Antiepileptogenesis after stroke-trials and tribulations: Methodological challenges and recruitment results of a Phase II study with eslicarbazepine acetate.

There is currently no evidence to support the use of antiseizure medications to prevent unprovoked seizures following stroke. Experimental animal models suggested a potential antiepileptogenic effect for eslicarbazepine acetate (ESL), and a Phase II, multicenter, randomized, double-blind, placebo-controlled study was designed to test this hypothesis and assess whether ESL treatment for 1 month can prevent unprovoked seizures following stroke. We outline the design and status of this antiepileptogenesis study, and discuss the challenges encountered in its execution to date. Patients at high risk of developing unprovoked seizures after acute intracerebral hemorrhage or acute ischemic stroke were randomized to receive ESL 800 mg/d or placebo, initiated within 120 hours after primary stroke occurrence. Treatment continued until Day 30, then tapered off. Patients could receive all necessary therapies for stroke treatment according to clinical practice guidelines and standard of care, and are being followed up for 18 months. The primary efficacy endpoint is the occurrence of a first unprovoked seizure within 6 months after randomization ("failure rate"). Secondary efficacy assessments include the occurrence of a first unprovoked seizure during 12 months after randomization and during the entire study; functional outcomes (Barthel Index original 10-item version; National Institutes of Health Stroke Scale); post-stroke depression (Patient Health Questionnaire-9; PHQ-9); and overall survival. Safety assessments include the evaluation of treatment-emergent adverse events; laboratory parameters; vital signs; electrocardiogram; suicidal ideation and behavior (PHQ-9 question 9). The protocol aimed to randomize approximately 200 patients (1:1), recruited from 21 sites in seven European countries and Israel. Despite the challenges encountered, particularly during the COVID-19 pandemic, the study progressed and included a remarkable number of patients, with 129 screened and 125 randomized. Recruitment was stopped after 30 months, the first patient entered in May 2019, and the study is ongoing and following up on patients according to the Clinical Trial Protocol.

Serum Neurofilament Light Chain as Biomarker for Cladribine-Treated Multiple Sclerosis Patients in a Real-World Setting.

Serum neurofilament light chain (sNfL) is an intensely investigated biomarker in multiple sclerosis (MS). The aim of this study was to explore the impact of cladribine (CLAD) on sNfL and the potential of sNfL as a predictor of long-term treatment response. Data were gathered from a prospective, real-world CLAD cohort. We measured sNfL at baseline (BL-sNfL) and 12 months (12Mo-sNfL) after CLAD start by SIMOA. Clinical and radiological assessments determined fulfilment of "no evidence of disease activity" (NEDA-3). We evaluated BL-sNfL, 12M-sNfL and BL/12M sNfL ratio (sNfL-ratio) as predictors for treatment response. We followed 14 patients for a median of 41.5 months (range 24.0-50.0). NEDA-3 was fulfilled by 71%, 57% and 36% for a period of 12, 24 and 36 months, respectively. We observed clinical relapses in four (29%), MRI activity in six (43%) and EDSS progression in five (36%) patients. CLAD significantly reduced sNfL (BL-sNfL: mean 24.7 pg/mL (SD ± 23.8); 12Mo-sNfL: mean 8.8 pg/mL (SD ± 6.2); p = 0.0008). We found no correlation between BL-sNfL, 12Mo-sNfL and ratio-sNfL and the time until loss of NEDA-3, the occurrence of relapses, MRI activity, EDSS progression, treatment switch or sustained NEDA-3. We corroborate that CLAD decreases neuroaxonal damage in MS patients as determined by sNfL. However, sNfL at baseline and at 12 months failed to predict clinical and radiological treatment response in our real-world cohort. Long-term sNfL assessments in larger studies are essential to explore the predictive utility of sNfL in patients treated with immune reconstitution therapies.

Humoral Response to SARS-CoV-2 Antigen in Patients Treated with Monoclonal Anti-CD20 Antibodies: It Is Not All about B Cell Recovery.

Anti-CD20 therapies decrease the humoral response to SARS-CoV-2 immunization. We aimed to determine the extent of the humoral response to SARS-CoV-2 antigens in correlation with peripheral B-cell dynamics among patients with central nervous system inflammatory disorders treated with anti-CD20 medications. We retrospectively included patients receiving anti-CD20 therapy after antigen contact who were divided into responders (>7 binding antibody units (BAU)/mL) and non-responders (<7 BAU/mL). In participants with first antigen contact prior to therapy, we investigated the recall response elicited once under treatment. We included 80 patients (responders n = 34, non-responders n = 37, recall cohort n = 9). The B-cell counts among responders were significantly higher compared to non-responders (mean 1012 cells/µL ± SD 105 vs. mean 17 cells/µL ± SD 47; p < 0.001). Despite very low B-cell counts (mean 9 cells/µL ± SD 20), humoral response was preserved among the recall cohort (mean 1653 BAU/mL ± SD 2250.1) and did not differ significantly from responders (mean 735 BAU/mL ± SD 1529.9; p = 0.14). Our data suggest that peripheral B cells are required to generate antibodies to neo-antigens but not for a recall response during anti-CD20 therapy. Evaluation of B-cell counts and pre-existing SARS-CoV-2 antibodies might serve as biomarkers for estimating the immune competence to mount a humoral response to SARS-CoV-2 antigens.

Tick-Borne Encephalitis Virus RNA Found in Frozen Goat's Milk in a Family Outbreak.

Tick-borne encephalitis (TBE) is one of the commonest arthropod-borne viral diseases in Middle-East Europe and North Asia. The main reservoir of the virus is comprised of small rodents and domestic mammals with the common tick (Ixodes) being the usual vector. The clinical spectrum of TBE ranges from mild meningitis to severe meningoencephalomyelitis. This disease can lead to severe sequelae and has a mortality up to 2% in Europe. Even though the majority of cases are transmitted through bites of infected ticks, infections through ingestion of contaminated milk and dairy products from farms in endemic areas have been reported. We report a family outbreak of a febrile disease, initially suggestive of human-to-human infection, during the early summertime in Austria. Tick-borne encephalitis was diagnosed following consumption of unpasteurised goat's milk and the virus was subsequently detected in frozen milk samples. Although this is a rare manifestation of TBE, this case series shows that TBE should be included in the differential diagnosis of an outbreak of febrile disease, and a careful clinical history with reference to unpasteurized dairy products is crucial in order to prevent further disease spread. The best preventive measure is active immunisation of people living in, or travelling to, endemic areas.

Long-term immunological consequences of anti-CD20 therapies on humoral responses to COVID-19 vaccines in multiple sclerosis: an observational study.

Background: Anti-CD20 therapies induce pronounced B-cell depletion and blunt humoral responses to vaccines. Recovery kinetics of anti-CD20 therapy-mediated cellular and humoral effects in people with multiple sclerosis (pwMS) are poorly defined. Objective: To investigate the duration of the anti-CD20 treatment-induced effects on humoral responses to COVID-19 vaccines. Methods: This retrospective observational study included pwMS who had discontinued anti-CD20 therapy for ⩾12 months and remained without immunomodulation. We retrieved demographics and laboratory parameters including B-cell counts and immunoglobulin (IgG, IgM, IgA) levels prior to anti-CD20 commencement (baseline) and longitudinally after anti-CD20 treatment discontinuation from electronic medical records. Humoral responses to SARS-CoV-2 vaccines were compared with a population of 11 pwMS with ongoing anti-CD20 medication (control cohort). Results: A total of 24 pwMS had discontinued anti-CD20 therapy for a median of 34 months (range: 16-38 months). Antibody responses to COVID-19 vaccines were available in 17 (71%). Most individuals (n = 15, 88%) elicited a measurable antibody response [mean: 774 BAU/ml (±SD 1283 BAU/ml)] to SARS-CoV-2 immunization on average 22 months (range: 10-30 months) from the last anti-CD20 infusion, which was higher compared with the population with ongoing anti-CD20 therapy (n = 11, mean: 12.36 ± SD 11.94 BAU/ml; p < 0.00001). Significantly increased antibody levels compared with the control cohort were found among pwMS who were vaccinated >18 months after treatment discontinuation (19-24 months: n = 2, p = 0.013; 25-36 months: n = 9; p < 0.001). The interindividual kinetics for B-cell reconstitution were heterogeneous and mean B-cell counts approached normal ranges 18 months after treatment discontinuation. There was no correlation of B-cell repopulation and vaccine responses. Mean total IgG, IgM, and IgA levels remained within the reference range. Conclusion: Anti-CD20-induced inhibition of humoral responses to COVID-19 vaccines is transient and antibody production was more pronounced >18 months after anti-CD20 treatment discontinuation. The immunological effect on B-cell counts appears to wane by the same time.

Vaccination and childhood epilepsies.

INTRODUCTION: The evidence relating vaccination to febrile seizures and epilepsy is evaluated with an emphasis on febrile seizures (FS), Dravet syndrome (DS), West syndrome, and other developmental and epileptic encephalopathies. METHODS: A systematic literature review using search words vaccination/immunization AND febrile seizures/epilepsy/Dravet/epileptic encephalopathy/developmental encephalopathy was performed. The role of vaccination as the cause/trigger/aggravation factor for FS or epilepsies and preventive measures were analyzed. RESULTS: From 1428 results, 846 duplicates and 447 irrelevant articles were eliminated; 120 were analyzed. CONCLUSIONS: There is no evidence that vaccinations cause epilepsy in healthy populations. Vaccinations do not cause epileptic encephalopathies but may be non-specific triggers to seizures in underlying structural or genetic etiologies. The first seizure in DS may be earlier in vaccinated versus non-vaccinated patients, but developmental outcome is similar in both groups. Children with a personal or family history of FS or epilepsy should receive all routine vaccinations. This recommendation includes DS. The known risks of the infectious diseases prevented by immunization are well established. Vaccination should be deferred in case of acute illness. Acellular pertussis DTaP (diphtheria-tetanus-pertussis) is recommended. The combination of certain vaccine types may increase the risk of febrile seizures however the public health benefit of separating immunizations has not been proven. Measles-containing vaccine should be administered at age 12-15 months. Routine prophylactic antipyretics are not indicated, as there is no evidence of decreased FS risk and they can attenuate the antibody response following vaccination. Prophylactic measures (preventive antipyretic medication) are recommended in DS due to the increased risk of prolonged seizures with fever.

Recall response to COVID-19 antigen is preserved in people with multiple sclerosis on anti-CD20 medications - A pilot study.

BACKGROUND: Antibody responses to SARS-CoV-2 vaccination are impaired in people with multiple sclerosis (MS) under anti-CD20 therapies. It is however unclear, whether patients who received the basic immunization prior to anti-B cell medication start respond to the COVID-19 booster dose, once B cells are depleted. AIM: To investigate the humoral response to recall antigen by COVID-19 booster vaccines in people with MS (pwMS), who recently started an anti-CD20 therapy compared to people with long-term B cell depletion. METHODS: We enrolled 15 pwMS who had received booster vaccination on anti-CD20 therapy. Of these, 11 had established anti-CD20 medications and were therefore vaccinated during a continuous state of B cell depletion (CD20-vaccine cohort). Four pwMS had received the basic immunization prior to anti-CD20 therapy commencement and only the booster dose (vaccine-CD20-vaccine cohort) under conditions of B cell depletion. We assessed SARS-CoV-2 specific antibody responses after booster vaccination among both groups and evaluated accompanying B cell numbers and proportions from the peripheral circulation. RESULTS: The booster dose of SARS-CoV-2 vaccination elicited measurable antibody responses in 18% of individuals from the CD20-vaccine cohort compared to 100% from the vaccine-CD20-vaccine cohort. Antibody-levels were significantly higher among patients from the vaccine-CD20-vaccine cohort compared to the CD20-vaccine cohort (mean 951.25 ± 1137.96 BAU/ml, vs mean 12.36 ± 11.94 BAU/ml; mean difference 938 BAU/ml (95% CI: 249-1629 BAU/ml), p <0.0001). Among the vaccine-CD20-vaccine cohort, the booster immunization led to augmentation of spike antibody levels in 75% despite concomitant B cell depletion, and values increased by 3.8 - 9.4-fold compared to basic immunization. We observed no correlation of B cell kinetics and SARS-CoV-2 antibody levels. CONCLUSION: Our study suggests that antibody production to recall COVID-19 antigens is preserved in pwMS despite concomitant anti-CD20 therapy. If corroborated in bigger cohorts, this could have implications in the management of individuals about to start B cell medications.

An international study of the effects of the COVID-19 pandemic on characteristics of functional seizures.

OBJECTIVE: We investigated whether the COVID-19 pandemic has affected the clinical characteristics of patients with functional seizure (FS) (at the time of diagnosis) in a large multicenter international study. METHODS: This was a retrospective study. We investigated all patients with FS, who were admitted at the epilepsy monitoring units at six centers in the world: 1. Shiraz, Iran; 2. Salzburg, Austria; 3. Nancy, France; 4. Atlanta, USA; 5. Kuwait City, Kuwait; and 6. Cairo, Egypt. Patients were studied during two time periods: admitted in 2018-2019 (pre-COVID era) and 2020-2021 (COVID era). RESULTS: Three hundred and twenty-six patients were studied. Two hundred and twenty-four (68.7%) patients were diagnosed before and 102 (31.3%) persons during the COVID-19 pandemic. Only, a history of family dysfunction was significantly associated with the COVID-19 pandemic era (Odds Ratio: 1.925, 95% Confidence Interval: 1.099-3.371; p = 0.022). A low level of education might also be associated with FS during the COVID-19 pandemic, at least in some cultures (e.g., the Middle-East). CONCLUSION: The COVID-19 pandemic has not affected the clinical characteristics of patients with FS (at the time of diagnosis). However, a history of family dysfunction was significantly more frequently associated with FS during the COVID-19 pandemic. Multiagency integration of law enforcement responses, social services, and social awareness is recommended to address family dysfunction and domestic violence and support the victims during this pandemic.

Pre-Existing Humoral Immunological Memory Is Retained in Patients with Multiple Sclerosis Receiving Cladribine Therapy.

Cladribine (CLAD) is a lymphodepleting agent approved for active relapsing multiple sclerosis (MS). The impact of CLAD on the adaptive humoral immune system has not sufficiently been studied. This study aimed to assess the influence of CLAD treatment on specific antibody titers to common pathogens. We included 18 MS patients treated with CLAD. Serum IgG antibody levels to measles, mumps, rubella, hepatitis B and varicella zoster virus (VZV), as well as diphtheria and tetanus toxins, were measured prior to the initiation of treatment and at 12 and 24 months after first CLAD administration. Moreover, specimens were longitudinally analyzed regarding absolute blood concentrations of IgG and main lymphocyte subsets. No reduction in antibody levels against measles, mumps, rubella, VZV, hepatitis B, diphtheria toxin and tetanus toxin associated with CLAD treatment was observed. Loss of seroprotection occurred in <1%. We found no significant impact of CLAD on absolute serum IgG levels. Absolute lymphocyte counts were significantly reduced at the end of each treatment year (p < 0.00001 and p < 0.000001). This study suggests that CLAD does not interfere with the pre-existing humoral immunologic memory in terms of pathogen-specific antibody titers.

Unraveling the enigma of new-onset refractory status epilepticus: a systematic review of aetiologies.

BACKGROUND AND PURPOSE: New-onset refractory status epilepticus (NORSE) is a clinical presentation, neither a specific diagnosis nor a clinical entity. It refers to a patient without active epilepsy or other pre-existing relevant neurological disorder, with a NORSE without a clear acute or active structural, toxic or metabolic cause. This study reviews the currently available evidence about the aetiology of patients presenting with NORSE and NORSE-related conditions. METHODS: A systematic search was carried out for clinical trials, observational studies, case series and case reports including patients who presented with NORSE, febrile-infection-related epilepsy syndrome or the infantile hemiconvulsion-hemiplegia and epilepsy syndrome. RESULTS: Four hundred and fifty records were initially identified, of which 197 were included in the review. The selected studies were retrospective case-control (n = 11), case series (n = 83) and case reports (n = 103) and overall described 1334 patients both of paediatric and adult age. Aetiology remains unexplained in about half of the cases, representing the so-called 'cryptogenic NORSE'. Amongst adult patients without cryptogenic NORSE, the most often identified cause is autoimmune encephalitis, either non-paraneoplastic or paraneoplastic. Infections are the prevalent aetiology of paediatric non-cryptogenic NORSE. Genetic and congenital disorders can have a causative role in NORSE, and toxic, vascular and degenerative conditions have also been described. CONCLUSIONS: Far from being a unitary condition, NORSE is a heterogeneous and clinically challenging presentation. The development and dissemination of protocols and guidelines to standardize diagnostic work-up and guide therapeutic approaches should be implemented. Global cooperation and multicentre research represent priorities to improve the understanding of NORSE.

Epilepsy care during the COVID-19 pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has affected the care of all patients around the world. The International League Against Epilepsy (ILAE) COVID-19 and Telemedicine Task Forces examined, through surveys to people with epilepsy (PWE), caregivers, and health care professionals, how the pandemic has affected the well-being, care, and services for PWE. The ILAE included a link on their website whereby PWE and/or their caregivers could fill out a survey (in 11 languages) about the impact of the COVID-19 pandemic, including access to health services and impact on mental health, including the 6-item Kessler Psychological Distress Scale. An anonymous link was also provided whereby health care providers could report cases of new-onset seizures or an exacerbation of seizures in the context of COVID-19. Finally, a separate questionnaire aimed at exploring the utilization of telehealth by health care professionals since the pandemic began was available on the ILAE website and also disseminated to its members. Seventeen case reports were received; data were limited and therefore no firm conclusions could be drawn. Of 590 respondents to the well-being survey (422 PWE, 166 caregivers), 22.8% PWE and 27.5% caregivers reported an increase in seizure frequency, with difficulty in accessing medication and health care professionals reported as barriers to care. Of all respondents, 57.1% PWE and 21.5% caregivers had severe psychological distress (k score >13), which was significantly higher among PWE than caregivers (p<0.01). An increase in telemedicine use during the COVID-19 pandemic was reported by health care professionals, with 40% of consultations conducted by this method. Although 74.9% of health care providers thought that this impacted positively, barriers to care were also identified. As we move forward, there is a need to ensure ongoing support and care for PWE to prevent a parallel pandemic of unmet health care needs.

Importance of access to epilepsy monitoring units during the COVID-19 pandemic: Consensus statement of the International League against epilepsy and the International Federation of Clinical Neurophysiology.

Restructuring of healthcare services during the COVID-19 pandemic has led to lockdown of Epilepsy Monitoring Units (EMUs) in many hospitals. The ad-hoc taskforce of the International League Against Epilepsy (ILAE) and the International Federation of Clinical Neurophysiology (IFCN) highlights the detrimental effect of postponing video-EEG monitoring of patients with epilepsy and other paroxysmal events. The taskforce calls for action to continue functioning of Epilepsy Monitoring Units during emergency situations, such as the COVID-19 pandemic. Long-term video-EEG monitoring is an essential diagnostic service. Access to video-EEG monitoring of the patients in the EMUs must be given high priority. Patients should be screened for COVID-19, before admission, according to the local regulations. Local policies for COVID-19 infection control should be adhered to during the video-EEG monitoring. In cases of differential diagnosis where reduction of antiseizure medication is not required, consider home video-EEG monitoring as an alternative in selected patients.

The initial impact of the SARS-CoV-2 pandemic on epilepsy research.

The COVID-19 pandemic has changed the face of many practices throughout the world. Through necessity to minimize spread and provide clinical care to those with severe disease, focus has been on limiting face-to-face contact. Research in many areas has been put on hold. We sought to determine the impact of the COVID-19 pandemic on epilepsy research from international basic science and clinical researchers. Responses to five questions were solicited through a convenience sample by direct email and through postings on the ILAE social media accounts and an ILAE online platform (utilizing Slack). Information was collected from 15 respondents in 11 countries by email or via Zoom interviews between May 19, 2020, and June 4, 2020. Several themes emerged including a move to virtual working, project delays with laboratory work halted and clinical work reduced, funding concerns, a worry about false data with regard to COVID research and concern about research time lost. However, a number of positive outcomes were highlighted, not least the efficiency of online working and other adaptations that could be sustained in the future.

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.