Inflammatory Disorder Of Central Nervous System Research Articles

Cyclophilin inhibitor NIM811 ameliorates experimental allergic encephalomyelitis

Cyclophilins have diverse functions that may affect the course of central nervous system (CNS) inflammatory disorders. Anti-inflammatory and neuroprotective mechanisms may be targeted by inhibition of cyclophilin A-dependent and cyclophilin D-dependent functions, respectively. We tested the effect of cyclophilin inhibition on CNS inflammation by administering N-methyl-4-isoleucine-cyclosporin (NIM811) to mice undergoing experimental allergic encephalomyelitis (EAE). Treatment with NIM811 resulted in significant reduction of EAE clinical severity. Analysis of mitochondrial calcium retention capacity and the course of EAE in cyclophilin D knockout mice indicated that the effect of NIM811 on EAE was not entirely cyclophilin D-dependent. NIM811-treated EAE animals showed reduction in interleukin-2 expression and reduction in CNS inflammatory infiltrates. These results indicate that anti-inflammatory rather than neuroprotective mechanisms associated with cyclophilins are likely involved in the mechanism of NIM811 in EAE.

Hypertensive encephalopathy mimicking cerebral vasculitis with pontine oedema, cerebellar white matter lesions and multiple cerebral infarctions

A 47-year-old man with poorly controlled hypertension presented with headaches, right-sided weakness and dysarthria. CT and MRI scans of the brain showed widespread abnormalities including significant pontine oedema, basal ganglia...

ANTI AQUAPORIN 4 POSITIVE NEUROMYELITIS OPTICA SPECTRUM DISORDER AND PRIMARY SJÖGREN SYNDROME FOLLOWING SUCCESSFUL THERAPY FOR CHRONIC HEPATITIS C – REPORT OF A CLINICAL CASE

Neuromyelitis optica spectrum disorders (NMOSD) are a heterogeneous group of potentially disabling central nervous system inflammatory disorders. Association with other organ-specific or multisystem autoimmune disorders is commonly encountered. We report the case of a Caucasian woman with AQP4-IgG positive NMOSD and primary Sjögren syndrome - previously reported as a poster at the 14th Congress of the Romanian Society of Neurology (abstract published in ROJN, Vol. XV, Suppl). The clinical onset followed the successful treatment of chronic hepatitis C with interferon alpha and ribavirin. To the best of our knowledge, similar clinical presentations have not been described. The etiopathogenic treatment included high dose methylprednisolone, immune suppression with cyclophosphamide, and periodic plasma exchanges. In spite of an active disease with very high baseline AQP4-IgG titres, during the four years of treatment the patient has had only one relapse and has no residual disability.

Adaptive Immunity Is the Key to the Understanding of Autoimmune and Paraneoplastic Inflammatory Central Nervous System Disorders.

There are common aspects and mechanisms between different types of autoimmune diseases such as multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSDs), and autoimmune encephalitis (AE) as well as paraneoplastic inflammatory disorders of the central nervous system. To our present knowledge, depending on the disease, T and B cells as well as antibodies contribute to various aspects of the pathogenesis. Possibly the events leading to the breaking of tolerance between the different diseases are of great similarity and so far, only partially understood. Beside endogenous factors (genetics, genomics, epigenetics, malignancy) also exogenous factors (vitamin D, sun light exposure, smoking, gut microbiome, viral infections) contribute to susceptibility in such diseases. What differs between these disorders are the target molecules of the immune attack. For T cells, these target molecules are presented on major histocompatibility complex (MHC) molecules as MHC-bound ligands. B cells have an important role by amplifying the immune response of T cells by capturing antigen with their surface immunoglobulin and presenting it to T cells. Antibodies secreted by plasma cells that have differentiated from B cells are highly structure specific and can have important effector functions leading to functional impairment or/and lesion evolvement. In MS, the target molecules are mainly myelin- and neuron/axon-derived proteins; in NMOSD, mainly aquaporin-4 expressed on astrocytes; and in AE, various proteins that are expressed by neurons and axons.

Lesions of the posterior limb of the internal capsule in neuromyelitis optica spectrum disorder

Posterior limb of the internal capsule lesions (PLICL) are one of the MRI features of neuromyelitis optica spectrum disorder (NMOSD). However, there is no evidence that such lesions are pathogenically related to NMOSD. We retrospectively analyzed features of PLICL in NMOSD, and other central nervous system inflammatory disorders, in 561 patients. We also examined the pathological samples of six patients. Of the 561 patients investigated, PLICL were found in 65 patients (11.6%). Lesions were bilateral in 26 cases (40%) and unilateral in 39 cases (60%). Unilateral lesions were mainly located on the left side (74.3%, 29/39). Of the 65 patients with PLICL, 46 patients had NMOSD (70.8%) and were positive for anti-aquaporin (AQP4-IgG), four had NMOSD (6.2%) and were AQP4-IgG negative, 10 patients had multiple sclerosis (MS), three patients had NMDAR encephalitis, and two had autoimmune meningoencephalitis. Of the six patients whose pathological samples were evaluated, all had PLICL and were negative for AQP4-IgG, and none had pathological NMOSD lesion features. These cases included three patients with multiple sclerosis, one with anti-N-methyl-D-aspartate receptor encephalitis, and two with autoimmune meningoencephalitis. In conclusion, PLICL are found not only in patients with NMOSD, but also in MS and other disorders.

Adults with suspected central nervous system infection: A prospective study of diagnostic accuracy

To study the diagnostic accuracy of clinical and laboratory features in the diagnosis of central nervous system (CNS) infection and bacterial meningitis. We included consecutive adult episodes with suspected CNS infection who underwent cerebrospinal fluid (CSF) examination. The reference standard was the diagnosis classified into five categories: 1) CNS infection; 2) CNS inflammation without infection; 3) other neurological disorder; 4) non-neurological infection; and 5) other systemic disorder. Between 2012 and 2015, 363 episodes of suspected CNS infection were included. CSF examination showed leucocyte count >5/mm3 in 47% of episodes. Overall, 89 of 363 episodes were categorized as CNS infection (25%; most commonly viral meningitis [7%], bacterial meningitis [7%], and viral encephalitis [4%]), 36 (10%) episodes as CNS inflammatory disorder, 111 (31%) as systemic infection, in 119 (33%) as other neurological disorder, and 8 (2%) as other systemic disorders. Diagnostic accuracy of individual clinical characteristics and blood tests for the diagnosis of CNS infection or bacterial meningitis was low. CSF leucocytosis differentiated best between bacterial meningitis and other diagnoses (area under the curve [AUC] 0.95) or any neurological infection versus other diagnoses (AUC 0.93). Clinical characteristics fail to differentiate between neurological infections and other diagnoses, and CSF analysis is the main contributor to the final diagnosis.

The Changing Landscape of Childhood Inflammatory Central Nervous System Disorders

The Changing Landscape of Childhood Inflammatory Central Nervous System Disorders

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.

Central nervous system inflammation across the age span.

This article reviews the influence of age on the development and course of central nervous system (CNS) inflammatory diseases and relates these to genetic and epidemiologic factors and to the age-related properties of both the immune and nervous systems and their interactions. There is increased recognition of the onset of multiple sclerosis, the prototype CNS inflammatory/demyelinating disease, outside the expected peak age in young adults. Study of childhood-onset MS cases with comparison to those with uniphasic acquired inflammatory demyelinating syndromes, has helped to better define the clinical spectrum of both types of disorders and provides opportunities to define mechanisms linking recognized genetic and environmental risk factors and disease. Studies of late-onset cases implicate the enhanced role of innate immune mechanisms and immune responses compartmentalized within the CNS in driving a more progressive disease course. The influence of age on incidence and course of multiple sclerosis is compared with the wider spectrum of CNS inflammatory disorders with identified pathogenic mechanisms. Intrinsic properties of the immune and nervous systems, coupled with the impacts on these systems by environmental factors and by the consequences of CNS tissue injury, underlie the age-related differences in incidence and course of inflammatory/demyelinating disorders of the CNS.

Focal point emergency departments

The number of patients treated in hospital emergency departments in Germany has risen in recent years to approximately 20million. This escalation also applies to the increasing numbers of patients presenting with neurological symptoms and diseases, which occur in approximately 20 % of emergency patients. In addition to patients with stroke, inflammatory or degenerative central nervous system (CNS) and peripheral nervous system (PNS) disorders who need urgent treatment, more and more patients with nonspecific complaints or conditions attend emergency departments for elective treatment, not least because timely appointments with specialist neurologists in practices could not be obtained. Neurological expertise and presence in emergency departments at the level of specialist standard are therefore indispensable for providing a professional level of treatment, which also corresponds to current legal requirements. The implementation of a generalist emergency physician in Germany, as introduced in some European countries, would mean a retrograde step for neurological expertise in emergency admission management. The discipline of neurology must work together with other emergency disciplines to improve the financing of emergency departments and provide neurologists working there with a substantive curriculum of further and continuing education in emergency-related aspects of neurology. The discipline of neurology has a responsibility to emergency patients within its range of competencies and must, therefore, strengthen and improve its role in healthcare politics and concerning organizational and personnel aspects of neurological emergencies.

A Single Amino Acid Substitution Prevents Recognition of a Dominant Human Aquaporin-4 Determinant in the Context of HLA-DRB1*03:01 by a Murine TCR.

BackgroundAquaporin 4 (AQP4) is considered a putative autoantigen in patients with Neuromyelitis optica (NMO), an autoinflammatory disorder of the central nervous system (CNS). HLA haplotype analyses of patients with NMO suggest a positive association with HLA-DRB1* 03:01. We previously showed that the human (h) AQP4 peptide 281–300 is the dominant immunogenic determinant of hAQP4 in the context of HLA-DRB1*03:01. This immunogenic peptide stimulates a strong Th1 and Th17 immune response. AQP4281-300-specific encephalitogenic CD4+ T cells should initiate CNS inflammation that results in a clinical phenotype in HLA-DRB1*03:01 transgenic mice.MethodsControlled study with humanized experimental animals. HLA-DRB1*03:01 transgenic mice were immunized with hAQP4281-300, or whole-length hAQP4 protein emulsified in complete Freund’s adjuvant. Humoral immune responses to both antigens were assessed longitudinally. In vivo T cell frequencies were assessed by tetramer staining. Mice were followed clinically, and the anterior visual pathway was tested by pupillometry. CNS tissue was examined histologically post-mortem. Flow cytometry was utilized for MHC binding assays and to immunophenotype T cells, and T cell frequencies were determined by ELISpot assay.ResultsImmunization with hAQP4281-300 resulted in an in vivo expansion of antigen-specific CD4+ T cells, and an immunoglobulin isotype switch. HLA-DRB1*03:01 TG mice actively immunized with hAQP4281-300, or with whole-length hAQP4 protein were resistant to developing a neurological disease that resembles NMO. Experimental mice show no histological evidence of CNS inflammation, nor change in pupillary responses. Subsequent analysis reveals that a single amino acid substitution from aspartic acid in hAQP4 to glutamic acid in murine (m)AQP4 at position 290 prevents the recognition of hAQP4281-300 by the murine T cell receptor (TCR).ConclusionInduction of a CNS inflammatory autoimmune disorder by active immunization of HLA-DRB1*03:01 TG mice with human hAQP4281-300 will be complex due to a single amino acid substitution. The pathogenic role of T cells in this disorder remains critical despite these observations.

Increased resistin levels in the serum and cerebrospinal fluid of patients with neuromyelitis optica

IntroductionResistin, which acts as a pro-inflammatory cytokine, has been implicated in the pathogenesis of several autoimmune diseases. However, the involvement of resistin in neuromyelitis optica (NMO), a severe inflammatory central nervous system disorder that targets the optic nerve and spinal cord, remains unclear. MethodsWe measured serum and cerebrospinal fluid (CSF) resistin levels in patients with NMO and controls matched by age and sex. The link between resistin levels and clinical variables in NMO was subsequently assessed. ResultsThe concentrations of serum and CSF resistin were significantly higher in patients with NMO than in controls, and decreased following treatment with methylprednisolone. High sensitivity C-reactive protein (hs-CRP) levels and annualized relapse rate positively correlated with resistin levels in patients with NMO. ConclusionResistin might be a useful biomarker of inflammation in NMO, and a potential target for the treatment of NMO.

Cerebrospinal fluid free light chain quantitation is a specific marker for inflammatory central nervous system disorders in a paediatric patient cohort

Cerebrospinal fluid free light chain quantitation is a specific marker for inflammatory central nervous system disorders in a paediatric patient cohort

Circulating levels of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases during Japanese encephalitis virus infection.

Matrix metalloproteinases (MMPs) are widely implicated in modulating blood brain barrier (BBB) integrity and affect the entry of peripheral immune cells into the central nervous system (CNS). The expression of MMPs is tightly regulated at the level of gene transcription, conversion of pro-enzyme to active MMPs and by the action of tissue inhibitors of metalloproteinases (TIMP). The crucial role of MMPs in inflammation indicates that perturbation of the MMP/TIMP balance decisively plays an important role in pathogenesis during viral encephalitis. The study was performed to evaluate the production of MMP-2, MMP-7, MMP-9, TIMP-1 and TIMP-3 in the sera of JEV i.e. GP 78668A (GP-78) infected BALB/c mouse model of encephalitis and gel zymography was performed for MMP-2 and MMP-9 activities. The estimation of MMP-2, MMP-7, MMP-9, TIMP-1, and TIMP-3 in JEV-infected mouse serum was analyzed by ELISA along with brain histopathology and immunohistochemistry. Evan's blue dye exclusion test was done to check the BBB integrity. Gelatin gel zymography was performed for MMP-2 and MMP-9 activities. We noticed an upregulated expression of MMPs in the sera of virus infected groups compared to controls at different days post inoculation (dpi). Post hoc analysis between days also reveals significant increase (p<0.05) in virus infected groups with disease progression. In contrast, TIMPs expressions were significantly (p<0.005) down regulated in the virus infected group. We provide preliminary evidence for a pattern of TIMP response in JEV infection distinct from that seen in acute inflammatory CNS conditions in JE, shown in our previous findings. Increased MMP-2 and MMP-9 activities were also found in a virus infected group with disease progression and are consistent with our previous finding of MMP-2 and MMP-9 activities in the CNS which clearly demonstrate worsen role of these immune mediators in JEV infection. This study will help to identify new targets for the therapeutic treatment of inflammatory mediated CNS disorders in JEV infection and may lead to the development of potential pharmacological targets in future.

Relapsing optic neuritis and isolated transverse myelitis are the predominant clinical phenotypes for patients with antibodies to myelin oligodendrocyte glycoprotein in India.

BackgroundClinical phenotypes of patients with antibodies to myelin oligodendrocyte glycoprotein (anti-MOG+) are unknown in India.ObjectivesRetrospectively to characterise anti-MOG+ patients with inflammatory central nervous system disorders in India.MethodA total of 87 patients with non-multiple sclerosis demyelinating disorders (excluding acute disseminated encephalomyelitis) who were seronegative for anti-aquaporin 4 antibody were retrospectively analysed using a cell-based assay for anti-MOG+ status.ResultsTwenty-five patients were anti-MOG+ in this cohort. They represented 28.7% (25/87) of patients who tested negative for anti-AQP4+. Sixty-four per cent (16/25) of anti-MOG+ patients were men and had a relapsing course. Patients with recurrent optic neuritis and those with a single attack of acute longitudinally extensive transverse myelitis were the most common phenotypes.ConclusionRelapsing optic neuritis was the most common phenotype, contrasting with a lower risk of relapses in transverse myelitis.

Flow cytometric analysis of T cell/monocyte ratio in clinically isolated syndrome identifies patients at risk of rapid disease progression

Background: Multiple sclerosis is a chronic inflammatory central nervous system disease diagnosed by clinical presentation and characteristic magnetic resonance imaging findings. The role of cerebrospinal fluid (CSF) analysis has been emphasized in particular in the context of differential diagnosis in patients with a first episode suggestive of multiple sclerosis. Objective: We investigated here the potential additional value of analysis of CSF cellularity by fluorescence activated cell sorting (FACS) in the setting of a routine diagnostic work-up in our inpatient clinic. Methods: CSF cells from back-up samples from patients with suspected chronic inflammatory central nervous system disorder were analyzed by FACS and correlated with clinical data, magnetic resonance imaging findings and oligoclonal band status. Results: We found distinct changes of T cell/monocyte (CD4/CD14) and B cell/monocyte (CD20/CD14) ratios between clinically isolated syndrome (CIS)/multiple sclerosis and other neurologic diseases or other inflammatory neurologic diseases. In particular, patients with a rapid transition from CIS to multiple sclerosis had an elevated CD4/CD14 ratio. A subgroup analysis showed diagnostic value of CD4/CD8 ratio in the differential diagnosis of CIS/multiple sclerosis to neurosarcoidosis. Conclusion: The diagnostic and prognostic accuracy of autoimmune neuroinflammatory diseases can be improved by FACS analysis of CSF cells.

Cell surface glycan engineering of neural stem cells augments neurotropism and improves recovery in a murine model of multiple sclerosis.

Neural stem cell (NSC)-based therapies offer potential for neural repair in central nervous system (CNS) inflammatory and degenerative disorders. Typically, these conditions present with multifocal CNS lesions making it impractical to inject NSCs locally, thus mandating optimization of vascular delivery of the cells to involved sites. Here, we analyzed NSCs for expression of molecular effectors of cell migration and found that these cells are natively devoid of E-selectin ligands. Using glycosyltransferase-programmed stereosubstitution (GPS), we glycan engineered the cell surface of NSCs ("GPS-NSCs") with resultant enforced expression of the potent E-selectin ligand HCELL (hematopoietic cell E-/L-selectin ligand) and of an E-selectin-binding glycoform of neural cell adhesion molecule ("NCAM-E"). Following intravenous (i.v.) injection, short-term homing studies demonstrated that, compared with buffer-treated (control) NSCs, GPS-NSCs showed greater neurotropism. Administration of GPS-NSC significantly attenuated the clinical course of experimental autoimmune encephalomyelitis (EAE), with markedly decreased inflammation and improved oligodendroglial and axonal integrity, but without evidence of long-term stem cell engraftment. Notably, this effect of NSC is not a universal property of adult stem cells, as administration of GPS-engineered mouse hematopoietic stem/progenitor cells did not improve EAE clinical course. These findings highlight the utility of cell surface glycan engineering to boost stem cell delivery in neuroinflammatory conditions and indicate that, despite the use of a neural tissue-specific progenitor cell population, neural repair in EAE results from endogenous repair and not from direct, NSC-derived cell replacement.

Corticospinal tract integrity measured using transcranial magnetic stimulation and magnetic resonance imaging in neuromyelitis optica and multiple sclerosis

Background: Both multiple sclerosis (MS) and neuromyelitis optica (NMO) can present with transverse myelitis; however, NMO symptoms are usually more severe and may present with more extensive axonal loss. Transcranial magnetic stimulation (TMS)-based input–output recruitment curves can quantitatively assess the excitability of corticospinal tract pathways and myelin water imaging can quantify the amount of myelin within this same pathway. Objective: To compare differential effects of MS and NMO on TMS recruitment curves and myelin water imaging. Methods: Ten healthy controls, 10 individuals with MS and 10 individuals with NMO completed clinical assessments, a TMS assessment and magnetic resonance imaging scan to measure recruitment curves and myelin water fraction in the corticospinal tract. Results: Individuals with NMO had lower recruitment curve slopes (mean 13.6±6 μV/%) than MS (23.6±11 μV/%) and controls (21.9±9 μV/%, analysis of variance (ANOVA) P=0.05). Corticospinal tract myelin water fraction was lower in individuals with NMO (mean 0.17±0.02) compared to MS (0.19±0.02) and controls (0.20±0.02, ANOVA P=0.0006). Conclusion: Corticospinal pathway damage in individuals with NMO was evident by reduced recruitment curve slope and lower myelin water fraction. These specific measures of corticospinal function and structure may be used to obtain a better understanding and monitor brain injury caused by inflammatory central nervous system disorders.

Clinical features and long-term outcome of a group of Japanese children with inflammatory central nervous system disorders and seropositivity to myelin-oligodendrocyte glycoprotein antibodies.

Myelin-oligodendrocyte glycoprotein and aquaporin-4 have been extensively analyzed as targets for humoral immune reactions in central nervous system (CNS) demyelinating diseases, and the results indicated a possible role of these antibodies in the pathogenesis of various demyelinating diseases. To investigate the antibody titer levels against myelin-oligodendrocyte glycoprotein and aquaporin-4 in pediatric patients with inflammatory CNS disorders, and to evaluate clinical significance to study anti-myelin-oligodendrocyte glycoprotein antibodies. Sera at onset from patients with acute disseminated encephalomyelitis (ADEM) in 7, optic neuritis (ON) in 5, pediatric MS in 4 and neuromyelitis optica in one were tested for myelin-oligodendrocyte glycoprotein and aquaporin-4 antibodies using cell-based assays with live transfected cells. The duration of the observation periods ranged from 1 to 21 years (median, 10 years). We also described clinical course of patients with positive anti-myelin-oligodendrocyte glycoprotein antibodies. Among 17 patients diagnosed with inflammatory CNS demyelinating diseases nine (52%) were positive to anti-myelin-oligodendrocyte glycoprotein antibodies. Of note, all cases with positive anti-myelin-oligodendrocyte glycoprotein antibodies showed seronegativity against anti-aquaporin-4 antibodies and had a favorable prognosis. This preliminary report showed that anti-myelin-oligodendrocyte glycoprotein antibodies testing at onset could be a useful tool predicting clinical outcome of children with ADEM, ON, and MS.

IgG dynamics of dietary antigens point to cerebrospinal fluid barrier or flow dysfunction in first-episode schizophrenia.

Schizophrenia is a complex brain disorder that may be accompanied by idiopathic inflammation. Classic central nervous system (CNS) inflammatory disorders such as viral encephalitis or multiple sclerosis can be characterized by incongruent serum and cerebrospinal fluid (CSF) IgG due in part to localized intrathecal synthesis of antibodies. The dietary antigens, wheat gluten and bovine milk casein, can induce a humoral immune response in susceptible individuals with schizophrenia, but the correlation between the food-derived serological and intrathecal IgG response is not known. Here, we measured IgG to wheat gluten and bovine milk casein in matched serum and CSF samples from 105 individuals with first-episode schizophrenia (n=75 antipsychotic-naïve), and 61 controls. We found striking correlations in the levels of IgG response to dietary proteins between serum and CSF of schizophrenia patients, but not controls (schizophrenia, R(2)=0.34-0.55, p⩽0.0001; controls R(2)=0.05-0.06, p>0.33). A gauge of blood-CSF barrier permeability and CSF flow rate, the CSF-to-serum albumin ratio, was significantly elevated in cases compared to controls (p⩽0.001-0.003). Indicators of intrathecal IgG production, the CSF IgG index and the specific Antibody Index, were not significantly altered in schizophrenia compared to controls. Thus, the selective diffusion of bovine milk casein and wheat gluten antibodies between serum and CSF in schizophrenia may be the function of a low-level anatomical barrier dysfunction or altered CSF flow rate, which may be transient in nature.