Severe disease exacerbation after mRNA COVID-19 vaccination unmasks suspected multiple sclerosis as neuromyelitis optica spectrum disorder: a case report.

BACKGROUND: Since the beginning of the COVID-19 pandemic and development of new vaccines, the issue of post-vaccination exacerbation or manifestation of demyelinating central nervous system (CNS) disorders has gained increasing attention. CASE PRESENTATION: We present a case of a 68-year-old woman previously diagnosed with multiple sclerosis (MS) since the 1980s who suffered a rapidly progressive severe sensorimotor paraparesis with loss of bladder and bowel control due to an acute longitudinal extensive transverse myelitis (LETM) after immunization with the mRNA Pfizer-BioNTech COVID-19 vaccine. Detection of Aquaporin-4-antibodies (AQP4) in both serum and CSF led to diagnosis of AQP4-antibody positive neuromyelitis optica spectrum disorder (NMOSD). Treatment with intravenous corticosteroids and plasmapheresis led to a slight improvement of the patient's symptoms. CONCLUSIONS: Pathogenic mechanisms of post-vaccination occurrence of NMOSD are still unknown. However, cases like this should make aware of rare neurological disorders manifesting after vaccination and potentially contribute to improvement of management of vaccinating patients with inflammatory CNS disorders in the future. So far two cases of AQP4-antibody positive NMOSD have been reported in association with viral vector COVID-19 vaccines. To our knowledge, we report the first case of AQP4-antibody positive NMOSD after immunization with an mRNA COVID-19-vaccine.

Long-term efficacy, tolerability, and retention of brivaracetam in epilepsy treatment: A longitudinal multicenter study with up to 5 years of follow-up.

OBJECTIVE: This study was undertaken to evaluate the long-term efficacy, retention, and tolerability of add-on brivaracetam (BRV) in clinical practice. METHODS: A multicenter, retrospective cohort study recruited all patients who initiated BRV between February and November 2016, with observation until February 2021. RESULTS: Long-term data for 262 patients (mean age = 40 years, range = 5-81 years, 129 men) were analyzed, including 227 (87%) diagnosed with focal epilepsy, 19 (7%) with genetic generalized epilepsy, and 16 (6%) with other or unclassified epilepsy syndromes. Only 26 (10%) patients had never received levetiracetam (LEV), whereas 133 (50.8%) were switched from LEV. The length of BRV exposure ranged from 1 day to 5 years, with a median retention time of 1.6 years, resulting in a total BRV exposure time of 6829 months (569 years). The retention rate was 61.1% at 12 months, with a reported efficacy of 33.1% (79/239; 50% responder rate, 23 patients lost-to-follow-up), including 10.9% reported as seizure-free. The retention rate for the entire study period was 50.8%, and at last follow-up, 133 patients were receiving BRV at a mean dose of 222 ± 104 mg (median = 200, range = 25-400), including 52 (39.1%) who exceeded the recommended upper dose of 200 mg. Fewer concomitant antiseizure medications and switching from LEV to BRV correlated with better short-term responses, but no investigated parameters correlated with positive long-term outcomes. BRV was discontinued in 63 (24%) patients due to insufficient efficacy, in 29 (11%) for psychobehavioral adverse events, in 25 (10%) for other adverse events, and in 24 (9%) for other reasons. SIGNIFICANCE: BRV showed a clinically useful 50% responder rate of 33% at 12 months and overall retention of >50%, despite 90% of included patients having previous LEV exposure. BRV was well tolerated; however, psychobehavioral adverse events occurred in one out of 10 patients. Although we identified short-term response and retention predictors, we could not identify significant predictors for long-term outcomes.

Informed DEcision for cerebrospinal fluid analysis after epiLeptic seizures- the IDEAL-score: A development and validation study.

BACKGROUND: This observational study was done to develop a score based on clinical predictors that enables a guided decision for the necessity of cerebrospinal fluid (CSF) analysis after first unprovoked epileptic seizures and to validate this score in a retrospective patient cohort. METHODS: Clinical predictors were identified by two panels of epilepsy experts and selected according to content validity ratios. Based on these predictors a score was created and applied to a cohort of patients with first epileptic seizures. RESULTS: The "IDEAL score" consists of 9 items (fever, prolonged disturbance of consciousness, headache, imaging results, cognitive dysfunction, status epilepticus, malignancy, autoimmune encephalitis symptoms) that are collected at two different time points (< 3 h [A-score]; > 3 h [B-score] after hospital admittance). A CSF analysis is recommended, if at least one clinical finding is present, either one of the items evaluated during the acute phase (A-score) or later in the diagnostic process (B-score). In 41 patients (13%) CSF analysis provided essential clues to the cause of the seizure. The combined IDEAL score reached a sensitivity of 98%, a specificity of 53%, a positive predictive value of 24% and a negative predictive value of 99% in this patient cohort. CONCLUSIONS: A CSF analysis after first epileptic seizures provided decisive etiological findings in only 13% of all investigated patients. The IDEAL score offers clinicians a simple and easy-to-implement algorithm to assess the necessity of a CSF analysis, and to prevent unnecessary diagnostic procedures.

Occurrence of status epilepticus in persons with epilepsy is determined by sex, epilepsy classification, and etiology: a single center cohort study.

BACKGROUND: Status epilepticus (SE) can occur in persons with or without epilepsy and is associated with high morbidity and mortality. METHODS: This survey aimed to record self-reported frequency of SE in persons with epilepsy, its association with clinical characteristics and patient level of information on SE and rescue medication. 251 persons with epilepsy at a tertiary epilepsy center were included in the study. RESULTS: 87 (35%) had a history of SE defined as seizure duration of more than 5 min. These patients were less likely to be seizure-free, and had a higher number of present and past anti-seizure medication. Female sex, cognitive disability, younger age at epilepsy onset, defined epilepsy etiology, and focal epilepsy were associated with a history of SE. On Cox regression analysis, female sex, defined etiology and focal classification remained significant. 67% stated that they had information about prolonged seizures, and 75% knew about rescue medication. 85% found it desirable to receive information about SE at the time of initial diagnosis of epilepsy, but only 16% had been offered such information at the time. CONCLUSION: SE is frequent among persons with epilepsy and there remain unmet needs regarding patient education.

Probing the relevance of the hippocampus for conflict-induced memory improvement.

The hippocampus plays a key role for episodic memory. In addition, a small but growing number of studies has shown that it also contributes to the resolution of response conflicts. It is less clear how these two functions are related, and how they are affected by hippocampal lesions in patients with mesial temporal lobe epilepsy (MTLE). Previous studies suggested that conflict stimuli might be better remembered, but whether the hippocampus is critical for supporting this interaction between conflict processing and memory formation is unknown. Here, we tested 19 patients with MTLE due to hippocampal sclerosis and 19 matched healthy controls. Participants performed a face-word Stroop task during functional magnetic resonance imaging (fMRI) followed by a recognition task for the faces. We tested whether memory performance and activity in brain regions implicated in long-term memory were modulated by conflict during encoding, and whether this differed between MTLE patients and controls. In controls, we largely replicated previous findings of improved memory for conflict stimuli. While MTLE patients showed response time slowing during conflict trials as well, they did not exhibit a memory benefit. In controls, neural activity of conflict resolution and memory encoding interacted within a hippocampal region of interest. Here, left hippocampal recruitment was less efficient for memory performance in incongruent trials than in congruent trials, suggesting an intrahippocampal competition for limited resources. They also showed an involvement of precuneus and posterior cingulate cortex during conflict resolution. Both effects were not observed in MTLE patients, where activation of the precuneus and posterior cingulate cortex instead predicted later memory. Further research is needed to find out whether our findings reflect widespread functional reorganization of the episodic memory network due to hippocampal dysfunction.

Reduced hippocampal recruitment during response conflict resolution in mesial temporal lobe epilepsy.

Recent evidence suggests that the human hippocampus (HC) is not only involved in the processing of motivationally relevant approach-avoidance conflicts but is also engaged in the resolution of more general response conflicts as measured in the Stroop paradigm. Here we investigated whether neural activity in the HC is necessary for successful response conflict resolution. We compared hippocampal recruitment during an auditory Stroop paradigm in 20 patients with mesial temporal lobe epilepsy (MTLE) due to hippocampal sclerosis and 20 age-matched healthy controls using functional magnetic resonance imaging (fMRI). We analyzed hippocampal activation and behavioral performance in conflict trials relative to non-conflict trials. Moreover, functional connectivity (FC) analyses with left and right HCs as seeds were performed. Subjects' regional gray matter volumes were analyzed based on high-resolution T2-weighted MRI scans. The current study replicated previous results showing increased activation in left HC during the processing of conflict trials in healthy subjects. By contrast, MTLE patients showed higher behavioral costs of response conflict resolution and reduced conflict-related HC activation. In patients with left MTLE, left HC activation was predictive of faster conflict-related response times (RTs). By contrast, right HC activation was related to RT slowing, suggestive of a maladaptive compensation attempt in MTLE patients. Our results provide evidence that left hippocampal activation is required for the successful resolution of response conflicts.

Two mutations in the nicotinic acetylcholine receptor subunit A4 (CHRNA4) in a family with autosomal dominant sleep-related hypermotor epilepsy.

Sleep-related hypermotor epilepsy, or nocturnal frontal lobe epilepsy, as it was formerly called, is a focal epilepsy with mostly sleep-related seizures of hypermotor, tonic or dystonic semiology. Sleep-related hypermotor epilepsy may be attributed to a monogenetic cause with autosomal dominant inheritance. Mutations are described in different genes, including the genes for three subunits of the nicotinic acetylcholine receptor. We present a family with members over four generations exhibiting sleep-related hypermotor epilepsy. Genetic testing was available for three members from three generations, and revealed two variants in the alpha-4 subunit of the nicotinic acetylcholine receptor (one of them being novel) which are likely to be disease-causing. As these mutations were identified in cis configuration (on the same allele), we do not know whether one of the variants alone or a combination of the two is responsible for the pathogenicity.

Impaired processing of response conflicts in mesial temporal lobe epilepsy.

Increasing evidence from neuroimaging studies points towards a hippocampal role in resolving approach-avoidance goal conflicts. Furthermore, previous neuroimaging findings suggest that the hippocampus (HC) contributes to successful conflict resolution as it is measured, for example, in a Stroop paradigm. However, it is still an open question whether the hippocampus is indeed causally relevant for resolving cognitive conflicts. Here, we investigated whether conflict resolution performance is affected by hippocampal pathology. N = 30 patients with mesial temporal lobe epilepsy (MTLE), almost exclusively showing MRI signs of hippocampal sclerosis, and an equal number of age-matched healthy controls performed an auditory Stroop paradigm. Participants listened to the words 'high' and 'low', spoken in either a high or a low pitch. Subjects' response time and accuracy to the phonetic information in the presence of incongruent (conflict trials) or congruent (non-conflict trials) semantic information were assessed. In addition, patients' regional grey matter (GM) brain volumes were analysed. We observed an increased effect of conflict on accuracy in patients with MTLE compared to healthy controls. This effect was negatively correlated with right HC volume. The results suggest that the impairment in the resolution of a response conflict is related to hippocampal structural integrity and thus add further support to the notion that the HC is not only involved but even causally relevant for successful cognitive conflict processing.

Seizures and epilepsy in multiple sclerosis: epidemiology and prognosis in a large tertiary referral center.

BACKGROUND: Seizures and epilepsy may substantially add to the burden of disease in multiple sclerosis (MS), whereas the exact prevalence and prognosis of seizures and epilepsy in patients with MS remains largely unknown. OBJECTIVES: We aimed to investigate the epidemiology and prognosis of seizures and epilepsy in MS. METHODS: We retrospectively analyzed a cohort of 4078 MS patients from a single tertiary referral clinic. RESULTS: After excluding 37 patients with unconfirmed MS and alternative seizure etiologies, we found seizures attributable to MS in 1.5% and epilepsy in 0.9% of patients. 40.4% of patients with a follow-up of at least twelve months experienced only a single seizure and 59.6% had recurring seizures. 39% of patients with recurrent seizures were considered drug-resistant, with 9.7% experiencing status epilepticus. Seizure recurrence after a first seizure depended significantly on the MS subtype and was seen more often if the first seizure occurred simultaneously with a MS relapse than in the absence of a relapse. CONCLUSION: Our study shows a lower number of seizures and epilepsy in MS than previously reported. While a single seizure in MS usually has a good prognosis, relapse-associated seizures and established epilepsy in MS may not be as benign as previously assumed.

Efficacy, Retention, and Tolerability of Brivaracetam in Patients With Epileptic Encephalopathies: A Multicenter Cohort Study From Germany.

Objective: To evaluate the efficacy and tolerability of brivaracetam (BRV) in a severely drug refractory cohort of patients with epileptic encephalopathies (EE). Method: A multicenter, retrospective cohort study recruiting all patients treated with EE who began treatment with BRV in an enrolling epilepsy center between 2016 and 2017. Results: Forty-four patients (27 male [61%], mean age 29 years, range 6 to 62) were treated with BRV. The retention rate was 65% at 3 months, 52% at 6 months and 41% at 12 months. A mean retention time of 5 months resulted in a cumulative exposure to BRV of 310 months. Three patients were seizure free during the baseline. At 3 months, 20 (45%, 20/44 as per intention-to-treat analysis considering all patients that started BRV including three who were seizure free during baseline) were either seizure free (n = 4; 9%, three of them already seizure-free at baseline) or reported at least 25% (n = 4; 9%) or 50% (n = 12; 27%) reduction in seizures. An increase in seizure frequency was reported in two (5%) patients, while there was no change in the seizure frequency of the other patients. A 50% long-term responder rate was apparent in 19 patients (43%), with two (5%) free from seizures for more than six months and in nine patients (20%, with one [2 %] free from seizures) for more than 12 months. Treatment-emergent adverse events were predominantly of psychobehavioural nature and were observed in 16%. Significance: In this retrospective analysis the rate of patients with a 50% seizure reduction under BRV proofed to be similar to those seen in regulatory trials for focal epilepsies. BRV appears to be safe and relatively well tolerated in EE and might be considered in patients with psychobehavioral adverse events while on levetiracetam.

Use of brivaracetam in genetic generalized epilepsies and for acute, intravenous treatment of absence status epilepticus.

OBJECTIVE: The objective of this study was to evaluate effectiveness, retention, and tolerability of brivaracetam (BRV) in genetic generalized epilepsies (GGE) in clinical practice. METHODS: A multicenter, retrospective cohort study recruiting all patients that started BRV in 2016 and 2017. RESULTS: A total of 61 patients (mean age = 29.8, range = 9-90 years, 41 female [67%]) were treated with BRV. They were difficult to control, with 2.4 failed antiepileptic drugs (AEDs) in the past, taking 1.9 AEDs on average at baseline. The length of exposure to BRV ranged from 7 days to 24 months, with a mean retention time of 7.9 months, resulting in a total exposure time to BRV of 483 months. The retention rate was 82% at 3 months and 69% at 6 months. Efficacy at 3 months was 36% (50% responder rate), with 25% seizure-free for 3 months. Patients with juvenile myoclonic epilepsy showed a responder rate of 60%, with 40% being free of any seizures. Long-term 50% responder rate was present in 17 patients (28%; 11 seizure-free [18%]) for >6 months and in 14 patients (23%; 10 seizure-free [16%]) for >12 months. Treatment-emergent adverse events were observed in 26% of the patients, with the most common being somnolence, ataxia, and psychobehavioral adverse events. Use of intravenous BRV with bolus injection of 200-300 mg in two females with absence status epilepticus was well tolerated, but did not result in cessation of status epilepticus. SIGNIFICANCE: Use of BRV in GGE is well tolerated, and 50% responder rates are similar to those observed in the regulatory trials for focal epilepsies. An immediate switch from levetiracetam (LEV) to BRV at a ratio of 15:1 is feasible. The occurrence of psychobehavioral adverse events seems less prominent than under LEV, and a switch to BRV can be considered in patients with LEV-induced adverse events.

The Effect of Head Model Simplification on Beamformer Source Localization.

Beamformers are a widely-used tool in brain analysis with magnetoencephalography (MEG) and electroencephalography (EEG). For the construction of the beamformer filters realistic head volume conductor modeling is necessary for accurately computing the EEG and MEG leadfields, i.e., for solving the EEG and MEG forward problem. In this work, we investigate the influence of including realistic head tissue compartments into a finite element method (FEM) model on the beamformer's localization ability. Specifically, we investigate the effect of including cerebrospinal fluid, gray matter, and white matter distinction, as well as segmenting the skull bone into compacta and spongiosa, and modeling white matter anisotropy. We simulate an interictal epileptic measurement with white sensor noise. Beamformer filters are constructed with unit gain, unit array gain, and unit noise gain constraint. Beamformer source positions are determined by evaluating power and excess sample kurtosis (g2) of the source-waveforms at all source space nodes. For both modalities, we see a strong effect of modeling the cerebrospinal fluid and white and gray matter. Depending on the source position, both effects can each be in the magnitude of centimeters, rendering their modeling necessary for successful localization. Precise skull modeling mainly effected the EEG up to a few millimeters, while both modalities could profit from modeling white matter anisotropy to a smaller extent of 5-10 mm. The unit noise gain or neural activity index beamformer behaves similarly to the array gain beamformer when noise strength is sufficiently high. Variance localization seems more robust against modeling errors than kurtosis.

Postmarketing experience with brivaracetam in the treatment of epilepsies: A multicenter cohort study from Germany.

OBJECTIVE: To evaluate factors predicting efficacy, retention, and tolerability of add-on brivaracetam (BRV) in clinical practice. METHODS: A multicenter, retrospective cohort study recruiting all patients who started BRV between February and November 2016 with observation time between 3 and 12 months. RESULTS: Of a total of 262 patients (mean age 40, range 5-81 years, 129 male) treated with BRV, 227 (87%) were diagnosed to have focal, 19 (7%) idiopathic generalized and 8 (3%) symptomatic generalized epilepsy, whereas 8 (3%) were unclassified. The length of exposure to BRV ranged from 1 day to 12 months, with a median retention time of 6.1 months, resulting in a total exposure time to BRV of 1,504 months. The retention rate was 79.4% at 3 months and 75.8% at 6 months. Efficacy at 3 months was 41.2% (50% responder rate) with 14.9% seizure-free for 3 months and, at 6 months, 40.5% with 15.3% seizure-free. Treatment-emergent adverse events were observed in 37.8% of the patients, with the most common being somnolence, dizziness, and behavioral adverse events (BAEs). BAE that presented under previous levetiracetam (LEV) treatment improved upon switch to BRV in 57.1% (20/35) and LEV-induced somnolence improved in 70.8% (17/24). Patients with BAE on LEV were more likely to develop BAE on BRV (odds ratio [OR] 3.48, 95% confidence interval [CI] 1.53-7.95). SIGNIFICANCE: BRV in broad clinical postmarketing use is a well-tolerated anticonvulsant drug with 50% responder rates, similar to those observed in the regulatory trials, even though 90% of the patients included had previously been exposed to LEV. An immediate switch from LEV to BRV at a ratio of 10:1 to 15:1 is feasible. The only independent significant predictor of efficacy was the start of BRV in patients not currently taking LEV. The occurrence of BAE during previous LEV exposure predicted poor psychobehavioral tolerability of BRV treatment. A switch to BRV can be considered in patients with LEV-induced BAE.

Voxel-based statistical analysis of fractional anisotropy and mean diffusivity in patients with unilateral temporal lobe epilepsy of unknown cause.

PURPOSE: To determine regional alterations of fractional anisotropy (FA) and mean diffusivity (MD) in patients with magnetic resonance imaging (MRI)-negative temporal lobe epilepsy with unknown cause (TLEu) using diffusion tensor imaging (DTI) and voxel-based statistics (VBS). METHODS: Ten patients with left TLEu and no abnormality on conventional MRI and 81 age-matched neurological healthy controls were studied. VBS analyses were used to compare FA and MD differences between patients and controls. All results were reported using stringent statistical thresholds corrected for multiple comparisons. RESULTS: Patients with TLEu had widespread and bilateral reduction of white matter FA, encompassing the temporal lobes, entire corpus callosum, thalamus, and other regions relative to controls. Increased MD was more spatially limited in patients, but was also observed in the thalamus. FA of the putamen was significantly increased bilaterally in patients relative to controls, which correlated with increasing macroscopic atrophy of the putamen. DISCUSSION: Water diffusion abnormalities are widespread and bilaterally distributed in patients with unilateral TLEu, which are beyond the resolution of conventional MRI. FA alterations are more widespread relative to MD alterations. This is the first study to show evidence of interrelated microscopic (ie, FA increase) and macroscopic (ie, atrophy) alterations of the putamen in patients with TLEu.

Microstructural and volumetric abnormalities of the putamen in juvenile myoclonic epilepsy.

PURPOSE: Patients with juvenile myoclonic epilepsy (JME) show evidence of microstructural white matter (WM) damage of thalamocortical fiber tracts and changes of blood oxygen level dependent (BOLD) signal in a striatothalamocortical network. The objective of the present study was to investigate microstructural and volumetric alterations of the putamen in patients with JME using diffusion tensor imaging (DTI) and conventional magnetic resonance imaging (MRI). METHODS: We performed DTI and MRI for 10 patients with JME and 59 age-matched neurologically healthy volunteers. Evaluation of microstructural damage was investigated using calculation of mean fractional anisotropy (FA) values in a priori regions of interest (ROIs) for the putamen, frontal lobe, and a thalamocortical region, after application of an improved eddy current correction method and a new statistical parametric mapping (SPM)-compatible toolbox incorporating intensive multicontrast FA image registration. Stereologic analysis on MRI was performed to estimate macroscopic volume of the putamen in both cerebral hemispheres for all subjects. KEY FINDINGS: Relative to controls, patients had significantly reduced FA in the frontal lobe (p = 0.01) and thalamocortical fiber WM (p < 0.001). In contrast, putamen FA was bilaterally increased (p = 0.01) and correlated with decreasing putamen volume (r(2) = -0.63, p = 0.004) in patients only. Putamen FA correlated negatively with onset of JME (total: r(2) = -0.50, p = 0.01), duration of JME (r(2) = 0.52, p = 0.01), and thalamocortical fiber FA (r(2) = -0.47, p = 0.01). SIGNIFICANCE: This is the first evidence of combined microstructural and macrostructural putamen abnormalities in patients with JME, with early age of onset and a longer duration of epilepsy being significant predictors for greater architectural alterations. These findings are consistent with studies indicating neurophysiologic abnormalities of frontostriatal networks in patients with JME, and may contribute to explain the frequent presentation of executive dysfunction in these patients. Confirmation and further exploration of the increase in putamen FA in patients with JME is required in larger samples.

Intravenous lacosamide--an effective add-on treatment of refractory status epilepticus.

Status epilepticus (SE) is a frequent neurological emergency requiring immediate treatment. Therapy usually requires intravenous anticonvulsive medication. Lacosamide is a novel anticonvulsant drug that is available as infusion solution. We describe seven patients with focal SE who were treated with intravenous Lacosamide. All patients in our case series were unsuccessfully treated with other antiepileptic drugs before Lacosamide i.v. was added. In all cases, SE was terminated within 24 h after Lacosamide. There were no serious side effects or adverse events attributable to Lacosamide i.v. Our data suggest that Lacosamide might be an effective add-on treatment, if standard drugs fail or are unsuitable.

Language assessment in Wada test: comparison of methohexital and amobarbital.

INTRODUCTION: Methohexital has replaced amobarbital during Wada testing at many centers. The objective of our study was to compare the use of methohexital and amobarbital during Wada testing regarding language and memory lateralization quotients as well as speech arrest times. METHODS: A chart review of 582 consecutive patients undergoing 1041 Wada-procedures was performed (left=60, right=63, bilateral=459). Language lateralization was calculated based on duration of speech arrest using a laterality index, defined as (L-R)/(L+R). Memory lateralization was expressed as percentage of retained objects and laterality quotient. RESULTS: Language and memory lateralization revealed a similar distribution with amobarbital and methohexital. Speech arrest after left and right-sided injection was significantly longer in the amobarbital group as compared to the methohexital group. Language lateralization did not differ in the two groups. Percentage of retained memory items was higher in the methohexital group and there were fewer presented test items in the methohexital group. DISCUSSION: Language and memory testing during the Wada test can successfully be performed with methohexital instead of amobarbital. The shorter half-life of methohexital allows repeated injections and shorter interhemispheric testing intervals, but also shortens the testing window.