). Also the mean and the median serum levels of IL-6 were higher in patients with TLE than in patients with extra-TLE (P = 0.042). Concentrations of IL-1RA were not significantly different in patients compared with controls. Indicated by increased levels of IL-6 in TLE, epilepsy type is important in determining chronic overproduction of cytokines in refractory focal epilepsy. The results may reflect a chronic immunological process in the brain in patients with refractory epilepsy.     

Sleep-wake behavior and responses to sleep deprivation of mice lacking both interleukin-1 beta receptor 1 and tumor necrosis factor-alpha receptor 1

Data indicate that interleukin (IL)-1β and tumor necrosis factor-α (TNFα) are involved in the regulation of non-rapid eye movement sleep (NREMS). Previous studies demonstrate that mice lacking the IL-1β type 1 receptor spend less time in NREMS during the light period, whereas mice lacking the p55 (type 1) receptor for TNFα spend less time in NREMS during the dark period. To further investigate roles for IL-1β and TNFα in sleep regulation we phenotyped sleep and responses to sleep deprivation of mice lacking both the IL-1β receptor 1 and TNFα receptor 1 (IL-1R1/TNFR1 KO). Male adult mice (IL-1R1/TNFR1 KO, n = 14; B6129SF2/J, n = 14) were surgically instrumented with EEG electrodes and with a thermistor to measure brain temperature. After recovery and adaptation to the recording apparatus, 48 h of undisturbed baseline recordings were obtained. Mice were then subjected to 6 h sleep deprivation at light onset by gentle handling. IL-1R1/TNFR1 KO mice spent less time in NREMS during the last 6 h of the dark period and less time in rapid eye movement sleep (REMS) during the light period. There were no differences between strains in the diurnal timing of delta power during NREMS. However, there were strain differences in the relative power spectra of the NREMS EEG during both the light period and the dark period. In addition, during the light period relative power in the theta frequency band of the REMS EEG differed between strains. After sleep deprivation, control mice exhibited prolonged increases in NREMS and REMS, whereas the duration of the NREMS increase was shorter and there was no increase in REMS of IL-1R1/TNFR1 KO mice. Delta power during NREMS increased in both strains after sleep deprivation, but the increase in delta power during NREMS of IL-1R1/TNFR1 KO mice was of greater magnitude and of longer duration than that observed in control mice. These results provide additional evidence that the IL-1β and TNFα cytokine systems play a role in sleep regulation and in the alterations in sleep that follow prolonged wakefulness.     

Predictors of seizure outcomes in patients with diffuse low-grade glioma-related epilepsy after complete glioma removal

Aims

We aimed to identify predictors of postoperative seizures in patients with diffuse low-grade glioma (DLGG)-related epilepsy after complete tumor resection in this study.

Methods

We retrospectively collected data from individuals with DLGG-related epilepsy whose tumors were completely resected at Xiangya Hospital, Central South University between January 2014 and January 2020. The predictors of seizure outcomes were assessed by employing univariate analysis and a multivariate logistic regression model in a backward binary logistic regression model.

Results

Among the 118 cases that met the inclusion criteria, 83.05% were seizure-free following an average follow-up of 4.27 ± 1.65 years, all of whom were classified as International League Against Epilepsy class I outcome. Univariate and multivariate analyses indicated that seizure duration of >6 years (odds ratio [OR], 6.62; 95% confidence interval [CI], 1.76–24.98; p = 0.005) and first clinical symptoms other than seizures (OR, 4.51; 95% CI, 1.43–14.23; p = 1.010) were both independent predictors of unfavorable seizure outcomes.

Conclusion

Our results imply that satisfactory seizure outcomes can be achieved in most patients with DLGG-related epilepsy after complete tumor resection. Patients with seizure duration of >6 years or first clinical symptoms other than seizures were more likely to experience postoperative seizure recurrence.     

Neurofilament light,glial fibrillary acidic protein,and tau in a regional epilepsy cohort: High plasma levels are rare but related to seizures

Objective

Higher levels of biochemical blood markers of brain injury have been described immediately after tonic–clonic seizures and in drug-resistant epilepsy, but the levels of such markers in epilepsy in general have not been well characterized. We analyzed neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and tau in a regional hospital-based epilepsy cohort and investigated what proportion of patients have levels suggesting brain injury, and whether certain epilepsy features are associated with high levels.

Methods

Biomarker levels were measured in 204 patients with an epilepsy diagnosis participating in a prospective regional biobank study, with age and sex distribution correlating closely to that of all patients seen for epilepsy in the health care region. Absolute biomarker levels were assessed between two patient groups: patients reporting seizures within the 2 months preceding inclusion and patients who did not have seizures for more than 1 year. We also assessed the proportion of patients with above-normal levels of NfL.

Results

NfL and GFAP, but not tau, increased with age. Twenty-seven patients had abnormally high levels of NfL. Factors associated with such levels were recent seizures (p = .010) and epileptogenic lesion on radiology (p = .001). Levels of NfL (p = .006) and GFAP (p = .032) were significantly higher in young patients (<65 years) with seizures ≤2 months before inclusion compared to those who reported no seizures for >1 year. NfL and GFAP correlated weakly with the number of days since last seizure (NfL: r_s = −.228, p = .007; GFAP: r_s = −.167, p = .048) in young patients. NfL also correlated weakly with seizure frequency in the last 2 months (r_s = .162, p = .047).

Significance

Most patients with epilepsy do not have biochemical evidence of brain injury. The association with seizures merits further study; future studies should aim for longitudinal sampling and examine whether individual variations in NfL or GFAP levels could reflect seizure activity.     

Lacosamide in patients with temporal lobe epilepsy: An observational multicentric open-label study

PurposeThe aim of this study was to evaluate the efficacy and tolerability of lacosamide (LCM) both as add-on therapy and monotherapy in patients with temporal lobe epilepsy (TLE) based on an observational, prospective, multicenter study.MethodsWe enrolled 100 patients (mean age: 43.4 ± 12.53 years, 57 females) with nonlesional TLE and TLE with hippocampal sclerosis (HS) that did not respond to the first drug and who were referred to epilepsy centers of the University of Catanzaro, University of Palermo, IRCSS Neuromed of Pozzilli, and Otto-von-Guericke University of Magdeburg. In this open-label, multicenter trial, patients were initiated on oral LCM as add-on therapy to first AED monotherapy or as a later add-on to two concomitant AEDs. Seizure frequency changes and adverse events were recorded for at least six months after LCM was added.ResultsFourteen patients dropped out because of positive MRI findings other than HS. Patients received LCM at 200–400 mg/day. Fifty-eight out of these 86 patients with seizures that were previously drug-resistant had reduced seizure frequency after introduction of LCM. Forty-five out of 86 patients were classified as responders (12 were seizure-free, 33 achieved a reduction > 50%). Interestingly, five patients out of 86 achieved seizure freedom for at least one year and progressively switched to monotherapy with LCM, and all five remained seizure-free at follow-up (6–48 months).ConclusionsOur results may suggest that LCM at doses of 200 to 400 mg/day reduces seizure frequency in adults with TLE regardless of the presence of HS, and that it may be considered as a first add-on treatment for patients with pharmacoresistant TLE.     

NK and CD4 T cell changes in blood after seizures in temporal lobe epilepsy

Immunological phenomena may affect the course of focal epilepsy. We analyzed prospectively the pre- and postictal distribution of leukocyte subsets in epileptic patients.

Methods

Twenty-two patients (age 36.6 ± 10.8 years, 50% men) with temporal lobe epilepsy were included. Distribution of leukocyte subsets and serum levels of epinephrine were measured in peripheral blood immediately and 24 h after seizures and compared to baseline values.

Results

In the immediate postictal state (10 ± 6 min), we observed a significant relative increase of total leukocytes (42%, p = 0.0004), neutrophil leukocytes (55%, p = 0.0007), total lymphocytes (45%, p = 0.0019), natural killer (NK) cells (104%, p = 0.0017), and epinephrine (454%, p = 0.0014). CD4⁺ T cells decreased by 13% (p = 0.0113). These postictal changes remained significant considering only complex partial seizures (n = 17). The alterations were more pronounced in patients with hippocampal sclerosis. Treatment with valproic acid (VPA) was accompanied by a greater postictal decrease of CD4⁺ T cells (25% compared to 5% in patients without VPA, p = 0.041) while treatment with levetiracetam (LEV) correlated with a low postictal increase of NK-like T cells (4% versus 41%, p = 0.016). Twenty-four hours after the seizures the alterations had resolved.

Conclusion

Profound postictal changes in the immune cell composition of the peripheral blood may have been mediated by epinephrine release. The greater immune response in patients with mesial temporal lobe epilepsy due to hippocampal sclerosis may reflect a close relationship between mesial temporal structures and the sympathetic nerve system. VPA and LEV may have an impact on seizure induced immunological changes.     

Does the seizure frequency increase in Ramadan?

During Ramadan, the ninth month of the Islamic lunar calendar, adult Muslims are required to refrain from taking any food, beverages, or oral drugs, as well as from sexual intercourse between dawn and sunset. In this study, we aimed at discovering alterations in drug regimens and the seizure frequency of epileptic patients during Ramadan (15 October 2004–13 November 2004). In the 3 months following Ramadan in the year 2004, 114 patients with epilepsy who were fasting during Ramadan were examined at our Epilepsy Department. Of the 114 patients who were included in the study, 38 patients had seizures and one of these patients developed status epilepticus during Ramadan. When the seizure frequency of these patients during Ramadan was compared to that in the last 1 year and last 3 months period just prior to Ramadan, a statistically significant increase was observed (p < 0.001). Moreover, there was an important increase in the risk of having seizures in the patients who changed their drug regimens compared with those who did not (p < 0.05). In the patients who received monotherapy or polytherapy, no difference in the frequency of seizures during Ramadan was seen (p > 0.05).During Ramadan, an increase in the seizure frequency of patients with epilepsy was observed. The most important reason for this situation was the alteration in the pharmacokinetics and pharmacodynamics of drugs, and consequently, in their efficacy. We believe that in the patients who received monotherapy and who did not change their drug regimes, the increase in seizure frequency may have been related to the changes in their daily rhythms, emotional stress, tiredness and their day-long fasting.     

Successful initiation of combined therapy with valproate sodium injection and divalproex sodium extended-release tablets in the epilepsy monitoring unit

Summary: Purpose: Patients in epilepsy monitoring units (EMUs) often require aggressive initiation or reinitiation of therapy before discharge. We developed a simple dosing scheme using valproate sodium injection (VPA‐IV) and divalproex sodium extended‐release (VPA‐ER) tablets to minimize the time required for initiation of therapy, without increasing the likelihood of seizures and adverse effects. Methods: We identified 42 patients in the EMU, naïve to VPA‐IV and VPA‐ER, for whom one of the discharge AEDs included divalproex sodium. On the day of discharge, patients were loaded with 20 mg/kg VPA‐IV at 6 mg/kg/min, followed by ～20 mg/kg VPA‐ER within 1 h. The discharge daily dose of VPA‐ER was identical to the dose given after the IV load. We assessed tolerability and seizure occurrence during infusion, at 1 h, 4 h, and 1 week after discharge. Results: All patients tolerated the VPA‐IV dose followed by VPA‐ER. Four patients reported mild nausea, and two patients reported mild dizziness within 4 h. No seizures or significant changes in heart rate or blood pressure occurred within 4 h, and all patients were discharged the same day. All patients denied systemic complaints at 1 week, and five had seizures during the week after discharge. All patients had improved seizure frequencies at the end of the first week. Conclusions: VPA‐IV is well tolerated and convenient for rapid loading in the EMU. When promptly followed by VPA‐ER, seizure control remains excellent.     

TRPV1 promotes repetitive febrile seizures by pro-inflammatory cytokines in immature brain

Febrile seizure (FS) is the most common seizure disorder in children, and children with FS are regarded as a high risk for the eventual development of epilepsy. Brain inflammation may be implicated in the mechanism of FS. Transient receptor potential vanilloid 1 (TRPV1) is believed to act as a monitor and regulator of body temperature. The role of inflammation in synaptic plasticity mediation indicates that TRPV1 is relevant to several nervous system diseases, such as epilepsy. Here, we report a critical role for TRPV1 in a febrile seizure mouse model and reveal increased levels of pro-inflammatory factors in the immature brain. Animals were subjected to hyperthermia for 30 min, which generates seizures lasting approximately 20 min, and then were used for experiments. To invoke frequently repetitive febrile seizures, mice are exposed to hyperthermia for three times daily at an interval of 4 h between every time induced seizure, and a total of 4 days to induce. Behavioral testing for febrile seizures revealed that a TRPV1 knock-out mouse model demonstrated a prolonged onset latency and a shortened duration and seizure grade of febrile seizure when compared with wild type (WT) mice. The expression levels of both TRPV1 mRNA and protein increased after a hyperthermia-induced febrile seizure in WT mice. Notably, TRPV1 activation resulted in a significant elevation in the expression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α and HMGB1) in the hippocampus and cortex. These data indicate that the reduction of TRPV1 expression parallels a decreased susceptibility to febrile seizures. Thus, preventative strategies might be developed for use during febrile seizures.     

Risk factors for valproic acid resistance in childhood absence epilepsy

AimsValproic acid (VPA) is reported to be effective for the control of absence seizures in 75% of children. The aim of this study was to determine the clinical and socio-demographic factors associated with VPA response in newly diagnosed childhood absence epilepsy (CAE) and to determine if these factors also influence the chances of achieving long-term seizure freedom.MethodsMedical charts of 180 children with CAE were retrospectively reviewed. Clinical, electroencephalographic and imaging findings were recorded to correlate with complete VPA response and long-term epilepsy outcome. Factors associated with non-responsiveness were identified individually and in a multivariable logistic regression analysis.ResultsTreatment was successful in 112 (58.3%) children. More children that were non-responsive to VPA experienced generalized tonic clonic seizures (GTCS) (33.8% vs. 13.4% for responders; p = 0.001) and 52.9% had a pre-treatment seizure frequency greater than 10/day (vs. 27.0% for responders; p < 0.001). Finally, responders were older at time of diagnosis versus non-responders (p = 0.001). Absence of long-term seizure freedom was linked to the presence of GTCS, the absence of initial response and the need for multiple AEDs to control seizures.InterpretationOur results suggest that clinical phenotypes are associated with reduced response rates to VPA. This should be taken into account when counselling families of children with newly diagnosed absence epilepsy.     

Levetiracetam as a first-line antiseizure medication in WHO grade 2 glioma: Time to seizure freedom and rates of treatment failure

Objective

The high seizure burden seen in World Health Association (WHO) grade 2 gliomas is well documented. This study aims to identify factors that influence the probability of seizure freedom (12 months of seizure remission) and treatment failure (antiseizure medication [ASM] cessation or introduction of an alternative) in patients with WHO grade 2 glioma.

Methods

This is a retrospective observational analysis of patients from a regional UK neurosurgical center with histologically proven (n = 146) WHO grade 2 glioma and brain tumor related epilepsy. Statistical analyses using both Kaplan-Meier and Cox proportional hazards models were undertaken, with a particular focus on treatment outcomes when the commonly prescribed ASM levetiracetam (n = 101) is used as first line.

Results

Treatment with levetiracetam as a first-line ASM resulted in a significant increase in the probability of seizure freedom (p < .05) at 2 years compared with treatment with an alternative ASM. Individuals presenting with focal seizures without bilateral tonic-clonic progression were between 39% and 42% significantly less likely to reach seizure freedom within 10 years (p < .05) and 132% more likely to fail treatment by 5 years (p < .01) when compared to individuals who had seizures with progression to bilateral tonic-clonic activity. ASM choice did not significantly affect treatment failure rates.

Significance

More than two-thirds of patients with WHO grade 2 glioma related epilepsy treated with levetiracetam first line achieve seizure freedom within 2 years and it is a reasonable first-choice agent. Experiencing mainly focal seizures without progression infers a significant long-term reduction in the chance of seizure freedom. Further studies are needed to inform ASM selection.     

Metyrapone abolishes spike–wave discharge seizures in genetic absence epilepsy rats from Strasbourg by reducing stress hormones

Objective

Stress is one of the most commonly reported triggers for seizures in patients with epilepsy, although the mechanisms that mediate this effect are not established. The clinical evidence supporting this is derived from patients' subjective experience of stress, and how this influences their own seizures. Animal models can be used to explore this phenomenon in controlled environments, free from subjective bias. Here, we used genetic absence epilepsy rats from Strasbourg (GAERS), a genetic rat model of absence epilepsy, to explore the influence of stress and stress hormones on spontaneous seizures.

Methods

Adult male GAERS (n = 38) and nonepileptic control (NEC) rats (n = 4) were used. First, rats were subjected to 30-min restraint stress to assess hypothalamic–pituitary–adrenal axis function. Next, we assessed the effects of 30-min noise stress, and cage tilt stress, on spike–wave discharge seizures in GAERS. We then performed pharmacological experiments to assess the direct effects of stress hormones on seizures, including corticosterone, metyrapone, and deoxycorticosterone.

Results

GAERS exhibited elevated baseline corticosterone levels, compared to NEC rats. Noise stress and cage tilt stress significantly enhanced seizure incidence (p < .05), but only during stress periods. Exogenous corticosterone administration also significantly increased seizure occurrence (p < .05). Metyrapone, an inhibitor of corticosterone synthesis, completely abolished seizures in GAERS, and seizures remained suppressed for >2 h. However, deoxycorticosterone, the precursor of corticosterone, increased seizures.

Significance

These results suggest that GAERS exhibit elevations in stress hormones, and this may contribute to seizures. Inhibiting corticosterone synthesis with metyrapone prevents seizures in GAERS, and shows potential for repurposing this drug as a future antiseizure medication.     

Blood levels of cytokines in children with idiopathic partial and generalized epilepsy

PurposeAntiepileptic drugs have been reported to reduce the levels of serum immunoglobulins and affect the production and levels of certain cytokines. We investigated the effects of valproic acid (VPA) and topiramate (TPM) on the blood levels of interleukin (IL)-1α, IL-1β, IL-6, IL-10, and TNF-α in children with idiopathic generalized and partial epilepsy.MethodsForty prepubertal children aged 6–12 (mean 8.3 ± 1.7) years, 19/40 (47.5%) female and 21/40 (52.5%) male, with idiopathic generalized or partial epilepsy diagnosed in the child neurology outpatient clinic were included. The patients were divided into two treatment groups: 20 were treated with VPA and 20 with TPM. The plasma levels of IL-1α, IL-1β, IL-6, IL-10, TNF-α were measured using ELISA method before the initiation of treatment and at the 6th and 12th months of the treatment. The Chi-square test was used to compare qualitative data. To compare the periods, recurrence measurements were done using variance analysis and Freidman 2-sided variance analysis. p < 0.05 was considered as statistically significant.ResultsIn the VPA group, the levels of IL-1α significantly increased at 12 months while the levels of IL-10 decreased at 6 months of treatment compared to values before treatment (p < 0.05). There was no significant difference in levels of IL-1β, IL-6, TNF-α (p > 0.05). In the TPM group, lower levels of IL-10 were observed at 6th and 12th months compared to the onset of treatment (p < 0.05).ConclusionThe results of this study demonstrated that VPA and TPM might lead to changes in the levels of cytokines in epileptic patients. The next step would be to investigate the relation of these findings to the outcome of epilepsy and response to treatment.     

The role of brain cytokines in mediating the behavioral and neuroendocrine effects of intracerebral Mycoplasma fermentans

Intracerebral administration of Mycoplasma fermentans (MF), a small microorganism that has been found in the brain of some AIDS patients, induces behavioral and neuroendocrine alterations in rats. To examine the role of tumor necrosis factor-α (TNFα) and interleukin-1 (IL-1) in mediating these effects we measured MF-induced expression of TNFα and IL-1β mRNA in various brain regions, and the effects of TNFα synthesis blockers and IL-1 receptor antagonist (IL-1ra) on MF-induced sickness behavior and adrenocortical activation. Intracerebroventricular (i.c.v.) administration of heat-inactivated MF induced the expression of both TNFα and IL-1β mRNA in the cortex, dorsal hippocampus, amygdala, and hypothalamus. Pre-treatment of rats with either TNFα synthesis blockers, pentoxifylline or rolipram, or with IL-1ra did not attenuate MF-induced anorexia, body weight loss, and suppression of social behavior. However, simultaneous administration of both pentoxifylline and IL-1ra markedly attenuated MF-induced anorexia and body weight loss, but had no effect on the suppression of social behavior. Pre-treatment with pentoxifylline, but not with IL-1ra, significantly attenuated MF-induced corticosterone (CS) secretion. Together, these findings indicate that both TNFα and IL-1 participate, in a complementary manner, in mediating some of the behavioral effects of MF, whereas only TNFα, but not IL-1, is involved in mediating MF-induced adrenocortical activation. We suggest that cytokines within the brain are involved in mediating at least some of the neurobehavioral and neuroendocrine abnormalities that may be produced by MF in AIDS patients.     

Atrophy of mesial structures in patients with temporal lobe epilepsy: Cause or consequence of repeated seizures?

We studied 70 epileptic patients by using magnetic resonance imaging volumetric measurements of amygdala (AM) and hippocampal formation (HF). Fifty patients presented with intractable temporal lobe epilepsy (TLE), 10 patients had focal extratemporal lobe epilepsy, and 10 had generalized epilepsy. In 91% of the 45 TLE patients without foreign tissue lesions, there was significant smallness of the AM and/or HF coinciding with the side of electroencephalographic seizure onset. No significant smallness or asymmetry was demonstrated in patients with focal extratemporal or generalized epilepsy. We performed a linear regression analysis, plotting the number of years of recurrent seizures and the estimated seizure frequency against the volumes of the AM and HF. There was no correlation between either of these two parameters and AM or HF volume (p > 0.9). There was also no correlation between the patient's age and volumetric measurements of AM or HF, nor did these measurements correlate with the occurrence of generalized seizures. On the other hand, patients with antecedent prolonged febrile convulsions in early childhood had significantly smaller AM and HF, compared with those without such a history (p < 0.001). The findings indicate that repeated seizures or longer duration of epilepsy do not cause increased atrophy of AM or HF that is measurable by volumetric magnetic resonance imaging.     

A randomized phase 2b efficacy study in patients with seizure episodes with a predictable pattern using Staccato® alprazolam for rapid seizure termination

Objective

Alprazolam administered via the Staccato® breath-actuated device is delivered into the deep lung for rapid systemic exposure and is a potential therapy for rapid epileptic seizure termination (REST). We conducted an inpatient study (ENGAGE-E-001 [NCT03478982]) in patients with stereotypic seizure episodes with prolonged or repetitive seizures to determine whether Staccato alprazolam rapidly terminates seizures in a small observed population after administration under direct supervision.

Methods

Adult patients with established diagnosis of focal and/or generalized epilepsy with a documented history of seizure episodes with a predictable pattern were enrolled. They were randomized 1:1:1 to double-blind treatment of a single seizure event with one dose of Staccato alprazolam 1.0 mg or 2.0 mg, or Staccato placebo in an inpatient unit. The primary end point of the study was the proportion of responders in each treatment group achieving seizure activity cessation within 2 min after administration of study drug and no recurrence of seizure activity within 2 h.

Results

A total of 273 patients were screened, and 116 randomized patients received treatment with the study drug in the double-blind part. The proportion of treated patients who were responders was 65.8% for each of Staccato alprazolam 1.0 mg (n = 38; p = .0392) and 2.0 mg (n = 38; p = .0392), compared with 42.5% for Staccato placebo (n = 40). Staccato alprazolam was well tolerated when administered as a single dose of 1.0 or 2.0 mg: cough and somnolence were the most common adverse events (AEs) (both 14.5%), followed by dysgeusia (13.2%). AEs were mostly mild or moderate in intensity; there were no treatment-related serious AEs.

Significance

Both 1.0 mg and 2.0 mg doses of Staccato alprazolam demonstrated efficacy in rapidly terminating seizures in an inpatient setting and were well tolerated. The next step is a Phase 3 confirmatory study to demonstrate efficacy and safety of Staccato alprazolam for rapid cessation of seizures in an outpatient setting.     

Expression of TH1 and TH17 cytokines and transcription factors in multiple sclerosis patients: Does baseline T-Bet mRNA predict the response to interferon-beta treatment?

We studied the effect of one-year interferon (IFN)-beta treatment on the in vivo mRNA expression of IFN-γ, interleukin (IL)-17, T-bet and RoR-γt, on peripheral blood mononuclear cells (PBMC) from 36 multiple sclerosis (MS) patients. In the total MS group, IFN-beta induced decrease in mRNA levels of IFN-γ and T-bet (p < 0.0001), while the levels of IL-17 and RoR-γt remained similar. In both responders and non-responders, IFN-beta induced significant decrease of IFN-γ (p < 0.0001 and p = 0.011, respectively), while decrease in T-bet was detected only in responders (p < 0.0001). Higher pre-treatment T-bet allowed prediction of the clinical response in the first year (β = 0.601, p = 0.036). Our preliminary findings suggest that T-bet expression might be a potential prognostic marker of treatment response to IFN-beta in MS.     

Multiple hippocampal transections for intractable hippocampal epilepsy: Seizure outcome

PurposeThe purpose of this study was to evaluate the seizure outcomes after transverse multiple hippocampal transections (MHTs) in 13 patients with intractable TLE.MethodsThirteen patients with normal memory scores, including 8 with nonlesional hippocampi on MRI, had temporal lobe epilepsy (TLE) necessitating depth electrode implantation. After confirming hippocampal seizure onset, they underwent MHT. Intraoperative monitoring was done with 5–6 hippocampal electrodes spaced at approximately 1-cm intervals and spike counting for 5–8 min before each cut. The number of transections ranged between 4 and 7. Neuropsychological assessment was completed preoperatively and postoperatively for all patients and will be reported separately.ResultsDuration of epilepsy ranged between 5 and 55 years. There were no complications. Intraoperatively, MHT resulted in marked spike reduction (p = 0.003, paired t-test). Ten patients (77%) are seizure-free (average follow-up was 33 months, range 20–65 months) without medication changes. One of the 3 patients with persistent seizures had an MRI revealing incomplete transections, another had an additional neocortical seizure focus (as suggested by pure aphasic seizures), and the third had only 2 seizures in 4 years, one of which occurred during antiseizure medication withdrawal. Verbal and visual memory outcomes will be reported separately. Right and left hippocampal volumes were not different preoperatively (n = 12, p = 0.64, Wilcoxon signed-rank test), but the transected hippocampal volume decreased postoperatively (p = 0.0173).ConclusionsMultiple hippocampal transections provide an effective intervention and a safe alternative to temporal lobectomy in patients with hippocampal epilepsy.     

In-session seizures during low-frequency repetitive transcranial magnetic stimulation in patients with epilepsy

Low-frequency repetitive transcranial magnetic stimulation (rTMS) is emerging as a therapeutic tool for patients with intractable epilepsy. Although seizures during treatment have been reported as adverse events in some patients, the nature and severity of seizures that may be provoked by low-frequency rTMS in patients with epilepsy have not been extensively studied. Accordingly, this article documents seizures in patients (n = 5) with intractable epilepsy and average seizure frequency greater than one per day who underwent 1-Hz rTMS for seizure suppression. We report three observations in the present case series: (1) in each instance the in-session seizure was typical in semiology to the patient’s habitual seizures, (2) the duration of each documented seizure was either the same as or shorter than the patients’ baseline seizures, and (3) the overall neurological outcome on follow-up was not affected by the in-session seizures. More data will be required for valid conclusions with respect to safety and tolerability of low-frequency rTMS in patients with epilepsy, but it is noteworthy from our perspective that seizures during rTMS in this series were similar to the patients’ habitual seizures, occurred in patients with epilepsy with baseline seizure frequency exceeding one per day, and did not correlate with a poor neurological outcome or with absence of clinical response to rTMS.