Occupation-Associated Fatal Limbic Encephalitis Caused by Variegated Squirrel Bornavirus 1, Germany, 2013.

Limbic encephalitis is commonly regarded as an autoimmune-mediated disease. However, after the recent detection of zoonotic variegated squirrel bornavirus 1 in a Prevost's squirrel (Callosciurus prevostii) in a zoo in northern Germany, we retrospectively investigated a fatal case in an autoantibody-seronegative animal caretaker who had worked at that zoo. The virus had been discovered in 2015 as the cause of a cluster of cases of fatal encephalitis among breeders of variegated squirrels (Sciurus variegatoides) in eastern Germany. Molecular assays and immunohistochemistry detected a limbic distribution of the virus in brain tissue of the animal caretaker. Phylogenetic analyses demonstrated a spillover infection from the Prevost's squirrel. Antibodies against bornaviruses were detected in the patient's cerebrospinal fluid by immunofluorescence and newly developed ELISAs and immunoblot. The putative antigenic epitope was identified on the viral nucleoprotein. Other zoo workers were not infected; however, avoidance of direct contact with exotic squirrels and screening of squirrels are recommended.

Status epilepticus associated with pregnancy: A cohort study.

BACKGROUND: Status epilepticus (SE) is a neurological emergency associated with a high mortality rate and long-term cognitive sequelae. Status epilepticus in pregnancy poses a tremendous threat to both mother and fetus, making a correct diagnosis and treatment a challenging task for clinicians. The prevalence, underlying etiology, and outcomes of pregnancy-related SE remain largely unknown. METHODS: We retrospectively studied all SE episodes (n=366) in patients admitted to our neurological ICU over a period of 8.5years. The patients who developed SE during pregnancy and within 6months after delivery were considered to have pregnancy-related SE. Patients with eclampsia were not included as they were usually cared for in our obstetric unit. RESULTS: Seven patients with pregnancy-related SE were identified (2.1% of all cases of SE), with the majority (85%) occurring de novo except for one patient who had a previous history of epilepsy-related SE due to withdrawal of antiepileptic medication. In terms of etiology, limbic encephalitis and cerebral venous sinus thrombosis were the two main etiologies of de novo SE associated with pregnancy. The overall mortality rate was 28.5% at discharge, and poor outcomes were especially noted in the patients with limbic encephalitis compared to other etiologies. CONCLUSIONS: Pregnancy-associated SE is rare and predominantly occurs in patients without a history of epilepsy. An autoimmune etiology should be considered in pregnant patients with de novo SE, which was associated with poor outcomes. Thorough investigations and prompt treatment according to the etiology may be required to improve the final outcomes of both mother and fetus.

Epidemiology of neuronal surface antibody-mediated autoimmune encephalitis and antibody-based diagnostics.

Epidemiologic data on neuronal surface antibody (NSAb)-associated autoimmune encephalitides (NSAE) are scarce and heterogeneous. We review our 13-year-long biobank-data collection and provide the incidence of NSAE in two Italian provinces (approx. Population of 1,400,000) over a 5-year period (July 2013-June 2018). NSAbs were diagnosed in 75 out of 1179 tested patients (6.4%). The most common NSAbs were anti-LGI1 (30 cases), followed by NMDAR (24). Eleven cases of NSAE were diagnosed in Treviso and Trento provinces with an estimated incidence of 1.54 per 1,000,000 population (LGI1-encephalitis 0.84; C.I. 0.38-1.88). LGI1-E is the most frequent NSAE among adults.

A single center retrospective study of paraneoplastic neurological syndromes with positive onconeural antibodies.

Paraneoplastic neurological syndromes (PNS) are rare immune-mediated disorders, and the detection of onconeural antibodies is helpful for PNS diagnosis. The aim of this study was to investigate the clinical characteristics of patients with PNS with positive onconeural antibodies in a single center in Hubei, China. We retrospectively analyzed the clinical characteristics of 54 patients with positive onconeural antibodies from January 2016 to September 2020. Among 780 patients with suspected PNS, 54 (6.9%) had positive onconeural antibodies. Of those 54 patients, 28 (51.8%) were diagnosed with definite PNS and 13 (24.1%) with possible PNS. Eighteen (33.3%) patients were confirmed with cancer. Ten PNS syndromes were detected among the 28 patients with definite PNS, and they had either classical (12/28, 42.8%) or non-classical syndromes (17/28, 60.7%). Peripheral neuropathy (9/28, 32.1%), subacute cerebellar degeneration (4/28, 14.3%), and limbic encephalitis (4/28, 14.3%) were the most common PNS syndromes. The anti-CV2/CRMP5-antibody was observed most frequently. Lung cancer was the most common tumor type. For patients with possible PNS, peripheral neuropathy was the most common PNS syndrome, and the anti-Tr-antibody was the most frequent onconeural antibody. Immunotherapy was effective in treating PNS. The anti-CV2/CRMP5-antibody was the most subsequently observed antibody. The manifestations of PNS are diverse and include peripheral neuropathy, subacute cerebellar degeneration, and limbic encephalitis. In patients with PNS, lung cancer was the most common tumor.

Neuronal Surface Antibody-Medicated Autoimmune Encephalitis (Limbic Encephalitis) in China: A Multiple-Center, Retrospective Study.

Objective: The epidemiological characteristics of patients with antibody-medicated autoimmune encephalitis in China remain unclear, and a large-scale epidemiological survey is necessary. Methods: A multiple-center retrospective study was performed. We collected 1,047 patients with suspected autoimmune encephalitis and ultimately enrolled 778 defined patients across centers in China. All patients were positive for serum [or cerebrospinal fluid (CSF)] antibodies. Demographic information and clinical data from January 2014 to January 2019 from 22 centers in China were reviewed. Results: A total of 778 patients with autoimmune encephalitis were enrolled in the study. In general, the ratio of males to females was ~1.2:1. The main subtypes of autoimmune encephalitis were NMDAR-AE (61.35%), LGI-1-AE (20.61%), and GABAbR-AE (12.40%). According to the characteristics of age of onset, the incidence of autoimmune encephalitis showed a "double peak" distribution entailing a 20-year-old age group and a 60-year-old age group. We next analyzed the proportion of patients with tumors in this cohort. More specifically, there were 34 patients with tumors and 85 with tumor marker positivity. Relapse occurred in 81 patients within at least 1 year's follow up study: 52 with NMDAR-AE (18.2%); 19 with LGI-1-AE (16.8%); 5 with GABAbR-AE (9%); and 3 with CASPR2-AE. Interpretation: Due to the vast differences in demographic features, the incidence of cancer and the genetic characteristics between the populations in China and Western countries, the demographics, sex distribution, concomitant tumor rate, clinical features, and relapse characteristics associated with autoimmune encephalitis in China shows a similar profile with Western countries with some minor differences.

New-Onset Seizure With Possible Limbic Encephalitis in a Patient With COVID-19 Infection: A Case Report and Review.

With the outbreak of COVID-19 (coronavirus disease 2019) as a global pandemic, various of its neurological manifestations have been reported. We report a case of a 54-year-old male with new-onset seizure who tested positive for severe acute respiratory syndrome coronavirus 2 from a nasopharyngeal swab sample. Investigative findings, which included contrast-enhancing right posterior temporal lobe T2-hyperintensity on brain magnetic resonance imaging, right-sided lateralized periodic discharges on the electroencephalogram, and elevated protein level on cerebrospinal fluid analysis, supported the diagnosis of possible encephalitis from COVID-19 infection. The findings in this case are placed in the context of the existing literature.

Epidemiology of paraneoplastic neurological syndromes: a population-based study.

BACKGROUND: The epidemiology of paraneoplastic neurological syndromes (PNS) remains to be defined. We present here the first population-based incidence study and report the clinical spectrum and antibody profile of PNS in a large area in Northeastern Italy. METHODS: We performed a 9-year (2009-2017) population-based epidemiological study of PNS in the provinces of Udine, Pordenone and Gorizia, in the Friuli-Venezia Giulia region (983,190 people as of January 1, 2017). PNS diagnosis and subgroups were defined by the 2004 diagnostic criteria. Age- and sex-adjusted incidence rates were calculated. RESULTS: We identified 89 patients with a diagnosis of definite PNS. Median age was 68 years (range 26-90), 52% were female. The incidence of PNS was 0.89/100,000 person-years. PNS incidence rates increased over time from 0.62/100,000 person-years (2009-2011), 0.81/100,000 person-years (2012-2014) to 1.22/100,000 person-years (2015-2017). The prevalence of PNS was 4.37 per 100,000. Most common PNS were limbic encephalitis (31%), cerebellar degeneration (28%) and encephalomyelitis (20%). Among antibody (Ab)-positive cases, most frequent specificities included: Yo (30%), Hu (26%), and Ma2 (22%), while the most frequent associated tumors were lung (17%) and breast cancer (16%), followed by lymphoma (12%). PNS developed in 1 in every 334 cancers in our region. Statistically significant associations were observed between cancer type and Ab-specificity (P < 0.001), and between neurological syndrome and Ab-specificity (P < 0.001). CONCLUSIONS: This first population-based study found an incidence of PNS that approximates 1/100,000 person-years and a prevalence of 4/100,000. Moreover, the incidence of PNS is increasing over time, probably due to increased awareness and improved detection techniques.

Paraneoplastic limbic encephalitis.

BACKGROUND: Paraneoplastic limbic encephalitis (PLE) is a syndrome characterized by the development of neuropsychiatric symptoms due to a misdirected tumor-activated antibody response that damages host neural tissue. Definitive treatment relies on the identification and ablation of the underlying tumor. Few publications describe the management of psychiatric symptoms associated with PLE. OBJECTIVE: Given the plethora of neuropsychiatric symptoms that may mimic primary psychiatric illness, and the possibility that PLE may herald a life-threatening malignancy, it is important that psychiatrists become familiar with this condition. METHOD: The authors review and discuss the consensus literature on the various aspects of PLE. DISCUSSION: In this review, authors summarize proposed mechanisms and treatments of PLE.

Voltage-gated potassium channel-associated limbic encephalitis in the West of Scotland: case reports and literature review.

BACKGROUND AND AIMS: The syndrome of limbic encephalitis (LE) associated with antibodies against voltage-gated potassium channels (VGKC-LE) has recently been described. The number of published cases is however small. We therefore aimed to review all cases seen at our centre and compare with published cases. METHODS: Retrospective cases of VGKC-LE were identified using a questionnaire to Neurologists at the Southern General hospital, Glasgow, and by reviewing patients with a positive VGKC antibody test (2002-2007). Case-note review of identified cases and a literature review of all published cases of VGKC-LE were performed. RESULTS: Seven cases were identified (four female, age range 51-81). Patients presented sub-acutely with seizures and anterograde memory loss. Five patients had medial temporal lobe change on cranial imaging. No paraneoplastic cases were identified. 5/7 patients made some improvement with immunotherapy. In 2006, 3/18 (17%) patients with a coded discharge of encephalitis were diagnosed with VGKC-LE. The literature review revealed 40 patients with VGKC-LE. Age, gender or VGKC level did not predict likelihood for a significant recovery. Patients treated < or =5 months of symptom onset with immunotherapy were more likely to make a significant recovery (83% vs. 45%, p=0.04). CONCLUSION: VGKC-LE is being increasingly diagnosed and is best identified early and treated with immunotherapy to offer the greatest chance of recovery. This series and literature review expands the current published evidence in VGKC-LE.

Limbic encephalitis: Experience of a moroccan center.

OBJECTIVES: Histologically defined as an inflammation-degeneration of limbic structures, limbic encephalitis (LE) is a rare disease and often difficult to diagnose particularly in institutions with limited access to laboratory tests such as antineuronal antibodies or HSV-PCR, and functional imaging. We aimed to describe the demographic, clinical, paraclinical, and etiological features of LE, as well as its medium-term prognosis in Moroccan patients. MATERIALS AND METHODS: We collected retrospectively all patients diagnosed with LE in the Department of Neurology of the University Hospital Hassan II of Fez (Morocco) between September 2008 and December 2016. We analyzed their demographic features, clinical manifestations, magnetic resonance imaging and laboratory findings, etiologies, and medium-term prognoses. RESULTS: We included 22 men and 9 women aged 14-76 years (mean age: 45.8 years). In 64.5% of cases, the onset of symptoms was acute. The clinical manifestations included generalized status epilepticus (16.1%), confusional syndrome (29%), epileptic seizures (38.7%), psychiatric disorders (48.4%), and memory disorders (45.2%). The nonlimbic symptoms were nuchal stiffness (22.6%), headaches (9.7%), fever (61.3%), vesicular rash (3.2%), and language disorders (6.5%). The different etiologies found were herpes simplex virus (6.5%), syphilis (16.1%), tuberculosis (3.2%), varicella (3.2%), paraneoplastic autoimmune LE (22.6%), anti-NMDA-R LE (6.5%), and sarcoidosis (3.2%). We found 12 cases (38.7%) of LE without definite etiology and with an incomplete diagnostic workup. The medium-term clinical course includes a complete remission in 45.2% of cases and partial remission in 45.1% of cases. The different sequelae were temporal lobe epilepsy (9.7%), anterograde amnesia (16.1%), and severe cognitive impairment (19.4%). The mortality rate was 9.7% (3 patients). CONCLUSION: Our study shows a wide diversity of etiologies of LE in Morocco with essentially an acute mode of onset of symptoms.

Epidemiological study of acute encephalitis in Tottori Prefecture, Japan.

BACKGROUND AND PURPOSE: To conduct an epidemiological survey of acute encephalitis focusing on non-herpetic acute limbic encephalitis (NHALE) in Tottori Prefecture, western area of Japan. METHODS: A questionnaire survey on the annual number of patients aged 16 years or more with acute encephalitis from 2001 to 2005 was undertaken in 2006. RESULTS: During the study period, 49 patients were diagnosed with acute encephalitis. The subtype of acute encephalitis was as follows: 10 patients with herpes simplex encephalitis (HSE), 12 patients with NHALE, 4 patients with paraneoplastic encephalitis, 2 patients with encephalitis associated with collagen disease, one patient with viral encephalitis other than HSE, 20 patients with encephalitis with unknown causes. The service-based incidence rate of acute encephalitis was 19.0 per million person-years. The incidence rate of NHALE subtype was 4.7 per million person-years. CONCLUSIONS: Our epidemiological survey indicated an estimated 550 patients would develop NHALE per year in Japan, suggesting that NHALE may not be a rare disorder.

Anti-LGI1 encephalitis: Clinical syndrome and long-term follow-up.

OBJECTIVE: This nationwide study gives a detailed description of the clinical features and long-term outcome of anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis. METHODS: We collected patients prospectively from October 2013, and retrospectively from samples sent to our laboratory from January 2007. LGI1 antibodies were confirmed with both cell-based assay and immunohistochemistry. Clinical information was obtained in interviews with patients and their relatives and from medical records. Initial MRI and follow-up MRI were revised blindly. Neuropsychological assessment was performed in those patients with follow-up over 2 years. RESULTS: Annual incidence in the Netherlands was 0.83/million. A total of 34/38 patients had a limbic encephalitis. Subtle focal seizures (66%, autonomic or dyscognitive) and faciobrachial dystonic seizures (FBDS, 47%) mostly occurred before onset of memory disturbance. Later in the disease course, 63% had tonic-clonic seizures. Initial MRI showed hippocampal T2 hyperintensity in 74% of the patients. These lesions evolved regularly into mesial temporal sclerosis (44%). Substantial response to immunotherapy was seen in 80%, with early response of seizures and slow recovery of cognition. At follow-up ≥2 years, most surviving patients reported mild residual cognitive deficit with spatial disorientation. A total of 86% had persistent amnesia for the disease period. Relapses were common (35%) and presented up to 8 years after initial disease. Two-year case fatality rate was 19%. CONCLUSIONS: Anti-LGI1 encephalitis is a homogenous clinical syndrome, showing early FBDS and other focal seizures with subtle clinical manifestations, followed by memory disturbances. Better recognition will lead to earlier diagnosis, essential for prompt start of treatment. Long-term outcome of surviving patients is mostly favorable, but relapses are common.

Differences in epileptic symptoms depending on the type of autoimmune-mediated limbic encephalitis.

Limbic encephalitis (LE) is an inflammatory disease of the central nervous system that is characterized by the selective involvement of limbic structures. The clinical manifestations of LE include the acute or sub-acute onset of recent memory disorders, mental disorders and seizures. Autoimmune-mediated LE is a major type of non-infectious LE; seizure is a hallmark of this type of LE. The treatment of epilepsy, which is a key factor that affects the prognosis of LE patients, warrants special attention. Understanding the characteristics of epilepsy caused by autoimmune-mediated LE and providing the appropriate treatment will help to improve patients' outcomes. In this article, we extensively review the literature related to autoimmune-mediated LE epidemiology, mechanisms, characteristics and seizure frequency and onset, and we discuss the possible diagnosis and treatment of this disease.

Pilomotor seizures: an autonomic semiology of limbic encephalitis?

PURPOSE: Ictal piloerection is an infrequent seizure semiology that is commonly overlooked as an ictal epileptic manifestation. Piloerection is considered to be principally caused by temporal lobe activity although frontal and hypothalamic seizure origins have been reported. The described etiology has shown a wide variety of structural causes such as mesial temporal sclerosis, tumors, posttraumatic, cavernomas and cryptogenic epilepsies. METHODS: We retrospectively reviewed the incidence of ictal piloerection in the clinical records of patients who underwent video-EEG monitoring (VEEGM) between 2007 and 2013 in a multicenter cooperative study. All patients presented refractory epilepsies and were evaluated with a protocol that included brain MRI, neuropsychology and VEEGM. RESULTS: A total of 766 patients were evaluated in four tertiary centers in Spain. Five patients showed piloerection as principal seizure semiology (prevalence 0.65%). The mean age at seizure onset was 39.6 years and the average epilepsy duration was 5.2 years (range 2-14) before diagnosis. Four patients were additionally examined with FDG-PET and/or SPECT-SISCOM. All presented temporal lobe epilepsy (TLE), three right-sided and two left-sided. A typical unilateral hippocampal sclerosis was described in 3 cases. The etiology detected in all cases was limbic encephalitis. Three had LGI1, one anti-Hu, and another Ma2 antibodies. CONCLUSION: Our series describes a so far not well-recognized autoimmune association of pilomotor seizures to limbic encephalitis. This etiology should be ruled out through a comprehensive diagnostic work-up even in cases of long-lasting TLE with typical hippocampal atrophy on MRI.

Autoimmune limbic encephalopathy and anti-Hu antibodies in children without cancer.

OBJECTIVE: The aim of this study was to describe the clinical presentation of children and adolescents with anti-Hu antibodies (Hu-Abs). METHODS: This was a retrospective study of children and adolescents with Hu-Abs collected by the French Paraneoplastic Neurological Syndrome (PNS) Reference Center between January 1, 2000 and December 31, 2011. RESULTS: The center identified 251 patients with Hu-Abs. Only 8 patients were younger than 18 years. All of the 243 adult patients had PNS. In contrast, of the 8 children, only 2 (25%, Fisher exact test p = 0.0003) had neuroblastoma and opsoclonus-myoclonus. The other 6 children (5 female and 1 male) presented with limbic encephalitis (progressive personality changes, memory loss, and seizure) and were free of cancer (mean follow-up time: 50 months; range: 34-72 months). Brain MRI scans were abnormal in 4 of the 6 patients, with left, right, or bitemporal T2/fluid-attenuated inversion recovery hyperintensity. Protein levels and cell counts in the CSF were normal in all patients, but numerous oligoclonal bands were observed in 4 patients. All 6 patients received antiepileptic drugs and immunotherapy, but management of epilepsy was difficult in all of them. Five of the children developed cognitive impairments. CONCLUSION: In children, as in adults, Hu-Abs can be a marker of PNS. However, in contrast to adults, Hu-Abs in children are also associated with an aggressive form of autoimmune nonparaneoplastic limbic encephalitis. Future studies should be conducted to determine the incidence of this syndrome and whether earlier diagnosis and T-cell-directed immunotherapies may improve its prognosis.

Limbic encephalitis in Taiwanese children and adolescence: a single center study.

BACKGROUND: Non-viral limbic encephalitis, which may be paraneoplastic or idiopathic, is increasingly recognized in adults and children. Early identification of potential patients, who have neuronal autoantibodies to intracellular or neuronal surface antigens in order to give appropriate immunotherapy, is key to improving the prognosis. This cross-sectional study describes the clinical manifestation and the serological evidence of the presence of neuronal antibodies in Taiwanese children with limbic encephalitis. METHOD: We enrolled children and adolescents who had been hospitalized due to nonviral limbic encephalitis. Serum samples from these patients were collected to screen antibodies against intracellular antigens [amphiphysin, Ma2, Ri, Yo, Hu and antiglutamic acid decarboxylase (GAD)] and neuronal surface antigens [N-methyl-d-aspartate (NMDA) receptor, γ-amino butyric acid (GABAB) receptor and voltage-gated potassium channel complexes (VGKCs)]. RESULTS: All of the 10 enrolled patients had acute onset of fever and rapid clinical deterioration. They had persistent neuropsychiatric symptoms and 90% developed refractory epilepsy, despite six patients having been treated with methylprednisolone pulse therapy or intravenous immunoglobulin (IVIG) at the acute stage. In the laboratory findings, half of the cases were positive for antibodies with regards to intracellular antigens (amphiphysin or GAD). The general outcomes, assessed by Glasgow Outcome Scale, were similar between patients with and those without the antibodies (Mann-Whitney U test, p = 0.43). One patient, who was positive for antibodies to amphiphysin 10 years after disease onset, still had a significant response to oral prednisolone therapy. At the end of the follow-up period, no cancer or insulin-dependent diabetes mellitus was detected in any of the patients. CONCLUSION: This study provides evidence for a potential association between antibodies and limbic encephalitis. The presence of antibodies, especially antibodies to GAD, may serve as an indicator for immunotherapy.

Nationwide survey of acute juvenile female non-herpetic encephalitis in Japan: relationship to anti-N-methyl-D-aspartate receptor encephalitis.

OBJECTIVE: To study the incidence and clinical features of acute juvenile female non-herpetic encephalitis (AJFNHE) in Japan. METHODS: A nationwide questionnaire on patients with severe non-herpetic encephalitis of unknown etiology with a prolonged clinical course or death was sent to the departments of Internal Medicine, Neurology, Pediatrics, and Emergency and Critical Care at all hospitals with 200 beds or more in Japan. RESULTS: The recovery rate was 25% (1,279 out of 5,030 departments) and 90 patients were enrolled in this study. The annual incidence was 0.33/10(6) population. 85% of patients were female. The means and standard deviations of age at onset and hospital stay were 26+/-10 years and 180+/-228 days. As first symptoms, fever and psychosis were presented in 90%. Among the neurological symptoms, disturbance of consciousness was presented in 92%, convulsions in 65%, and involuntary movements in 55%. Respiratory failure during hospitalization was observed in 71% and required care with mechanical ventilation. The detection rate of anti-GluR epsilon2 and/or delta1 antibodies was 67% of patients. Anti-N-methyl-D-aspartate receptor NR1/NR2 antibody was detected in all four examined patients with anti-GluR epsilon2 antibody, and also detected in both of the two examined patients without anti-GluR epsilon2 antibody. As for outcome, 46% returned to work and 37% returned home, but 7% died. Associated tumors were demonstrated in 39%. All reported patients had ovarian tumors, among which teratoma was the most frequent. CONCLUSION: A nationwide survey provided data for the annual incidence and clinical features of AJFNHE in Japan.