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.

New-onset Myasthenia Gravis after SARS-CoV-2 infection: case report and literature review.

We report the case of a 19-year-old female patient who developed Myasthenia Gravis 13 days after SARS-CoV-2 infection with positive RT-PCR testing. Her symptoms initially involved the oculo-bulbar district, but they gradually worsened in 3 months converting into a generalized form of Myasthenia Gravis complicated with a myasthenic crisis. A high level of anti-acetylcholine receptor antibodies was found in the serum, while anti-MuSK antibodies were negative; Repetitive Nerve Stimulation and Single-fiber Electromyography were suggestive of Myasthenia Gravis. Intravenous immunoglobulin courses and specific therapy were able to improve her symptoms, but thymic resection was needed to control the disease. This is a report of new-onset Myasthenia Gravis correlated to COVID-19 in which thymic resection was described and the histologic analysis of the thymus was performed showing thymic hyperplasia despite negative thoracic Magnetic Resonance Imaging. SARS-CoV-2 infection releases inflammatory cytokines that could dysregulate the immune system and lead to Myasthenia Gravis in susceptible subjects.

The impact of COVID-19 on myocardial infarctions, strokes and out-of-hospital cardiopulmonary arrests: an observational retrospective study on time-sensitive disorders in the Friuli Venezia Giulia region (Italy).

The COVID-19 global pandemic has changed considerably the way time-sensitive disorders are treated. Home isolation, people's fear of contracting the virus and hospital reorganisation have led to a significant decrease in contacts between citizens and the healthcare system, with an expected decrease in calls to the Emergency Medical Services (EMS) of the Friuli-Venezia Giulia (FVG) region. However, mortality in clinical emergencies like acute ST-elevation myocardial infarction (STEMI), stroke and out-of-hospital cardiopulmonary arrest (OHCA) remained high. An observational retrospective cross-sectional study was carried out in FVG, taking into account the period between March 1, 2020, and May 31, 2020, the first wave of the COVID-19 pandemic, and comparing it with the same period in 2019. The flow of calls to the EMS was analysed and COVID-19 impact on time-sensitive disorders (STEMIs, ischemic strokes and OHCPAs) was measured in terms of hospitalisation, treatment and mortality. Despite a -8.01% decrease (p value ˂0.001) in emergency response, a 10.89% increase in calls to the EMS was observed. A lower number of advanced cardiopulmonary resuscitations (CPR) (75.8 vs 45.2%, p=0.000021 in April) and ROSC (39.1 vs 11.6%, p=0.0001 in April) was remarked, and survival rate dropped from 8.5 to 5%. There were less strokes (-27.5%, p value=0.002) despite a more severe onset of symptoms at hospitalisation with NHISS˃10 in 38.47% of cases. Acute myocardial infarctions decreased as well (-20%, p value=0.05), but statistical significances were not determined in the variables considered and in mortality. Despite a lower number of emergency responses, the number of calls to the EMS was considerably higher. The number of cardiac arrests treated with advanced CPR (ALS) was lower, but mortality was higher. The number of strokes decreased as well, but at the time of hospitalisation the clinical picture of the patient was more severe, thus affecting the outcome when the patient was discharged. Finally, STEMI patients decreased; however, no critical issues were observed in the variables taken into account, neither in terms of response times nor in terms of treatment times.

Sleep alterations following COVID-19 are associated with both neuroinflammation and psychological disorders, although at different times.

Introduction: By the end of 2019, severe acute respiratory syndrome coronavirus 2 rapidly spread all over the world impacting mental health and sleep habits. Insomnia, impaired sleep quality, and circadian rhythm alterations were all observed during the pandemic, especially among healthcare workers and in patients with acute and post-acute COVID-19. Sleep disruption may induce a pro-inflammatory state associated with an impairment of immune system function. Objective: We investigated the relationship between sleep alterations, psychological disorders, and inflammatory blood biomarkers in patients with post-acute COVID-19. Methods: We enrolled 47 subjects diagnosed with COVID-19 pneumonia at Santa Maria della Misericordia University Hospital (Udine, Italy) between March and May 2020. Selected patients were evaluated at 2 months (T1) and 10 months (T2) after discharge. Each time, we collected clinical interviews, neurological examinations, and self-administered questionnaires to assess sleep and life quality, anxiety, depression, and post-traumatic stress disorder. Blood biomarkers of endothelial activation, neuroinflammation, and inflammatory cytokines were also measured at each follow-up. Collected variables were analyzed using comparisons between groups and linear regression models. Results: Prevalence of insomnia increased from 10.6% up to 27.3% after COVID-19. Poor sleep quality was found in 41.5% of patients at both study visits. At T1 follow-up, poor sleepers showed higher levels of neurofilament light chain, vascular cell adhesion molecule 1, and interleukin 10; no significant associations were found between sleep quality and psychological disorders. At T2 follow-up, lower sleep quality was associated with higher levels of vascular cell adhesion molecule 1 and interleukin 8, but also with higher scores for anxiety, depression, and post-traumatic stress disorder. Conclusion: Our results suggest an association of poor sleep quality with both psychological disorders and neuroinflammation, although at different times, in previously hospitalized patients with moderate-to-critical COVID-19.

Neurological disorders in COVID-19: a case of Acute Disseminated Encephalomyelitis in an adult patient.

Different neurological complications associated with the severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection have been widely documented. Acute disseminated encephalomyelitis (ADEM) is a rare immune-mediated demyelinating disorder, described within the spectrum of neurological manifestations of COVID-19. Herein, we describe a case of adult-ADEM presenting with diplopia and slowly progressive ataxia developed one month after SARS-CoV-2 infection. Brain magnetic resonance imaging (MRI) revealed acute multifocal demyelinating lesions throughout the brain. Other possible etiologies have been ruled out. After treatment with high-dose steroids, we observed a progressive clinical and radiological improvement. A 4-months follow-up showed complete clinical recovery. Although extremely rare, ADEM could be associated to SARS-CoV-2 infection and should be considered in the differential diagnosis. Early recognition of this COVID-19 neurological complication, even in the absence of pulmonary involvement, is important to start a prompt immune-modulatory treatment and, consequently, ensure a good outcome.

Acute ischemic stroke due to floating thrombus of ascending aorta: an acute and subacute complication of SARS-CoV-2 infection

Objective To describe ischemic stroke due to floating thrombus of ascending aorta occurring as acute and subacute complication of SARS-CoV-2 infection. Material and Methods consecutive identification in clinical practice of ischemic strokes secondary to aortic arch thrombosis and history of acute or recent Covid-19 infection. Results two patients had ischemic stroke with evidence of aortic arch thrombosis. The first case had concomitant acute Covid-19 infection, the second had recent Covid-19 infection. Both patients underwent intravenous thrombolysis, and subsequent anticoagulation. One patient died due to cerebral hemorrhage. Discussion and Conclusions aortic arch thrombosis can be an incidental finding in acute ischemic stroke in patients with concomitant and recent COVID-19 disease. However, the infection may lead to thrombosis in non-atherosclerotic vessels and to cerebral embolism. Our findings support active radiological search for aortic thrombosis during acute stroke in patients with acute or recent COVID-19 disease.

Multisensory mental representation in covid-19 patients and the possibility of long-lasting gustatory and olfactory dysfunction in the CNS.

Gustatory (GD) and olfactory (OD) dysfunctions are the most frequent neurological manifestations of COVID-19. We used mental imagery as an experimental psychological paradigm to access olfactory and gustatory brain representations in 80 Italian COVID-19 adult patients (68.75% reported both OD and GD). COVID-19 patients with OD + GD have a significantly and selectively decreased vividness of odor and taste imagery, indicating that COVID-19 has an effect on their chemosensory mental representations. OD + GD length and type influenced the status of mental chemosensory representations. OD + GD were become all COVID-19 negative at the time of testing. Data suggest that patients are not explicitly aware of long-term altered chemosensory processing. However, differences emerge when their chemosensory function is implicitly assessed using self-ratings. Among patients developing OD + GD, self-ratings of chemosensory function (taste, flavor) were significantly lower as compared to those who did not. At the level of mental representation, such differences can be further detected, in terms of a reduced ability to mentally activate an odor or taste mental image. Our study shows that COVID-19 infection not only frequently causes hyposmia and dysgeusia, but that may also alter the mental representations responsible for olfactory and gustatory perception.

Creutzfeldt-Jakob disease after COVID-19: infection-induced prion protein misfolding? A case report.

Creutzfeldt-Jakob disease (CJD) is a rare, fatal disease presenting with rapidly progressive neurological deficits caused by the accumulation of a misfolded form (PrPSc) of prion protein (PrPc). Coronavirus disease 2019 (COVID-19) is a primarily respiratory syndrome caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); many diverse neurological complications have been observed after COVID-19. We describe a young patient developing CJD two months after mild COVID-19. Presenting symptoms were visuospatial deficits and ataxia, evolving into a bedridden state with preserved consciousness and diffuse myoclonus. Diagnostic work-up was suggestive of CJD. The early age of onset and the short interval between respiratory and neurological symptoms might suggest a causal relationship: a COVID-19-related neuroinflammatory state may have induced the misfolding and subsequent aggregation of PrPSc. The present case emphasizes the link between neuroinflammation and protein misfolding. Further studies are needed to establish the role of SARS-CoV-2 as an initiator of neurodegeneration.

Failure of Therapeutic Anticoagulation in COVID-19 Patients With Acute Ischemic Stroke. A Retrospective Multicenter Study.

Background: Acute ischemic stroke (AIS) is a possible complication of coronavirus disease 2019 (COVID-19) infection. Although peculiar clinical features and underlying specific mechanisms of thrombogenesis have been suggested so far, there is no consensus on the appropriate vascular preventive drug regimen in patients with COVID-19. Aim and Methods: From a larger clinical series of consecutive acute ischemic strokes related to COVID-19 admitted to three cerebrovascular units in Northern Italy, herein, we describe the clinical features of a subgroup of patients in whom stroke occurred despite therapeutic anticoagulation. Results: A total of seventeen/80 AIS related to COVID-19 (21.2%) occurred in anticoagulated patients. Although no blood level was available for Direct Oral AntiCoagulant, the drug dosage was appropriate according to guidelines. Their National Institute of Health Stroke Scale (NIHSS) at admission was 12.0 (SD = 7.4) and 58.8% of them had evidence of large vessel occlusion. The case fatality rate was as high as 64.7%. Discussion and Conclusions: The occurrence of an anticoagulation failure seems to be increased in the setting of COVID-19 infection, with worse clinical outcomes if compared to non-COVID-19 related ischemic strokes. We discuss the diagnostic and therapeutic implications of such evidence, suggesting that some arterial thrombotic complications might be either resistant to or independent of the anticoagulation effect.

Pre-Existing Lymphopenia Increases the Risk of Hospitalization and Death after SARS-CoV-2 Infection.

There is limited information regarding the severity of COVID-19 in immunocompromized patients. We conducted a retrospective cohort study considering the period from 1 March 2020 to 31 December 2020 to determine whether previously existing lymphopenia increases the risk of hospitalization and death after SARS-CoV-2 infection in the general population. The laboratory and hospital discharge databases of the Azienda Sanitaria Universitaria Friuli Centrale were used, and 5415 subjects infected with SARS-CoV-2 and with at least one recent absolute lymphocyte count determination before SARS-CoV-2 positivity were included. In total, 817 (15.1%) patients had severe COVID-19. Patients developing severe COVID-19 were more frequently males (44.9% of the severe COVID-19 group vs. 41.5% in the non-severe COVID-19 group; p < 0.0001) and were older (73.2 ± 13.8 vs. 58.4 ± 20.3 years; p < 0.0001). Furthermore, 29.9% of the lymphopenic patients developed severe COVID-19 vs. 14.5% of the non-lymphopenic patients (p < 0.0001). In a logistic regression model, female sex remained a protective factor (OR = 0.514, 95%CI 0.438-0.602, p < 0.0001), while age and lymphopenia remained risk factors for severe COVID-19 (OR = 1.047, 95%CI 1.042-1.053, p < 0.0001 for each additional year of age; OR = 1.715, 95%CI 1.239-2.347, p = 0.0011 for lymphopenia). This provides further information to stratify the risk of COVID-19 severity, which may be an important element in the management of immunosuppressive therapies.

Recurrent Status Epilepticus and SARS-CoV-2 infection: the "perfect storm".

Respiratory involvement is the most common clinical manifestation of COVID-19, but neurological symptoms and complications are increasingly being recognized. Seizures and status epilepticus (SE) have been described as possible consequences of hypoxia and metabolic derangements during SARS-CoV-2 infection, direct viral invasion of the central nervous system, or as para or post-infectious complications. Single episodes of SE have been described, occurring during the acute phase of COVID-19 or once the patients have been recovered. Herein, we present the case of a patient with a positive serology test for SARS-CoV-2 (IgG+, IgM-) and recurrent SE occurring within 36 days. Diagnostic work-up ruled out other known causes of SE. A post-COVID-19 infectious inflammatory/immune response is hypothesized as the possible trigger of SE.

New-onset status epilepticus in SARS-CoV-2 infection: a case series.

BACKGROUND: Neurological manifestations of COVID-19 infection are well recognized. Seizures and status epilepticus (SE) have been reported as possible manifestations and/or complications of SARS-CoV-2 infection at different disease stages, but few data are known about the type, severity, treatment response, and recurrence. METHODS: Single-center retrospective case series. RESULTS: This case series describes four COVID-19-positive patients admitted to an Italian University Hospital, who developed status epilepticus during the active phase of disease, independently from the severity of respiratory symptoms. Two of them presented a relapse after resolution of the acute viral infection, a feature that has not been previously reported. CONCLUSIONS: Although a possible association between SE and COVID-19 has been reported, the exact etiopathogenetic mechanism remains still not understood. Our series adds new insights to shed further light on this controversial issue.

Acute disseminated encephalomyelitis after SARS-CoV-2 vaccination.

Several central and peripheral nervous system complications associated with the severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection have been recently described. An effective mass vaccination program is necessary to effectively reduce infection spread and, consequently, limit long-term sequelae, including those affecting the nervous system. Nevertheless, as more patients gain access to coronavirus disease 2019 (COVID-19) vaccines, it is important to report potential adverse events. Herein, we report a patient with previous history of post-infectious rhombencephalitis who developed an acute disseminated encephalomyelitis (ADEM) two weeks after being vaccinated for COVID-19.