Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) with Limbic Encephalitis.
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ABSTRACT:
SUBMITTER: Ohta Y
PROVIDER: S-EPMC5643184 | biostudies-literature | 2017 Sep
REPOSITORIES: biostudies-literature
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Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) with Limbic Encephalitis.
Ohta Yasuyuki Y Nomura Emi E Tsunoda Keiichiro K Yamashita Toru T Takahashi Yoshiaki Y Sato Kota K Takemoto Mami M Hishikawa Nozomi N Abe Koji K
Internal medicine (Tokyo, Japan) 20170821 18
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory central nervous system disorder that mainly involves in the brainstem, basal ganglia and cerebellum. We herein report the case of a patient with CLIPPERS, which was diagnosed based on the clinical and radiological features. After initially responded to steroid treatment, the patient developed limbic encephalitis. The patient presented with memory disturbance, a delirious st ...[more]
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Project description:Objective:Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a rare syndrome with relapsing brainstem/cerebellar symptoms. To examine the pathogenic processes and investigate potential biomarkers, we analyzed combined materials of brain and cerebrospinal fluid (CSF) by comprehensive methodologies. Materials and methods:To identify major pathways of perivascular inflammation in CLIPPERS, we first compared the CSF proteome (n = 5) to a neurodegenerative condition, Alzheimer's disease (AD, n = 5). Activation of complement was confirmed by immunohistochemistry (IHC) on CLIPPERS brain samples (n = 3) and by ELISA in the CSF. For potential biomarkers, we used biomarker arrays, and compared inflammatory and vessel-associated proteins in the CSF of CLIPPERS (n = 5) with another inflammatory relapsing CNS disease, multiple sclerosis (RMS, n = 9) and healthy subjects (HS, n = 7). Results:Two hundred and seven proteins in the CSF discriminated CLIPPERS from AD. The complement cascade, immunoglobulins, and matrix proteins were among the most frequently represented pathways. Pathway analysis of upstream regulators suggested the importance of vascular cell adhesion protein 1 (VCAM1), IFN-γ, interleukin (IL)-1, and IL-10. Differential regulation of more than 10 complement proteins of the 3 complement pathways in the CSF pointed to the role of complement activation. IHC on brain samples confirmed the perivascular complement activation, i.e., deposition of C3bc, C3d, and the terminal C5b-9 complement complex that partially overlapped with accumulation of IgG in the vessel wall. Besides endothelial cell damage, reactivity to smooth muscle actin was lost in the walls of inflamed vessels, but the glia limitans was preserved. The semi-quantitative array indicated that increased level of IL-8/CXCL8 (p < 0.05), eotaxin/CCL11 (p < 0.01), and granulocyte colony-stimulating factor (p < 0.05) in CSF could distinguish CLIPPERS from HS. The quantitative array confirmed elevated concentration of IL-8/CXCL8 and eotaxin/CCL11 compared to HS (p < 0.05, respectively) besides increased levels of ICAM-1 (p < 0.05) and VCAM-1 (p < 0.001). The increased concentration of VCAM-1 were able to differentiate CLIPPERS from RMS (p < 0.01), and a trend of elevated levels of ICAM-1 and IL-8/CXCL8 compared to RMS was also observed (p = 0.06, respectively). Conclusion:Complement activation, IgG deposition, and alterations of the extracellular matrix may contribute to inflammation in CLIPPERS. VCAM1, ICAM1, and IL-8 in the CSF may differentiate CLIPPERS from RMS.
| S-EPMC5925867 | biostudies-literature
Project description:Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a relatively newly discovered and characterized condition affecting the central nervous system (CNS) that involves the brainstem almost ubiquitously and that focuses primarily on the pons. Characteristically, CLIPPERS represents a combination of clinical symptoms related to the pathology of the brainstem in particular and has a characteristic appearance on magnetic resonance imaging (MRI), with punctate and curvilinear gadolinium enhancement 'peppering' the pons. The lesions can be viewed via neuroimaging with a predominance in the pons and adjacent rhombencephalic structures, such as the cerebellar peduncles, cerebellum, medulla, and middle brain. These lesions may also spread and appear in other areas of the brain such as the thalamus or white matter. As the name suggests, this clinical syndrome responds to immunosuppressive treatment based on glucocorticosteroids (GCSs), expressed as both clinical and radiological improvements. Support for this treatment is required for a long period, since exacerbations may occur without. Thus, the diagnosis of CLIPPERS has garnered increased attention from clinicians and the active exclusion of differential alternative diagnoses is needed. A specific biomarker of serum or cerebrospinal fluid (CSF) for this condition has not been discovered. The pathophysiology of this condition is not fully elucidated, and it is not yet clear whether CLIPPERS is a disease in its own right or is the culmination of several already known syndromes. Clinicians and radiologists should pay close attention to this condition as it is relatively easy to treat and patients can benefit from the early introduction of GCSs, which can produce significant results through long-term immunosuppression. Taking into account previous reports in the literature, which currently include over 50 cases reported as CLIPPERS, this analysis addressed the clinical features, and paraclinical and differential diagnoses of cases described in the literature.
| S-EPMC8406757 | biostudies-literature
Project description:BackgroundChronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory disorder with unclear causes. Paraneoplastic etiology may be a cause. We report a case of CLIPPERS with parotid carcinoma.Case presentationA 54-year-old man with a history of lymphoma was hospitalized with a pontocerebellar syndrome. Brain MRI revealed that the pons and cerebellum were "peppered" with punctate and curvilinear enhancement lesions that supported the diagnosis of CLIPPERS. The relapse of lymphoma was excluded by a further cerebellum biopsy revealing predominantly CD3+ T cells in white matter. The patient was relieved after pulse therapy with intravenous methylprednisolone and a large dose of corticosteroids, but he complained of a worsening gait problem when corticosteroids were tapered to a lower dose. Although the clinical symptoms gradually improved again by increasing the dosage of corticosteroids with Azathioprine, the patient still had a slight unsteady gait during follow-up. At the 7-month follow-up, a parotid mass was detected by MRI and was verified as carcinoma by biopsy. After resection of parotid carcinoma, the residual symptoms and previous MRI lesions disappeared, and no relapse occurred.ConclusionsCLIPPERS may not be a distinct nosologic entity but an overlapping diagnosis with other diseases. Some cases of CLIPPERS might be a subtype of paraneoplastic neurological syndromes (PNS) due to the similar mechanism of antibody-mediated encephalitis. Tumor screening and serum paraneoplastic autoantibody tests are recommended for patients with CLIPPERS, especially for those who relapse when corticosteroids treatment is stopped or tapered.
| S-EPMC7944626 | biostudies-literature
Project description:Cases of autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy who were initially diagnosed with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) were rarely reported. Herein, we reported a 31-year-old woman who presented with 7 years of recurrent headache. Her clinical history, symptoms, brain MRI enhancement features, and response to treatment during each attack were reviewed. Her brain MRI 7 years ago demonstrated characteristic pepper-like enhancement of pontine and cerebellum and her symptoms resolved completely after taking a high-dose of steroids. She was suspected with the diagnosis of CLIPPERS, and she experienced five relapses once the oral steroid was tapered below 20 mg/day. During her last relapse, she experienced fever and psychosis, and GFAPα-antibodies were detected in her serum and cerebrospinal fluid by antigen-transfected HEK293 cell-based assay (indirect immunofluorescence assay). She obtained relief again after steroid therapy, and her diagnosis converted to autoimmune GFAP astrocytopathy. Autoimmune GFAP astrocytopathy may mimic CLIPPERS, both clinically and radiologically. Long-term follow-up is essential for necessary diagnosis revision at each new attack in patients with a diagnosis of CLIPPERS.
| S-EPMC7705065 | biostudies-literature
Project description:We report seven patients, six from a single institution, who developed subacute limbic encephalitis initially considered of uncertain aetiology. Four patients presented with symptoms of hippocampal dysfunction (i.e. severe short-term memory loss) and three with extensive limbic dysfunction (i.e. confusion, seizures and suspected psychosis). Brain MRI and [(18)F]fluorodeoxyglucose (FDG)-PET complemented each other but did not overlap in 50% of the patients. Combining both tests, all patients had temporal lobe abnormalities, five with additional areas involved. In one patient, FDG hyperactivity in the brainstem that was normal on MRI correlated with central hypoventilation; in another case, hyperactivity in the cerebellum anticipated ataxia. All patients had abnormal CSF: six pleocytosis, six had increased protein concentration, and three of five examined had oligoclonal bands. A tumour was identified and removed in four patients (mediastinal teratoma, thymoma, thymic carcinoma and thyroid cancer) and not treated in one (ovarian teratoma). An immunohistochemical technique that facilitates the detection of antibodies to cell surface or synaptic proteins demonstrated that six patients had antibodies to the neuropil of hippocampus or cerebellum, and one to intraneuronal antigens. Only one of the neuropil antibodies corresponded to voltage-gated potassium channel (VGKC) antibodies; the other five (two with identical specificity) reacted with antigens concentrated in areas of high dendritic density or synaptic-enriched regions of the hippocampus or cerebellum. Preliminary characterization of these antigens indicates that they are diverse and expressed on the neuronal cell membrane and dendrites; they do not co-localize with VGKCs, but partially co-localize with spinophilin. A target autoantigen in one of the patients co-localizes with a cell surface protein involved in hippocampal dendritic development. All patients except the one with antibodies to intracellular antigens had dramatic clinical and neuroimaging responses to immunotherapy or tumour resection; two patients had neurological relapse and improved with immunotherapy. Overall, the phenotype associated with the novel neuropil antibodies includes dominant behavioural and psychiatric symptoms and seizures that often interfere with the evaluation of cognition and memory, and brain MRI or FDG-PET abnormalities less frequently restricted to the medial temporal lobes than in patients with classical paraneoplastic or VGKC antibodies. When compared with patients with VGKC antibodies, patients with these novel antibodies are more likely to have CSF inflammatory abnormalities and systemic tumours (teratoma and thymoma), and they do not develop SIADH-like hyponatraemia. Although most autoantigens await characterization, all share intense expression by the neuropil of hippocampus, with patterns of immunolabelling characteristic enough to suggest the diagnosis of these disorders and predict response to treatment.
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Project description:Autoimmune encephalitis is an uncommon complication of immune checkpoint inhibitor therapy. This article reports a case of fatal anti-Hu-associated autoimmune limbic encephalitis presenting within 8 weeks following anti-PD1 therapy in a patient with myxoid chondrosarcoma and pre-existing anti-Hu antibodies. Although tumor reduction occurred in response to PD-1 inhibitor therapy, the patient had a rapidly progressive decline in neurologic function despite initial stabilization with immunosuppression. Considering the increasing use of immune checkpoint inhibitors for the treatment of various malignancies, an increase in the occurrence of neurologic adverse events is likely, requiring prompt intervention and enhanced pharmacovigilance in malignancies associated with onconeuronal antibodies.
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Project description:Limbic encephalitis (LE) is a rare cause of encephalitis presenting as an acute and subacute onset of neuropsychiatric manifestations, particularly with memory deficits and confusion as core features, along with seizure occurrence, movement disorders, or autonomic dysfunctions. LE is caused by neuronal antibodies targeting the cellular surface, synaptic, and intracellular antigens, which alter the synaptic transmission, especially in the limbic area. Immunologic mechanisms involve antibodies, complements, or T-cell-mediated immune responses in different degree according to different autoantibodies. Sensitive cerebrospinal fluid markers of LE are unavailable, and radiographic findings may not reveal a typical mesiotemporal involvement at neurologic presentations; therefore, a high clinical index of suspicions is pivotal, and a neuronal antibody testing is necessary to make early diagnosis. Some patients have concomitant tumors, causing paraneoplastic LE; therefore, tumor survey and treatment are required in addition to immunotherapy. In this study, a review on the molecular and immunologic aspects of LE was conducted to gain awareness of its peculiarity, which we found quite different from our knowledge on traditional psychiatric illness.
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Project description:Human leucine-rich glioma-inactivated protein 1 encephalitis (LGI1) is an autoimmune limbic encephalitis in which serum and cerebrospinal fluid contain antibodies targeting LGI1, a protein of the voltage gated potassium channel (VGKC) complex. Recently, we showed that a feline model of limbic encephalitis with LGI1 antibodies, called feline complex partial seizures with orofacial involvement (FEPSO), is highly comparable to human LGI1 encephalitis. In human LGI1 encephalitis, neuropathological investigations are difficult because very little material is available. Taking advantage of this natural animal model to study pathological mechanisms will, therefore, contribute to a better understanding of its human counterpart. Here, we present a brain-wide histopathological analysis of FEPSO. We discovered that blood-brain barrier (BBB) leakage was present not only in all regions of the hippocampus but also in other limbic structures such as the subiculum, amygdale, and piriform lobe. However, in other regions, such as the cerebellum, no leakage was observed. In addition, this brain-region-specific immunoglobulin leakage was associated with the breakdown of endothelial tight junctions. Brain areas affected by BBB dysfunction also revealed immunoglobulin and complement deposition as well as neuronal cell death. These neuropathological findings were supported by magnetic resonance imaging showing signal and volume increase in the amygdala and the piriform lobe. Importantly, we could show that BBB disturbance in LGI1 encephalitis does not depend on T cell infiltrates, which were present brain-wide. This finding points toward another, so far unknown, mechanism of opening the BBB. The limbic predilection sites of immunoglobulin antibody leakage into the brain may explain why most patients with LGI1 antibodies have a limbic phenotype even though LGI1, the target protein, is ubiquitously distributed across the central nervous system.
| S-EPMC5651237 | biostudies-other
Project description:Objective: The epidemiological characteristics of patients with antibody-medicated autoimmune encephalitis in China remain unclear, and a large-scale epidemiological survey is necessary. Methods: A multiple-center retrospective study was performed. We collected 1,047 patients with suspected autoimmune encephalitis and ultimately enrolled 778 defined patients across centers in China. All patients were positive for serum [or cerebrospinal fluid (CSF)] antibodies. Demographic information and clinical data from January 2014 to January 2019 from 22 centers in China were reviewed. Results: A total of 778 patients with autoimmune encephalitis were enrolled in the study. In general, the ratio of males to females was ~1.2:1. The main subtypes of autoimmune encephalitis were NMDAR-AE (61.35%), LGI-1-AE (20.61%), and GABAbR-AE (12.40%). According to the characteristics of age of onset, the incidence of autoimmune encephalitis showed a "double peak" distribution entailing a 20-year-old age group and a 60-year-old age group. We next analyzed the proportion of patients with tumors in this cohort. More specifically, there were 34 patients with tumors and 85 with tumor marker positivity. Relapse occurred in 81 patients within at least 1 year's follow up study: 52 with NMDAR-AE (18.2%); 19 with LGI-1-AE (16.8%); 5 with GABAbR-AE (9%); and 3 with CASPR2-AE. Interpretation: Due to the vast differences in demographic features, the incidence of cancer and the genetic characteristics between the populations in China and Western countries, the demographics, sex distribution, concomitant tumor rate, clinical features, and relapse characteristics associated with autoimmune encephalitis in China shows a similar profile with Western countries with some minor differences.
| S-EPMC7928315 | biostudies-literature
Project description:To report the clinical and immunological features of a novel autoantigen related to limbic encephalitis (LE) and the effect of patients' antibodies on neuronal cultures.We conducted clinical analyses of 10 patients with LE. Immunoprecipitation and mass spectrometry were used to identify the antigens. Human embryonic kidney 293 cells expressing the antigens were used in immunocytochemistry and enzyme-linked immunoabsorption assay. The effect of patients' antibodies on cultures of live rat hippocampal neurons was determined with confocal microscopy.Median age was 60 (38-87) years; 9 were women. Seven had tumors of the lung, breast, or thymus. Nine patients responded to immunotherapy or oncological therapy, but neurological relapses, without tumor recurrence, were frequent and influenced the long-term outcome. One untreated patient died of LE. All patients had antibodies against neuronal cell surface antigens that by immunoprecipitation were found to be the glutamate receptor 1 (GluR1) and GluR2 subunits of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). Human embryonic kidney 293 cells expressing GluR1/2 reacted with all patients' sera or cerebrospinal fluid, providing a diagnostic test for the disorder. Application of antibodies to cultures of neurons significantly decreased the number of GluR2-containing AMPAR clusters at synapses with a smaller decrease in overall AMPAR cluster density; these effects were reversed after antibody removal.Antibodies to GluR1/2 associate with LE that is often paraneoplastic, treatment responsive, and has a tendency to relapse. Our findings support an antibody-mediated pathogenesis in which patients' antibodies alter the synaptic localization and number of AMPARs.
| S-EPMC2677127 | biostudies-literature