Prodromal headache in anti-NMDAR encephalitis: An epiphenomenon of NMDAR autoimmunity.

OBJECTIVE: To investigate the nature of prodromal headache in anti-NMDA receptor (NMDAR) encephalitis. METHODS: Retrospective review of the clinical information of 39 patients with anti-NMDAR encephalitis admitted between January 1999 and September 2017. Five patients with an atypical presentation were excluded. Thus, in 34 patients (median 27 years [range, 12-47 years]; 28 [82%] female), the clinical features were compared between patients who initially reported headache and those who did not report. RESULTS: Twenty-two patients (65%) reported headache either transiently (n = 5) or continuously (n = 17). Encephalitic symptoms (psychobehavioral memory alterations, seizure, dyskinesias, or altered level of consciousness) developed in 20 patients with median 5.5 days (range, 1-29 days) after headache onset. In one patient, NMDAR antibodies were detected in CSF 3 days after headache onset. Patients with headache had more frequently fever (14/22 [64%] vs. 2/12 [17%] p = 0.013) and higher CSF pleocytosis (median white blood cells 79/µl [range, 6-311/µl] vs. 30/µl [range, 2-69/µl], p = 0.035) than those without headache, but there was no difference in gender, age at onset, seizure, migraine, CSF oligoclonal band detection, elevated IgG index, tumor association, or brain MRI abnormalities between them. CONCLUSIONS: Headache often developed with fever and pleocytosis, but it was rapidly replaced by psychiatric symptoms. Based on current knowledge on the antibody-mediated mechanisms that cause a decrease of synaptic NMDAR through crosslinking and internalization leading to a state mimicking "dissociative anesthesia," we speculated that prodromal headache is not likely caused by direct effect of the autoantibodies but rather meningeal inflammation (noninfectious aseptic meningitis) that occurs in parallel to intrathecal antibody synthesis as an epiphenomenon of NMDAR autoimmunity. Psychobehavioral alterations following headache is an important clue to the diagnosis.

Clinical presentation of anti-N-methyl-d-aspartate receptor and anti-voltage-gated potassium channel complex antibodies in children: A series of 24 cases.

OBJECTIVE: The symptomatology and paraclinical findings of antibody-mediated encephalitis, a relatively novel disorder, are still being characterized in adults and children. A high index of suspicion is needed in order to identify these cases among children presenting with various neurological symptoms. The aim of this study is to examine the clinical, demographic and laboratory findings and outcome of children with anti-NMDAR and anti-VGKC encephalitis for any typical or distinctive features. METHODS: Cases diagnosed with anti-N-Methyl d-aspartate receptor (NMDAR) and anti-voltage gated potassium channel (VGKC) antibody-mediated encephalopathy in four major child neurology centers are described. RESULTS: In four years, 16 children with NMDAR and 8 children with VGKC antibody-associated disease were identified in the participating centers. The most frequent initial manifestation consisted of generalized seizures and cognitive symptoms in both groups. Movement abnormalities were frequent in anti-NMDAR patients and autonomic symptoms, in anti-VGKC patients. Cerebrospinal fluid (CSF) protein, cell count and IgG index were normal in 9/15 anti-NMDAR and 5/8 anti-VGKC patients tested. EEG and MRI findings were usually nonspecific and non-contributory. The rate and time of recovery was not related to age, sex, acute or subacute onset, antibody type, MRI, EEG or CSF results. Treatment within 3 months of onset was associated with normal neurological outcome. CONCLUSIONS: Our results suggest anti-NMDAR and VGKC encephalopathies mostly present with non-focal neurological symptoms longer than 3 weeks. In contrast with adult cases, routine CSF testing, MRI and EEG did not contribute to the diagnosis in this series.

Anti-Yo, chorea and hemiballismus: A case report.

68-year-old female presented with involuntary movements. MRI was normal. Cerebrospinal fluid analysis was normal. whole body CT and biopsy confirmed diagnosis of metastatic adenocarnimoa. The autoimmune panel was positive for anti-Yo antibodies.

Focal status epilepticus and progressive dyskinesia: A novel phenotype for glycine receptor antibody-mediated neurological disease in children.

BACKGROUND: Antibody-associated disorders of the central nervous system are increasingly recognised in adults and children. Some are known to be paraneoplastic, whereas in others an infective trigger is postulated. They include disorders associated with antibodies to N-methyl-d-aspartate receptor (NMDAR), voltage-gated potassium channel-complexes (VGKC-complex), GABAB receptor or glycine receptor (GlyR). With antibodies to NMDAR or VGKC-complexes, distinct clinical patterns are well characterised, but as more antibodies are discovered, the spectra of associated disorders are evolving. GlyR antibodies have been detected in patients with progressive encephalopathy with rigidity and myoclonus (PERM), or stiff man syndrome, both rare but disabling conditions. CASE REPORT: We report a case of a young child with focal seizures and progressive dyskinesia in whom GlyR antibodies were detected. Anticonvulsants and immunotherapy were effective in treating both the seizures and movement disorder with good neurological outcome and with a decline in the patient's serum GlyR-Ab titres. CONCLUSION: Glycine receptor antibodies are associated with focal status epilepticus and seizures, encephalopathy and progressive dyskinesia and should be evaluated in autoimmune encephalitis.

[Antibodies to native and denatured DNA in the serum of patients with schizophrenia depending on the clinical features of the disease].

OBJECTIVE: To study the correlations between the level of antibodies to native and denatured DNA and psychopathological symptoms and illness duration in patients with schizophrenia. MATERIAL AND METHODS: The level of antibodies to native (double-stranded) DNA and denatured (single-stranded) DNA was studied in the serum of 50 patients with schizophrenia, including 12 patients with tardive dyskinesia (TD). The control group consisted of 30 people. RESULTS: A significant twofold increase in antibodies to native DNA was detected in patients with TD. There was no correlation of the amount of antibodies to double-stranded DNA with the duration of disease and leading symptoms both between the groups of patients as well as in comparison with controls. A significant decrease in antibody levels to the denatured (single-stranded) DNA was found in schizophrenic patients compared to the control group (p=0.009). A significant decrease in the concentration of antibodies to single-stranded DNA in patients with increasing duration of the disease, as well as in patients with leading negative symptoms was revealed. CONCLUSION: The results suggest that anti-DNAantibodies may not play a major role in the pathogenesis of schizophrenia.

Anti-N-Methyl-D-Aspartate Receptor-Mediated Encephalitis: Recent Advances in Diagnosis and Treatment in Children.

Anti-N-methyl-d-aspartate receptor-mediated encephalitis (anti-NMDAR encephalitis) is increasingly recognized in children and adolescents. There is a recognizable pattern of clinical symptoms, similar between children and adults. There are some differences in children including the frequency of presenting symptoms, the presence of hypoventilation, and the identification of an associated tumor. Early tumor removal and treatment with immunotherapy is important for rapid recovery. The prognosis can be surprisingly good but some children have lasting neurocognitive deficits.

Immunology, autoimmunity, and autoantibodies in Parkinson's disease.

Recent revelations of immune alterations in Parkinson's disease have led to the convergence that an autoimmune mechanism may play a role in the etiopathogenesis of this neurodegenerative disease. In the current study, 77 Parkinson's disease patients and 77 matched healthy controls were analyzed for the presence of seven autoantibodies previously found to be associated with central nervous system manifestations namely: antineuronal-cells, anti-brain lysate, anti-dsDNA, anti-phosphatidylserine, anti-cardiolipin, anti-serotonin, and anti-melanocytes antibodies. Patients underwent systematic assessments of demographics, clinical, and biochemical manifestations. Three autoantibodies were found to be more prevalent among Parkinson's disease patients (antineuronal cells10.3% vs. 1.3%, p = 0.017; anti-brain lysate 9.1% vs. 1.3%, p = 0.032; anti-dsDNA 10.3% vs. 2.6%, p = 0.049). Clinical manifestations of Parkinson's disease, particularly dyskinesia and depression, were found to be associated with the presence of these autoantibodies.

Pseudo-piano playing motions and nocturnal hypoventilation in anti-NMDA receptor encephalitis: response to prompt tumor removal and immunotherapy.

Tumor resection is recommended in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, however it is often difficult during an early stage of the disease. We report here the efficacy of early tumor removal in a patient with anti-NMDAR encephalitis. This 21-year-old woman was admitted to another hospital with rapidly progressive psychiatric symptoms, a decreased level of consciousness, and seizures. Abdominal CT showed a pelvic mass. On day 1 of admission to our center, she developed hypoventilation requiring mechanical support. She had orofacial dyskinesias with well-coordinated, pseudo-piano playing involuntary finger movements. Based on these clinical features, she was immediately scheduled for tumor resection on day 3. While awaiting surgery, she began to receive high-dose intravenous methylprednisolone. After tumor removal, she received plasma exchange, followed by intravenous immunoglobulin and additional high-dose methylprednisolone. Two weeks after tumor removal, she started following simple commands and progressive improvement, although she remained on mechanical ventilation for 10 weeks due to nocturnal central hypoventilation. Anti-NMDAR antibodies in serum/CSF were detected. Pathological examination showed immature teratoma with foci of infiltrates of B- and T-cells. Early tumor resection with immunotherapy facilitates recovery from this disease, but central hypoventilation may require long mechanical support. Non-jerky elaborate finger movements suggest antibody-mediated disinhibition of the cortico-striatal systems.

Kinesigenic dyskinesia in a case of voltage-gated potassium channel-complex protein antibody encephalitis.

OBJECTIVE: To describe the first case (to our knowledge) of voltage-gated potassium channel-complex protein antibody encephalitis with kinesigenic dyskinesia and cramp-fasciculation syndrome. DESIGN: Case report. SETTING: Hospitalized care. PATIENT: A 38-year-old man with a history of bronchial asthma, eczema, vitiligo, and immune complex mesangiopathic glomerulonephritis presented with abnormal movements. MAIN OUTCOME MEASURES: Clinical examination, magnetic resonance imaging, single-photon emission computed tomography, electromyography and nerve conduction studies, video-electroencephalographic monitoring, plasmapheresis exchange therapy, and intravenous immunoglobulin administration. RESULTS: Clinical examination revealed paroxysmal kinesigenic dyskinesia and fasciculations. Magnetic resonance imaging of the brain revealed a left caudate and left putamen increased signal lesion on T2-weighted and fluid-attenuated inversion recovery sequences as well as increased flow in the same region on single-photon emission computed tomographic scans. Electromyography and nerve conduction studies revealed significant afterdischarges, cramp potentials, and continuous motor activity. The video-electroencephalographic monitoring revealed no epileptiform discharges. The patient dramatically improved after 5 plasmapheresis exchange treatments and a course of intravenous immunoglobulin at 2 gm/kg over 5 divided doses. CONCLUSION: To our knowledge, this is the first report of paroxysmal kinesigenic dyskinesia with voltage-gated potassium channel-complex protein antibody encephalitis associated with the cramp fasciculation syndrome.

[Update on anti-NMDA receptor encephalitis].

A new category of treatment-responsive encephalitis has been proposed in association with antibodies to neuronal cell membrane antigens, including voltage-gated potassium channel (VGKC), N-methyl-D-aspartic acid receptor (NMDAR), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), gamma-aminobutyric acid (GABA) B receptor and other antigens that have not yet been characterized. Among the forms of encephalitis under this category, anti-NMDAR encephalitis is a distinct disorder characterized by the predictable sequential development of symptoms; prodromal symptoms are initially noted, followed by prominent psychiatric symptoms, seizures, an unresponsive/catatonic state, hypoventilation, and involuntary orofacial-limb movements. This disorder usually affects young women with ovarian teratoma but may also affect women of any age or even men. A recent study revealed that the main epitope targeted by anti-NMDAR antibodies lies in the extracellular N-terminal domain of the NR1 subunit (25-380 amino-acid residues); the NR2B subunit is not necessarily involved. The antibodies are shown to produce selectively and reversibly reduce postsynaptic NMDARs clusters without complement activation. Considering the symptomatology of anti-NMDAR encephalitis and the results of cell culture analysis, we speculate that the overall antibody-mediated inhibition of NMDARs expressed on GABAergic interneurons, glutamatergic neurons and dopaminergic neurons may cause neuropsychiatric symptoms and dyskinesias via dopamine and glutamate dysregulation. We also hypothesize that these antibodies affect not only trafficking/localization/clustering of postsynaptic NMDARs, but also the expression of other receptors including AMPAR and dopamine receptors, by including a chronic state of exposure to excessive or decreased neurotransmitters release. The establishment of an animal model is awaited to resolve these issues. Anecdotal reports have revealed that recovery may be spontaneous without tumor resection but early tumor resection along with aggressive immunotherapy facilitates early functional recovery. In a recent case, a microscopic teratoma was detected on autopsy; therefore exploratory laparotomy may be considered in severe refractory cases.

Chronic expression of low levels of tumor necrosis factor-alpha in the substantia nigra elicits progressive neurodegeneration, delayed motor symptoms and microglia/macrophage activation.

Inflammation, and in particular microglia activation, is regarded as a constant component of brain pathology in Parkinson's disease (PD). Microglial activation has been found in the substantia nigra (SN), one of the main brain regions affected in PD, for many years after the initiation of the disease. Although many studies point towards a deleterious role of inflammation on PD, the functional role of many of its main components has not been clarified yet. For example, tumor necrosis factor-alpha (TNF-alpha), a key pro-inflammatory cytokine, has been shown to exert toxic or no effects on the viability of dopaminergic neurons. No study has evaluated the effects of the long-lasting TNF-alpha expression in the SN, an experimental set-up most probably resembling the clinical situation. The aim of this study was to investigate the effects of the chronic expression of TNF-alpha in the adult SN at different time points. Adenoviral expression of low TNF-alpha levels (17-19 pg/mg) lasted for 14 days in the SN and did not induce interleukin-1beta (IL-1beta) expression. Long-lasting TNF-alpha expression caused dopaminergic cell death from day 14, increasing at 21 and 28 days compared with control animals injected with adenovectors expressing beta-galactosidase. TNF-alpha overexpression elicited irreversible, unilateral akinesia starting at 14 days, but not earlier. These effects were accompanied by microglial activation to stage 4 and/or monocyte/macrophage recruitment from the periphery from day 7 post adenovector inoculations. Thus, we conclude that extended duration of the expression of TNF-alpha is necessary and sufficient for a univocal toxic effect of TNF-alpha on dopaminergic neurons and motor disabilities. This study provides an animal model to study early events that lead to TNF-alpha-mediated neuronal demise in the SN. In addition, the cellular components of the inflammation elicited by TNF-alpha and the lack of IL-1beta expression support the growing idea of a distinct cytokine network in the brain.

Anti-N-methyl-D-aspartate receptor antibodies: a potentially treatable cause of encephalitis in the intensive care unit.

OBJECTIVE: To report the occurrence of an unusual neurologic disorder requiring admission to the intensive care unit. DESIGN: Analysis of an observational cohort study of 31 patients with encephalitis admitted over a 4-yr period. SETTING: Neurologic intensive care unit in a tertiary referral center. PATIENTS: We identified N-methyl-D-aspartate receptor antibodies in six patients (two male and four female). All seropositive patients presented with a psychiatric prodrome, before developing seizures and obtundation requiring intensive care unit admission. They exhibited limb and truncal stereotypies and orofacial dyskinesias upon weaning sedation. Two patients had ovarian tumors. INTERVENTIONS: Patients were treated with sedation, antiepileptic drugs, and immunotherapy. One patient received a magnesium infusion and ketamine. MEASUREMENTS AND MAIN RESULTS: N-methyl-D-aspartate receptor antibodies were identified in serum samples by an immunofluorescent cell-based assay. Three patients made a good but slow recovery; two were left with severe neurologic deficits; and one died after return to the referring hospital. These patients accounted for approximately 20% of all patients admitted with encephalitis to this referral center. CONCLUSIONS: N-methyl-D-aspartate receptor antibodies should be tested in patients with hyperkinetic encephalitis and neuropsychiatric prodrome admitted to the intensive care unit. The disorder is probably not rare and is potentially treatable.

Hemichorea-hemiballismus associated with nonketotic hyperglycemia: a possible role of inflammation.

Three cases of hemichorea-hemiballismus (HC-HB) associated with nonketotic hyperglycemia were reported. Of them two patients presented as HC-HB and the remaining one as generalized chorea-ballismus (CB). Brain MRI showed characteristic T1-weighted high-intensity lesions in the contralateral or bilateral striatum without edema or mass effect. They all had a prior history of respiratory or urinary infection. Cerebrospinal fluid test in two patients showed an elevation of protein concentration with normal cell and an increased IgG content and elevated IgG index or 24 h IgG intrathecal synthesis rate. These results suggested that inflammation within the central nervous system may participate in the pathogenesis of chorea and ballismus induced by NKH.

The synaptic impact of the host immune response in a parkinsonian allograft rat model: Influence on graft-derived aberrant behaviors.

Graft-induced dyskinesias (GIDs), side-effects found in clinical grafting trials for Parkinson's disease (PD), may be associated with the withdrawal of immunosuppression. The goal of this study was to determine the role of the immune response in GIDs. We examined levodopa-induced dyskinesias (LIDs), GID-like behaviors, and synaptic ultrastructure in levodopa-treated, grafted, parkinsonian rats with mild (sham), moderate (allografts) or high (allografts plus peripheral spleen cell injections) immune activation. Grafts attenuated amphetamine-induced rotations and LIDs, but two abnormal motor syndromes (tapping stereotypy, litter retrieval/chewing) emerged and increased with escalating immune activation. Immunohistochemical analyses confirmed immune activation and graft survival. Ultrastructural analyses showed increases in tyrosine hydroxylase-positive (TH+) axo-dendritic synapses, TH+ asymmetric specializations, and non-TH+ perforated synapses in grafted, compared to intact, striata. These features were exacerbated in rats with the highest immune activation and correlated statistically with GID-like behaviors, suggesting that immune-mediated aberrant synaptology may contribute to graft-induced aberrant behaviors.

Anti-NMDA receptor encephalitis in Japan: long-term outcome without tumor removal.

OBJECTIVE: To report the definitive diagnosis of anti-NMDA receptor (NMDAR) encephalitis in four Japanese women previously diagnosed with "juvenile acute nonherpetic encephalitis" of unclear etiology, and to describe their long-term follow-up in the absence of tumor resection. METHODS: We extensively reviewed the case histories with current clinical and laboratory evaluations that include testing for antibodies to NR1/NR2 heteromers of the NMDAR in serum/CSF available from the time of symptom onset (4 to 7 years ago) and the present. RESULTS: All patients sequentially developed prodromal symptoms, psychosis, hypoventilation, severe orofacial dyskinesias, and bizarre immunotherapy-resistant involuntary movements that lasted 1 to 12 months. Two patients required mechanical ventilation for 6 and 9 months. Initial tests were normal or unrevealing, including the presence of nonspecific CSF pleocytosis, and normal or mild changes in brain MRI. Eventually, all patients had dramatic recovery of cognitive functions, although one had bilateral leg amputation due to systemic complications. Antibodies to NR1/NR2 heteromers were found in archived serum or CSF but not in long-term follow-up samples. An ovarian teratoma was subsequently demonstrated in three patients (all confirmed pathologically). CONCLUSION: 1) These findings indicate that "juvenile acute nonherpetic encephalitis" or a subset of this disorder is mediated by an antibody-associated immune response against NR1/NR2 heteromers of the NMDA receptor (NMDAR). 2) Our patients' clinical features emphasize that anti-NMDAR encephalitis is severe but potentially reversible and may precede by years the detection of an ovarian teratoma. 3) Although recovery may occur without tumor removal, the severity and extended duration of symptoms support tumor removal.

Antiphospholipid- associated recurrent chorea and ballism in a child with cerebral palsy.

We present the case of a 9-year-old female with cerebral palsy and repeated episodes of ballism associated with antiphospholipid and anticardiolipin antibodies. She was treated unsuccessfully with varying medications, including neuroleptics, anticholinergics, antiepileptics, dopamine, dopamine agonists, and monoamine oxidase inhibitors. Intravenous immunoglobulin and corticosteroids led to resolution of the movements. We postulate an immune mechanism of disease for ballism associated with antiphospholipid and anticardiolipin antibodies.