Clinical specificities of adult male patients with NMDA receptor antibodies encephalitis.

OBJECTIVE: The aim of this study was to describe the clinical features and specificities of adult male patients with NMDA receptor antibodies (NMDAr-Abs) encephalitis. METHODS: Observational study of 13 adult male patients who were diagnosed with NMDAr-Abs encephalitis at the French Paraneoplastic Neurological Syndrome Reference Center. RESULTS: Adult male patients frequently presented initially with a seizure (8/13, 61.5%). Seizures were partial in 5/8 patients and were followed only a few days later (median 12 days; range 2-17 days) by psychiatric or cognitive symptoms. Conversely, adult female patients rarely presented with a seizure initially (8/58, 14%, p < 0.001), and most of their seizures were generalized and were rapidly followed (median 2 days; range 1-7 days) by behavioral and psychiatric features. Additionally, in male patients the disease was rarely associated with a tumor (1/13 or 8%, a perineal schwannoma); in contrast, 41% of female patients had an associated tumor (95% of which were ovarian teratomas; p = 0.02 male vs female association with tumor). The incidences of abnormalities in ancillary tests, treatment modalities, clinical evolution, and outcome were equal for both subgroups. CONCLUSION: Adult male patients who have partial seizures, normal MRI results, and no clear etiology should be tested for NMDAr-Abs to avoid any delays in treatment initiation. Adult female patients who had a seizure as the first symptom are infrequent when NMDAr-Abs encephalitis is diagnosed; additionally, their clinical pattern is different from male patients, with more generalized seizures and rapid development of behavioral and psychiatric symptoms. The differences in hormonal influence could contribute to this difference in clinical pattern.

Aquaporin-4 antibody-negative neuromyelitis optica: distinct assay sensitivity-dependent entity.

OBJECTIVE: To optimize aquaporin-4 (AQP4) antibody (Ab) detection and to assess the influence of the increased sensitivity of the assay on the demographic and disease-related characteristics of a group of AQP4-Ab-negative patients. METHODS: Serum samples were obtained from patients included in the French NOMADMUS database with a definite diagnosis of neuromyelitis optica (NMO) (n = 87) and were compared with controls (n = 54). They were tested by indirect immunofluorescence and cell-based assays (CBAs) in various conditions and with several plasmids. RESULTS: We identified the CBA on live cells transfected with the untagged AQP4-M23 isoform as the best method, with a sensitivity of 74.4% and a specificity of 100%. We demonstrated a direct relationship between improvement of the sensitivity of the detection method and the distinctiveness and characteristics of the AQP4-Ab-negative NMO group. Whereas with the classic indirect immunofluorescence or current AQP4-M1 CBA we found only slight differences between the 2 populations, using the AQP4-M23 CBA, we demonstrated that patients with AQP4-Ab-negative NMO expressed specific demographic and disease-related features. They were characterized by an equal male/female ratio (p < 0.001), a Caucasian ethnicity (p = 0.029), and an overrepresentation of simultaneous optic neuritis and transverse myelitis at first episode (p = 0.015). In terms of disability, they experienced a better visual acuity at last follow-up compared with seropositive NMO (p = 0.007). CONCLUSION: This raises the question of a distinct physiopathology for patients with AQP4-Ab-negative NMO and of their place in the spectrum of the disease.

Autoimmune limbic encephalopathy and anti-Hu antibodies in children without cancer.

OBJECTIVE: The aim of this study was to describe the clinical presentation of children and adolescents with anti-Hu antibodies (Hu-Abs). METHODS: This was a retrospective study of children and adolescents with Hu-Abs collected by the French Paraneoplastic Neurological Syndrome (PNS) Reference Center between January 1, 2000 and December 31, 2011. RESULTS: The center identified 251 patients with Hu-Abs. Only 8 patients were younger than 18 years. All of the 243 adult patients had PNS. In contrast, of the 8 children, only 2 (25%, Fisher exact test p = 0.0003) had neuroblastoma and opsoclonus-myoclonus. The other 6 children (5 female and 1 male) presented with limbic encephalitis (progressive personality changes, memory loss, and seizure) and were free of cancer (mean follow-up time: 50 months; range: 34-72 months). Brain MRI scans were abnormal in 4 of the 6 patients, with left, right, or bitemporal T2/fluid-attenuated inversion recovery hyperintensity. Protein levels and cell counts in the CSF were normal in all patients, but numerous oligoclonal bands were observed in 4 patients. All 6 patients received antiepileptic drugs and immunotherapy, but management of epilepsy was difficult in all of them. Five of the children developed cognitive impairments. CONCLUSION: In children, as in adults, Hu-Abs can be a marker of PNS. However, in contrast to adults, Hu-Abs in children are also associated with an aggressive form of autoimmune nonparaneoplastic limbic encephalitis. Future studies should be conducted to determine the incidence of this syndrome and whether earlier diagnosis and T-cell-directed immunotherapies may improve its prognosis.

Oligodendrocytes are damaged by neuromyelitis optica immunoglobulin G via astrocyte injury.

Devic's neuromyelitis optica is an inflammatory demyelinating disorder normally restricted to the optic nerves and spinal cord. Since the identification of a specific autoantibody directed against aquaporin 4, neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody, neuromyelitis optica has been considered an entity distinct from multiple sclerosis. Recent findings indicate that the neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody has a pathogenic role through complement-dependent astrocyte toxicity. However, the link with demyelination remains elusive. Autoantibodies can act as receptor agonists/antagonists or alter antigen density in their target cells. We hypothesized that the neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody impairs astrocytic function and secondarily leads to demyelination. Rat astrocytes and oligodendrocytes from primary cultures and rat optic nerves were exposed long-term (24 h) to immunoglobulin G in the absence of complement. Immunoglobulin G was purified from the serum of patients with neuromyelitis optica who were either neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody positive or negative, as well as from healthy controls. Flow cytometry analysis showed a reduction of membrane aquaporin 4 and glutamate transporter type 1 on astrocytes following contact with immunoglobulin G purified from neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody positive serum only. The activity of glutamine synthetase, an astrocyte enzyme converting glutamate into glutamine, decreased in parallel, indicating astrocyte dysfunction. Treatment also reduced oligodendrocytic cell processes and approximately 30% oligodendrocytes died. This deleterious effect was confirmed ex vivo; exposed optic nerves showed reduction of myelin basic protein. Immunoglobulin G from neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody seronegative patients and from healthy controls had no similar effect. Neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody did not directly injure oligodendrocytes cultured without astrocytes. A toxic bystander effect of astrocytes damaged by neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody on oligodendrocytes was identified. Progressive accumulation of glutamate in the culture medium of neuromyelitis optica-immunoglobulin G/aquaporin 4-antibody-treated glial cells supported the hypothesis of a glutamate-mediated excitotoxic death of oligodendrocytes in our models. Moreover, co-treatment of glial cultures with neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody and d+2-amino-5-phosphonopentanoic acid, a competitive antagonist at the N-methyl-d-aspartate/glutamate receptor, partially protected oligodendrocytes. Co-immunolabelling of oligodendrocyte markers and neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody showed that astrocytic positive processes were in close contact with oligodendrocytes and myelin in rat optic nerves and spinal cord, but far less so in other parts of the central nervous system. This suggests a bystander effect of neuromyelitis optica-immunoglobulin G-damaged astrocytes on oligodendrocytes in the nervous tissues affected by neuromyelitis optica. In conclusion, in these cell culture models we found a direct, complement-independent effect of neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody on astrocytes, with secondary damage to oligodendrocytes possibly resulting from glutamate-mediated excitotoxicity. These mechanisms could add to the complement-induced damage, particularly the demyelination, seen in vivo.

Metabotropic glutamate receptor type 1 autoantibody-associated cerebellitis: a primary autoimmune disease?

OBJECTIVES: To report the third case of subacute cerebellar ataxia associated with metabotropic glutamate receptor type 1 autoantibodies (mGluR1-Abs), an uncommon syndrome known to be part of the group of paraneoplastic cerebellar degeneration syndromes linked to antineuronal antibodies and previously reported in only 2 other patients with long-term remission of Hodgkin lymphoma, and to discuss the underlying immunopathogenesis. DESIGN: Case report. SETTING: University hospital. PATIENT: A 50-year-old woman admitted for acute severe isolated static and kinetic cerebellar syndrome. Magnetic resonance imaging of the brain showed diffuse abnormal hyperintensity in the whole cerebellum on fluid-attenuated inversion recovery and diffusion sequences. RESULTS: Results of the biological workup were negative for general inflammation, vitamin deficiency, and bacterial and viral infections. Immunohistochemical analysis of the serum and cerebrospinal fluid of the patient demonstrated staining for Purkinje cell bodies and the molecular layer of the cerebellum. Finally, mGluR1-Abs were detected in serum and cerebrospinal fluid by a cell-based assay. Complete clinical examination, thoracoabdominal-pelvic computed tomography, and whole-body fludeoxyglucose F 18-positron emission tomography failed to show any underlying tumor, including Hodgkin lymphoma. The disease was stabilized after a course of intravenous immunoglobulins and continuous mycophenolate mofetil treatment during a follow-up of 40 months. CONCLUSIONS: Cerebellitis associated with mGluR1-Abs should be considered in the differential diagnosis of patients with subacute cerebellar ataxia. This first case without any tumor found suggests a possible idiopathic autoimmune rather than a paraneoplastic mechanism. In consideration of this possible primitive autoimmune ataxia involving the directly pathogenic mGluR1-Abs, immunoactive therapy should be initiated as early as possible.

NMO-IgG and Devic's neuromyelitis optica: a French experience.

BACKGROUND: A serum autoantibody biomarker, NMO-IgG has been recently described in patients with Devic's neuromyelitis optica (DNMO) and so called ;high-risk' patients for this disease. Our objectives were to replicate the test and to assess its usefulness. METHODS: Indirect immunofluorescence with a substrate of adult rat cerebellum and midbrain was used to identify the distinctive NMO-IgG staining pattern. We tested masked sera from 26 patients with DNMO (group 1), 21 patients with idiopathic acute transverse myelitis (ATM) (group 2), 21 patients with bilateral and/or recurrent idiopathic optic neuritis (group 3), 52 patients with classical multiple sclerosis (MS) (group 4), 36 patients with HTLV-1 infection (group 5) and 7 patients with miscellaneous disorders (group 6). RESULTS: We identified a vascular staining pattern typical of NMO-IgG. This particular staining was observed in 14/26 samples in group 1, 7/21 in group 2 (positive only in longitudinally extensive acute transverse myelitis: 7/13), 4/21 in group 3 (with bilateral loss of vision in all seropositive cases), 5/52 in group 4 (none of them suggestive of DNMO), 0/36 in group 5 and 0/7 in group 6. Sensitivity of the test was 54% considering detection of DNMO (group 1), and specificity was respectively 94% and 90% when considering groups 4, 5 and 6 altogether or group 4 of MS patients only. CONCLUSION: Detection of NMO-IgG is contributory to the distinction of DNMO and 'DNMO high-risk' syndromes from MS. This test may allow earlier diagnosis and help therapeutic decisions.

Brain and bone damage in KARAP/DAP12 loss-of-function mice correlate with alterations in microglia and osteoclast lineages.

Human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy, also known as Nasu-Hakola disease, has been described to be associated with mutations affecting the immunoreceptor tyrosine-based activation motif-bearing KARAP/DAP12 immunoreceptor gene. Patients present bone fragilities and severe neurological alterations leading to presenile dementia. Here we investigated whether the absence of KARAP/DAP12-mediated signals in loss-of-function (KDelta75) mice also leads to bone and central nervous system pathological features. Histological analysis of adult KDelta75 mice brains revealed a diffuse hypomyelination predominating in anterior brain regions. As this was not accompanied by oligodendrocyte degeneration or microglial cell activation it suggests a developmental defect of myelin formation. Interestingly, in postnatal KDelta75 mice, we observed a dramatic reduction in microglial cell numbers similar to in vitro microglial cell differentiation impairment. Our results raise the intriguing possibility that defective microglial cell differentiation might be responsible for abnormal myelin development. Histomorphometry revealed that bone remodeling is also altered, because of a resorption defect, associated with a severe block of in vitro osteoclast differentiation. In addition, we show that, among monocytic lineages, KARAP/DAP12 specifically controls microglial and osteoclast differentiation. Our results confirm that KARAP/DAP12-mediated signals play an important role in the regulation of both brain and bone homeostasis. Yet, important differences exist between the symptoms observed in Nasu-Hakola patients and KDelta75 mice.