Evidence based noninvasive presurgical evaluation for patients with drug resistant epilepsies.

PURPOSE OF REVIEW: To review the current practices and evidence for the diagnostic accuracy and the benefits of presurgical evaluation. RECENT FINDINGS: Preoperative evaluation of patients with drug-resistant focal epilepsies and subsequent epilepsy surgery leads to a significant proportion of seizure-free patients. Even those who are not completely seizure free postoperatively often experience improved quality of life with better social integration. Systematic reviews and meta-analysis on the diagnostic accuracy are available for Video-electroencephalographic (EEG) monitoring, magnetic resonance imaging (MRI), electric and magnetic source imaging, and functional MRI for lateralization of language and memory. There are currently no evidence-based international guidelines for presurgical evaluation and epilepsy surgery. SUMMARY: Presurgical evaluation is a complex multidisciplinary and multiprofessional clinical pathway. We rely on limited consensus-based recommendations regarding the required staffing or methodological expertise in epilepsy centers.

Treatment and care of women with epilepsy before, during, and after pregnancy: a practical guide.

Women with epilepsy (WWE) wishing for a child represent a highly relevant subgroup of epilepsy patients. The treating epileptologist needs to delineate the epilepsy syndrome and choose the appropriate anti-seizure medication (ASM) considering the main goal of seizure freedom, teratogenic risks, changes in drug metabolism during pregnancy and postpartum, demanding for up-titration during and down-titration after pregnancy. Folic acid or vitamin K supplements and breastfeeding are also discussed in this review. Lamotrigine and levetiracetam have the lowest teratogenic potential. Data on teratogenic risks are also favorable for oxcarbazepine, whereas topiramate tends to have an unfavorable profile. Valproate needs special emphasis. It is most effective in generalized seizures but should be avoided whenever possible due to its teratogenic effects and the negative impact on neuropsychological development of in utero-exposed children. Valproate still has its justification in patients not achieving seizure freedom with other ASMs or if a woman decides to or cannot become pregnant for any reason. When valproate is the most appropriate treatment option, the patient and caregiver must be fully informed of the risks associated with its use during pregnancies. Folate supplementation is recommended to reduce the risk of major congenital malformations. However, there is insufficient information to address the optimal dose and it is unclear whether higher doses offer greater protection. There is currently no general recommendation for a peripartum vitamin K prophylaxis. During pregnancy most ASMs (e.g. lamotrigine, oxcarbazepine, and levetiracetam) need to be increased to compensate for the decline in serum levels; exceptions are valproate and carbamazepine. Postpartum, baseline levels are reached relatively fast, and down-titration is performed empirically. Many ASMs in monotherapy are (moderately) safe for breastfeeding and women should be encouraged to do so. This review provides a practically oriented overview of the complex management of WWE before, during, and after pregnancy.

Development and Validation of the 5-SENSE Score to Predict Focality of the Seizure-Onset Zone as Assessed by Stereoelectroencephalography.

Importance: Stereoelectroencephalography (SEEG) has become the criterion standard in case of inconclusive noninvasive presurgical epilepsy workup. However, up to 40% of patients are subsequently not offered surgery because the seizure-onset zone is less focal than expected or cannot be identified. Objective: To predict focality of the seizure-onset zone in SEEG, the 5-point 5-SENSE score was developed and validated. Design, Setting, and Participants: This was a monocentric cohort study for score development followed by multicenter validation with patient selection intervals between February 2002 to October 2018 and May 2002 to December 2019. The minimum follow-up period was 1 year. Patients with drug-resistant epilepsy undergoing SEEG at the Montreal Neurological Institute were analyzed to identify a focal seizure-onset zone. Selection criteria were 2 or more seizures in electroencephalography and availability of complete neuropsychological and neuroimaging data sets. For validation, patients from 9 epilepsy centers meeting these criteria were included. Analysis took place between May and July 2021. Main Outcomes and Measures: Based on SEEG, patients were grouped as focal and nonfocal seizure-onset zone. Demographic, clinical, electroencephalography, neuroimaging, and neuropsychology data were analyzed, and a multiple logistic regression model for developing a score to predict SEEG focality was created and validated in an independent sample. Results: A total of 128 patients (57 women [44.5%]; median [range] age, 31 [13-58] years) were analyzed for score development and 207 patients (97 women [46.9%]; median [range] age, 32 [16-70] years) were analyzed for validation. The score comprised the following 5 predictive variables: focal lesion on structural magnetic resonance imaging, absence of bilateral independent spikes in scalp electroencephalography, localizing neuropsychological deficit, strongly localizing semiology, and regional ictal scalp electroencephalography onset. The 5-SENSE score had an optimal mean (SD) probability cutoff for identifying a focal seizure-onset zone of 37.6 (3.5). Area under the curve, specificity, and sensitivity were 0.83, 76.3% (95% CI, 66.7-85.8), and 83.3% (95% CI, 72.30-94.1), respectively. Validation showed 76.0% (95% CI, 67.5-84.0) specificity and 52.3% (95% CI, 43.0-61.5) sensitivity. Conclusions and Relevance: High specificity in score development and validation confirms that the 5-SENSE score predicts patients where SEEG is unlikely to identify a focal seizure-onset zone. It is a simple and useful tool for assisting clinicians to reduce unnecessary invasive diagnostic burden on patients and overutilization of limited health care resources.

A case report: New-onset refractory status epilepticus in a patient with FASTKD2-related mitochondrial disease.

Objectives: New-onset refractory status epilepticus (NORSE) is associated with high morbidity and mortality. Despite extensive work-up, the underlying etiology remains unknown in 50% of affected individuals. Mitochondrial disorders represent rare causes of NORSE. Biallelic variants in FASTKD2 were reported as a cause of infantile encephalomyopathy with refractory epilepsy. Case description: In the study, we report a previously healthy 14-year-old with a new, homozygous FASTKD2 variant presenting with NORSE. Following a seizure-free period of 7 years, he experienced another super-refractory SE and subsequently developed drug-resistant focal epilepsy, mild myopathy, optic atrophy, and discrete psychomotor slowing. Structural MRI at the time of NORSE showed right temporo-parieto-occipital FLAIR hyperintensity and diffusion restriction, with extensive right hemispheric atrophy at the age of 22 years. Whole-exome sequencing revealed a novel homozygous loss of function variant [c.(1072C>T);(1072C>T)] [p.(Arg358Ter);(Arg358Ter)] in FASTKD2 (NM_001136193), resulting in a premature termination codon in the protein-coding region and loss of function of FASTKD2. Oxidative phosphorylation (OXPHOS) in muscle and skin fibroblasts was unremarkable. Conclusion: This is the first case of a normally developed adolescent with a new homozygous loss of function variant in FASTKD2, manifesting with NORSE. The phenotypical spectrum of FASTKD2-related mitochondrial disease is heterogeneous, ranging from recurrent status epilepticus and refractory focal epilepsy in an adolescent with normal cognitive development to severe forms of infantile mitochondrial encephalopathy. Although mitochondrial diseases are rare causes of NORSE, clinical features such as young age at onset and multi-system involvement should trigger genetic testing. Early diagnosis is essential for counseling and treatment considerations.

VarioGuide® frameless neuronavigation-guided stereoelectroencephalography in adult epilepsy patients: technique, accuracy and clinical experience.

BACKGROUND: Stereoelectroencephalography (SEEG) allows the identification of deep-seated seizure foci and determination of the epileptogenic zone (EZ) in drug-resistant epilepsy (DRE) patients. We evaluated the accuracy and treatment-associated morbidity of frameless VarioGuide® (VG) neuronavigation-guided depth electrode (DE) implantations. METHODS: We retrospectively identified all consecutive adult DRE patients, who underwent VG-neuronavigation DE implantations, between March 2013 and April 2019. Clinical data were extracted from the electronic patient charts. An interdisciplinary team agreed upon all treatment decisions. We performed trajectory planning with iPlan® Cranial software and DE implantations with the VG system. Each electrode's accuracy was assessed at the entry (EP), the centre (CP) and the target point (TP). We conducted correlation analyses to identify factors associated with accuracy. RESULTS: The study population comprised 17 patients (10 women) with a median age of 32.0 years (range 21.0-54.0). In total, 220 DEs (median length 49.3 mm, range 25.1-93.8) were implanted in 21 SEEG procedures (range 3-16 DEs/surgery). Adequate signals for postoperative SEEG were detected for all but one implanted DEs (99.5%); in 15/17 (88.2%) patients, the EZ was identified and 8/17 (47.1%) eventually underwent focus resection. The mean deviations were 3.2 ± 2.4 mm for EP, 3.0 ± 2.2 mm for CP and 2.7 ± 2.0 mm for TP. One patient suffered from postoperative SEEG-associated morbidity (i.e. conservatively treated delayed bacterial meningitis). No mortality or new neurological deficits were recorded. CONCLUSIONS: The accuracy of VG-SEEG proved sufficient to identify EZ in DRE patients and associated with a good risk-profile. It is a viable and safe alternative to frame-based or robotic systems.

Status epilepticus admissions during the COVID-19 pandemic in Salzburg-A population-based study.

Several emergencies were admitted less frequently to the hospital during the coronavirus disease 2019 (COVID-19) pandemic. To investigate whether this also occurred with status epilepticus (SE) we compared admissions due to first SE from March to April 2020 ("Time of COVID," TOC) with January to February 2020 ("pre-COVID," preCOV). We also compared admission numbers in TOC and preCOV with the respective 2-month periods in 2018 and 2019 in a retrospective cohort analysis. Two investigators independently searched the hospital patient database for various forms of SE. There was no significant change in the 2-month incidences of first SE in the city of Salzburg from preCOV of 6.1 (95% confidence interval [CI] 2.9-12.3) to TOC of 6.9/100 000 adults (95% CI 3.4-13.3). Admission numbers did not differ significantly from previous years. Estimated adjusted incidence was in line with a recent 5-year epidemiological study in Salzburg. However, a trend toward less-frequent nonconvulsive SE (NCSE) and loss of female predominance were indirect hints of underdiagnosing SE. In contrast to other medical conditions, SE most often presents clinically with impaired consciousness, which may promote admission to emergency departments even in times of lock-down. Further research of medical support of women and patients with NCSE during pandemic-related restrictions is warranted.

Correlation of EEG spectra, connectivity, and information theoretical biomarkers with psychological states in the epilepsy monitoring unit - A pilot study.

At the level of individual experience, the relation between electroencephalographic (EEG) phenomena and subjective ratings of psychological states is poorly examined. This study investigated the correlation of quantitative EEG markers with systematic high-frequency monitoring of psychological states in patients admitted to the epilepsy monitoring unit (EMU). We used a digital questionnaire, including eight standardized items about stress, energy level, mood, ward atmosphere, seizure likelihood, hopefulness/frustration, boredom, and self-efficacy. Self-assessments were collected four times per day, in total 15 times during the stay in the EMU. We extracted brainrate, Hjorth parameters, Hurst exponent, Wackermann parameters, and power spectral density from the EEG. We performed correlation between these quantitative EEG measures and responses to the 8 items and evaluated their significance on single subject and on group level. Twenty-one consecutive patients (12 women/9 men, median age: 29 years, range: 18-74 years) were recruited. On group level, no significant correlations were found whereas on single-subject level, we found significant correlations for 6 out of 21 patients. Most significant correlations were found between Hjorth parameters and items that reflect changes in mood or stress. This study supports the feasibility of correlating quantitative EEG measures with psychological states in routine EMU settings and emphasizes the need for single-subject statistics when assessing aspects with high interindividual variance. Future studies should select samples with high within-subject variability of psychological states and examine a subsample with patients encountering a critical number of seizures needed in order to relate the psychological states to the ultimate question: Are psychological states potential indicators for seizure likelihood?

Epidemiology of status epilepticus in adults: A population-based study on incidence, causes, and outcomes.

OBJECTIVE: In 2015, the International League Against Epilepsy (ILAE) proposed a new definition of status epilepticus (SE): 5 minutes of ongoing seizure activity to diagnose convulsive SE (CSE, ie, bilateral tonic-clonic SE) and 10 minutes for focal SE and absence SE, rather than the earlier criterion of 30 minutes. Based on semiology, several types of SE with prominent motor phenomena at any time (including CSE) were distinguished from those without (ie, nonconvulsive SE, NCSE). We present the first population-based incidence study applying the new 2015 ILAE definition and classification of SE and report the impact of the evolution of semiology and level of consciousness (LOC) on outcome. METHODS: We conducted a retrospective population-based incidence study of all adult patients with SE residing in the city of Salzburg between January 2011 and December 2015. Patients with hypoxic encephalopathy were excluded. SE was defined and classified according to the ILAE 2015. RESULTS: We identified 221 patients with a median age of 69 years (range 20-99 years). The age- and sex-adjusted incidence of a first episode of SE, NCSE, and SE with prominent motor phenomena (including CSE) was 36.1 (95% confidence interval [CI] 26.2-48.5), 12.1 (95% CI 6.8-20.0), and 24.0 (95% CI 16.0-34.5; including CSE 15.8 [95% CI 9.4-24.8]) per 100 000 adults per year, respectively. None of the patients whose SE ended with or consisted of only bilateral tonic-clonic activity died. In all other clinical presentations, case fatality was lower in awake patients (8.2%) compared with patients with impaired consciousness (33%). SIGNIFICANCE: This first population-based study using the ILAE 2015 definition and classification of SE found an increase of incidence of 10% compared to previous definitions. We also provide epidemiologic evidence that different patterns of status evolution and LOCs have strong prognostic implications.

Diagnostic and prognostic value of noninvasive long-term video-electroencephalographic monitoring in epilepsy surgery: A systematic review and meta-analysis from the E-PILEPSY consortium.

OBJECTIVE: The European Union-funded E-PILEPSY network (now continuing within the European Reference Network for rare and complex epilepsies [EpiCARE]) aims to harmonize and optimize presurgical diagnostic procedures by creating and implementing evidence-based guidelines across Europe. The present study evaluates the current evidence on the diagnostic accuracy of long-term video-electroencephalographic monitoring (LTM) in identifying the epileptogenic zone in epilepsy surgery candidates. METHODS: MEDLINE, Embase, CENTRAL, and ClinicalTrials.gov were searched for relevant articles. First, we used random-effects meta-analytical models to calculate pooled estimates of sensitivity and specificity with respect to postsurgical seizure freedom. In a second phase, we analyzed individual patient data in an exploratory fashion, assessing diagnostic accuracy within lesional and nonlesional temporal lobe epilepsy (TLE) and extratemporal lobe epilepsy (ETLE) patients. We also evaluated seizure freedom rate in the presence of "localizing" or "nonlocalizing" LTM within each group. The quality of evidence was assessed using the QUADAS-2 tool and the GRADE approach. RESULTS: Ninety-four studies were eligible. Forty-four were included in sensitivity meta-analysis and 34 in specificity meta-analysis. Pooled sensitivity was 0.70 (95% confidence interval [CI] = 0.60-0.80) and specificity was 0.40 (95% CI = 0.27-0.54). Subgroup analysis was based on individual data of 534 patients (41% men). In lesional TLE patients, sensitivity was 0.85 (95% CI = 0.81-0.89) and specificity was -0.19 (95% CI = 0.13-0.28). In lesional ETLE patients, a sensitivity of 0.47 (95% CI = 0.36-0.58) and specificity of 0.35 (95% CI = 0.21-0.53) were observed. In lesional TLE, if LTM was localizing and concordant with resection site, the seizure freedom rate was 247 of 333 (74%), whereas in lesional ETLE it was 34 of 56 (61%). The quality of evidence was assigned as "very low." SIGNIFICANCE: Long-term video-electroencephalographic monitoring is associated with moderate sensitivity and low specificity in identification of the epileptogenic zone. Sensitivity is remarkably higher in lesional TLE compared to lesional ETLE. Substantial heterogeneity across the studies indicates the need for improved design and quality of reporting.

Integrating the systematic assessment of psychological states in the epilepsy monitoring unit: Concept and compliance.

BACKGROUND: Admission to the epilepsy monitoring unit (EMU) for long-term video-electroencephalography (EEG) monitoring (VEEG) constitutes the gold standard for seizure diagnosis and presurgical evaluation. This study applied the concept of a high-frequency systematic monitoring of psychological states and tested patients' compliance in order to evaluate if its integration in the EMU is feasible and if patients benefit from the graphically underpinned discussion of their EMU stay-related cognitions and emotions. METHODS: The process-monitoring is technically realized by an internet-based device for data collection and data analysis, the Synergetic Navigation System (SNS). A convenient sample was enrolled: All eligible patients who were admitted to the EMU of the Department of Neurology, Christian Doppler Medical Center, Salzburg, Austria, between November 6th 2017 and January 26th 2018 were approached and recruited upon consent. After a short resource-oriented interview, each enrolled patient was provided with a tablet. The daily questionnaire included eight standardized and up to three personalized items. Self-assessments were collected every 5 h prior to meal times (6:30 am, 11:30 am, and 4:30 pm) and at 9:30 pm. The detailed visualizations of the patients' replies were discussed with the participants during a feedback session at the end of the EMU stay. RESULTS: Twenty-one patients (12 women/9 men, median age 29 years [range 18-74 years]) were consecutively recruited (72% of all eligible patients). Compliance rates were high (median: 82%, range 60%-100%) among the respondents. Mood correlated strongly with hopefulness (r = 0.71) and moderately with energy (r = 0.63) in all patients. When correlating the intraindividual medians of the process questionnaire time series with the pretest total scores, energy correlated moderately and negatively with the Perceived Stress Scale (PSS) (r = -0.45), while self-efficacy correlated moderately and negatively with the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) total scores in all patients (r = -0.5). Nine patients (43%) reported that they learned something meaningful about themselves after the feedback discussion of their individual time series. CONCLUSION: The results support the feasibility of high-frequency monitoring of psychological states and processes in routine EMU settings. Repeated daily collections four times per day of psychological surveys allow for the assessment of highly resolved, equidistant time series data, which gives insight into psychological states and processes during EMU admission.

Perampanel in patients with refractory and super-refractory status epilepticus in a neurological intensive care unit: A single-center audit of 30 patients.

In refractory status epilepticus (SE), γ-aminobutyric acidergic drugs become less effective and glutamate plays a major role in seizure perpetuation. Data on the efficacy of perampanel (PER) in treatment of refractory SE in humans are limited. Here, we present a single-center case series of patients with refractory SE who received PER orally in an intensive care unit. We retrospectively analyzed treatment response, outcome, and adverse effects of all patients with refractory SE in our Neurological Intensive Care Unit who received add-on PER between September 2012 and February 2018. Thirty patients with refractory SE (median = 72 years, range = 18-91, 77% women) were included. In 14 patients (47%), a high-dose approach was used, with a median initial dose of 24 mg (range = 16-32). In five patients (17%), SE could be terminated after PER administration (median dose = 6 mg, range = 6-20 mg, 2/5 patients in high-dose group). Clinical response was observed after a median of 24 hours (range = 8-48 hours), whereas electroencephalogram resolved after a median of 60 hours (range = 12-72 hours). Time to treatment response tended to be shorter in patients receiving high-dose PER (median clinical response = 16 hours vs 18 hours; electroencephalographic response = 24 hours vs 72 hours), but groups were too small for statistical analysis. Continuous cardiorespiratory monitoring showed no changes in cardiorespiratory function after "standard" and "high-dose" treatment. Elevated liver enzymes without clinical symptoms were observed after a median of 6 days in seven of 30 patients (23%; 57% high dose vs 43% standard dose), of whom six also received treatment with phenytoin (PHT). Outcome was unfavorable (death, persistent vegetative state) in 13 patients (43%; 39% high dose vs 61% standard dose), and good recovery (no significant disability, moderate disability) was achieved in nine patients (56% high dose vs 44% standard dose). Oral PER in loading doses up to 32 mg were well tolerated but could terminate SE only in a few patients (5/30; 17%). Long duration of SE, route of administration, and severe underlying brain dysfunction might be responsible for the modest result. An intravenous formulation is highly desired to explore the full clinical utility in the treatment of refractory SE.

Intravenous brivaracetam in status epilepticus: A retrospective single-center study.

Brivaracetam (BRV) is a high-affinity synaptic vesicle glycoprotein 2A ligand that is structurally related to levetiracetam (LEV). Compared to LEV, its affinity to the ligand is >10%-30% higher. Due to its more lipophilic characteristics, it might have a quicker penetration across the blood-brain barrier and potentially also a stronger anticonvulsant effect. Thus, we aimed to explore its usefulness in the treatment of status epilepticus (SE). We retrospectively assessed treatment response and adverse events in adjunctive treatment with intravenous BRV in patients with SE from January 2016 to July 2017 at our institution. Seven patients aged median 68 years (range = 29-79) were treated with intravenous BRV. Three patients had SE with coma and four without. SE arose de novo in two patients; etiology was remote symptomatic in four patients and progressive symptomatic in one patient. The most frequent etiology was remote vascular in two patients. BRV was administered after median four antiepileptic drugs (range = 2-11). Time of treatment initiation ranged from 0.5 hours to 105 days (median = 10.5 hours). Immediate clinical and electrophysiological improvement was observed in two patients (29%). Median loading dose was 100 mg intravenously over 15 minutes (range = 50-200 mg), titrated up to a median dose of 100 mg/d (range = 100-300). Median Glasgow Outcome Scale score was 3 (range = 3-5), with an improvement in 86% of patients compared to admission. We observed no adverse events regarding cardiorespiratory function. BRV might have potential as a novel antiepileptic drug in early stages of SE. Its potential may lie its ability to cross the blood-brain barrier more quickly than LEV and its favorable safety profile. Prospective studies for the use of BRV in SE are required.

Reliability of EEG Interactions Differs between Measures and Is Specific for Neurological Diseases.

Alterations of interaction (connectivity) of the EEG reflect pathological processes in patients with neurologic disorders. Nevertheless, it is questionable whether these patterns are reliable over time in different measures of interaction and whether this reliability of the measures is the same across different patient populations. In order to address this topic we examined 22 patients with mild cognitive impairment, five patients with subjective cognitive complaints, six patients with right-lateralized temporal lobe epilepsy, seven patients with left lateralized temporal lobe epilepsy, and 20 healthy controls. We calculated 14 measures of interaction from two EEG-recordings separated by 2 weeks. In order to characterize test-retest reliability, we correlated these measures for each group and compared the correlations between measures and between groups. We found that both measures of interaction as well as groups differed from each other in terms of reliability. The strongest correlation coefficients were found for spectrum, coherence, and full frequency directed transfer function (average rho > 0.9). In the delta (2-4 Hz) range, reliability was lower for mild cognitive impairment compared to healthy controls and left lateralized temporal lobe epilepsy. In the beta (13-30 Hz), gamma (31-80 Hz), and high gamma (81-125 Hz) frequency ranges we found decreased reliability in subjective cognitive complaints compared to mild cognitive impairment. In the gamma and high gamma range we found increased reliability in left lateralized temporal lobe epilepsy patients compared to healthy controls. Our results emphasize the importance of documenting reliability of measures of interaction, which may vary considerably between measures, but also between patient populations. We suggest that studies claiming clinical usefulness of measures of interaction should provide information on the reliability of the results. In addition, differences between patient groups in reliability of interactions in the EEG indicate the potential of reliability to serve as a new biomarker for pathological memory decline as well as for epilepsy. While the brain concert of information flow is generally variable, high reliability, and thus, low variability may reflect abnormal firing patterns.

Personalized safety measures reduce the adverse event rate of long-term video EEG.

Objective: Safety in epilepsy monitoring units (EMUs) has become an increasing concern because adverse events occur in up to 10% of patients undergoing long-term video EEG in EMUs. The aim of this study was to assess the effectiveness of a specific safety protocol in an EMU. Methods: We retrospectively assessed the adverse event rates in a group without (group 1, 84-month period, Innsbruck, Austria) and a group with (group 2, 33-month period, Salzburg, Austria) personalized safety measures utilizing a standardized protocol for long-term epilepsy monitoring in high-risk patients. Differences in adverse event rates during and after long-term video EEG between the two groups were calculated and compared. Results: In group 1, 44/507 (9%, 95% confidence interval [CI] 6.5-11.5%) patients experienced 53 adverse events: 20/507 (4%, 95% CI 2.6-6.0%) patients had psychiatric events, 15/507 (3%, 95% CI 1.8-4.8%) patients sustained a total of 19 injuries during seizures, and 10/507 (2%, 95% CI 1.1-3.6%) patients had 13 episodes of status epilepticus; one adverse event was treatment-related (valproic acid-induced encephalopathy; 1/507, 0.2%, 95% CI 0.0-1.1%). By using the new safety protocol in group 2, the adverse event rate was only 5% (95% CI 3.4-7.6%; 30 adverse events in 26/491; 45% reduction; p = 0.036), in contrast. These events included 13 psychiatric complications in 13/491 (2%, 95% CI 1.6-4.5%, p = 0.252) patients, 12 seizure-related injuries in 9/491 (2%, 95% CI 1.0-3.4%, p = 0.250) patients, and 5 episodes of status epilepticus in 4/491 (1%, 95% CI 0.3-2.1%, p = 0.120) patients. Significance: Implementation of personalized safety measures in high-risk patients resulted in a clinically relevant reduction of adverse events in the EMU. Safety protocols are a valid tool to reduce the occurrence of adverse events in EMUs.

Two-year real-world experience with perampanel in patients with refractory focal epilepsy: Austrian data.

BACKGROUND: The aim of this study was to analyse registry data of seizure outcome and adverse events (AEs) for perampanel as add-on therapy in patients with focal epilepsy since its approval in 2012 for adjunctive treatment of focal epilepsy in patients ⩾12 years. METHOD: A retrospective 2-year chart review of all patients receiving perampanel was carried out. RESULTS: A total of 122 patients received perampanel [median treatment length: 20.1 (range: 3.4-26.8) months]; 71 (58%) remained on treatment at last follow up. Overall, 33 patients (27%) were seizure-free for ⩾3 months at last follow up; of these, eight were seizure free for ⩾3 times the longest interictal interval before perampanel therapy; 18 (15%) had reduced seizure frequency ⩾50%. A total of 58 (47%) had an AE and 34 (28%) withdrew from treatment because of AEs. AEs included dizziness (33%), fatigue (12%), psychiatric symptoms (8%), cognitive deficits (7%), speech problems (5%), nausea (4%) and gait problems (4%). AEs subsided in 17/18 patients (94%) following a 2 mg dose reduction. A total of 43 (35%) took a concomitant enzyme inducer. Patients not taking enzyme inducers were more likely to be seizure free (p = 0.002); there were no other between-group differences. CONCLUSIONS: Perampanel was well tolerated and improved seizure control in 42% of patients (50- 100% reduction), with higher rates in those not receiving a concomitant enzyme inducer. AEs, particularly dizziness, were common but often disappeared with a slight dose reduction. The results are consistent with those from randomized controlled trials.

Status epilepticus in the elderly-A retrospective study on 120 patients.

PURPOSE: Status epilepticus (SE) is one of the most common neurological emergencies with a high incidence in the elderly. Major determinants of prognosis are patients' age, duration of SE and underlying etiology. We aimed identifying differences in clinical presentation of SE, etiologies and outcome between patients (pts.) sixty years or older (≥60) and younger than sixty (<60) years (yrs). METHODS: We retrospectively analyzed 120 patients (48 women) with SE admitted to the Neurological Intensive Care Unit (NICU), Department of Neurology, Paracelsus Medical University Salzburg, Austria between 1/2011 and 01/2013. KEY FINDINGS: Median age was 69 years (range 14-90) (63% ≥60yrs). Generalized tonic clonic SE was the most common SE type, whereas non convulsive SE with and without coma tended to occur more frequently in the elderly (33% ≥60 yrs. vs. 20%<60 yrs, Chi2=3.511, p=0.061). Preexisting history of epilepsy was more common in the younger age group (64% vs 41% p=0.014). An acute symptomatic cause of SE was identified in 25% (31/120), with cerebrovascular diseases being more frequent in the elderly (47% vs. 11%; p<0.01). Duration of SE did not differ between the age groups (p=0.63). Mortality was higher in elderly patients (31% vs. 7%, p=0.028, Chi Square=5.18) and moderate disability in younger patients (42% vs 17%; p=0.005, Chi Square=7.83). After Bonferroni correction only the higher rate of cerebrovascular etiologies in the elderly was statistically significant. SIGNIFICANCE: In the elder population, SE occurs more often in patients without preexisting epilepsy and is most frequently caused by cerebrovascular diseases. NCSE tends to be more frequent in the elderly and diagnosis is complicated by subtle clinical presentation. Even though comorbidities represent treatment limitations, in our sample no differences in choice of AED as well as dosage were observed between the age groups, reflecting a trend toward AEDs with more favorable adverse event profile in all patients. SE in older patients is associated with poorer outcome and higher mortality.

Diagnostic accuracy of the Salzburg EEG criteria for non-convulsive status epilepticus: a retrospective study.

BACKGROUND: Several EEG criteria have been proposed for diagnosis of non-convulsive status epilepticus (NCSE), but none have been clinically validated. We aimed to assess the diagnostic accuracy of the EEG criteria proposed by a panel of experts at the fourth London-Innsbruck Colloquium on Status Epilepticus in Salzburg, 2013 (henceforth called the Salzburg criteria). METHODS: We did a retrospective, diagnostic accuracy study using EEG recordings from patients admitted for neurological symptoms or signs to three centres in two countries (Danish Epilepsy Centre, Dianalund, Denmark; Aarhus University Hospital, Aarhus, Denmark; and Paracelsus Medical University, Salzburg, Austria). Participants were included from the Danish centres if they were aged 4 months or older, and from the Austrian centre if aged 18 years or older. Participants were sorted into two groups: consecutive patients under clinical suspicion of having NCSE (the clinical validation group) or consecutive patients with abnormal EEG findings but no clinical suspicion of NCSE (the control group). Two raters blinded to all other patient data retrospectively analysed the EEG recordings and, using the Salzburg criteria, categorised patients as in NCSE or not in NCSE. By comparing with a reference standard inferred from all clinical and para-clinical data, therapeutic response, and the final outcome, we calculated sensitivity, specificity, overall diagnostic accuracy, positive and negative predictive values, and inter-rater agreement for the Salzburg criteria. The reference standard was inferred by two raters who were blinded to the scorings of the Salzburg criteria. FINDINGS: We retrospectively reviewed EEG data from 220 patients. EEGs in the clinical validation group were recorded in 120 patients between Jan 1, and Feb 28, 2014 (Austria), and Aug 1, 2014, and Jan 31, 2015 (Denmark). EEGs in the control group were recorded in 100 patients between Jan 13 and Jan 22, 2014 (Austria) and Jan 12 and Jan 26, 2015 (Denmark). According to the reference standard, 43 (36%) of the 120 patients in the validation group had NCSE. In the validation cohort sensitivity was 97·7% (95% CI 87·9-99·6) and specificity was 89·6% (80·8-94·6); overall accuracy was 92·5% (88·3-97·5). Positive predictive value was 84·0% (95% CI 74·1-91·5) and negative predictive value was 98·6% (94·4-100). Three people in the control group (n=100) fulfilled the Salzburg criteria and were therefore false positives (specificity 97·0%, 95% CI 91·5-99·0; sensitivity not calculable). Inter-rater agreement was high for both the Salzburg criteria (k=0·87) and for the reference standard (k=0·95). Therapeutic changes occurred significantly more often in the group of patients fulfilling Salzburg criteria (42 [84%] of 50 patients) than in those who did not (11 [16%] of 70; p<0·0001). INTERPRETATION: The Salzburg criteria for diagnosis of NCSE have high diagnostic accuracy and excellent inter-rater agreement, making them suitable for implementation in clinical practice. FUNDING: None.

(S)-Ketamine in Refractory and Super-Refractory Status Epilepticus: A Retrospective Study.

OBJECTIVE: The aim was to describe the safety and efficacy of (S)-ketamine [(S)-KET] in a series of patients with refractory and super-refractory status epilepticus (RSE and SRSE) in a specialized neurological intensive care unit (NICU). METHODS: We retrospectively analyzed the data of patients with RSE and SRSE treated with (S)-KET in the NICU, Salzburg, Austria, from 2011 to 2015. Data collection included demographic features, clinical presentation, diagnosis, electroencephalogram (EEG) data, anticonvulsant treatment, timing, and duration of treatment with (S)-KET. Outcomes were seizure control and death. RESULTS: A total of 42 patients (14 women) with RSE and SRSE were treated with (S)-KET. The median duration of status epilepticus (SE) was 10 days [first quartile (Q1) 5.0, Q3 21.0]; the median latency from SE onset to the first administration of (S)-KET was 3 days (Q1 2.0, Q3 6.8). Prior to (S)-KET administration, patients had received a median of two (Q1 2.0, Q3 3.0) anesthetics and three (Q1 2.0, Q3 4.0) antiepileptic drugs. Forty percent of patients (17/42) received propofol: 65 % prior to (S)-KET; 35 % at the same time with (S)-KET. Seven patients received a median bolus of (S)-KET of 200 mg (Q1 200, Q3 250) followed by a continuous infusion, while 35 started with a continuous infusion (maximum rate median 2.55 mg/kg/h; Q1 2.09, Q3 3.22). In 64 % of patients (27/42), (S)-KET was the last drug before SE cessation; in five patients, it was given with propofol at the same time. Median duration of administration was 4 days (Q1 2.0, Q3 6.8). Overall (S)-KET treatment was well tolerated, adverse effects were not observed, and overall mortality was 45.2 %. CONCLUSIONS: Treatment of SRSE in adult patients with (S)-KET led to resolution of status in 64 %. No adverse events were found, indicating a favorable safety profile.

Perampanel for the treatment of primary generalized tonic-clonic seizures in idiopathic generalized epilepsy.

INTRODUCTION: The non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) - receptor antagonist perampanel (PER) was approved in 2015 for treatment of primary generalized tonic-clonic seizures (pGTCS). The aim of this narrative review is to summarize available data on pharmacological properties, efficacy and tolerability of PER in pGTCs. AREAS COVERED: Data sources included MEDLINE, EMBASE, Google Scholar and ClinicalTrials.gov, conference proceedings of the ILAE congresses and the most recent conference proceedings of the American Epilepsy Society (2013 to 2015). EXPERT OPINION: A placebo-controlled clinical phase III study including 164 patients (≥ 12 years) with pGTCS in idiopathic generalized epilepsies (IGE) demonstrated efficacy of PER in reducing pGTCS with good tolerability profile, and without aggravating absence seizures or myoclonic seizures. Dizziness, the main adverse event (AE), can be avoided by bedtime administration. Psychiatric AEs ranging from mild depression to aggression and suicidal attempts should be especially monitored in patients with a history of psychiatric disorders. Co-administration of enzyme inducing antiepileptic drugs (AEDs) might decrease PER plasma levels and make dose adjustment necessary. A reduced efficacy of progesterone-containing oral contraceptives should be considered when administering PER to young women. There is lack of evidence on PER treatment in pregnancy. Although no teratogenic effects were observed in animal models, PER is not recommended for women of childbearing age without contraception.