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.”     

Transverse myelitis and polymyositis associated with antiphospholipid antibody syndrome

Antiphospholipid antibody syndrome (APS) has been widely recognized to be associated with various neurological complications. In addition to the classical notion of APS as a thrombotic disorder, APS has been suggested to be an autoinflammatory disease as well. We present a previously healthy 46-year-old man who concurrently developed transverse myelitis and polymyositis whose laboratory studies were significant for the elevated antiphospholipid antibodies such as anti-cardiolipin (CL)/β2-glycoprotein I (β2GPI) antibody. This report further enhances the recognized clinical phenotypes of the neurological complications of APS and the understanding of its pathomechanism.     

Serum NfL associated with anti-NMDA receptor encephalitis

Neurological Sciences - Neurofilament light chains (NfL) have been reported as potential markers for neuronal-axonal injury in neuroinflammatory diseases. In the current study, we describe serum...     

Anti-NMDA receptor encephalitis associated with ictal asystole

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis usually presents with psychiatric symptoms, behavioural changes, impaired consciousness, seizures and autonomic instability. Ictal asystole is a rare phenomenon associated with complex partial seizures. It is implicated as a potential cause of sudden unexpected death in epilepsy. We report a 41-year-old woman who presented with anti-NMDAR encephalitis. During continuous video electroencephalogram and cardiac monitoring, an episode of ictal asystole was detected. We discuss the potential link between anti-NMDAR encephalitis and ictal asystole. Treatment options for ictal asystole in the setting of anti-NMDAR encephalitis are also discussed.     

West Nile encephalitis and myelitis

PURPOSE OF REVIEW: This article will review the recent experience with West Nile virus encephalitis and myelitis. RECENT FINDINGS: In the summer of 2003, the majority of cases of West Nile virus infection in the United States were reported from the western states. The transmission of West Nile virus through blood transfusion and organ transplantation was recognized and blood collection agencies implemented West Nile virus nucleic acid-amplification tests to identify infected donors. Intrauterine transmission of West Nile virus infection was reported. The identification of West Nile virus immunoglobulin M in cerebrospinal fluid is the recommended test to document central nervous system infection, but this test may not be positive in spinal fluid collected less than 8 days after the onset of symptoms. Serial samples of cerebrospinal fluid may be required to identify the antibodies. A clinical trial got underway to evaluate the efficacy of human immunoglobulin with high titers of antibodies to West Nile virus in the therapy of West Nile virus encephalitis and myelitis. SUMMARY: In the summer of 2003, the majority of cases of West Nile virus infection in the United States were reported from states west of the Mississippi river. The identification of West Nile virus IgM in CSF is the recommended test to document CNS infection. A single serum antibody titer is an unreliable test of recent infection.     

Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma

OBJECTIVE: To report the autoantigens of a new category of treatment-responsive paraneoplastic encephalitis. METHODS: Analysis of clinical features, neuropathological findings, tumors, and serum/cerebrospinal fluid antibodies using rat tissue, neuronal cultures, and HEK293 cells expressing subunits of the N-methyl-D-aspartate receptor (NMDAR). RESULTS: Twelve women (14-44 years) developed prominent psychiatric symptoms, amnesia, seizures, frequent dyskinesias, autonomic dysfunction, and decreased level of consciousness often requiring ventilatory support. All had serum/cerebrospinal fluid antibodies that predominantly immunolabeled the neuropil of hippocampus/forebrain, in particular the cell surface of hippocampal neurons, and reacted with NR2B (and to a lesser extent NR2A) subunits of the NMDAR. NR2B binds glutamate and forms heteromers (NR1/NR2B or NR1/NR2A/NR2B) that are preferentially expressed in the adult hippocampus/forebrain. Expression of functional heteromers (not single subunits) was required for antibody binding. Eleven patients had teratoma of the ovary (six mature) and one a mature teratoma in the mediastinum; five of five tumors examined contained nervous tissue that strongly expressed NR2 subunits and reacted with patients' antibodies. Tumor resection and immunotherapy resulted in improvement or full recovery of eight of nine patients (paralleled by decreased antibody titers); two of three patients without tumor resection died of neurological deterioration. Autopsies showed extensive microgliosis, rare T-cell infiltrates, and neuronal degeneration predominantly involving, but not restricted to, the hippocampus. INTERPRETATION: Antibodies to NR2B- and NR2A-containing heteromers of the NMDAR associate with a severe but treatment-responsive encephalitis. Our findings provide a diagnostic test and suggest a model of autoimmune NMDAR-related encephalitis with broad implications for other immune-mediated disorders of memory, behavior, and cognition.     

Anti-NMDA receptor encephalitis with associated catatonia during pregnancy

Anti-NMDA-R encephalitis has been described as a cause of acute psychosis in young females. It is rare during pregnancy. We describe a primigravida 32-year-old woman with acute onset psychosis during the first trimester. Eight weeks after becoming pregnant, the patient became psychotic with associated catatonia and autonomic disturbance. Serum anti-NMDA-R antibodies were found. She responded to plasma exchange. At caesarean section, a healthy baby boy was born and a benign mature cystic teratoma was removed from the left ovary. Catatonia associated with psychosis may occur in pregnancy secondary to anti-NMDA-R encephalitis. Prompt and aggressive treatment can lead to a good outcome for both baby and mother.     

Carotid artery thrombosis, encephalitis, myelitis and optic neuritis associated with rubella virus infections.

The clinical, virological and pathological findings in 5 patients with neurological complications associated with rubella virus infection are described. The neurological illnesses began four to ten days after the rubella illnesses. The patients were all males aged between 6 and 17 years and were diagnosed during one non-epidemic year in a population of 1-5 million people. All the patients had rubella specific IgM in their sera. Two patients had no rash. In one of the patients who died, left internal carotid artery thrombosis and cerebral infarction were found at post-mortem. Rubella virus antigen and particles resembling rubella virus were found in the brain together with IgG and IgM in the same areas. This patient also had extensive liver necrosis. The other patient had a severe meningomyelitis and radiculitis and he recovered completely after two years. His serum rubella antibody rose significantly and was shown to leak into CSF during the acute stage of his illness. Three patients had a rash. Two of these patients had encephalitis: one recovered completely and the other had residual disability. The third patient had bilateral optic neuritis from which he recovered completely. Rubella specific IgM was, however, present in his serum for the abnormally long time of twenty-eight weeks indicating possible persistence of rubella virus.     

抗N-甲基-D-天冬氨酸受体脑炎的抗体检测及临床意义

目的探讨抗N-甲基-D-天冬氨酸受体(NMDAR)脑炎的抗体检测意义及临床特征。方法选取本院收治的脑炎病人35例及对照组30例,分析临床资料,采用转染细胞间接免疫荧光法检测两组患者其血清及脑脊液抗NMDAR机体结果抗NMDAR抗体检测仅1例边缘叶脑炎患者结果阳性,该患者腑脊液细胞数增多、蛋白轻度升高、脑电图见双侧慢波、其余检查无异常。精神症状及意识水平障碍明显,免疫治疗有效。结论抗NMDAR脑炎发病率低,临床表现复杂多样,怀疑该病时需行抗NMDAR抗体检测。     

Paroxysmal EEG pattern in a child with N-methyl-D-aspartate receptor antibody encephalitis

A previously healthy 8-year-old male presented with cognitive regression, sleep disturbance, hallucinations, and severe attacks of agitation and oligoclonal bands in the cerebrospinal fluid. N-methyl-d-aspartate receptor (NMDAR) antibodies in serum and cerebrospinal fluid were detected 2 months after onset of symptoms. Bursts of agitation were initially considered to be epileptic leading to the administration of a high dose of benzodiazepines. Video-electroencephalography (EEG) failed to disclose any correlation between the episodes of agitation and paroxysmal rhythmic slow activity on EEG persisting throughout and after attacks of agitation. Clinical improvement and EEG normalization followed an initial plasma exchange performed 3 months after onset of disease. This particular paroxysmal EEG pattern in NMDAR antibody encephalitis suggests that it may result from the combination of reduced NMDAR function and major γ-aminobutyric acid (GABA)-ergic activation.     

Limbic encephalitis associated with anti-GAD antibody and common variable immune deficiency

A variety of autoantibodies have been identified with complex neurological disorders including limbic encephalitis. The underlying trigger for the immune-mediated process and the role of autoantibodies in the pathogenesis of limbic encephalitis remain to be clarified. Here, we report a 16-year-old female who was diagnosed with acute-onset non-neoplastic limbic encephalitis. The initial treatment with pulse doses of i.v. methylprednisolone improved the neurological symptoms. During the next 12 months, progressive decline was reported in her academic functioning and seizure control. Additional diagnostic evaluation revealed no evidence of malignancy or central nervous system infection but circulating anti-GAD antibodies were present in the serum and cerebrospinal fluid. Intravenous gammaglobulin infusion was initiated and continued monthly. Intravenous and oral steroids were added to the intravenous immunoglobulin treatment because of the worsening course and seizures, despite treatment with antiepileptic medications. Screening for quantitative immunoglobulins demonstrated hypogammaglobulinaemia with low immunoglobulin M and G in addition to low immunoglobulin A levels. There was a lack of protective pneumococcal antibody titers before and after immunization. Therefore, common variable immunodeficiency was suspected despite there being no history of recurrent infections. To our knowledge, this is the first report describing a possible link between immune-mediated limbic encephalitis and immune deficiency.     

Longitudinal myelitis associated with yellow fever vaccination

Severe adverse reaction to yellow fever (YF) vaccine includes the yellow fever vaccine-associated neurotropic disease. This terminology includes postvaccinal encephalitis, acute disseminated encephalomyelitis, and Guillain-Barré syndrome. The objective of this communication is to report a patient who received a YF vaccine in Argentina and subsequently developed longitudinal myelitis with a symptom that had previously gone unreported in the literature. A 56-year-old man began with progressive paraparesia, urinary retention, and constipation 48 h previous to admission. The patient received YF vaccine 45 days prior to the onset of the symptoms. There was no history of other immunization or relevant condition. MR of the spine showed longitudinal intramedullary hyperintense signal (D5-12) without gadolinium enhancement. A high concentration of YFV-specific IgM vaccine antibody was found in the cerebrospinal fluid (CSF). Serological tests for other flavivirus were negative. A diagnosis of longitudinal myelitis without encephalitis associated with YF vaccine was performed and symptoms improved 5 days later. This is the first report dealing with longitudinal myelitis as a serious adverse event associated with YF vaccination in which confirmation of the presence of antibodies in CSF was found. To date, it is also the first report with serological confirmation in Argentina and in South America. We consider that the present investigation will raise awareness in the region in the reporting of adverse events related to YF vaccine and improve our knowledge of adverse reactions to the vaccine.     

Recurrent transverse myelitis associated with collagen disease

Summary A 43-year-old woman who had four recurrences of acute transverse myelitis (ATM) at the fifth thoracic vertebral level in 7 years is reported. Her haematological and immunological abnormalities included antibodies to DNA and nRNP and markedly reduced serum complement during the course of the disease. These findings suggest systemic lupus erythematosus although she had no symptoms other than those of ATM. Methylprednisolone and prednisolone were effective in treating the ATM.