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.

Prioritization process for European Academy of Neurology clinical practice guidelines.

BACKGROUND AND PURPOSE: The development of high-quality clinical practice guidelines (CPGs) takes substantial time, effort, and resources. During the past years, the European Academy of Neurology (EAN) guideline production was significantly increased, so the need to develop clear, transparent, and methodologically solid criteria for prioritizing guideline topics became apparent. With this paper, we aim to define a set of criteria to be applied for prioritizing topics for future EAN guidelines, as well as the procedure for their implementation. METHODS: After review of the literature, we identified a recent systematic review that reported on the main prioritization criteria used by health organizations. Based on these, we developed a list of 20 preliminary criteria, which were voted on through a Delphi consensus procedure, including 160 stakeholders. Finally, we established a working procedure on how to submit and select new guideline topic proposals within the EAN. This procedure was reviewed by the EAN Scientific Committee and the Board. RESULTS: The first round, 61.3% of the participants voted, and 86% of them participated in the second round. Seven criteria were approved with this procedure. After the selection of the criteria, a prioritization procedure was launched, and the first 30 topics are reported in this paper. This bottom-up process that involved the whole EAN community was followed by a top-down process, using additional criteria for further selection by the EAN board members. CONCLUSIONS: We describe the development of prioritization criteria to be applied in the process of topic selection for future EAN CPGs. We will perform regular reviews and adjustments of the process.

European Academy of Neurology guidance for developing and reporting clinical practice guidelines on rare neurological diseases.

BACKGROUND AND PURPOSE: Rare diseases affect up to 29 million people in the European Union, and almost 50% of them affect the nervous system or muscles. Delays in diagnosis and treatment onset and insufficient treatment choices are common. Clinical practice guidelines (CPGs) may improve the diagnosis and treatment of patients and optimize care pathways, delivering the best scientific evidence to all clinicians treating these patients. Recommendations are set for developing and reporting high-quality CPGs on rare neurological diseases (RNDs) within the European Academy of Neurology (EAN), through a consensus procedure. METHODS: A group of 27 experts generated an initial list of items that were evaluated through a two-step Delphi consensus procedure and a face-to-face meeting. The final list of items was reviewed by an external review group of 58 members. RESULTS: The consensus procedure yielded 63 final items. Items are listed according to the domains of the AGREE instruments and concern scope and purpose, stakeholder involvement, rigour of development, and applicability. Additional items consider reporting and ethical issues. Recommendations are supported by practical examples derived from published guidelines and are presented in two tables: (1) items specific to RND CPGs, and general guideline items of special importance for RNDs, or often neglected; (2) items for guideline development within the EAN. CONCLUSIONS: This guidance aims to provide solutions to the issues specific to RNDs. This consensus document, produced by many experts in various fields, is considered to serve as a starting point for further harmonization and for increasing the quality of CPGs in the field of RNDs.

Diagnostic value of MRI in the presurgical evaluation of patients with epilepsy: influence of field strength and sequence selection: a systematic review and meta-analysis from the E-PILEPSY Consortium.

MRI is a cornerstone in presurgical evaluation of epilepsy. Despite guidelines, clinical practice varies. In light of the E-PILEPSY pilot reference network, we conducted a systematic review and meta-analysis on the diagnostic value of MRI in the presurgical evaluation of epilepsy patients. We included original research articles on diagnostic value of higher MRI field strength and guideline-recommended and additional MRI sequences in detecting an epileptogenic lesion in adult or paediatric epilepsy surgery candidates. Lesion detection rate was used as a metric in meta-analysis. Eighteen studies were included for MRI field strength and 25 for MRI sequences, none were free from bias. In patients with normal MRI at lower-field strength, 3T improved lesion detection rate by 18% and 7T by 23%. Field strengths higher than 1.5T did not have higher lesion detection rates in patients with hippocampal sclerosis (HS). The lesion detection rate of epilepsy-specific MRI protocols was 83% for temporal lobe epilepsy (TLE) patients. Dedicated MRI protocols and evaluation by an experienced epilepsy neuroradiologist increased lesion detection. For HS, 3DT1, T2, and FLAIR each had a lesion detection rate at around 90%. Apparent diffusion coefficient indices had a lateralizing value of 33% for TLE. DTI fractional anisotropy and mean diffusivity had a localizing value of 8% and 34%. A dedicated MRI protocol and expert evaluation benefits lesion detection rate in epilepsy surgery candidates. If patients remain MRI negative, imaging at higher-field strength may reveal lesions. In HS, apparent diffusion coefficient indices may aid lateralization and localization more than increasing field strength. DTI can add further diagnostic information. For other additional sequences, the quality and number of studies is insufficient to draw solid conclusions. Our findings may be used as evidence base for developing new high-quality MRI studies and clinical guidelines.

Exploring the prevalence and profile of epilepsy across Europe using a standard retrospective chart review: Challenges and opportunities.

OBJECTIVE: This study aimed to determine the prevalence of epilepsy in four European countries (Austria, Denmark, Ireland, and Romania) employing a standard methodology. The study was conducted under the auspices of ESBACE (European Study on the Burden and Care of Epilepsy). METHODS: All hospitals and general practitioners serving a region of at least 50 000 persons in each country were asked to identify patients living in the region who had a diagnosis of epilepsy or experienced a single unprovoked seizure. Medical records were accessed, where available, to complete a standardized case report form. Data were sought on seizure frequency, seizure type, investigations, etiology, comorbidities, and use of antiseizure medication. Cases were validated in each country, and the degree of certainty was graded as definite, probable, or suspect cases. RESULTS: From a total population of 237 757 in the four countries, 1988 (.8%) patients were identified as potential cases of epilepsy. Due to legal and ethical issues in the individual countries, medical records were available for only 1208 patients, and among these, 113 had insufficient clinical information. The remaining 1095 cases were classified as either definite (n = 706, 64.5%), probable (n = 191, 17.4%), suspect (n = 153, 14.0%), or not epilepsy (n = 45, 4.1%). SIGNIFICANCE: Although a precise prevalence estimate could not be generated from these data, the study found a high validity of epilepsy classification among evaluated cases (95.9%). More generally, this study highlights the significant challenges facing epidemiological research methodologies that are reliant on patient consent and retrospective chart review, largely due to the introduction of data protection legislation during the study period. Documentation of the epilepsy diagnosis was, in some cases, relatively low, indicating a need for improved guidelines for assessment, follow-up, and documentation. This study highlights the need to address the concerns and requirements of recruitment sites to engage in epidemiological research.

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.

Epidemiology of status epilepticus in adults: Apples, pears, and oranges - A critical review.

OBJECTIVE: Status epilepticus (SE) is a severe neurologic condition associated with high morbidity and mortality. Population-based studies in adults have found a wide range of incidences in various regions in the world. Although the incidence of SE increases almost exponentially in the elderly, data on census-based population statistics in these studies are scarce. This study provides a critical review with an emphasis on census-based population statistics and study characteristics in adults. METHODS: We performed a systematic search of population-based studies on SE in adults in PubMed using "status epilepticus" in combination with "epidemiology", "population", and "incidence" as search terms, and also screened references. For each identified study, we assessed and extracted the respective population pyramids of study and reference population, and study characteristics. RESULTS: We identified 22 population-based studies (eleven from Europe, six from North America, three from Asia, one from Africa, and one from Australasia). Incidence rates of patients with SE ranged from 1.29 to 73.7/100,000 adults (95% confidence interval (CI): 76.6-80.3) and of SE episodes up to 81.1/100,000 adults (95% CI: 75.8-87.0). The proportions of elderly and very old patients varied by a factor of 2.6 and 8.5, respectively, depending on study period and place. Further major reasons for heterogeneity were retrospective or prospective study design, definition of time to diagnose SE, variable detection of nonconvulsive SE (NCSE), different etiologies, inclusion of children, recurrent episodes, postanoxic patients, exclusion of patients with preexisting epilepsy or patients identified outside the emergency department, and choice of reference population for age- and gender adjustment. The most recent definition and classification of SE by the International League Against Epilepsy (ILAE) 2015 was used in two studies. Four studies (18.2%) reported incidences per ten-year age strata necessary for age adjustment to various reference populations. CONCLUSIONS: This critical review reveals a marked heterogeneity among population-based studies on SE in adults. It provides comprehensive details on census-based population statistics in study and reference populations and various study designs and characteristics essential for direct comparisons between studies. Reporting on these essential key features should be improved in population-based studies on SE.

Diagnostic accuracy of interictal source imaging in presurgical epilepsy evaluation: A systematic review from the E-PILEPSY consortium.

OBJECTIVE: Interictal high resolution (HR-) electric source imaging (ESI) and magnetic source imaging (MSI) are non-invasive tools to aid epileptogenic zone localization in epilepsy surgery candidates. We carried out a systematic review on the diagnostic accuracy and quality of evidence of these modalities. METHODS: Embase, Pubmed and the Cochrane database were searched on 13 February 2017. Diagnostic accuracy studies taking post-surgical seizure outcome as reference standard were selected. Quality appraisal was based on the QUADAS-2 framework. RESULTS: Eleven studies were included: eight MSI (n = 267), three HR-ESI (n = 127) studies. None was free from bias. This mostly involved: selection of operated patients only, interference of source imaging with surgical decision, and exclusion of indeterminate results. Summary sensitivity and specificity estimates were 82% (95% CI: 75-88%) and 53% (95% CI: 37-68%) for overall source imaging, with no statistical difference between MSI and HR-ESI. Specificity is higher when partially concordant results were included as non-concordant (p < 0.05). Inclusion of indeterminate test results as non-concordant lowered sensitivity (p < 0.05). CONCLUSIONS: Source imaging has a relatively high sensitivity but low specificity for identification of the epileptogenic zone. SIGNIFICANCE: We need higher quality studies allowing unbiased test evaluation to determine the added value and diagnostic accuracy of source imaging in the presurgical workup of refractory focal epilepsy.

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.

Diagnostic accuracy of functional magnetic resonance imaging, Wada test, magnetoencephalography, and functional transcranial Doppler sonography for memory and language outcome after epilepsy surgery: A systematic review.

OBJECTIVE: The European Union-funded E-PILEPSY project was launched to develop guidelines and recommendations for epilepsy surgery. In this systematic review, we aimed to assess the diagnostic accuracy of functional magnetic resonance imaging (fMRI), Wada test, magnetoencephalography (MEG), and functional transcranial Doppler sonography (fTCD) for memory and language decline after surgery. METHODS: The literature search was conducted using PubMed, Embase, and CENTRAL. The diagnostic accuracy was expressed in terms of sensitivity and specificity for postoperative language or memory decline, as determined by pre- and postoperative neuropsychological assessments. If two or more estimates of sensitivity or specificity were extracted from a study, two meta-analyses were conducted, using the maximum ("best case") and the minimum ("worst case") of the extracted estimates, respectively. RESULTS: Twenty-eight papers were eligible for data extraction and further analysis. All tests for heterogeneity were highly significant, indicating large between-study variability (P < 0.001). For memory outcomes, meta-analyses were conducted for Wada tests (n = 17) using both memory and language laterality quotients. In the best case, meta-analyses yielded a sensitivity estimate of 0.79 (95% confidence interval [CI] = 0.67-0.92) and a specificity estimate of 0.65 (95% CI = 0.47-0.83). For the worst case, meta-analyses yielded a sensitivity estimate of 0.65 (95% CI = 0.48-0.82) and a specificity estimate of 0.46 (95% CI = 0.28-0.65). The overall quality of evidence, which was assessed using Grading of Recommendations Assessment, Development, and Evaluation methodology, was rated as very low. Meta-analyses concerning diagnostic accuracy of fMRI, fTCD, and MEG were not feasible due to small numbers of studies (fMRI, n = 4; fTCD, n = 1; MEG, n = 0). This also applied to studies concerning language outcomes (Wada test, n = 6; fMRI, n = 2; fTCD, n = 1; MEG, n = 0). SIGNIFICANCE: Meta-analyses could only be conducted in a few subgroups for the Wada test with low-quality evidence. Thus, more evidence from high-quality studies and improved data reporting are required. Moreover, the large between-study heterogeneity underlines the necessity for more homogeneous and thus comparable studies in future research.

Current standards of neuropsychological assessment in epilepsy surgery centers across Europe.

We explored the current practice with respect to the neuropsychological assessment of surgical epilepsy patients in European epilepsy centers, with the aim of harmonizing and establishing common standards. Twenty-six epilepsy centers and members of "E-PILEPSY" (a European pilot network of reference centers in refractory epilepsy and epilepsy surgery), were asked to report the status of neuropsychological assessment in adults and children via two different surveys. There was a consensus among these centers regarding the role of neuropsychology in the presurgical workup. Strong agreement was found on indications (localization, epileptic dysfunctions, adverse drugs effects, and postoperative monitoring) and the domains to be evaluated (memory, attention, executive functions, language, visuospatial skills, intelligence, depression, anxiety, and quality of life). Although 186 different tests are in use throughout these European centers, a core group of tests reflecting a moderate level of agreement could be discerned. Variability exists with regard to indications, protocols, and paradigms for the assessment of hemispheric language dominance. For the tests in use, little published evidence of clinical validity in epilepsy was provided. Participants in the survey reported a need for improvement concerning the validity of the tests, tools for the assessment of everyday functioning and accelerated forgetting, national norms, and test co-normalization. Based on the present survey, we documented a consensus regarding the indications and principles of neuropsychological testing. Despite the variety of tests in use, the survey indicated that there may be a core set of tests chosen based on experience, as well as on published evidence. By combining these findings with the results of an ongoing systematic literature review, we aim for a battery that can be recommended for the use across epilepsy surgical centers in Europe.

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.

Current practices in long-term video-EEG monitoring services: A survey among partners of the E-PILEPSY pilot network of reference for refractory epilepsy and epilepsy surgery.

PURPOSE: The European Union-funded E-PILEPSY network aims to improve awareness of, and accessibility to, epilepsy surgery across Europe. In this study we assessed current clinical practices in epilepsy monitoring units (EMUs) in the participating centers. METHOD: A 60-item web-based survey was distributed to 25 centers (27 EMUs) of the E-PILEPSY network across 22 European countries. The questionnaire was designed to evaluate the characteristics of EMUs, including organizational aspects, admission, and observation of patients, procedures performed, safety issues, cost, and reimbursement. RESULTS: Complete responses were received from all (100%) EMUs surveyed. Continuous observation of patients was performed in 22 (81%) EMUs during regular working hours, and in 17 EMUs (63%) outside of regular working hours. Fifteen (56%) EMUs requested a signed informed consent before admission. All EMUs performed tapering/withdrawal of antiepileptic drugs, 14 (52%) prior to admission to an EMU. Specific protocols on antiepileptic drugs (AED) tapering were available in four (15%) EMUs. Standardized Operating Procedures (SOP) for the treatment of seizure clusters and status epilepticus were available in 16 (59%). Safety measures implemented by EMUs were: alarm seizure buttons in 21 (78%), restricted patient's ambulation in 19 (70%), guard rails in 16 (59%), and specially designated bathrooms in 7 (26%). Average costs for one inpatient day in EMU ranged between 100 and 2200 Euros. CONCLUSION: This study shows a considerable diversity in the organization and practice patterns across European epilepsy monitoring units. The collected data may contribute to the development and implementation of evidence-based recommended practices in LTM services across Europe.

Current use of imaging and electromagnetic source localization procedures in epilepsy surgery centers across Europe.

OBJECTIVE: In 2014 the European Union-funded E-PILEPSY project was launched to improve awareness of, and accessibility to, epilepsy surgery across Europe. We aimed to investigate the current use of neuroimaging, electromagnetic source localization, and imaging postprocessing procedures in participating centers. METHODS: A survey on the clinical use of imaging, electromagnetic source localization, and postprocessing methods in epilepsy surgery candidates was distributed among the 25 centers of the consortium. A descriptive analysis was performed, and results were compared to existing guidelines and recommendations. RESULTS: Response rate was 96%. Standard epilepsy magnetic resonance imaging (MRI) protocols are acquired at 3 Tesla by 15 centers and at 1.5 Tesla by 9 centers. Three centers perform 3T MRI only if indicated. Twenty-six different MRI sequences were reported. Six centers follow all guideline-recommended MRI sequences with the proposed slice orientation and slice thickness or voxel size. Additional sequences are used by 22 centers. MRI postprocessing methods are used in 16 centers. Interictal positron emission tomography (PET) is available in 22 centers; all using 18F-fluorodeoxyglucose (FDG). Seventeen centers perform PET postprocessing. Single-photon emission computed tomography (SPECT) is used by 19 centers, of which 15 perform postprocessing. Four centers perform neither PET nor SPECT in children. Seven centers apply magnetoencephalography (MEG) source localization, and nine apply electroencephalography (EEG) source localization. Fourteen combinations of inverse methods and volume conduction models are used. SIGNIFICANCE: We report a large variation in the presurgical diagnostic workup among epilepsy surgery centers across Europe. This diversity underscores the need for high-quality systematic reviews, evidence-based recommendations, and harmonization of available diagnostic presurgical methods.

Premature mortality in a Georgian cohort of people with epilepsy.

Mortality in people with epilepsy has not previously been estimated in Georgia. We identified a prevalent cohort of people with epilepsy from a tertiary referral centre in Tbilisi, Georgia and attempted to establish survivorship status for all. One-way sensitivity analysis estimating mortality rates in those lost to follow-up was also used. Of 1952 people, 1250 (64%) were located; 93 (7%) had died over a median of 11 years follow up. The main cause specific Proportional Mortality Ratios were: underlying diseases (39%) and accidental death (9%). One SUDEP was confirmed with a further 4 possible, but the cause of death was unknown in 47%. The overall SMR was 1.4, with much higher SMRs (up to 12) in young people. The sensitivity analysis suggested an SMR of 3.0.