Perivascular Enhancement Research Articles

Idiopathic Central Nervous System Inflammatory Disease in the Setting of HLA-B27 Uveitis

ABSTRACTPurpose: The purpose of the article is to describe a novel case of idiopathic central nervous system inflammatory disease with bilateral human leukocyte antigen (HLA)-B27-positive anterior uveitis.Methods/Results: A 15-year-old African American boy with bilateral HLA-B27-positive anterior uveitis controlled with topical and oral steroids for 8 months acutely developed headaches, left eyelid ptosis, and binocular diplopia. Imaging showed lesions in the right midbrain, superior colliculus, cerebellar peduncles, and cerebellar vermis and leptomeningeal enhancement along the vermian foliae. Cerebral spinal fluid tests showed mild lymphohistiocytic pleocytosis with negative cytology; inflammatory and infectious workup were negative. He received intravenous methylprednisolone without initial symptomatic improvement; repeat magnetic resonance imaging (MRI) showed reduced lesion burden. Oral steroids were continued; his symptoms resolved in 1 month. Repeat MRI 2 months after presentation showed almost complete lesion resolution.Conclusions: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) was diagnosed. HLA-B27 positivity may represent a novel association with CLIPPERS.

Neuroimaging of Dilated Perivascular Spaces: From Benign and Pathologic Causes to Mimics.

Perivascular spaces (PVSs), also known as Virchow-Robin spaces, are pial-lined, fluid-filled structures found in characteristic locations throughout the brain. They can become abnormally enlarged or dilated and in rare cases can cause hydrocephalus. Dilated PVSs can pose a diagnostic dilemma for radiologists because of their varied appearance, sometimes mimicking more serious entities such as cystic neoplasms, including dysembryoplastic neuroepithelial tumor and multinodular and vacuolating neuronal tumor, or cystic infections including toxoplasmosis and neurocysticercosis. In addition, various pathologic processes, including cryptococcosis and chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, can spread into the brain via PVSs, resulting in characteristic magnetic resonance imaging appearances. This review aims to describe the key imaging characteristics of normal and dilated PVSs, as well as cystic mimics and pathologic processes that directly involve PVSs.

Distinguishing CLIPPERS from Non-CLIPPERS Etiologies

In 2010, Pittock and colleagues described a condition that they termed chronic lymphocytic inflammation with perivascular enhancement responsive to

Chapter 20 - Immune-mediated disorders

Paraneoplastic and autoimmune encephalitis comprise a group of immune-mediated disorders that are associated with different immune effector mechanisms. Classic paraneoplastic neurologic syndromes are triggered by an antitumor immune response. The disease is considered to result from a T-cell response; in addition, patients harbour high titers of autoantibodies against intracellular antigens that are considered as epiphenomenon but are useful diagnostic markers. Neuropathology consists of T-cell-dominated inflammation, marked neuronal loss, and microglial activation with upregulation of HLA-DR. In the last decade, an increasing number of diseases associated with autoantibodies against neuronal surface antigens have been described. There is strong evidence that these autoantibodies are pathogenic and the associated syndromes are generally termed as antineuronal autoimmune encephalitis. Patients typically present with limbic, multifocal, or diffuse encephalitis and respond to immunotherapy. Neuropathologic descriptions are restricted to few biopsy and autopsy specimens and show mild inflammatory infiltrates and microglial activation, together with reduced expression of the respective target antigens, immunoglobulin deposits, and a variable degree of complement activation. Other putative autoimmune disorders of the central nervous system include, among others, Rasmussen encephalitis, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS), acute cerebellitis, Susac syndrome, and Hashimoto encephalitis. While pathologic studies suggest an immune-mediated disease for Rasmussen encephalitis, CLIPPERS, acute cerebellitis, and Susac syndrome, neuropathologic descriptions of Hashimoto encephalitis are rare and the pathogenesis deserves further study.

Chronic lymphocytic infiltration with pontine perivascular enhancement responsive to steroids (CLIPPERS) - case report in a Hongkong Chinese patient with relapsing-remitting course over 13 years

Background: Chronic Lymphocytic Infiltration with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) was first described in 2010, with a characteristic relapsing-remitting course and distinct radiological feature. Case reports were scarce, especially in Chinese.

Clippers syndrome in a young patient with ataxia and dizziness

Introduction Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids: A rare central nervous system inflammatory disorder involving predominantly the pons as a distinct form of brainstem encephalitis centered on the pons, and/or the spinal cord. Usually presented with symptoms/signs referable to brainstem, cranial nerve-and/or cerebellar dysfunction. Symptoms related to long tract affections and/or spinal cord syndrome. Paresis, spasticity, plantar response, hyperreflexia, altered sensation of the extremities, decrease vibration sense, neurogenic bladder and cognitive deficits. Responsive to steroids and long term immunosuppression. MRI with contrast is a useful tool to help for early diagnosis of such cases. Case description Here we are going to report a case of a 28-year-old, previously healthy female presented to the ED with a history of blurring of vision, dizziness, headache, and parasthesia of lower limbs, not alcoholic or smoker, no H/O drug intake. No family history of chronic disease. On examination the patient had normal vital signs (Temp. 37.2, RR 18 and SpO2 100%) her ENT examination is unremarkable. Her neck movements are unrestricted. Cardiovascular, respiratory and abdominal examinations are unremarkable. Her pupils are equal and reactive; fundoscopy is normal. She is orientated and follows commands, horizontal Nystagmus, DTRS exaggerated symmetrically, planter reflex down going on the left equivocal on the right, positive Romberg sign to the left and dysdiadochokinesis. Results and conclusions Non contrast CT head showed left periventricular parenchyma calcification suspicious of hemorrhagic spots. MRI brain showed multiple punctuate and curvilinear enhancing foci, B/L cerebral scattered ovoid bright signal intensity ring enhancement small nodules workup was done to exclude Meningitis, TB encephalitis, CNS lymphoma, Toxoplasmosis, HIV, Vasculitis and Demyelination. Results were negative. Steroids started and the patient improved. Take-home message Careful history taking and a high index of suspicion of central causes of vertigo is needed when a patient presents with dizziness.

Poster 324: CLIPPERS (Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids): A Treatable and Reversible Inflammatory Disorder of the Central Nervous System. A Case Report

Poster 324: CLIPPERS (Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids): A Treatable and Reversible Inflammatory Disorder of the Central Nervous System. A Case Report

Diagnostic criteria for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS).

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a central nervous system inflammatory syndrome predominantly affecting the brainstem, cerebellum, and spinal cord. Following its initial description, the salient features of CLIPPERS have been confirmed and expanded upon, but the lack of formalized diagnostic criteria has led to reports of patients with dissimilar features purported to have CLIPPERS. We evaluated clinical, radiological and pathological features of patients referred for suspected CLIPPERS and propose diagnostic criteria to discriminate CLIPPERS from non-CLIPPERS aetiologies. Thirty-five patients were evaluated for suspected CLIPPERS. Clinical and neuroimaging data were reviewed by three neurologists to confirm CLIPPERS by consensus agreement. Neuroimaging and neuropathology were reviewed by experienced neuroradiologists and neuropathologists, respectively, both of whom were blinded to the clinical data. CLIPPERS was diagnosed in 23 patients (18 male and five female) and 12 patients had a non-CLIPPERS diagnosis. CLIPPERS patients' median age of onset was 58 years (interquartile range, 24-72) and were followed a median of 44 months (interquartile range 38-63). Non-CLIPPERS patients' median age of onset was 52 years (interquartile range, 39-59) and were followed a median of 27 months (interquartile range, 14-47). Clinical symptoms of gait ataxia, diplopia, cognitive impairment, and facial paraesthesia did not discriminate CLIPPERS from non-CLIPPERS. Marked clinical and radiological corticosteroid responsiveness was observed in CLIPPERS (23/23), and clinical worsening occurred in all 12 CLIPPERS cases when corticosteroids were discontinued. Corticosteroid responsiveness was common but not universal in non-CLIPPERS [clinical improvement (8/12); radiological improvement (2/12); clinical worsening on discontinuation (3/8)]. CLIPPERS patients had brainstem predominant perivascular gadolinium enhancing lesions on magnetic resonance imaging that were discriminated from non-CLIPPERS by: homogenous gadolinium enhancing nodules <3 mm in diameter without ring-enhancement or mass effect, and homogenous T2 signal abnormality not significantly exceeding the T1 enhancement. Brain neuropathology on 14 CLIPPERS cases demonstrated marked CD3-positive T-lymphocyte, mild B-lymphocyte and moderate macrophage infiltrates, with perivascular predominance as well as diffuse parenchymal infiltration (14/14), present in meninges, white and grey matter, associated with variable tissue destruction, astrogliosis and secondary myelin loss. Clinical, radiological and pathological feature define CLIPPERS syndrome and are differentiated from non-CLIPPERS aetiologies by neuroradiological and neuropathological findings.

CLIPPERS.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a recently described treatable, inflammatory, brainstem predominant encephalomyelitis. The diagnosis of CLIPPERS is challenging without a specific biomarker, and thus it is important to consider if both the clinical and radiographic features are consistent with the diagnosis, or rather a disease mimicker. Many patients with CLIPPERS-like lesions have been described in the literature with follow-up revealing a range of alternative diagnoses, such as malignancies, vasculitis, and other specific inflammatory diseases. As a result, some have proposed that CLIPPERS might represent a pre-malignancy state or simply an initial clinical syndrome of a variety of possible etiologies. We describe the typical clinical, radiographic, and pathological features of CLIPPERS and emphasize consideration for alternative diagnoses when findings are not classic. A recommended diagnostic evaluation and initial treatment plan is provided.

High versus low energy administration in the early phase of acute pancreatitis (GOULASH): Pre-publication protocol of a multicentre randomized double-blind clinical trial

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroid (CLIPPERS) was first described in 2010. The characteristic clinical picture, radiological distribution and steroid response have been well-described in previous reports. However, the underlying pathogenesis and nosological position of CLIPPERS in the CNS require further investigation for the primary CNS lymphoma have been identified by autopsy subsequently. Here, we report a 51-year-old woman who was diagnosed with CLIPPERS but progressed to primary CNS lymphomatoid granulomatosis, which supports that CLIPPERS is not just an inflammatory CNS disorder.

A case of SLIPPERS (Supratentorial Lymphocytic Inflammation with Parenchymal Perivascular Enhancement Responsive to Steroids) presenting with isolated cognitive dysfunction. (P1.336)

A case of SLIPPERS (Supratentorial Lymphocytic Inflammation with Parenchymal Perivascular Enhancement Responsive to Steroids) presenting with isolated cognitive dysfunction. (P1.336)

Therapeutic Approaches in CLIPPERS.

CLIPPERS for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, is a steroid-sensitive and steroid-dependent brainstem inflammatory disease of unknown origin. Since its first description in 2010, about 60 cases have been reported throughout the world. The mean age at onset is 50years and men seem to be more frequently affected. In patients without chronic corticosteroid therapy or immunosuppressive agents, the disease had a relapsing remitting course, and the mean annualized relapse rate was 0.5. During attacks, although clinical and radiological improvement after high doses of corticosteroids was systematically observed, patients could display subsequent disability and hindbrain atrophy. Since no progressive course was observed, clinical and radiological sequelae were correlated with previous severe attacks. Therefore, maintaining the disease in remission may prevent the accumulation of disability. In the literature, no relapse occurred when chronic corticosteroid therapy was maintained above 20mg per day. However, steroids side effects led to propose corticosteroid-sparing therapies. Unfortunately, no controlled therapy studies for CLIPPERS have been performed yet, and no therapeutic recommendations exist. Using the PubMed database, all articles having the following keywords "chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids" and "CLIPPERS" have been analysed. Considering that the mean annual relapse rate was 0.5, and that no relapse occurred when corticosteroid therapy was maintained above 20mg per day, the therapeutic efficiency of corticosteroid-sparing agents was considered as "probable" when patients had a relapse-free period ≥24months, in the absence of concomitant corticosteroid therapy. Corticosteroid-sparing agents whose efficiency is "probable" are methotrexate in two cases, cyclophosphamide in one case and hydroxychloroquine in one case. Considering the risk benefit ratio of corticosteroid-sparing agents, methotrexate seems to be the most suitable. Nevertheless, randomized controlled trials testing the different corticosteroid-sparing agents in CLIPPERS are necessary.

Glial fibrillary acidic protein immunoglobulin G as biomarker of autoimmune astrocytopathy: Analysis of 102 patients

A novel autoimmune central nervous system (CNS) disorder with glial fibrillary acidic protein (GFAP)-IgG as biomarker was recently characterized. Here, 102 patients with GFAP-IgG positivity are described. The 102 included patients had: (1) serum, cerebrospinal fluid (CSF), or both that yielded a characteristic astrocytic pattern of mouse tissue immunostaining; (2) confirmation of IgG reactive with specific GFAP isoforms (α, ɛ, or κ) by cell-based assays; and (3) clinical data available. Control specimens (n = 865) were evaluated by tissue (n = 542) and cell-based (n = 323) assays. Median symptom onset age was 44 years (range = 8-103), and 54% were women. The predominant phenotype (83 patients; 81%) was inflammation of meninges, brain, spinal cord, or all 3 (meningoencephalomyelitis). Among patients, highest specificity for those phenotypes was observed for CSF testing (94%), and highest sensitivity was for the GFAPα isoform (100%). Rare GFAP-IgG positivity was encountered in serum controls by tissue-based assay (0.5%) or cell-based assay (1.5%), and in CSF controls by cell-based assay (0.9%). Among patients, striking perivascular radial enhancement was found on brain magnetic resonance imaging in 53%. Although cases frequently mimicked vasculitis, angiography was uniformly negative, and spinal imaging frequently demonstrated longitudinally extensive myelitic lesions. Diverse neoplasms encountered were found prospectively in 22%. Ovarian teratoma was most common and was predicted best when both N-methyl-D-aspartate receptor-IgG and aquaporin-4-IgG coexisted (71%). Six patients with prolonged follow-up had brisk corticosteroid response, but required additional immunosuppression to overcome steroid dependency. GFAPα-IgG, when detected in CSF, is highly specific for an immunotherapy-responsive autoimmune CNS disorder, sometimes with paraneoplastic cause. Ann Neurol 2017;81:298-309.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS): A lymphocytic reactive response of the central nervous system? A case report

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroid (CLIPPERS) was first described in 2010. The characteristic clinical picture, radiological distribution and steroid response have been well-described in previous reports. However, the underlying pathogenesis and nosological position of CLIPPERS in the CNS require further investigation for the primary CNS lymphoma have been identified by autopsy subsequently. Here, we report a 51-year-old woman who was diagnosed with CLIPPERS but progressed to primary CNS lymphomatoid granulomatosis, which supports that CLIPPERS is not just an inflammatory CNS disorder.

Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy

A novel astrocytic autoantibody has been identified as a biomarker of a relapsing autoimmune meningoencephalomyelitis that is immunotherapy responsive. Seropositivity distinguishes autoimmune glial fibrillary acidic protein (GFAP) meningoencephalomyelitis from disorders commonly considered in the differential diagnosis. To describe a novel IgG autoantibody found in serum or cerebrospinal fluid that is specific for a cytosolic intermediate filament protein of astrocytes. Retrospective review of the medical records of seropositive patients identified in the Mayo Clinic Neuroimmunology Laboratory from October 15, 1998, to April 1, 2016, in blinded comprehensive serologic evaluation for autoantibody profiles to aid the diagnosis of neurologic autoimmunity (and predict cancer likelihood). Frequency and definition of novel autoantibody, the autoantigen's immunochemical identification, clinical and magnetic resonance imaging correlations of the autoantibody, and immunotherapy responsiveness. Of 103 patients whose medical records were available for review, the 16 initial patients identified as seropositive were the subject of this study. Median age at neurologic symptom onset was 42 years (range, 21-73 years); there was no sex predominance. The novel neural autoantibody, which we discovered to be GFAP-specific, is disease spectrum restricted but not rare (frequency equivalent to Purkinje cell antibody type 1 [anti-Yo]). Its filamentous pial, subventricular, and perivascular immunostaining pattern on mouse tissue resembles the characteristic magnetic resonance imaging findings of linear perivascular enhancement in patients. Prominent clinical manifestations are headache, subacute encephalopathy, optic papillitis, inflammatory myelitis, postural tremor, and cerebellar ataxia. Cerebrospinal fluid was inflammatory in 13 of 14 patients (93%) with data available. Neoplasia was diagnosed within 3 years of neurologic onset in 6 of 16 patients (38%): prostate and gastroesophageal adenocarcinomas, myeloma, melanoma, colonic carcinoid, parotid pleomorphic adenoma, and teratoma. Neurologic improvement followed treatment with high-dose corticosteroids, with a tendency of patients to relapse without long-term immunosuppression. Glial fibrillary acidic protein-specific IgG identifies a distinctive, corticosteroid-responsive, sometimes paraneoplastic autoimmune meningoencephalomyelitis. It has a lethal canine equivalent: necrotizing meningoencephalitis. Expression of GFAP has been reported in some of the tumor types identified in paraneoplastic cases. Glial fibrillary acidic protein peptide-specific cytotoxic CD8+ T cells are implicated as effectors in a transgenic mouse model of autoimmune GFAP meningoencephalitis.

Psychological Symptoms in Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS): A Case Report

Psychological Symptoms in Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS): A Case Report

CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids)

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) has been recently identified as an inflammatory central nervous system (CNS) disorder. Punctate and curvilinear gadolinium enhancement (peppering) the pons is a characteristic magnetic resonance imaging (MRI) feature of CLIPPERS. Pathogenesis of this disorder remains unknown. A specific serum or cerebrospinal fluid biomarker for this disorder is currently unknown. Whether CLIPPERS is an actual new disease or just represents overlapping symptoms from multiple diseases is still debated. Many differential diagnoses exist even when using imaging as a tool. Pre-lymphoma states, such as grade I LYG (lymphomatoid granulomatosis) and sentinel lesions of primary CNS lymphoma are the most difficult to distinguish.

Poster 330 Rehabilitation of a Patient with Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) Syndrome: A Case Report

Poster 330 Rehabilitation of a Patient with Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) Syndrome: A Case Report

Haemophagocytosis and encephalitis in chronic lymphocytic leukaemia

A 77-year-old man was hospitalized with progressive confusion and gait disorder of 3 weeks duration. He had been diagnosed with quiescent chronic lymphocytic leukaemia (CLL) 5 years previously without having required treatment. Examination showed fever, confusion, a right hemiparesis and ataxia. A full blood count showed: leucocytes 24·3 × 109/l (neutrophils 1·4 × 109/l, lymphocytes 22·6 × 109/l), haemoglobin concentration 110 g/l and platelet count 57 × 109/l. Serum ferritin was increased to 669 μg/l (normal < 400). Other laboratory tests, including fibrinogen concentration, triglycerides, soluble CD25, lactate dehydrogenase and transaminases levels, were normal. Magnetic resonance imaging (MRI) of the brain showed multiple hyperintensities on fluid-attenuated inversion recovery (FLAIR) sequences spanning the periventricular white matter, corpus callosum, basal ganglia, left internal capsule, midbrain and cerebellum (left). There was a subtle perivascular enhancement on gadolinium. Cerebrospinal fluid (CSF) analysis showed pleocytosis (140 cells/μl) with 85% lymphocytes, a high protein of 0·74 g/l and normal glucose. Despite an extensive workup, no infectious aetiology was identified on CSF testing. Blood cultures were repeatedly negative. Epstein‒Barr virus (EBV) polymerase chain reaction (PCR) on peripheral blood showed 1477 copies/ml and a low-grade EBV reactivation was diagnosed. PCR on the CSF for other herpes virus, flavivirus, enterovirus and EBV was negative. A bone marrow aspirate was hypercellular with a normal number of megakaryocytes and stable CLL. Histiocytes were seen (<0·5% of cells), of which 80% were observed to have engulfed mainly numerous CLL lymphocytes (top right), but also erythroid cells (bottom right). Further diagnostic images are shown in Appendix S1. Whole body positron emission tomography‒computerized tomography (PET-CT) scanning showed no change in the number, size or metabolic activity of lymph nodes or spleen. Vaccination against influenza 1 week before the clinical onset led us to consider a diagnosis of acute disseminated encephalomyelitis (ADEM). The patient was started on intravenous corticosteroids then intravenous immunoglobulin, with progressive clinical, CSF and MRI improvement and normalization of platelet count within 2 weeks. Histiocytes engulfing numerous lymphocytes is an unusual observation. It has rarely been associated with haemophagocytic lymphohistiocytosis (HLH) in CLL. However, the findings of this patient do not meet the diagnostic criteria of HLH. ADEM is a potentially severe inflammatory demyelinating immunomediated cerebral condition triggered by infection or vaccination. ADEM must be differentiated from infectious encephalitis as the treatment is different. CLL is associated with various immunological complications but the coincidence of haemophagocytosis and ADEM is rare. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

CLIPPERS with diffuse white matter and longitudinally extensive spinal cord involvement

Zhang et al.1 reported confluent lesions in fluid-attenuated inversion recovery (FLAIR) involving the centrum semiovale matching with subcortical punctate and curvilinear gadolinium enhancements (PCGE). PCGE in chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) invariably involve the brainstem and could spread rostrally up to the juxtacortical areas and caudally up to the conus. FLAIR lesions present in the corresponding areas of PCGE are usually faint and indicate a blood–brain barrier disruption. In our case series, we also described confluent lesions …