NMDAR Encephalitis Research Articles

G330(P) Brain biopsy in children being investigated for undiagnosed neurological conditions

ObjectiveBrain biopsy has a diagnostic yield of >95% in neoplastic conditions. There is limited knowledge about the usefulness of brain biopsy in children with undiagnosed neurological conditions and the aim...

Management of psychiatric symptoms in anti-NMDAR encephalitis: a case series, literature review and future directions

Anti-NMDA receptor (NMDAR) encephalitis, formally recognized in 2007, has been increasingly identified as a significant cause of autoimmune and paraneoplastic encephalitis. Approximately 80% of the patients are females. The characteristic syndrome evolves in several stages, with approximately 70% of the patients presenting with a prodromal phase of fever, malaise, headache, upper respiratory tract symptoms, nausea, vomiting and diarrhoea. Next, typically within two weeks, patients develop psychiatric symptoms including insomnia, delusions, hyperreligiosity, paranoia, hallucinations, apathy and depression. Catatonic symptoms, seizures, abnormal movements, autonomic instability, memory deficits may also develop during the course of the disease. Presence of antibodies against the GluN1 subunit of the NMDAR in the CSF and serum confirm the diagnosis of NMDAR encephalitis, which also should prompt a thorough search for an underlying tumor. Age, gender, and ethnicity may all play a role, as black females older than 18 years of age have an increased likelihood of an underlying tumor. Treatment is focused on tumor resection and first-line immunotherapy [corticosteroids, plasma exchange, and intravenous immunoglobulin]. In non-responders, second- line immunotherapy [rituximab or cyclophosphamide or combined] is required. More than 75% of the patients recover completely or have mild sequelae, while the remaining patients end up demonstrating persistent severe disability or death. There is a paucity of literature on the management of psychiatric symptoms in this population. Given the neuropsychiatric symptoms in the relatively early phase of the illness, approximately 77 % of the patients are first evaluated by a psychiatrist. Earlier recognition of this illness is of paramount importance as prompt diagnosis and treatment can potentially improve prognosis. We describe two patients diagnosed with NMDAR encephalitis presenting with two different psychiatric manifestations. The first patient presented with psychotic mania and catatonic symptoms, while the second suffered from depression with psychotic and catatonic features refractory to psychotropic medications. We review of the use of psychotropic medications and ECT to address insomnia, agitation, psychosis, mood dysregulation and catatonia in NMDAR encephalitis.

Autoimmune encephalitis-update: roles of autoantibodies in the pathogenesis

Autoimmune encephalitis is increasingly recognized having autoantibodies to synaptic cell surface antigens, such as anti-N-methyl-D-aspartate receptor (NMDAR) and leucine-rich glioma-inactivated protein 1 (LGI1) by neurologists as well as pediatricians and psychiatrists, because these antibodies have been detected in cases of intractable epilepsy or atypical psychosis and in some demyelinating diseases, together with typical limbic encephalitis. Each group have characteristic clinical features, however, the disease spectrum has been expanding. To understand the significance of anti-NMDAR antibodies in the pathogenesis of NMDAR encephalitis, the role of the antibody in the disease process have been evaluated. The binding of antibody is shown to dimerize NMDARs and trigger their internalization on the postsynaptic site, thereby suppressing NMDAR-mediated transmission. To evaluate the antibody-induced dysfunction of NMDARs, we tested and showed the antibodies from the patients suppress the induction of NMDAR-dependent long-term potentiation (LTP) in mouse hippocampal slices. We also tested the antibody-effects on the cognitive functions of mice and revealed the CSF from NMDAR encephalitis patients had effects on disturbing spacial memory in mice. These results firmly support the proposal that the anti-NMDAR encephalitis autoantibody is responsible for cognitive disorders accompanying in this disease.

New autoantibodies in childhood encephalitis

Autoimmune and inflammatory brain disease constitute a significant proportion of acute neurological presentations in children, and untreated these disorders can result in neurological disability. New autoantibodies are improving the awareness of these treatable autoimmune CNS disorders. A recent paradigm in the autoantibody field is that autoantibodies that are ‘disease-causing' or ‘disease-contributing' bind to the extracellular domain of receptors, channels or proteins essential for neurotransmission or cell function. Therefore, assays that measure these autoantibodies typically use cell based assays that express the antigen of interest in its conformational state. These paradigms have resulted in the discovery of autoantibodies that are associated with a significant proportion of patients with encephalitis and other autoimmune encephalopathy. Autoantibodies and their disease associations include anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in CNS demyelination, anti-NMDA receptor antibodies in NMDAR encephalitis, antibodies against the voltage gated potassium channel complex in autoimmune limbic encephalitis and autoimmune epilepsy, and antibodies that bind to dopamine-2 receptor in basal ganglia encephalitis. These disorders are generally reversible with immune suppression, and the outcome appears better with early treatment. Second line immune suppression such as rituximab is increasingly being used in this context, and the risk versus benefit of these therapies is being assessed

Autoantibody-induced encephalitis

Neurologists often encounter encephalitis caused by unknown agents. Autoantibody-induced encephalitis is a new and exciting group of disorders that must be considered in the differential diagnosis as they are reversible if treated early in the course of the disease, but fatal if unrecognized. We describe the first report from the Indian subcontinent of three rare cases of different autoantibody-induced disorders, which were successfully managed with immunosuppressive therapy resulting in a good clinical outcome. Case 1 was a young woman with anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, not associated with tumor, who showed significant improvement with Rituximab. NMDA receptor encephalitis occurs typically in young females with psychiatric features, followed by an altered level of consciousness, dysautonomia, hyperkinetic movement disorder, seizures, and hypoventilation. Rituximab, which aims to suppress antibody production is an effective treatment modality. Anti-voltage-gated potassium channel antibodies (anti-VGKC-Ab) cause hyperexcitability of the peripheral nerve and central nervous system. Case 2 was a patient of limbic encephalitis presenting with complex partial seizures responding dramatically to steroids. Anti-VGKC-Ab-associated limbic encephalopathy is considered to be an autoimmune, non-paraneoplastic, potentially treatable encephalitis. The clinical features of anti-VGKC-Ab-associated limbic encephalitis are: Subacute onset of episodic memory impairment, disorientation, and agitation. Case 3 presented with Morvan's fibrillary chorea. Peripheral nerve hyperexcitability is the chief manifestation of the Morvan syndrome or cramp-fascilulation syndrome. The Morvan syndrome is characterized by neuromyotonia with autonomic and central nervous syndrome (CNS) involvement. Both VGKC-Ab-associated limbic encephalitis and Morvan syndrome can be successfully treated. Therefore, when these diseases are suspected, it is important to measure the anti-VGKC-Ab level.

Autoantibody-Associated Movement Disorders

Autoantibodies to the extracellular domain of neuronal proteins cause different neurological conditions with movement disorders as a prominent feature. We reviewed the literature of autoantibody-mediated and autoantibody-associated diseases focusing on anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, autoimmune basal ganglia encephalitis, Sydenham chorea, and the rare syndrome of progressive encephalomyelitis with rigidity and myoclonus. NMDAR encephalitis is a diffuse encephalitis with psychiatric and cognitive features associated with autoantibodies against the NR1 subunit of the NMDAR. The movement disorder phenotype is diverse and often generalized in young children. Although orofacial dyskinesia was the initial movement phenotype, chorea, dystonia, catatonia, and stereotypical movements are now described. The stereotypical movements can be bizarre and include cycling movements and compulsive self-injurious behavior. Autoimmune basal ganglia encephalitis is an inflammatory encephalitis localizing to the basal ganglia that is sometimes associated with serum antibodies against dopamine-2 receptor. Although psychiatric features are common, the dominant problem is a movement disorder, with dystonia-parkinsonism being characteristic. Sydenham chorea is the prototypic poststreptococcal autoimmune neuropsychiatric disorder and several autoantibodies may be involved in disease generation. The syndrome is characterized by a pure chorea, although hypotonia, dysarthria, and emotional lability are common. Progressive encephalomyelitis with rigidity and myoclonus is a rare autoimmune disorder causing rigidity, stimulus sensitive spasms, and myoclonus of nonepileptic origin and is associated with autoantibodies of multiple types including those against the glycine receptor. These disorders are important to recognize and diagnose, as immune therapy can shorten disease duration and improve outcome.

N‐methyl‐D‐aspartate receptor antibody‐associated movement disorder without encephalopathy

N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis is a well-recognized clinico-immunological syndrome that presents with a movement disorder, cognitive decline, psychiatric symptoms, and epileptic seizures. A pure monosymptomatic presentation is rare; however, some patients present predominantly with a movement disorder in the absence of encephalopathy. Here, we describe three paediatric patients with an NMDAR antibody-mediated movement disorder: a 5-year-old female with acute onset hemichorea, a 10-year-old female with generalized chorea, and a 12-year-old male with abdominal myoclonus. These patients did not develop the characteristic encephalopathy syndrome seen in NMDAR encephalitis, but all three had other associated subtle cognitive deficits. The patients demonstrated good responses to immunotherapy.

Comment: Infection antedating autoimmunity— Shared mechanisms in the brain?

Anti-NMDA receptor (NMDAR) encephalitis is a well-recognized immunotherapy-responsive condition, often diagnosed in younger individuals with characteristic clinical symptoms. In women, ovarian teratomas are frequently found and thought to trigger the antibody response against the NMDAR by ectopically expressing neuronal antigens. The present study describes the case of a patient with HSV encephalitis (HSVE) who develops a second episode of neurologic abnormalities, which is in fact NMDAR encephalitis.(1.)

Immunological profiles of the CSF from anti-NMDA receptor encephalitis patients

Background: Anti-N-methyl-D-aspartate receptor autoantibodies (NMDAR-Abs) are thought to relate closely to the pathogenesis of NMDAR encephalitis. The antibody-titre /INS;parallels with the disease activities and antibody-deprivation treatments are effective. This disease is thought to be immune-mediated;/INS; however, studies have not been done extensively from the immunological aspects.

NMDA Receptor Encephalitis May Present As a Pure Psychiatric Episode

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, which can present as a schizophrenic or depressive disorder, is rare and is diagnosed by the

Anti-N-Methyl-D-Aspartate Receptor Encephalitis

Investigators at Universities of Barcelona, Pennsylvania, Oviedo, and Valencia, and the Spanish NMDAR Encephalitis Work Group report the clinical features of 20 pediatric patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis seen in a single center in Spain in the last 4 years.

Autoimmune epilepsy in children: Case series and proposed guidelines for identification

Antibodies against neuronal surface proteins are increasingly recognized in autoimmune central nervous system (CNS) disorders in which seizures are the main or an important feature. The disorders include antibody-associated limbic encephalitis and N-methyl-D-aspartate receptor (NMDAR) encephalitis; however, seizures of autoimmune etiology may exist beyond the spectrum of these recognized syndromes. Because these seizures are potentially treatable with immune therapy, guidelines are needed to help in their early recognition. We describe 13 representative children seen at our tertiary institution over a period of 3.5 years with suspected autoimmune epilepsy. Autoimmune epilepsy was suspected clinically when there was any of the following: (1) recognizable syndromes such as NMDAR encephalitis or limbic encephalitis, (2) evidence of CNS inflammation in cerebrospinal fluid or on magnetic resonance imaging (MRI), (3) the presence of other autoimmune diseases, or (4) positive response to immunotherapy. We tested these patients for neuronal surface antibodies (voltage gated potassium channel [VGKC]-complex, leucine rich glioma inactivated 1 [LGI1], contactin-associated protein-like 2 [CASPR2], and NMDAR) and glutamic acid decarboxylase (GAD) antibodies. We modified the J Neurol Neurosurg Psychiatry, 83, 2012, 638 guidelines that were designed to classify adults with neuronal surface antibody syndromes (NSAS), to be more appropriate for children with suspected autoimmune epilepsy. Using the modified guidelines, the 13 patients were classified into definite, probable, possible, unlikely, or unknown autoimmune epilepsy according to the presence of neuronal surface or GAD antibodies, and the response to immune therapy when given. Of the 13 patients, 11 were females, and the mean age was 6 years (range 1-13 years). Three patients had classical NMDAR encephalitis, two had VGKC encephalitis, two had limbic encephalitis with negative antibodies, three had epilepsy with other autoimmune diseases (one with high titer GAD antibodies), two had fever-induced refractory epileptic encephalopathy in school-aged children (FIRES), and one epileptic encephalopathy associated with VGKC antibodies. Seven patients of the 13 children with suspected autoimmune epilepsy were positive for neuronal surface antibodies (NMDAR, n = 3; VGKC-complex, n = 3; and GAD, n = 1). Immunotherapy was given to nine cases, and a positive response was more common in patients with positive neuronal surface antibodies (5/5) compared to those with negative antibodies (2/4). Applying the proposed guidelines, the classification of autoimmune epilepsy was definite in five, probable in one, possible in three, unlikely in two, and unknown in two patients. Neuronal surface antibodies and GAD antibodies are present in a proportion of children with suspected autoimmune epilepsy and may define a treatable subgroup of childhood epilepsy. The proposed guidelines can be useful in the recognition of children with seizures of autoimmune etiology.

Psychiatric phenomena as initial manifestation of encephalitis by anti‐NMDAR antibodies

Autoimmune encephalitis associated with autoantibodies against the N-methyl-d-aspartate receptor (NMDAR) often presents with behavioural change. Our objective was to describe in detail the psychiatric presentation and pathways to care in order to aid the early diagnosis of NMDAR encephalitis. Sera and cerebrospinal fluid (CSF) from patients with suspected NMDAR encephalitis were tested on HEK 293 cells transfected with the NR1 subunit of the NMDAR. Clinical information was obtained from the referring psychiatrists and neurologists and by review of the clinical records. Samples from 15 patients (13 female, 2 male, mean age 24 years, range 5-56 years) tested anti-NMDAR positive. Twelve of the 15 patients (80%) presented with prominent psychiatric symptoms and 8 were initially referred to a psychiatric service. The most prominent initial psychiatric symptoms were anxiety in seven (47%), behavioural change (often bizarre) in six (40%) and agitation in five (33%). All patients developed psychiatric symptoms in the first 6 weeks of illness. Thirteen patients received psychotropic medications: antipsychotics in 12 and benzodiazepines in 11. Treating physicians considered the psychotropic medication not effective in 11 patients resulting in many drug switches. At nadir, all patients were in a very poor condition. However, eight patients (53%) recovered (almost) completely. Outcome tended to be better in patients who had received early immunotherapy or tumour removal. Autoimmune encephalitis and anti-NMDAR testing in serum and CSF should be considered in patients, especially young females, presenting with atypical psychiatric phenomena. Early diagnosis and treatment will likely improve the prognosis of NMDAR encephalitis.

In vitro neuronal network activity in NMDA receptor encephalitis

BackgroundAnti-NMDA-encephalitis is caused by antibodies against the N-methyl-D-aspartate receptor (NMDAR) and characterized by a severe encephalopathy with psychosis, epileptic seizures and autonomic disturbances. It predominantly occurs in young women and is associated in 59% with an ovarian teratoma.ResultsWe describe effects of cerebrospinal fluid (CSF) from an anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis patient on in vitro neuronal network activity (ivNNA). In vitro NNA of dissociated primary rat cortical populations was recorded by the microelectrode array (MEA) system.The 23-year old patient was severely affected but showed an excellent recovery following multimodal immunomodulatory therapy and removal of an ovarian teratoma. Patient CSF (pCSF) taken during the initial weeks after disease onset suppressed global spike- and burst rates of ivNNA in contrast to pCSF sampled after clinical recovery and decrease of NMDAR antibody titers. The synchrony of pCSF-affected ivNNA remained unaltered during the course of the disease.ConclusionPatient CSF directly suppresses global activity of neuronal networks recorded by the MEA system. In contrast, pCSF did not regulate the synchrony of ivNNA suggesting that NMDAR antibodies selectively regulate distinct parameters of ivNNA while sparing their functional connectivity. Thus, assessing ivNNA could represent a new technique to evaluate functional consequences of autoimmune encephalitis-related CSF changes.

Ketamine Infusion Associated with Improved Neurology in a Patient with NMDA Receptor Encephalitis.

A young lady was ventilated on intensive care for a prolonged period with NMDA receptor encephalitis. She had undergone steroid, immunoglobulin, and plasmapheresis with no evidence of recovery. Her main management issue was the control of severe orofacial and limb dyskinesia. Large doses of sedating agents had been used to control the dystonia but were ineffective, unless she was fully anaesthetised. The introduction of a ketamine infusion was associated with a dramatic improvement in her symptoms such that it was possible to remove her tracheostomy two days after commencement. She was discharged shortly after that and is making a good recovery. The successful use of ketamine has not previously been described in this context, and we hope this case report will provide some insight into the management of this rare but serious condition.

多発性硬化症様の脳病変をくりかえし，NMDA受容体脳炎を呈した1例

We present the case of a 31-year-old woman who developed N-methyl-d-aspartate (NMDA) receptor encephalitis during the course of relapsing and remitting multiple brain lesions. The patient developed a tingling sensation in the left upper and lower extremities, and was first admitted to our hospital at age 27. She was tentatively diagnosed with multiple sclerosis on the basis of multiple lesions with Gd-enhancement in the brainstem, and 2 separate clinical relapses by age 28. At age 31, she developed a headache and pyrexia, followed by confusion and abnormal behavior. Her symptoms acutely progressed to stupor, and subsequently, she developed oral dyskinesia and athetosis-like involuntary movement of the left arm. The stupor state continued over 2 months. However, she had completely recovered by 3 months after the onset of psychiatric symptoms. Her serum and CSF samples tested positive for anti-NMDA receptor antibodies, and she was diagnosed with NMDA receptor encephalitis. Her serum was negative for anti-AQP4 antibody, but showed weak positivity for antinuclear antibody. Between ages 32 and 34, she experienced 2 clinical relapses, including right-hand clumsiness, confusion, aphasia, and dysphagia. FLAIR images showed a high-intensity area in the brain stem, thalamus, and subcortical white matter. No tumors were found throughout the course. A clinical entity of NMDA receptor encephalitis can include various neurologic disorders, such as the development of recurrent demyelinating brain lesions. Further investigation is required to clarify the pathophysiological role of anti-NMDA receptor antibody in our patient.

Anti-NMDA Receptor Paraneoplastic Encephalitis: An Important Differential Diagnosis in Subacute Psychosis

Anti NMDA (N-methyl D-aspartate) receptor encephalitis has been recently described in young women with ovarian teratoma. Memory and psychiatric disturbances are frequent followed by respiratory and autonomic failure warranting long intensive care admissions. We report on a female patient with paraneoplastic encephalitis manifested by behavioural changes and neurological impairment, followed by respiratory and hemodynamic instability. Anti-NMDA receptor antibodies were found in blood and spinal fluid in association with an imamature grade 2 ovarian teratoma. She made a full recovery after complete oophorectomy and institution of intravenous immunoglobulin and corticosteroids. Anti-NMDA encephalitis should be considered in any female patient presenting with de novo psychiatric symptoms. As in other paraneoplastic syndrome, its therapy is based in resection of the underlying tumor associated with immunomodulators. Timely initiation of therapy may significantly improve outcome as in this case. J Med Cases. 2013;4(3):135-138 doi: https://doi.org/10.4021/jmc986w

Neuropsychological Profile of Anti-NMDA Receptor Encephalitis

Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is a life-threatening disorder that often occurs as a paraneoplastic encephalitis and usually begins with neuropsychological or psychiatric symptoms. We report a case of NMDA receptor encephalitis due to an ovarian teratoma, which began with severe and progressive amnesia and behavioral changes, reversed after surgical treatment and plasmapheresis. Using a battery of cognitive tests, its neuropsychological profile before treatment showed a complete alteration of the short and long term memory of both verbal and visual fixation, with clear improvement with cues and with intrusions, and saving other cognitive domains, such as working, episodic and semantic memory, executive, visuospatial, praxical thinking and language functions. These deficits reverted to normalcy with treatment. So, we can conclude that anti-NMDA receptor encephalitis is a rare entity that can be potentially serious depending on early management and diagnosis. We must suspect this entity in children or young people presenting with behavioural disturbances and crisis, with a cognitive pattern of complete alteration in short and long term memory improving with cues, and respecting other cognitive domains.

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.

Anti-NMDA Receptor Paraneoplastic Encephalitis: An Important Differential Diagnosis in Subacute Psychosis

Anti NMDA (N-methyl D-aspartate) receptor encephalitis has been recently described in young women with ovarian teratoma. Memory and psychiatric disturbances are frequent followed by respiratory and autonomic failure warranting long intensive care admissions. We report on a female patient with paraneoplastic encephalitis manifested by behavioural changes and neurological impairment, followed by respiratory and hemodynamic instability. Anti-NMDA receptor antibodies were found in blood and spinal fluid in association with an imamature grade 2 ovarian teratoma. She made a full recovery after complete oophorectomy and institution of intravenous immunoglobulin and corticosteroids. Anti-NMDA encephalitis should be considered in any female patient presenting with de novo psychiatric symptoms. As in other paraneoplastic syndrome, its therapy is based in resection of the underlying tumor associated with immunomodulators. Timely initiation of therapy may significantly improve outcome as in this case. doi: http://dx.doi.org/10.4021/jmc986w