Form Of Encephalitis Research Articles

Anti-NMDA Receptor Encephalitis in Children Is Associated with Variable Outcome (P07.140)

Objective: To describe the presentation, clinical course and outcome of a series of pediatric anti-N-methyl-D-aspartate (NMDA) receptor encephalitis patients. Background Anti-NMDA receptor encephalitis is a recently described form of autoimmune encephalitis that typically presents with psychiatric disturbance, seizures, dyskinesias and autonomic instability. The condition is frequently associated with ovarian teratoma and is more common in adults. Prognosis is usually good with most patients experiencing either complete recovery or the persistence of only mild deficits. The clinical course and outcome is less well known in children. Design/Methods: Case series. We report on three pediatric patients who had similar clinical presentations and were ultimately found to have anti-NMDA receptor encephalitis. Results: Three previously healthy female children ages 4, 6 and 10 years presented with new onset complex partial seizures that proved intractable. Repeated electroencephalograms showed focal abnormalities. Cerebrospinal fluid studies showed mild to moderate pleocytosis with negative culture. All patients subsequently developed psychiatric disturbances varying from delirium to visual hallucinations. Oral motor dyskinesias were seen in all patients and labile blood pressure was present in two patients. CSF was found to be positive for anti-NMDA receptor antibodies in all three patients. Repeated pelvic ultrasounds have been normal. All patients received high dose steroids and IVIG and two patients received cyclophosphamide. One patient has recovered with only minimal deficits and only occasional seizures, one patient is in a vegetative state with daily seizures and one patient has severe cognitive and motor deficits with frequent seizures. Conclusions: Anti-NMDA receptor encephalitis is associated with variable outcome in children with poor outcome possibly being more prevalent than in adults. Disclosure: Dr. Aaen has nothing to disclose. Dr. Michelson has nothing to disclose. Dr. De La Pena has nothing to disclose. Dr. Przekop has nothing to disclose. Dr. Roddy has nothing to disclose. Dr. Shu has nothing to disclose. Dr. Ashwal has nothing to disclose.

NMDA receptor autoantibodies in sporadic Creutzfeldt-Jakob disease

Sporadic Creutzfeldt-Jakob disease (sCJD) and N-methylD-aspartate receptor antibody (NMDAR-Ab) encephalitis [1], share similar clinical features including prominent psychiatric symptoms, memory problems, and seizures (Table 1). Previously, other forms of autoimmune encephalitis have been misdiagnosed as CJD, including Hashimoto’s and voltage-gated potassium channel complex antibody-associated encephalopathies [2, 3]. Here, conversely, we describe two patients presenting with progressive cognitive impairment and NMDAR-Abs with confirmed sCJD at post mortem. A retrospective review of 100 pathologically confirmed cases of sCJD seen by the UK National CJD surveillance unit [4] over the past 2 years identified six tested for NMDAR-Abs at presentation in whom results were available: four were negative and two positive. Both NMDAR-Ab positive cases presented with subacute cognitive decline and behavioral disturbance leading to serum testing for the antibodies. Patient A progressed to an akinetic mute state over 3 months and patient B over 9 months. Both had basal ganglia high signal on MRI brain imaging, a positive 14-3-3 immunoassay and elevated S100b level. Patient A twice had positive serum NMDARAb levels at dilutions up to 1:80. He was given 3 days of intravenous methylprednisolone and continued to deteriorate, dying 9 days later. Patient B deteriorated over 9 months. Some months after discharge to palliative care, his earlier positive serum NMDAR-Ab titre of 1:80 was discovered. Both had sporadic CJD confirmed at post mortem. CSFs were negative for NMDAR-Abs in all six cases. The presentation and clinical evolution in these two cases was consistent with sCJD and the positive NMDARAb results were surprising. Detecting NMDAR-Abs involves the demonstration of autoantibodies binding to a cell line expressing the NR1 and NR2B subunits [5]. All positive sera (tested at 1:20 initially) are checked against cells expressing other antigens, and the cells alone, to exclude any false-positive results [5, 6]. Positive results in healthy individuals or other disease controls are very rare; not found in 160 neurological disease controls [5]. The existence of these antibodies in two out of six patients with confirmed CJD is therefore intriguing. The titres were low, but at a level seen in patients with NMDAR-Ab encephalitis. One possibility is that these antibodies occurred as a secondary event resulting from an immune response to NMDARs released from damaged neurons. An altered composition of NMDAR has been implicated in cell death Electronic supplementary material The online version of this article (doi:10.1007/s00415-012-6489-3) contains supplementary material, which is available to authorized users.

Fenofibrate Reduces Mortality and Precludes Neurological Deficits in Survivors in Murine Model of Japanese Encephalitis Viral Infection

BackgroundJapanese encephalitis (JE), the most common form of viral encephalitis occurs periodically in endemic areas leading to high mortality and neurological deficits in survivors. It is caused by a flavivirus, Japanese encephalitis virus (JEV), which is transmitted to humans through mosquitoes. No effective cure exists for reducing mortality and morbidity caused by JEV infection, which is primarily due to excessive inflammatory response. Fenofibrate, a peroxisome proliferator-activated receptor-α (PPARα) agonist is known to resolve inflammation by repressing nuclear factor-κB (NF-κB) and enhancing transcription of anti-oxidant and anti-inflammatory genes. In addition, fenofibrate also up-regulates a class of proteins, cytochrome P4504Fs (Cyp4fs), which are involved in detoxification of the potent pro-inflammatory eicosanoid, leukotriene B4 (LTB4) to 20-hydroxy LTB4.Methodology/Principal FindingsThe neuroprotective effect of fenofibrate was examined using in vitro (BV-2 microglial cell line) and in vivo (BALB/c mice) models of JEV infection. Mice were treated with fenofibrate for 2 or 4 days prior to JEV exposure. Pretreatment with fenofibrate for 4 but not 2 days reduced mortality by 80% and brain LTB4 levels decreased concomitantly with the induction of Cyp4f15 and 4f18, which catalyze detoxification of LTB4 through hydroxylation. Expression of cytokines and chemokine decreased significantly as did microglial activation and replication of the JEV virus.Conclusions/SignificanceFenofibrate confers neuroprotection against Japanese encephalitis, in vivo, in mouse model of JEV infection. Thus, fenofibrate, a PPARα agonist that is commonly used as a hypolipidemic drug could potentially be used for prophylaxis during JE epidemics to reduce mortality and morbidity.

Nonparaneoplastic Anti-N-Methyl-d-Aspartate Receptor Encephalitis: A Case Series of Four Children

A rare, severe form of immune-mediated encephalitis recently has been described, associated with antibodies against N-methyl-D-aspartate receptors. It is reported mostly in women with ovarian tumors. Nonparaneoplastic presentations are less common. We describe four children with a neuropsychiatric and extrapyramidal syndrome associated with the presence of anti-N-methyl-D-aspartate receptor antibodies in cerebrospinal fluid and serum, without evidence of neoplasia. Three children recovered completely after immunomodulatory therapy, i.e., intravenous immunoglobulin and/or steroids, methylprednisolone, and/or adrenocorticotrophic hormone.

Electroconvulsive therapy can improve psychotic symptoms in anti‐NMDA‐receptor encephalitis

ANTI-N-METHYL-d-ASPARTATE (NMDA) RECEPTOR encephalitis has recently been described as paraneoplastic encephalitis often associated with ovarian teratoma.1 This form of encephalitis is important to psychiatrists because of the possibility of misdiagnosis as schizophrenia. Tumor removal and immunotherapy are usually recommended for anti-NMDA-receptor encephalitis. Reports on the effectiveness of electroconvulsive therapy (ECT), however, are limited.2, 3 We present here a case of anti-NMDA-receptor encephalitis accompanied by schizophrenia-like psychosis with catatonia. To our knowledge, this is the first report on the successful treatment of this encephalitis with ECT, unaccompanied by immunotherapy or tumor removal. After recuperating from influenza, an 18-year-old Japanese man felt fatigue and vertigo. Five days later, he developed acute-onset behavioral abnormalities and personality change. Another 6 days later, he developed delusions and committed violence, and was admitted to hospital. At the first visit, he was found to be in a confusional state with catalepsy, stereotypy, convulsions, and involuntary movements of the tongue. Initial electroencephalography, brain magnetic resonance imaging, and cerebrospinal fluid (CSF) were normal. Full body computed tomography (CT) showed no malignant neoplasm. A CSF sample for anti-NMDA antibody testing was obtained at the time of admission. The first attempt to treat him for catatonic schizophrenia with antipsychotics, lorazepam, and sodium valproate only reduced his confusional states. Therefore, ECT was carried out. ECT improved catatonia and psychosis, and confusional states gradually. After 13 ECT sessions and use of antipsychotics, the patient made a full recovery. He did not show any central hypoventilation in the course of the disease. After discharge we were informed that the anti-NMDA antibody in his CSF was positive. At 1-year follow-up the patient had fully recovered, and required no medication. Without information on anti-NMDA-receptor antibody, we would have misdiagnosed the patient as having schizophrenia and passed over the encephalitis. Because treatment for anti-NMDA-receptor encephalitis differs from that of schizophrenia, the differential diagnosis is crucial. Pharmaceutical therapy for schizophrenia was not effective in the present case, but ECT ameliorated the psychotic symptoms. The present finding suggests that ECT is an effective treatment option for catatonia and psychosis in anti-NMDA-receptor encephalitis. The current literature shows only a limited effect of ECT for anti-NMDA-receptor encephalitis: one patient made a full recovery after ECT but only in conjunction with methylprednisolone pulse therapy,2 while another patient's symptoms were partially improved with ECT, but full recovery was attained only after tumor removal.3 We do not fully understand the mechanism of ECT in anti-NMDA-receptor encephalitis. In the present case, it is possible that ECT temporarily attenuated the symptoms while encephalitis was improved in the natural course.4 Recent studies, however, have shown that ECT modulates the glutamatergic synapses in animal models.5 Thus, studying anti-NMDA-receptor encephalitis may lead to a better understanding of the function of NMDA receptors and ECT. Further studies are needed to confirm the present observation.

Diversity in anti‐N‐methyl‐D‐aspartate receptor encephalitis: Case‐based evidence

Antibodies against N-methyl-D-aspartate receptor (NMDAR) are identified in the form of immune-mediated encephalitis in which typical manifestations include neuropsychiatric symptoms, seizures, abnormal movements, dysautonomia and hypoventilation. The authors report two cases of anti-NMDAR encephalitis with different presentations and patterns of progression. The first patient presented with status epilepticus and later developed psychosis, pyramidal signs and diffuse encephalopathy. The second patient presented with acute psychosis followed a week later by seizures, dystonia, rigidity, oromandibular dyskinesias and dysautonomia. Possible mechanisms responsible for the clinical manifestations of this disease are discussed in light of recently described additional clinical and laboratory findings.

Anti-N-methyl-D-aspartate receptor encephalitis: an emerging cause of centrally mediated sinus node dysfunction

Anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) is a recently recognized form of autoimmune encephalitis that typically affects young women, often as a paraneoplastic syndrome related to ovarian teratoma. Clinical features include psychiatric and neurological disturbances, central hypoventilation, autonomic instability, and cardiac dysrhythmias. The prevalence, nature, and outcomes of cardiac dysrhythmias in patients with NMDARE have not been well described. Records of 10 consecutive patients with NMDARE were reviewed to obtain clinical, laboratory, echocardiographic, electrocardiographic, and radiological data. Patients were all female with an average age of 23 ± 5.5 years. Echocardiograms revealed structurally normal hearts with the exception of mild left ventricular hypertrophy in two cases. Eight patients had inappropriate sinus tachycardia. Six patients developed significant sinus bradycardia, which included periods of sinus arrest in four cases. Five patients manifested both sinus bradycardia and tachycardia. Bradycardia was often triggered by identifiable vagal stimuli. Temporary pacing was instituted in three patients, but permanent pacing was not required in any of the patients. Magnetic resonance imaging (MRI) scans revealed mesial temporal abnormalities in nine patients. In all cases, the dysrhythmias resolved with treatment of the underlying immune disorder with immunotherapy and/or teratoma resection. There was no evidence of dysrhythmia recurrence in any patient at follow-up. Anti-N-methyl-D-aspartate receptor encephalitis is a recently recognized cause of autoimmune encephalitis with a predilection to cause severe sinus node abnormalities. Temporary pacing is occasionally required, but permanent pacing appears to be unnecessary. An analysis of the clinical syndrome coupled with MRI and experimental data may offer insight into central mechanisms of heart rate regulation.

Epstein-Barr virus co-infection in a patient with dengue fever presenting with post-infectious cerebellitis: a case report

IntroductionPost-infectious cerebellitis is an acute form of inflammatory encephalitis mainly limited to the cerebellum. It is commonly found in children, especially after viral infections such as Epstein-Barr virus. Post-infectious cerebellitis presents with acute onset dysarthria and ataxia. To the best of our knowledge, this is the first case report of post-infectious cerebellitis in a patient with both dengue and Epstein-Barr viral infection confirmed on serology.Case presentationA 43-year-old Sri Lankan Sinhala man presented with an acute febrile illness associated with thrombocytopenia. While being managed as uncomplicated dengue fever, our patient developed dysarthria, ataxia and cerebellar signs. Our patient's infectious disease screen was positive for both dengue and Epstein-Barr specific immunoglobulin M. A cerebrospinal fluid analysis was suggestive of viral meningoencephalitis while cerebrospinal fluid serology was positive for dengue immunoglobulin G. T2-weighted magnetic resonance images were consistent with post-viral cerebellitis. The patient was given full supportive care and he made an uneventful complete recovery.ConclusionThere have been no previously reported cases of post-infectious cerebellitis associated with both Epstein-Barr and dengue viral infections confirmed by serology. Our patient's clinical features and findings on the imaging studies were consistent with post-viral cerebellitis. This report highlights the need to screen for other possible more common etiologies of a particular presentation before coming to a specific diagnosis based on initial findings. Uncomplicated cases of cerebellitis can be successfully managed with appropriate supportive measures with good prognosis, as in this case.

Chronic Granulomatous Herpes Encephalitis in a Child with Clinically Intractable Epilepsy

Most patients with herpes simplex virus Type I encephalitis experience an acute, monophasic illness. Chronic encephalitis is much less common, and few late relapses are associated with intractable seizure disorders. A 10-year-old boy was admitted to our institution for intractable epilepsy as part of an evaluation for epilepsy surgery. His history was significant for herpes meningitis at age 4 months. At that time, he presented to an outside hospital with fever for three days, with acyclovir treatment beginning on day 4 of his 40-day hospital course. He later developed infantile spasms and ultimately a mixed seizure disorder. Video electroencephalogram showed a Lennox-Gastaut-type pattern with frequent right frontotemporal spikes. Imaging studies showed an abnormality in the right frontal operculum. Based on these findings, he underwent a right frontal lobectomy. Neuropathology demonstrated chronic granulomatous inflammation with focal necrosis and mineralizations. Scattered lymphocytes, microglial nodules and nonnecrotizing granulomas were present with multinucleated giant cells. Immunohistochemistry for herpes simplex virus showed focal immunoreactivity. After undergoing acyclovir therapy, he returned to baseline with decreased seizure frequency. This rare form of herpes encephalitis has only been reported in children, but the initial presentation of meningitis and the approximate 10-year-time interval in this case are unusual.

New serological markers for the differential diagnosis of autoimmune limbic encephalitis1)

Abstract Recently, several novel autoantibodies have been identified which are closely associated with different subtypes of autoimmune encephalitis. These antibodies are directed against structures located on the neuronal cell surface: glutamate receptors (types NMDA and AMPA), GABAB receptors, as well as the voltage-gated potassium channel-associated proteins LGI1 and CASPR2. They are much more common than the classical paraneoplastic antibodies (anti-Hu, -Yo, -Ri, -Ma, -CV2, -amphiphysin), less frequently associated with a tumor, and the corresponding clinical syndromes respond significantly better to immunotherapy. Monospecific detection of these autoantibodies in the serum or cerebrospinal fluid of patients is primarily performed by indirect immunofluorescence using transfected HEK293 cell lines recombinantly expressing the membrane-associated target antigens. Owing to the symptom overlap of the respective disorders, it is highly appropriate to determine these parameters in parallel for each patient (autoantibody profiles). Early diagnosis (substantially supported by the serological laboratory), the immediate initiation of immunotherapeutic intervention and, in cases of paraneoplastic etiology, tumor resection are crucial for prognosis. In our own investigations, antibodies against glutamate receptors (type NMDA) are most frequently found among the newly identified forms of autoimmune encephalitis, accounting for 42% of cases. In laboratory practice, one-third of positive reactions were caused by an autoantibody whose determination was not requested by the clinician. Considering the urgency for therapeutic measures in positive cases, these findings substantiate the need to implement multiparametric serological test systems in this diagnostic area.

Single nucleotide polymorphism in the promoter region of the CD209 gene is associated with human predisposition to severe forms of tick-borne encephalitis

Tick-borne encephalitis virus (TBEV) is a neurotropic, positive-sense RNA virus of the genus Flavivirus (family Flaviviridae) which can cause a variety of clinical manifestations in humans. Previously the severity and outcome of dengue fever and hepatitis C (diseases caused by viruses from the family Flaviviridae) were associated with the rs4804803 single nucleotide polymorphism (SNP) located in the promoter region of the human CD209 gene. This gene encodes dendritic cell-specific ICAM3-grabbing nonintegrin (DC-SIGN), a C-type lectin pathogen-recognition receptor expressed on the surface of dendritic cells and some types of macrophages. In the current study, a possible association between two SNPs in the promoter region of the CD209 gene (rs4804803 and rs2287886) and predisposition to severe forms of TBEV-induced disease was investigated. The genotypic, allelic and haplotypic frequencies of these SNPs were analyzed in 136 non-immunized Russian patients with different clinical manifestations of tick-borne encephalitis (TBE) and in a control group. An increase in the frequency of the rs2287886 SNP AA homozygotes and the A allele was detected among patients with severe central nervous system disease compared with the group of patients with meningitis (P=0.003 and 0.019), or a combined group of patients with mild forms (fever and meningitis) (P=0.003 and 0.026), or the control group (P=0.007 and 0.035). Thus, our results suggest that the CD209 gene promoter region rs2287886 SNP is associated with predisposition to severe forms of TBE in the Russian population.

Potentially pathogenic autoantibodies associated with epilepsy and encephalitis in children and adults

Autoantibodies to surface proteins that influence neuronal excitability are increasingly found in different forms of epilepsy or encephalitis in adults, and are also beginning to be identified in children. The conditions are often refractory to traditional antiepileptic drugs. Detection of these antibodies can help to identify forms of epilepsy that may respond to immunotherapies.

The horse with stripes: a case of anti-NMDA receptor encephalitis.

The horse with stripes: a case of anti-NMDA receptor encephalitis.

The Horse With Stripes

The Horse With Stripes

P.5.c.004 Psychiatric manifestation of a mild form of limbic encephalitis in a 71 year old patient

P.5.c.004 Psychiatric manifestation of a mild form of limbic encephalitis in a 71 year old patient

Development and Field Testing of a Real-Time PCR Assay for Caprine Arthritis-Encephalitis-Virus (CAEV)

Caprine arthritis/encephalitis (CAE) of goats and occasionally sheep are persistent virus infections caused by a lentivirus (CAEV). This viral infection results in arthritis in adult animals and encephalitis in kids. Prognosis for the encephalitic form is normally poor, with substantial economic loss for the farm. In this context an early/fast laboratory diagnosis for CAEV infection could be useful for effective prophylactic action. In this work we performed a quantitative real time PCR designed on the CAEV env gene to detect/quantify in goat/sheep samples, viral RNA or proviral DNA forms of CAEV. This procedure was validated in 15 sheep, experimentally infected with CAEV or with a highly correlated lentivirus (visna maedi, MVV); in addition, a total of 37 clinical goat specimens recruited in CAEV positive herds were analyzed and compared using serological analysis (Elisa and AGID). All samples infected with MVV resulted negative. In sheep experimentally infected with CAEV, proviral DNA was detectable 15 days post infection, whereas the serological methods revealed an indicative positivity after 40-60 days.This method showed a sensitivity of 102 env fragments/PCR) with a linear dynamic range of quantitation from 103 to 107 env fragments/PCR; the R2 correlation coefficient was 0.98. All subjects with a clinical diagnosis for Caprine Arthritis-Encephalitis (CAE) resulted CAEV DNA positive.

Profound Sinus Node Dysfunction in Anti‐N‐Methyl‐D‐Aspartate Receptor Limbic Encephalitis

A form of limbic encephalitis associated with antibodies against the N-methyl-D-aspartate receptor (NMDAR) was discovered in 2007. It is often a multistage illness that progresses from psychosis, memory deficits, seizures into a state of unresponsiveness with catatonic features, abnormal movements, autonomic, and respiratory instability. We present two cases of anti-NMDAR encephalitis to highlight the cardiac complications and their management.

Voltage-Gated Potassium Channel/LGI1 Antibody–Associated Encephalopathy May Cause Brief Psychotic Disorder

Article AbstractLetter to the Editor Because this piece does not have an abstract, we have provided for your benefit the first 3 sentences of the full text. Voltage-gated potassium channel (VGKC) antibody-associated encephalopathy has been identified as a potentially immunotherapy-responsive form of limbic encephalitis. A recent study showed that the target antigen in this condition is in fact LGI1, a secreted neural protein that functions as a ligand for 2 epilepsy-related proteins, ADAM22 and ADAM23. Limbic encephalitis is typically a paraneoplastic syndrome with a poor prognosis.

Malignant catatonia due to anti-NMDA-receptor encephalitis in a 17-year-old girl: case report

Anti-NMDA-Receptor encephalitis is a severe form of encephalitis that was recently identified in the context of acute neuropsychiatric presentation. Here, we describe the case of a 17-year-old girl referred for an acute mania with psychotic features and a clinical picture deteriorated to a catatonic state. Positive diagnosis of anti-NMDA-receptor encephalitis suggested specific treatment. She improved after plasma exchange and immunosuppressive therapy. Post-cognitive sequelae (memory impairment) disappeared within 2-year follow-up and intensive cognitive rehabilitation.

Granulomatous amebic encephalitis: an under‐recognized cause of infectious mortality after hematopoietic stem cell transplantation

Granulomatous amebic encephalitis (GAE) is a rare, nearly always fatal form of encephalitis that occurs mostly in the setting of immune compromise or chronic disease. The prevalence and clinical characteristics of this Acanthamoeba infection in hematopoietic stem cell transplant (HSCT) recipients are not well described. We present an HSCT patient in whom the diagnosis of GAE was made at autopsy. A systematic review of previously reported cases is provided to highlight the clinical presentation and early diagnostic features of GAE in HSCT recipients. Amebic infection usually initially involves the skin or lungs over a period of months, and becomes rapidly fatal once it crosses the blood-brain barrier. GAE is usually discovered postmortem owing to lack of awareness of this deadly infection and delay in diagnosis. Subacute presentation of multiple recurrent panniculitis-like subcutaneous nodules associated with eosinophilia and a history of chronic rhinitis or sinusitis warrant investigation for a possible amebic infection. Prolonged corticosteroid use and a recent exposure to unhygienic water are potential risk factors for GAE. Successful outcomes may be achieved with early intensive treatment using a combination of effective drugs.