MyD88-mediated signaling is critical for the generation of seizure responses and cognitive impairment in a model of anti-N-methyl-D-aspartate receptor encephalitis.

OBJECTIVE: We previously demonstrated that interleukin-1 receptor-mediated immune activation contributes to seizure severity and memory loss in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. In the present study, we assessed the role of the myeloid differentiation primary response gene 88 (MyD88), an adaptor protein in Toll-like receptor signaling, in the key phenotypic characteristics of anti-NMDAR encephalitis. METHODS: Monoclonal anti-NMDAR antibodies or control antibodies were infused into the lateral ventricle of MyD88 knockout mice (MyD88-/-) and control C56BL/6J mice (wild type [WT]) via osmotic minipumps for 2 weeks. Seizure responses were measured by electroencephalography. Upon completion of the infusion, the motor, anxiety, and memory functions of the mice were assessed. Astrocytic (glial fibrillary acidic protein [GFAP]) and microglial (ionized calcium-binding adaptor molecule 1 [Iba-1]) activation and transcriptional activation for the principal inflammatory mediators involved in seizures were determined using immunohistochemistry and quantitative real-time polymerase chain reaction, respectively. RESULTS: As shown before, 80% of WT mice infused with anti-NMDAR antibodies (n = 10) developed seizures (median = 11, interquartile range [IQR] = 3-25 in 2 weeks). In contrast, only three of 14 MyD88-/- mice (21.4%) had seizures (0, IQR = 0-.25, p = .01). The WT mice treated with antibodies also developed memory loss in the novel object recognition test, whereas such memory deficits were not apparent in MyD88-/- mice treated with anti-NMDAR antibodies (p = .03) or control antibodies (p = .04). Furthermore, in contrast to the WT mice exposed to anti-NMDAR antibodies, the MyD88-/- mice had a significantly lower induction of chemokine (C-C motif) ligand 2 (CCL2) in the hippocampus (p = .0001, Sidak tests). There were no significant changes in the expression of GFAP and Iba-1 in the MyD88-/- mice treated with anti-NMDAR or control antibodies. SIGNIFICANCE: These findings suggest that MyD88-mediated signaling contributes to the seizure and memory phenotype in anti-NMDAR encephalitis and that CCL2 activation may participate in the expression of these features. The removal of MyD88 inflammation may be protective and therapeutically relevant.

Trends in management of patients with new-onset refractory status epilepticus (NORSE) from 2016 to 2023: An interim analysis.

In response to the evolving treatment landscape for new-onset refractory status epilepticus (NORSE) and the publication of consensus recommendations in 2022, we conducted a comparative analysis of NORSE management over time. Seventy-seven patients were enrolled by 32 centers, from July 2016 to August 2023, in the NORSE/FIRES biorepository at Yale. Immunotherapy was administered to 88% of patients after a median of 3 days, with 52% receiving second-line immunotherapy after a median of 12 days (anakinra 29%, rituximab 25%, and tocilizumab 19%). There was an increase in the use of second-line immunotherapies (odds ratio [OR] = 1.4, 95% CI = 1.1-1.8) and ketogenic diet (OR = 1.8, 95% CI = 1.3-2.6) over time. Specifically, patients from 2022 to 2023 more frequently received second-line immunotherapy (69% vs 40%; OR = 3.3; 95% CI = 1.3-8.9)-particularly anakinra (50% vs 13%; OR = 6.5; 95% CI = 2.3-21.0), and the ketogenic diet (OR = 6.8; 95% CI = 2.5-20.1)-than those before 2022. Among the 27 patients who received anakinra and/or tocilizumab, earlier administration after status epilepticus onset correlated with a shorter duration of status epilepticus (ρ = .519, p = .005). Our findings indicate an evolution in NORSE management, emphasizing the increasing use of second-line immunotherapies and the ketogenic diet. Future research will clarify the impact of these treatments and their timing on patient outcomes.

Comparative analysis of patients with new onset refractory status epilepticus preceded by fever (febrile infection-related epilepsy syndrome) versus without prior fever: An interim analysis.

Febrile infection-related epilepsy syndrome (FIRES) is a subset of new onset refractory status epilepticus (NORSE) that involves a febrile infection prior to the onset of the refractory status epilepticus. It is unclear whether FIRES and non-FIRES NORSE are distinct conditions. Here, we compare 34 patients with FIRES to 30 patients with non-FIRES NORSE for demographics, clinical features, neuroimaging, and outcomes. Because patients with FIRES were younger than patients with non-FIRES NORSE (median = 28 vs. 48 years old, p = .048) and more likely cryptogenic (odds ratio = 6.89), we next ran a regression analysis using age or etiology as a covariate. Respiratory and gastrointestinal prodromes occurred more frequently in FIRES patients, but no difference was found for non-infection-related prodromes. Status epilepticus subtype, cerebrospinal fluid (CSF) and magnetic resonance imaging findings, and outcomes were similar. However, FIRES cases were more frequently cryptogenic; had higher CSF interleukin 6, CSF macrophage inflammatory protein-1 alpha (MIP-1a), and serum chemokine ligand 2 (CCL2) levels; and received more antiseizure medications and immunotherapy. After controlling for age or etiology, no differences were observed in presenting symptoms and signs or inflammatory biomarkers, suggesting that FIRES and non-FIRES NORSE are very similar conditions.

Visualization of the Spatiotemporal Propagation of Interictal Spikes in Temporal Lobe Epilepsy: A MEG Pilot Study.

Magnetoencephalography (MEG) is clinically used to localize interictal spikes in discrete brain areas of epilepsy patients through the equivalent current dipole (ECD) method, but does not account for the temporal dynamics of spike activity. Recent studies found that interictal spike propagation beyond the temporal lobe may be associated with worse postsurgical outcomes, but studies using whole-brain data such as in MEG remain limited. In this pilot study, we developed a tool that visualizes the spatiotemporal dynamics of interictal MEG spikes normalized to spike-free sleep activity to assess their onset and propagation patterns in patients with temporal lobe epilepsy (TLE). We extracted interictal source data containing focal epileptiform activity in awake and asleep states from seven patients whose MEG ECD clusters localized to the temporal lobe and normalized the data against spike-free sleep recordings. We calculated the normalized activity over time per cortical label, confirmed maximal activity at onset, and mapped the activity over a 10 ms interval onto each patient's brain using a custom-built Multi-Modal Visualization Tool. The onset of activity in all patients appeared near the clinically determined epileptogenic zone. By 10 ms, four of the patients had propagated source activity restricted to within the temporal lobe, and three had propagated source activity spread to extratemporal regions. Using this tool, we show that noninvasively identifying the onset and propagation of interictal spike activity in MEG can be achieved, which may help provide further insight into epileptic networks and guide surgical planning and interventions in patients with TLE.

Review and standard operating procedures for collection of biospecimens and analysis of biomarkers in new onset refractory status epilepticus.

New onset refractory status epilepticus (NORSE), including its subtype with a preceding febrile illness known as febrile infection-related epilepsy syndrome (FIRES), is one of the most severe forms of status epilepticus. The exact causes of NORSE are currently unknown, and there is so far no disease-specific therapy. Identifying the underlying pathophysiology and discovering specific biomarkers, whether immunologic, infectious, genetic, or other, may help physicians in the management of patients with NORSE. A broad spectrum of biomarkers has been proposed for status epilepticus patients, some of which were evaluated for patients with NORSE. Nonetheless, none has been validated, due to significant variabilities in study cohorts, collected biospecimens, applied analytical methods, and defined outcome endpoints, and to small sample sizes. The NORSE Institute established an open NORSE/FIRES biorepository for health-related data and biological samples allowing the collection of biospecimens worldwide, promoting multicenter research and sharing of data and specimens. Here, we suggest standard operating procedures for biospecimen collection and biobanking in this rare condition. We also propose criteria for the appropriate use of previously collected biospecimens. We predict that the widespread use of standardized procedures will reduce heterogeneity, facilitate the future identification of validated biomarkers for NORSE, and provide a better understanding of the pathophysiology and best clinical management for these patients.

International consensus recommendations for management of New Onset Refractory Status Epilepticus (NORSE) incl. Febrile Infection-Related Epilepsy Syndrome (FIRES): Statements and Supporting Evidence.

OBJECTIVE: To develop consensus-based recommendations for the management of adult and paediatric patients with NORSE/FIRES based on best evidence and experience. METHODS: The Delphi methodology was followed. A facilitator group of 9 experts was established, who defined the scope, users and suggestions for recommendations. Following a review of the current literature, recommendation statements concerning diagnosis, treatment and research directions were generated which were then voted on a scale of 1 (strongly disagree) to 9 (strongly agree) by a panel of 48 experts in the field. Consensus that a statement was appropriate was reached if the median score was greater or equal to 7, and inappropriate if the median score was less than or equal to 3. The analysis of evidence was mapped to the results of each statement included in the Delphi survey. RESULTS: Overall, 85 recommendation statements achieved consensus. The recommendations are divided into five sections: 1) disease characteristics, 2) diagnostic testing and sampling, 3) acute treatment, 4) treatment in the post-acute phase, and 5) research, registries and future directions in NORSE/FIRES. The detailed results and discussion of all 85 statements are outlined herein. A corresponding summary of findings and practical flowsheets are presented in a companion article. SIGNIFICANCE: This detailed analysis offers insight into the supporting evidence and the current gaps in the literature that are associated with expert consensus statements related to NORSE/FIRES. The recommendations generated by this consensus can be used as a guide for the diagnosis, evaluation, and management of patients with NORSE/FIRES, and for planning of future research.

International consensus recommendations for management of New Onset Refractory Status Epilepticus (NORSE) including Febrile Infection-Related Epilepsy Syndrome (FIRES): Summary and Clinical Tools.

OBJECTIVE: To develop consensus-based recommendations for the management of adult and pediatric patients with NORSE/FIRES based on best available evidence and expert opinion. METHODS: The Delphi methodology was followed. A facilitator group of 9 experts was established, who defined the scope, users and suggestions for recommendations. Following a review of the current literature, recommendation statements concerning diagnosis, treatment and research directions were generated which were then voted on a scale of 1 (strongly disagree) to 9 (strongly agree) by a panel of 48 experts in the field. Consensus that a statement was appropriate was reached if the median score was greater than or equal to 7, and inappropriate if the median score was less than or equal to 3. RESULTS: Overall, 85 recommendation statements achieved consensus. The recommendations are divided into five sections: 1) disease characteristics, 2) diagnostic testing and sampling, 3) acute treatment, 4) treatment in the post-acute phase, and 5) research, registries and future directions in NORSE/FIRES. These are summarized in this article along with two practical clinical flowsheets: one for diagnosis and evaluation and one for acute treatment. A corresponding evidence-based analysis of all 85 recommendations alongside responses by the Delphi panel is presented in a companion article. SIGNIFICANCE: The recommendations generated by this consensus can be used as a guide for the diagnosis, evaluation, and management of patients with NORSE/FIRES, and for planning of future research.

Movement disorders associated with antiseizure medications: A systematic review.

New-onset movement disorders have been frequently reported in association with the use of antiseizure medications (ASMs). The frequency of specific motor manifestations and the spectrum of their semiology for various ASMs have not been well characterized. We carried out a systematic review of literature and conducted a search on CINAHL, Cochrane Library, EMBASE, MEDLINE, PsycINFO, and Scopus from inception to April 2021. We compiled the data for all currently available ASMs using the conventional terminology of movement disorders. Among 5123 manuscripts identified by the search, 437 met the inclusion criteria. The largest number of reports of abnormal movements were in association with phenobarbital, valproic acid, lacosamide, and perampanel, and predominantly included tremor and ataxia. The majority of attempted interventions for all agents were discontinuation of the offending drug or dose reduction which led to the resolution of symptoms in most patients. Familiarity with the movement disorder phenomenology previously encountered in relation with specific ASMs facilitates early recognition of adverse effects and timely institution of targeted interventions.

Seizures and memory impairment induced by patient-derived anti-N-methyl-D-aspartate receptor antibodies in mice are attenuated by anakinra, an interleukin-1 receptor antagonist.

OBJECTIVE: Neuroinflammation associated with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis may facilitate seizures. We previously showed that intraventricular administration of cerebrospinal fluid from patients with anti-NMDAR encephalitis to mice precipitates seizures, thereby confirming that antibodies are directly pathogenic. To determine whether interleukin (IL)-1-mediated inflammation exacerbates autoimmune seizures, we asked whether blocking the effects of IL-1 by anakinra, a selective IL-1 receptor antagonist, blunts antibody-induced seizures. METHODS: We infused C57BL/6 mice intraventricularly with purified serum IgG from patients with anti-NMDAR encephalitis or monoclonal anti-NMDAR IgG; subdural electroencephalogram was continuously recorded. After a 6-day interval, mice received anakinra (25 mg/kg sc, twice daily) or vehicle for 5 days. Following a 4-day washout period, we performed behavioral tests to assess motor function, anxiety, and memory, followed by hippocampus tissue analysis to assess astrocytic (glial fibrillary acidic protein [GFAP]) and microglial (ionized calcium-binding adapter molecule [Iba]-1) activation. RESULTS: Of 31 mice infused with purified patient NMDAR-IgG (n = 17) or monoclonal NMDAR-IgG (n = 14), 81% developed seizures. Median baseline daily seizure count during exposure to antibodies was 3.9; most seizures were electrographic. Median duration of seizures during the baseline was 82.5 s. Anakinra administration attenuated daily seizure frequency by 60% (p = .02). Anakinra reduced seizure duration; however, the effect was delayed and became apparent only after the cessation of treatment (p = .04). Anakinra improved novel object recognition in mice with antibody-induced seizures (p = .03) but did not alter other behaviors. Anakinra reduced the expression of GFAP and Iba-1 in the hippocampus of mice with seizures, indicating decreased astrocytic and microglial activation. SIGNIFICANCE: Our evidence supports a role for IL-1 in the pathogenesis of seizures in anti-NMDAR encephalitis. These data are consistent with therapeutic effects of anakinra in other severe autoimmune and inflammatory seizure syndromes. Targeting inflammation via blocking IL-1 receptor-mediated signaling may be promising for developing novel treatments for refractory autoimmune seizures.

Association between kinetic semiology of psychogenic nonepileptic spells and seizure type in dual disorder.

PURPOSE: Epilepsy is diagnosed in 20% of patients with psychogenic nonepileptic spells (PNES). The semiology of PNES and epileptic seizures (ES) overlaps in some patients. It is unclear whether the motor phenotype of PNES predicts the type of ES. METHODS: Video segments of EEGs in patients with PNES and ES treated in the Epilepsy Monitoring Unit at the University of Nebraska Medical Center were reviewed. Videos were categorized according to the validated motor-based classification of PNES. Ratings of kinetic PNES events were analyzed to determine if there was an association with focal or generalized ES. If available, the video segments of ES were categorized as hypokinetic or hyperkinetic based on the constellation of focal or generalized movements and other semiological features. RESULTS: Among 43 patients with documented PNES-ES (median age 34, interquartile range (IQR) 26-45), 27.9% were male. The largest proportion of patients (39.5%) had focal temporal epilepsy (TE). Other diagnostic groups included focal frontal (FE, 25.6%), generalized (GE, 25.6%), or other (9.3%) epilepsies. Thirty-three PNES patients (82.5%) were rated as having a hypokinetic phenotype. On average, hypokinetic PNES patients were receiving a median of 3 (IQR 2-4) anticonvulsants, compared to a median of 2 (IQR 2-3) in hyperkinetic PNES patients (p = 0.06). While the group with coexisting FE had a higher prevalence of hyperkinetic semiology (45.4%) than either the TE (11.7%) or GE (18.1%) patients, there was no significant association between the ES type and kinetic status of PNES. Among 20 patients who had video recordings of both PNES and ES, 40% displayed the concordant hypokinetic phenotypes for PNES and seizures while 15% had hyperkinetic presentation of both event types. Among additional 16 patients with scalp EEG-negative suspected nonepileptic events and documented ES, 6 had the recordings of seizures and 3 have presented with concordant hypokinetic PNES and ES. CONCLUSION: In patients with PNES and ES, the hypokinetic semiology of PNES prevails over hyperkinetic semiology in TE and GE syndromes. The motor status of PNES does not predict the phenotype of coexisting ES. The concordant kinetic semiology is present in more than half of the patients with dual diagnosis and available video data.

Ambulatory care for epilepsy via telemedicine during the COVID-19 pandemic.

OBJECTIVE: To assess feasibility, patient satisfaction, and financial advantages of telemedicine for epilepsy ambulatory care during the current COVID-19 pandemic. METHODS: The demographic and clinical characteristics of all consecutive patients evaluated via telemedicine at a level 4 epilepsy center between March 20 and April 20, 2020 were obtained retrospectively from electronic medical records. A telephone survey to assess patient satisfaction and preferences was conducted within one month following the initial visit. RESULTS: Among 223 telehealth patients, 85.7% used both synchronous audio and video technology. During the visits, 39% of patients had their anticonvulsants adjusted while 18.8% and 11.2% were referred to laboratory/diagnostic testing and specialty consults, respectively. In a post-visit survey, the highest degree of satisfaction with care was expressed by 76.9% of patients. The degree of satisfaction tended to increase the further a patient lived from the clinic (p = 0.05). Beyond the pandemic, 89% of patients reported a preference for continuing telemedicine if their epilepsy symptoms remained stable, while only 44.4% chose telemedicine should their symptoms worsen. Inclement weather and lack of transportation were factors favoring continued use of telemedicine. An estimated cost saving to patient attributed to telemedicine was $30.20 ±â€¯3.8 per visit. SIGNIFICANCE: Our findings suggest that epilepsy care via telemedicine provided high satisfaction and economic benefit, without compromising patients' quality of care, thereby supporting the use of virtual care during current and future epidemiological fallouts. Beyond the current pandemic, patients with stable seizure symptoms may prefer to use telemedicine for their epilepsy care.

Concurrent EEG monitoring helps interpret neuropsychological testing results in patients with epilepsy.

OBJECTIVE: We sought to determine if global cognitive function in patients with epilepsy (PWE) differs when electroencephalographic (EEG) abnormalities are present during concurrent neuropsychological (NP) evaluation. METHODS: We explored the association between subclinical epileptiform discharges (sEDs) and interictal epileptiform discharges (IEDs) and global aspects of cognition in 79 consecutive PWE who underwent continuous EEG monitoring during NP evaluation for diagnostic (15%) or presurgical (85%) purposes while on their standard antiseizure medication (ASM) regimens. As some researchers have suggested that the apparent link between IEDs and cognition represent epiphenomena of an underlying damaged neural substrate, we used functional status as a stratifying covariate to allow us to address this position. RESULTS: Despite being on their standard ASM regimen, EEG was abnormal in 68% of patients. Epileptiform abnormalities (IEDs, sEDs, or both) were seen in isolation or coupled with diffuse or focal slowing in 38% of patients. Individuals with IEDs occurring during their NP evaluation demonstrated poorer scores in attention/working memory (forward and backward digit span), processing speed (symbol searching and coding), and speeded components of language (semantic fluency) tests compared with those with normal EEG tracings matched by their real-world, functional status. In two high functioning patients, performance was significantly better when these individuals were tested in the absence of IEDs, with performances appearing invalid when tested during periods of IED activity. No significant association was found between NP performance and nonepileptiform EEG abnormalities. SIGNIFICANCE: A substantial proportion of PWE undergoing NP evaluation manifest concurrent EEG abnormalities, with epileptiform abnormalities associated with poorer global cognitive performance. As this pattern was observed regardless of functional status, this association appears to represent more than unrelated features coincidentally shared by the lowest functioning cohort. Coupled with our individual case data, our findings suggest that NP testing may be adversely affected by IEDs and sEDs going unrecognized in the absence of simultaneous EEG recordings, and set the stage for future studies to definitively establish this possible relationship.

A mouse model of seizures in anti-N-methyl-d-aspartate receptor encephalitis.

OBJECTIVE: Seizures develop in 80% of patients with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis, and these represent a major cause of morbidity and mortality. Anti-NMDAR antibodies have been linked to memory loss in encephalitis; however, their role in seizures has not been established. We determined whether anti-NMDAR antibodies from autoimmune encephalitis patients are pathogenic for seizures. METHODS: We performed continuous intracerebroventricular infusion of cerebrospinal fluid (CSF) or purified immunoglobulin (IgG) from the CSF of patients with anti-NMDAR encephalitis or polyclonal rabbit anti-NMDAR IgG, in male C57BL/6 mice. Seizure status during a 2-week treatment was assessed with video-electroencephalography. We assessed memory, anxiety-related behavior, and motor function at the end of treatment and assessed the extent of neuronal damage and gliosis in the CA1 region of hippocampus. We also performed whole-cell patch recordings from the CA1 pyramidal neurons in hippocampal slices of mice with seizures. RESULTS: Prolonged exposure to rabbit anti-NMDAR IgG, patient CSF, or human IgG purified from the CSF of patients with encephalitis induced seizures in 33 of 36 mice. The median number of seizures recorded in 2 weeks was 13, 39, and 35 per mouse in these groups, respectively. We observed only 18 brief nonconvulsive seizures in 11 of 29 control mice (median seizure count of 0) infused with vehicle (n = 4), normal CSF obtained from patients with noninflammatory central nervous system (CNS) conditions (n = 12), polyclonal rabbit IgG (n = 7), albumin (n = 3), and normal human IgG (n = 3). We did not observe memory deficits, anxiety-related behavior, or motor impairment measured at 2 weeks in animals treated with CSF from affected patients or rabbit IgG. Furthermore, there was no evidence of hippocampal cell loss or astrocyte proliferation in the same mice. SIGNIFICANCE: Our findings indicate that autoantibodies can induce seizures in anti-NMDAR encephalitis and offer a model for testing novel therapies for refractory autoimmune seizures.

Driving with drug-resistant and controlled seizures from a patient's perspective: Assessment of attitudes and practices.

BACKGROUND: Driving restrictions in epilepsy are intended to safeguard public and personal safety; however, these limitations inhibit socialization, restrict employment, and reduce self-esteem in patients with seizures. A large proportion of patients with seizures continue to drive, and factors leading to noncompliance with driving regulations are poorly understood. Thus, the patients' perspective on driving safety is not incorporated into the existing counseling tools on driving safety in epilepsy. The present study assessed social, economic, and psychological perceptions related to driving restrictions in patients with refractory and pharmacotherapy-controlled seizures at the single epilepsy center and identified impediments for safe driving. METHODS: Data were obtained from an anonymous survey completed by 25 adult patients in the presurgical group (PG) with refractory epilepsy and 46 patients in the ambulatory group (AG) with confirmed epilepsy which did not meet criteria for refractoriness. The questionnaire (administered via Research Electronic Data Capture (REDCap)) addressed seizure and driving history, knowledge of driving restrictions, and social consequences of losing driving privileges. RESULTS: Eighty-seven percent of all responders experienced seizures with alteration of awareness; however, 34% of patients continued to drive during the time when they were legally restricted, and 6% had accidents related to seizures. All responders reported their seizure status accurately to the treating physician, and 93% understood state-based driving restrictions. The median time from the last seizure was shorter, and the duration of last driving restriction was longer in the PG compared with the AG (1 vs. 20weeks, and 12 vs. 24weeks, respectively). Despite that, the proportions of patients driving at the time of survey were not significantly different between the two groups. Nearly 80% of all patients stated that driving restrictions reduced their quality of life, and 70% believed that these restrictions carry a social stigma. Employment was chosen to be the most affected by driving restrictions from a list of four social domains by the majority of patients in both groups. Notably, the employment rate was 26% higher in the AG compared with the PG. The lack of public transportation was regarded as a hurdle by more than 60% of patients in each group with greater than two-thirds of patients relying on other drivers for transportation. CONCLUSIONS: These findings suggest that patients with refractory and pharmacotherapy-controlled seizures are similarly likely to drive a vehicle, disregarding a practitioner's advice and state restrictions. The lack of public transportation is a shared constraint and likely leads to reduced compliance with driving regulations. Driving restrictions carry social stigma and limit the employment of patients with epilepsy, regardless of the refractory seizure status.

Utilization of brain imaging in evaluating patients with psychogenic nonepileptic spells.

BACKGROUND: Psychogenic nonepileptic spells (PNES) are paroxysmal movements or sensory events that resemble epileptic seizures but lack corresponding ictal electrographic changes. A confirmed diagnosis of PNES is only accomplished via video electroencephalogram (vEEG) monitoring. Prior to diagnosis, patients are often assessed with neurodiagnostic imaging and their conditions treated with anticonvulsant medications, both of which are of limited clinical value and contribute to the higher cost of care. In this study, we assessed the relationship between the semiological features of PNES, medication regimen, or psychiatric comorbidities and the frequency of referrals for brain imaging tests prior to diagnosis of PNES. METHODS: This is a retrospective chart review of 224 adult patients diagnosed as having PNES at a level 4 epilepsy care center from 2012 to 2017. Patients with coexisting epilepsy were excluded. The 882 segments of vEEG records were reviewed for semiology of spells, and patients were categorized into one of seven distinct phenotypic classes according to the accepted clinical classification. The frequency of neurodiagnostic tests completed for each patient prior to vEEG was correlated with PNES phenotype and other clinical characteristics. RESULTS: There were 68 (30%) males and 156 (70%) females diagnosed as having PNES with a median age of 36 years. Seventy-four percent of patients were receiving one or several anticonvulsant medications, and 67% of patients were treated with psychotropic medications other than benzodiazepines. The most prevalent PNES events were characterized by semirhythmic small amplitude movements in the extremities (class 2; 34%) followed by those resembling tonic-clonic seizures (class 4; 28%). Neurodiagnostic imaging tests including computed tomography (CT) and magnetic resonance imaging (MRI) of the brain were performed at least once in 60% of patients and 4 times or more in 11% prior to vEEG. There was a significant association between the frequency of neurodiagnostic tests and the PNES phenotype (p = 0.02). Specifically, patients with sensory changes (class 6) had more imaging tests than those with primitive gesturing and truncal posturing (classes 1 and 5, respectively). Additionally, patients diagnosed with 3 or more psychiatric disorders underwent significantly more neurodiagnostic tests relative to patients diagnosed with two or fewer psychiatric disorders (p = 0.03). Furthermore, patients whose conditions were treated with anticonvulsant medications tended to undergo more imaging scans prior to vEEG as compared with the patients whose conditions were not being treated with anticonvulsants. CONCLUSIONS: These findings suggest that the frequency of brain imaging obtained prior to the definitive diagnosis of PNES is influenced by semiology of spells and the psychiatric health of patients. Patients who demonstrate minimal paroxysmal movements in the settings of multiple psychiatric comorbidities represent a particularly challenging patient phenotype which is linked to more frequent referrals for brain imaging. These patients should be promptly referred for vEEG to improve diagnostic accuracy and prevent treatment with anticonvulsants as well as referrals for serial neurodiagnostic tests.

Lateral medullary stroke in patient with granulomatous polyangiitis.

Granulomatous polyangiitis (GPA), also known as Wegener granulomatosis, is a systemic antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis that infrequently affects the central nervous system. We report a 41-year-old man with lateral medullary infarction who developed rapidly progressive renal failure. He was diagnosed with GPA based on positive serum c-ANCA and antiproteinase 3 antibodies and demonstration of pauci-immune crescentic glomerulonephritis on kidney biopsy. He was treated with Coumadin, pulse steroids, cyclophosphamide, and plasmapheresis. He had resolution of his neurologic deficits and improvement in renal function. This case report highlights the importance to consider GPA vasculitis in the differential diagnosis of stroke in patients with development of acute kidney injury.

Patient Handoff Practices at the Epilepsy Centers in the United States: A Survey of the Medical Directors.

PURPOSE: Communication failure is one of the most significant causes of medical errors. Providing care to patients with seizures at comprehensive epilepsy centers requires uninterrupted coverage and a multidisciplinary approach. However, handoff practices in these settings have not been comprehensively assessed, and recommendations for their standardization are currently lacking. The aim of this observational study was to define the scope of existing practices for patient handoffs across epilepsy centers in the United States and provide relevant recommendations. METHODS: A 79-question survey was developed to establish the patterns of transition of care for patients undergoing continuous EEG recording, including the periodicity of handoffs and specifics of the relevant workflow. With permission from the National Association of Epilepsy Centers (NAEC), the survey was distributed to the medical directors of all Level 3 and 4 NAEC-accredited epilepsy centers in the United States. RESULTS: The responses were obtained from 70 institutions yielding a survey response rate of 26%. Of these, more than 77% had established weekly handoff processes for both the epilepsy monitoring unit and continuous EEG (cEEG) monitoring services. However, only 53% and 43% of centers had procedures for daily service transfers for the patients admitted to the epilepsy monitoring unit or the patients undergoing cEEG, respectively. The patterns of handoffs were complex and utilized group handoffs in < 50% of institutions. In most centers (>70%), patient data transmitted through handoffs included history, clinical information, and EEG findings. However, templates were not applied to standardize this information. All participants agreed or strongly agreed that a culture of patient safety was maintained in their place of practice; however, 12% of participants felt that insufficient time was allowed to discuss these patients or carry out the handoffs without interruptions. CONCLUSIONS: Existing handoff practices are not uniform or fully established across epilepsy centers in the United States. This study recommends that guidelines for formal handoff procedures be developed and introduced as a quality metric for all NAEC-accredited epilepsy centers.

Memory loss and aberrant neurogenesis in mice exposed to patient anti-N-methyl-d-aspartate receptor antibodies.

OBJECTIVE: Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis results in chronic epilepsy and permanent cognitive impairment. One of the possible causes of cognitive impairment in anti-NMDAR could be aberrant neurogenesis, an established contributor to memory loss in idiopathic drug-resistant epilepsy. We developed a mouse model of anti-NMDAR encephalitis and showed that mice exposed to patient anti-NMDAR antibodies for 2 weeks developed seizures and memory loss. In the present study, we assessed the delayed effects of patient-derived antibodies on cognitive phenotype and examined the corresponding changes in hippocampal neurogenesis. METHODS: Monoclonal anti-NMDAR antibodies or control antibodies were continuously infused into the lateral ventricle of male C56BL/6J mice (8-12 weeks) via osmotic minipumps for 2 weeks. The motor and anxiety phenotypes were assessed using the open field paradigm, and hippocampal memory and learning were assessed using the object location, Y maze, and Barnes maze paradigms during weeks 1 and 3-4 of antibody washout. The numbers of newly matured granule neurons (Prox-1+) and immature progenitor cells (DCX+) as well as their spatial distribution within the hippocampus were assessed at these time points. Bromodeoxyuridine (BrdU, 50 mg/kg, i.p., daily) was injected on days 2-12 of the infusion, and proliferating cell immunoreactivity was compared in antibody-treated mice and control mice during week 4 of the washout. RESULTS: Mice infused with anti-NMDAR antibodies demonstrated spatial memory impairment during week 1 of antibody washout (p = 0.02, t-test; n = 9-11). Histological analysis of hippocampal sections from these mice revealed an increased ectopic displacement of Prox-1+ cells in the dentate hilus compared to the control-antibody-treated mice (p = 0.01; t-test). Mice exposed to anti-NMDAR antibodies also had an impairment of spatial memory and learning during weeks 3-4 of antibody washout (object location: p = 0.009; t-test; Y maze: p = 0.006, t-test; Barnes maze: p = 0.008, ANOVA; n = 8-10). These mice showed increased ratios of the low proliferating (bright) to fast proliferating (faint) BrdU+ cell counts and decreased number of DCX+ cells in the hippocampal dentate gyrus (p = 0.006 and p = 0.04, respectively; t-tests) suggesting ectopic migration and delayed cell proliferation. SIGNIFICANCE: These findings suggest that memory and learning impairments induced by patient anti-NMDAR antibodies are sustained upon removal of antibodies and are accompanied by aberrant hippocampal neurogenesis. Interventions directed at the manipulation of neuronal plasticity in patients with encephalitis and cognitive loss may be protective and therapeutically relevant.

Improving Clinician Performance in Classifying EEG Patterns on the Ictal-Interictal Injury Continuum Using Interpretable Machine Learning.

BACKGROUND: In intensive care units (ICUs), critically ill patients are monitored with electroencephalography (EEG) to prevent serious brain injury. EEG monitoring is constrained by clinician availability, and EEG interpretation can be subjective and prone to interobserver variability. Automated deep-learning systems for EEG could reduce human bias and accelerate the diagnostic process. However, existing uninterpretable (black-box) deep-learning models are untrustworthy, difficult to troubleshoot, and lack accountability in real-world applications, leading to a lack of both trust and adoption by clinicians. METHODS: We developed an interpretable deep-learning system that accurately classifies six patterns of potentially harmful EEG activity - seizure, lateralized periodic discharges (LPDs), generalized periodic discharges (GPDs), lateralized rhythmic delta activity (LRDA), generalized rhythmic delta activity (GRDA), and other patterns - while providing faithful case-based explanations of its predictions. The model was trained on 50,697 total 50-second continuous EEG samples collected from 2711 patients in the ICU between July 2006 and March 2020 at Massachusetts General Hospital. EEG samples were labeled as one of the six EEG patterns by 124 domain experts and trained annotators. To evaluate the model, we asked eight medical professionals with relevant backgrounds to classify 100 EEG samples into the six pattern categories - once with and once without artificial intelligence (AI) assistance - and we assessed the assistive power of this interpretable system by comparing the diagnostic accuracy of the two methods. The model's discriminatory performance was evaluated with area under the receiver-operating characteristic curve (AUROC) and area under the precision-recall curve. The model's interpretability was measured with task-specific neighborhood agreement statistics that interrogated the similarities of samples and features. In a separate analysis, the latent space of the neural network was visualized by using dimension reduction techniques to examine whether the ictal-interictal injury continuum hypothesis, which asserts that seizures and seizure-like patterns of brain activity lie along a spectrum, is supported by data. RESULTS: The performance of all users significantly improved when provided with AI assistance. Mean user diagnostic accuracy improved from 47 to 71% (P<0.04). The model achieved AUROCs of 0.87, 0.93, 0.96, 0.92, 0.93, and 0.80 for the classes seizure, LPD, GPD, LRDA, GRDA, and other patterns, respectively. This performance was significantly higher than that of a corresponding uninterpretable black-box model (with P<0.0001). Videos traversing the ictal-interictal injury manifold from dimension reduction (a two-dimensional representation of the original high-dimensional feature space) give insight into the layout of EEG patterns within the network's latent space and illuminate relationships between EEG patterns that were previously hypothesized but had not yet been shown explicitly. These results indicate that the ictal-interictal injury continuum hypothesis is supported by data. CONCLUSIONS: Users showed significant pattern classification accuracy improvement with the assistance of this interpretable deep-learning model. The interpretable design facilitates effective human-AI collaboration; this system may improve diagnosis and patient care in clinical settings. The model may also provide a better understanding of how EEG patterns relate to each other along the ictal-interictal injury continuum. (Funded by the National Science Foundation, National Institutes of Health, and others.).