D-aspartate Receptor Encephalitis Research Articles

A case of teratoma-associated encephalitis

Anti-<i>N</i>-methyl D-aspartate receptor encephalitis (NMDARE) is a newly described autoimmune encephalitis. Patients develop autoantibodies to the receptor, which results in psychiatric symptoms then neurological dysfunction, including autonomic instability, seizures and decreased consciousness.¹ This disorder carries a significant risk of serious neurological impairment or death, but in many cases is completely reversible. Approximately 60% of cases are associated with a neoplasm, almost always a teratoma. These teratomas contains neuroglial tissue which has been shown to express part of the anti-<i>N</i>-methyl D-aspartate receptor (NDMA receptor).¹ We detail the case of a 15-year-old girl who presented with seizures. Serology confirmed the presence of anti-NDMA receptor antibodies. An oopherectomy was performed which revealed a mature teratoma, 7 mm in size. This contained neuroglial tissue with an associated robust inflammatory response. Limited data is available on the histological features of teratomas associated with NMDARE, and we review the literature and discuss the potential significance for the reporting pathologist.

Early recognition of anti-N-methyl D-aspartate (NMDA) receptor encephalitis presenting as acute psychosis

We present a case of anti-N-methyl D-aspartate (NMDA) receptor encephalitis that illustrates the dilemma that psychiatrists face in evaluating patients with first episode psychosis. The discovery that acute psychosis can be the presenting feature of autoimmune encephalitis (in particular encephalitis caused by anti-NMDA receptor antibodies) has both practical and theoretical consequences. First, this condition is an important, but often overlooked, differential diagnosis of first episode psychosis. Antibody testing is not currently part of routine screening, though delayed (or missed) diagnosis can lead to prolonged hospital stay, medical complications and incomplete or delayed recovery. Widespread screening of patients with first presentation psychosis for anti-NMDA receptor and anti-voltage-gated potassium channel (anti-VGKC) antibodies is warranted for a number of reasons: to expedite appropriate treatment, to determine the true proportion of patients with these conditions presenting as psychosis, and to help elucidate the neurochemical causes of psychosis.

Secondary psychoses: an update

Psychotic disorders due to a known medical illness or substance use are collectively termed secondary psychoses. In this paper, we first review the historic evolution of the concept of secondary versus primary psychosis and how this distinction supplanted the earlier misleading classification of psychoses into organic and functional. We then outline the clinical features and approach to the diagnosis of secondary psychotic disorders. Features such as atypical presentation, temporal relation to detectable medical cause, evidence of direct physiological causal relationship to the etiological agent, and the absence of evidence of a primary psychotic illness that may better explain the presentation suggest consideration of a secondary psychosis. Finally, we discuss how careful studies of secondary psychotic disorders can help elucidate the pathophysiology of primary, or idiopathic, psychotic disorders such as schizophrenia. We illustrate this issue through a discussion of three secondary psychotic disorders - psychoses associated with temporal lobe epilepsy, velocardiofacial syndrome, and N-methyl D-aspartate (NMDA) receptor encephalitis - that can, respectively, provide neuroanatomical, genetic, and neurochemical models of schizophrenia pathogenesis.

A Typical Neurological Presentations in the ICU: Limbic Encephalitis

Common neurological emergencies include overdose or withdrawal from illegal substance abuse, adverse effects of prescription medications, seizures, metabolic encephalopathy, infections and cerebrovascular accidents. Following a thorough clinical and radiologic assessment, a small group of patients escape definitive diagnosis and autoimmune encephalitides should be considered. Of these, limbic encephalitis (LE) is the most common and may result from paraneoplastic or nonparaneoplastic sources. Common to both is the production of antibodies targeting epitopes in the brain parenchyma thought to be responsible for the clinical manifestations. Paraneoplastic Anti-N-methyl D-aspartate receptor (NMDAR) encephalitis is a common cause of LE and has gained awareness in neurological and psychiatric literature. Paraneoplastic and nonparaneoplastic anti NMDAR encephalitis typically presents in young, previously healthy females with subacute onset of psychiatric symptoms, respiratory insufficiency, orofacial dyskinesias, autonomic instability and seizures. Paraneoplastic LE is induced by antibody production against NMDAR with occult ovarian teratoma being the most common inciting tumor. LE has also been described in association with other tumors and also without tumors. The latter are known as nonparaneoplastic or primary autoimmune disease. Diagnosis requires both clinical suspicion along with prompt serum and cerebrospinal fluid analysis for antibody detection. Immunotherapy to remove and suppress these antibodies along with resection of an identified tumor is the therapy of choice. This article will review the clinical presentation and management of LE in patients who present to the medical intensive care unit.

Ovarian Teratoma Associated With Anti-N-Methyl D-Aspartate Receptor Encephalitis

Anti-N-methyl D-aspartate receptor (NMDAR) encephalitis is a recently described severe neurological disorder predominantly affecting young women, which presents with psychosis, memory deficits, seizures, and encephalopathy, often requiring prolonged hospitalization. The condition is frequently associated with an underlying neoplasm, most often an ovarian teratoma, and in such cases appears to be a para-neoplastic, immune-mediated encephalopathy. The histologic features of the teratomas associated with anti-NMDAR encephalitis have seldom been described in detail. Therefore, in this report, we have compared ovarian teratomas (4 mature and 1 immature) from 5 patients with anti-NMDAR encephalitis with 22 sporadic control teratomas (14 mature and 8 immature) that included neuroglial elements. The encephalitis-associated tumors ranged from 0.7 to 9.5 cm diameter, and 1 case was bilateral; the second teratoma was discovered 13 mo after the first when symptoms recurred. In comparison with control teratomas, the anti-NMDAR-associated tumors showed a more marked intratumoral lymphoid infiltrate that colocalized to the mature neuroglial elements. Reactive germinal centers (3 cases) and diffuse lymphoplasmacytic infiltrates within the neuroglial matrix (4 cases), and degenerative neuronal changes (2 cases), were seen only in the anti-NMDAR-positive cases. Pathologists encountering ovarian teratomas with these distinctive reactive lymphoid elements should consider the possibility of anti-NMDAR encephalitis, particularly because the neurological symptoms may develop after tumor resection. Careful histopathologic examination may be required to identify small, radiologically occult teratomas, and to demonstrate the presence of subtle neoplastic neuroglial components in teratomas associated with anti-NMDAR encephalitis.

Anti-N-methyl D-aspartate receptor encephalitis in childhood

To discuss the differential diagnosis of encephalitis beyond that of infectious etiology and to inform pediatricians about the possibility of anti-N-methyl-D-aspartate receptor (NMDAr) encephalitis in children by highlighting its most important clinical features. Three patients presented with an initial neuropsychiatric syndrome followed by encephalopathy and movement disorder. The initial neuropsychiatric features which developed over days to weeks included a change in personality, anxiety, confusion, and speech regression. This was followed by a choreoathetoid or dystonic movement disorder affecting the orofacial region and the limbs. After the exclusion of the major causes of encephalitis, NMDAr antibodies were identified in serum and cerebrospinal fluid, and neoplasm screening did not detect any tumor. Patients were submitted to immunosuppression, and two of them had a full neurological recovery. One of them still presents a mild dystonic posture in a limb. Clinical signs of anti-NMDAr encephalitis in children are similar to those previously described in adults. Tumors are not usually detected by this age. The diagnosis of anti-NMDAr encephalitis must be addressed only after the exclusion of infectious and other recognizable causes of encephalitis. Pediatricians should be aware of this treatable autoimmune condition.

Anti-NMDA receptor encephalitis with the initial presentation of psychotic mania

We report a 16-year-old girl with suspected psychotic mania, who subsequently developed amnesia, catatonia, oro-lingual dyskinesia, consciousness disturbance, seizure and respiratory failure. Repeated studies of the cerebrospinal fluid (CSF), viral culture and serology, brain MRI, single photon emission CT scan, and autoimmune profiles were all normal. She was finally diagnosed with anti-N-methyl D-aspartate receptor (NMDAR) encephalitis based on the positive finding of NMDAR antibodies in CSF. Her abdominal CT scan showed no detectable malignancy and pulse steroid therapy failed to have any effect. After administration of intravenous immunoglobulin her consciousness improved gradually. Anti-NMDAR encephalitis, with a characteristic neuropsychiatric syndrome, predominantly affects females with an ovarian tumor and is frequently misdiagnosed as a psychiatric disorder. Immunotherapy and eradication of associated malignancy are the main treatment strategies. Early recognition and early intervention of the disease should improve the outcome.

Abnormal sensory-motor integration in a patient with anti-NMDA-receptor encephalitis.

In this report, we describe the case of patient who showed abnormal corticomotor responses after peripheral afferent stimulation, namely sensory afferent inhibition (SAI) and sensory afferent facilitation (SAF), and its reversibility after treatment in a patient with anti-N-methyl D-aspartate receptor (NMDAR) encephalitis. A 26-year-old woman was admitted to a hospital after experiencing fever and headache for 11 days. Comprehensive serological studies, a brain magnetic resonance imaging scan, and cerebrospinal fluid (CSF) analysis were unremarkable. In the following days, she developed hallucinations and generalized tonic seizures. A repeat CSF analysis showed lymphocytic pleocytosis (261 white blood cells/ mm; 97% lymphocytes) and a normal protein concentration (63 mg/dl). She continued to have hyperkinetic movements and hyper-pyrexia despite receiving antibacterial and antiviral treatments. Electroencephalography showed diffuse slow waves with unremarkable somatosensory evoked potentials and brainstem auditory evoked potentials. After 30 days, she became unresponsive and had respiratory failure, and was then transferred to our hospital. On examination, she presented with dystonic posturing, oro-lingual-facial dyskinesia, and myoclonic movements. A computed tomography scan of the chest and abdomen and a trans-vaginal sonogram disclosed no abnormalities. Her serum and CSF studies were positive for anti-NMDAR antibodies. Transcranial magnetic stimulation (TMS) demonstrated intact corticospinal tracts with normal latencies and thresholds for motor-evoked potentials (MEPs). However, the conditioned peripheral afferent stimulation failed to show an SAI response at inter-stimulus intervals (ISIs) in the range of 15–25 ms, while exaggerated SAF responses were observed at ISIs between 30 and 70 ms. These data are contrasted to data from a healthy control subject in Fig. 1a, b and Table 1. The patient’s condition showed a little improvement in that she started to have some slow responses to verbal stimulation after steroid pulse therapy and plasmapheresis. Intravenous immunoglobulin was then started, and her condition improved dramatically. In a 3-week follow-up SAI/SAF study, the SAF had made notable progress toward normalization, but a normal SAI response was still absent (Fig. 1c; Table 1). NMDARs are expressed at high levels in the central nervous system, and play an important role in excitatory synaptic transmission and synaptic plasticity. Patients with anti-NMDAR antibodies usually present with various neurological symptoms presumably resulting from an AMPA receptor-mediated hyperglutamatergic state [1]. The MEP amplitude and latency of the patient described herein were similar to normal values. Impaired SAI and exaggerated SAF, such as observed in the presently described case, are suggestive of abnormal motor-sensory Y.-H. Dou K.-L. Lai K.-K. Liao S.-P. Chen (&) Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, 112 Taipei, Taiwan e-mail: chensp1977@gmail.com

Fine mapping of a monoclonal antibody to the N‐Methyl D‐aspartate receptor reveals a short linear epitope

Anti-N-Methyl D-aspartate receptor encephalitis is an autoimmune disease in which autoantibodies are produced against extracellular regions of the N-Methyl D-aspartate receptor (NMDAR). In this study, we used resin-bound peptides equipped with a base labile linker to map the epitope of a monoclonal NMDAR antibody against the NMDAR NR1 subunit. The antigenicity of the synthesized resin-bound peptides was determined by enzyme-linked immunosorbent assay. Distinct reactivity was found to two extracellular overlapping peptides (amino acids, 658-687). Using N- and C-terminally truncated resin-bound peptides, the minimum functional epitope was identified as the NPSDK sequence. The peptide sequence RNPSDK (amino acids, 673-678) was identified as the complete epitope, which was found to be located in the extracellular S2 domain of the NR1 subunit. Especially, the N-terminal arginine residue was found to be essential for reactivity, whereas the remaining amino acids could be replaced with amino acids of similar side-chain functionality, indicating the importance of backbone interaction in antibody reactivity.

Central Neurogenic Hyperventilation in Anti-NMDA Receptor Encephalitis

Central neurogenic hyperventilation (CNH) is a rare condition that is generally associated with infiltrative tumors of the brainstem. Respiratory dysfunction, particularly central hypoventilation, is common in anti-N-methyl D-aspartate (NMDA) receptor encephalitis. CNH, to the best of our knowledge, has not been described previously in this disease. A 24-year-old woman was diagnosed with anti-NMDA receptor encephalitis secondary to ovarian teratoma. In addition to the typical symptoms of the disease, recurrent CNH episodes were observed during the course of the illness, which subsided with midazolam and propofol infusion. Supportive and disease-specific treatments, including oopherectomy, plasmapheresis and intravenous immunoglobulin, provided excellent recovery. These observations suggest that NMDA receptors may play a role in the pathophysiology of CNH.

Anti-N-Methyl- d-aspartate-receptor encephalitis: Cognitive profile in two children

Background Anti-N-Methyl d-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder associated with antibodies against NMDAR resulting in a characteristic neuropsychiatric syndrome characterized by seizures, dyskinesias, and cognitive impairment. The extent and specific tasks associated with cognitive dysfunction in anti-NMDAR encephalitis have not been fully investigated. Aims To describe cognitive and neuropsychological profile in two children with anti-NMDAR encephalitis. Methods Clinical, laboratory, cognitive and neuropsychological assessments have been performed. Cognitive functions have been evaluated one year after the disease onset, at age 4 years and 10 months in one patient and at age 5 years and 5 months in the other subject. The first patient has been re-assessed one year after the first evaluation. Results Both children, who were reported to be normal before disease onset, showed a severe neurological impairment during the acute phase of disease with progressive substantial recovery following treatment. Selective and prolonged attention, activation and integration of semantic information and verbal fluency were particularly impaired. Significant improvements were observed at neuropsychological re-assessment. Conclusions Executive dysfunction seems to be the “core” of the neuropsychological profile of children with anti-NMDAR encephalitis. Cognitive abilities may be, at least to some extent, recovered providing that immunomodulatory treatment and specific psychomotor and pedagogical therapy are started soon after disease onset.

Anesthetic management of ovarian teratoma excision associated with anti- N-methyl- D-aspartate receptor encephalitis

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Detection of autoantibody against extracellular epitopes of N-methyl- d-aspartate receptor by cell-based assay

The concept of anti- N-methyl- d-aspartate receptor (NMDAR) encephalitis, a severe, potentially lethal, treatment-responsive disorder, mediated by autoantibodies against NMDAR was proposed. Because paraneoplastic anti-NMDAR encephalitis has a better prognosis after tumor resection and immunotherapy, rapid quantitative systems for detecting functional autoantibodies against extracellular epitopes of NMDAR are necessary. To detect autoantibodies recognizing extracellular epitopes of NMDAR, we stably expressed mutant NMDAR that decreases Ca 2+ permeability on a heterologous cell surface without any antagonist. Serum and CSF samples from patients were analysed using the cells expressing mutant NMDAR subunits by immunocytochemistry and on-cell Western analysis using live cells stably expressing mutant NMDAR. Furthermore, we were able to express mutant GluRζ1(NR1, GluN1) subunit of NMDAR alone on the cell surface and obtained direct evidence of the presence of autoantibodies recognizing extracellular epitopes of GluRζ1 and the induction of internalization by autoantibodies in serum and CSF from patients. The specificity of on-cell Western analysis was improved at 37 °C. The combination of this rapid quantitative assay using our on-cell Western analysis, detailed analysis of extracellular epitopes of NMDAR, and internalization assay of NMDAR will be valuable for the diagnosis, evaluation of clinical treatments, and follow-up of anti-NMDAR encephalitis.

N-methyl D-aspartate receptor encephalitis: A new addition to the spectrum of autoimmune encephalitis

A large proportion of “encephalitis” is caused by unknown agents. Of late, a new category of disorders, “autoimmune encephalitis,” has been described, which present with features similar to viral encephalitides. A well-delineated and common entity among this group is the recently described anti-NMDAR encephalitis (NMDARE). Although this entity was initially described in young women harboring ovarian teratomas, it is now characterised as well in children and men. Approximately 60% of the patients have an underlying tumor, usually an ovarian teratoma. In 40% of the patients, no cause can be found (idiopathic NMDARE). NMDARE typically presents with psychiatric features followed by altered level of consciousness, severe dysautonomia, hyperkinetic movement disorders, seizures and central hypoventilation. Orofacial dyskinesias resulting in lip and tongue mutilation are quite common. Seizures, are common and may be difficult to treat. The disease can be confirmed by serum and cerebrospinal fluid anti-NMDAR antibodies. Titers of these antibodies can also guide response to treatment. Tumor removal is necessary if identified, followed by immunological treatment. Intravenous methylprednisolone and immunoglobulins aim to suppress/modulate immune response while plasma exchange attempts to remove antibodies and other inflammatory cytokines. Rituximab and cyclophosphamide aim to suppress antibody production. Recovery is slow and often with neurological deficits if treatment is delayed. With many distinctive clinical features, a specific antibody that aids diagnosis, and early effective treatment with commonly available drugs leading to good outcomes, NMDARE is a diagnosis that should be considered early in any case of “unexplained encephalitis.”

Laparoscopic Cystectomy of Ovarian Teratoma in Anti-NMDAR Encephalitis: 2 Case Reports

We present 2 case reports of anti- N-methyl- d-aspartate receptor (NMDAR) encephalitis that was successfully treated via laparoscopic ovarian cystectomy. In both cases, resection of an ovarian teratoma resulted in eventual full recovery. Although adnexectomy has been reported for tumor resection in anti-NMDAR encephalitis, we chose ovarian cystectomy to preserve ovarian function. The efficacy of cystectomy is equivalent to that of adnexectomy. This suggests that ovarian adnexectomy may not be necessary in anti-NMDAR encephalitis with ovarian teratoma.

Anti-NMDA receptor encephalitis presenting with imaging findings and clinical features mimicking Rasmussen syndrome

Background Antibody mediated anti-N-methyl- d-aspartate (NMDA) receptor encephalitis is a recently reported diagnosis of clinical importance. Recognition of the syndrome, especially in pediatric populations, is difficult and often undiagnosed and/or confused with neurological disorders with similar clinical features. Results We report a case of an 11 year old female with explosive-onset epilepsy and predominantly unilateral frontal lobe abnormalities on magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) neuroimaging. A diagnosis of Rasmussen syndrome (RS) was considered. Cerebrospinal fluid analysis revealed strong positivity for NMDA receptor antibodies. Screening for occult ovarian teratoma with computed tomography (CT) and MRI initially did not demonstrate associated tumor. Treatment with steroids and plasma exchange improved her clinical course and subsequent MRI showed resolution. Conclusion NMDA receptor encephalitis has variable neuroimaging manifestations, and can mimic other entities. We emphasize the clinical syndrome of NMDA receptor encephalitis and consideration of the diagnosis in evaluating a child with explosive-onset epilepsy, unilateral imaging abnormalities, and neurocognitive decline.

Anti– N-methyl- d-aspartate receptor encephalitis associated with an ovarian teratoma in an adolescent female

Anti– N-methyl- d-aspartate (NMDA) receptor encephalitis is a recently described paraneoplastic syndrome with prominent neuropsychiatric symptoms. We report a case of NMDA receptor encephalitis in a 15-year-old female related to the development of NMDA receptor autoantibodies triggered by an ovarian teratoma. Removal of the mature teratoma proved curative with eventual resolution of the paraneoplastic disease process and associated psychiatric symptoms. Increasingly, reports of anti-NMDA receptor encephalitis associated with ovarian teratomas in pediatric patients, as well as a novel assay to measure these antibodies, suggest an etiology for this disease process that may be amenable to prompt surgical excision. The clinical presentation, diagnosis, and surgical management of the disease, as well as a review of the literature, are included.