Increased IL-22 in cerebrospinal fluid of neuro-behçet's disease patients.

Remitting-Relapsing Multiple Sclerosis (RRMS) and Neuro-Behçet Disease (NBD) are two chronic neuro-inflammatory disorders leading to brain damage and disability in young adults. Herein, we investigated in these patients the cytokine response by beads-based multiplex assays during the early stages of these disorders. Cytokine investigations were carried out on treatment-naive patients suffering from RRMS and NBD recruited at the first episode of clinical relapse. Our findings demonstrate that Cerebrospinal Fluid (CSF) cells from NBD patients, but not RRMS, secrete significant high levels of IL-22 which is associated with elevated IL-22 mRNA expression. We also observed an increase in IL-22 levels in the definite NBD subgroup as compared to the probable NBD one, indicating a clear relationship between elevated IL-22 levels and diagnostic certainty. Interestingly, we found no correlation of IL-22 secretion between CSF and serum arguing about intrathecal release of IL-22 in the CNS of NBD patients. Moreover, we showed by correlogram analysis that this cytokine doesn't correlate with IL-17A, IL-17F and IL-21 suggesting that this cytokine is secreted by Th22 cells and not by Th17 cells in the CSF of NBD patients. Finally, we found elevated levels of IL-6 and a positive correlation between IL and 6 and IL-22 in the CSF of NBD. In conclusion, these results suggest that IL-6 contributes to the production of IL-22 by T cells leading to the exacerbation of inflammation and damage within the CNS of NBD patients.

Significance of immunoglobulins synthesis with central nervous system involvement in Neuro-Behçet's disease.

OBJECTIVES: Demyelination and immunocyte-infiltrated lesions have been found in neuro-Behçet's disease (NBD) pathology. Lacking satisfying laboratory biomarkers in NBD impedes standard clinical diagnostics. We aim to explore the ancillary indicators for NBD diagnosis unveiling its potential etiology. METHODS: 28 NBD with defined diagnosis, 29 patients with neuropsychiatric lupus erythematosus, 30 central nervous system idiopathic inflammatory demyelination diseases (CNS-IIDD), 30 CNS infections, 30 cerebrovascular diseases, and 30 noninflammatory neurological diseases (NIND) were retrospectively enrolled. Immunoglobulins (Ig) in serum and cerebral spinal fluid (CSF) were detected by immunonephelometry and myelin basic protein (MBP) by quantitative enzyme-linked immunosorbent assay. RESULTS: IgA index is almost twice enhanced in NBD than NIND with an accuracy of 0.8488 in differential diagnosis, the sensitivity and specificity of which were 75.00 % and 90.00 % when the cutoff was > 0.6814. The accuracy of CSF Ig and quotient of Ig all exceed 0.90 in discerning NBD with damaged and intact blood-brain barrier (BBB). Clustering analyses divided NBD into two different phenotypes: one with BBB damage has lower Ig synthesis, the other with extra-synthesis in parenchymal sites but with intact BBB. MBP index is significantly correlated with kappa (KAP) index and lambda (LAM) index (r = 0.358, 0.575, P < 0.001), hinting the NBD pathogenesis of CNS demyelination in triggering excessive intrathecal Ig productions and humoral responses. CONCLUSIONS: IgA index acts as a potential diagnostic indicator in differentiating NBD from NIND and CNS-IIDD. Excessive immunoglobulin production induced by CNS inflammation and demyelination might be latent immunopathogenesis of NBD.

Intrathecal oligoclonal IgG bands are infrequently found in neuro-Behçet's disease.

OBJECTIVES: Oligoclonal bands (OCB) of immunoglobulins (IgG) in the cerebrospinal fluid (CSF) provides an evidence for the humoral response and have been screened in the CSF and serum of patients revealing 5 different patterns. In this study, patients with Behçet's disease (BD) are screened in a larger sample to potentially provide information about the possible role of CSF oligoclonal immunoglobulins in the diagnosis of this disease. METHODS: Paired CSF and serum samples from 121 consecutive BD patients with neurological complaints (43 women and 78 men) were included in this study. Parenchymal NBD was diagnosed in 74 patients, and 22 patients had cerebral venous sinus thrombosis (CVST); of the remaining patients, 18 had primary headache disorders not directly associated with BD, and 7 had a cerebrovascular event. OCB of IgG were detected by isoelectric focusing on agarose and immunoblotting of matched serum and CSF sample pairs. Intrathecal production of IgG only is considered positive (Pattern 2 or 3). RESULTS: In the whole group, only 8 patients had OCB in the CSF showing pattern 2. All these positive cases had parenchymal neuro-BD (10.8% positive and 78.4% negative in parenchymal neuro-BD group). All other groups were negative. CONCLUSIONS: The rare presence of oligoclonal IgG bands in CSF can be utilized as another laboratory finding in the diagnosis of NBD.

Elevated BAFF levels in the cerebrospinal fluid of patients with neuro-Behçet's disease: BAFF is correlated with progressive dementia and psychosis.

Neuro-Behçet's disease (NBD) is a serious complication of Behçet's disease. Generally, NBD patients with a chronic course are refractory to immunosuppressive treatment, resulting in the deterioration of personality. In this study, levels of B cell-activating factor belonging to the TNF family (BAFF) were measured in the cerebrospinal fluid (CSF) from 18 patients with NBD, 27 patients with epidemic aseptic meningitis (AM), 24 patients with multiple sclerosis (MS) and 34 healthy controls. BAFF levels in patients with NBD were significantly elevated compared with healthy controls, but showed no statistically significant elevation compared with either of the disease controls. In contrast, CSF IL-6 levels were slightly elevated in patients with NBD and significantly elevated in patients with AM and MS compared with healthy controls. Patients with NBD were subdivided into two groups according to their clinical course (eight patients with a slowly progressive course presenting with psychosis and dementia and 10 patients with an acute course including aseptic meningitis, brainstem involvement and myelopathy). BAFF levels were significantly increased in those with a slowly progressive course compared with those with an acute course. CSF BAFF levels did not correlate with serum BAFF levels, CSF cell counts or CSF IL-6 levels in patients with NBD. These data suggested that BAFF was produced within the central nervous system and may be associated with the development of NBD, particularly with a progressive course.

Clinical characteristics of neuro-Behcet's disease in Japan: a multicenter retrospective analysis.

To delineate the clinical characteristics of neuro-Behçet's disease (NBD), a multicenter retrospective survey was performed in BD patients who had presented any neurological manifestations between 1988 and 2008. The diagnosis of acute NBD, chronic progressive (CP) NBD, and non-NBD was confirmed by retrospective review of clinical records. Data on a total of 144 patients were collected; 76 with acute NBD, 35 with CP NBD, and 33 with non-NBD. High-intensity lesions on T2-weighted magnetic resonance imaging (MRI) were found in 60.5% of the patients with acute NBD, 54.2% with CP NBD, and 42.4% with non-NBD, whereas brainstem atrophy was observed in 7.5% with acute NBD, 71.4% with CP NBD, and 9.0% with non-NBD. The cerebrospinal fluid (CSF) cell count was prominently elevated in patients with acute NBD, but was normal in about 15% of those with CP NBD. The sensitivity and specificity of the CSF cell count for the diagnosis of acute NBD versus non-NBD were 97.4 and 97.0%, respectively (cut-off 6.2/mm(3)). The sensitivity and specificity of CSF interleukin (IL)-6 for the diagnosis of CP NBD versus the recovery phase of acute NBD were 86.7 and 94.7%, respectively (cut-off 16.55 pg/ml). The results indicate that elevation of the CSF cell count and CSF IL-6 and the presence of brainstem atrophy on MRI are useful for the diagnosis of NBD.

Elevated levels of IL-32 in cerebrospinal fluid of neuro-Behcet disease: Correlation with NLRP3 inflammasome.

Interleukin-32 (IL-32) is a pro-inflammatory cytokine that induces other cytokines involved in inflammation, including tumour necrosis factor (TNF)-α, IL-6 and IL-1ß. The objective of this study was to evaluate IL-32, NLRP3 inflammasome, IL-1ß, IL-6, IL-17A, TNF-a, IL-10 and IL-37 in cerebrospinal fluid (CSF) and paired serum samples of patients with neuro-Behcet disease (NBD) by ELISA, RT-PCR and Western blotting analysis. A receiver operating characteristic (ROC) curve was employed to explore of the predictive value of IL-32 levels. IL-32, IL-1ß, IL-6, IL-17 and TNF-α, were highly expressed in CSF of NBD and multiple sclerosis (MS) patients contrasting with their low levels in patients with noninflammatory neurological diseases (NIND) and Headache attributed to BD (HaBD). IL-32 and NLRP3 inflammasome in NBD, correlate significantly with CRP and ESR. IL-32 should be studied further as potential BD biomarker of inflammation in NBD.

Infliximab for reversible dementia in acute onset of neuro-Behçet's disease: A case report and cytokine analysis.

We describe a 49-year-old female patient with neuro-Behçet's disease (NBD) with acute onset of fever and symptoms of dementia. High-dose glucocorticoid was partially effective for cognitive impairment, and infliximab, an anti-TNF-α antibody, gradually improved the symptoms. An analysis of cytokines showed that IP-10 in the cerebrospinal fluid was higher than that in the peripheral blood, and both decreased after treatment. This is the first known case of NBD wherein the patient with acute onset of dementia responded to a treatment with infliximab. In glucocorticoid-resistant patients, it is important to consider the introduction of infliximab to prevent irreversible brain dysfunction.

Elevated levels of MMP-9 and TIMP-1 in the cerebrospinal fluid of neuro-Behçet's disease.

Matrix metalloproteinases (MMP-) are involved in leukocyte invasion into the central nervous system (CNS) during inflammation. In a retrospective cohort study of 18 neuro-BD patients, CSF samples were studied for MMP-9, TIMP-1 and cell characteristics in neuro-BD patients compared to 12 Headache attributed to BD (HaBD) patients, 15 multiple sclerosis (MS) and 20 Non-inflammatory Neurological Disease (NIND) patients. Concentrations of MMP-9 and TIMP-1 were measured in CSF by using an enzyme-linked immunosorbent assay (ELISA). The MMP-9/TIMP-1 ratio was significantly increased in neuro-BD group (mean +/- SD: 0.145+/-0.045) compared to (HaBD) (0.065+/-0.029; p=0.0001) and NIND patients (0.070+/-0.031; p=0.0001). No significant differences were observed between neuro-BD and MS patients. A significant correlation was observed between CSF-PMN cells and MMP-9 in neuro-BD patients (r=0.714; p=0.0009), indicating probably that PMN cells were in part the source of MMP-9. A significantly positive correlation was also observed between MMP-9 and CSF-mononuclear cells in neuro-BD patients (r=0.623; p=0.0012). This is the first study to evaluate the expression of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinase-1 in cerebrospinal fluid of neuro-BD patients. It demonstrates increased matrix metalloproteinase-9/tissue inhibitors of metalloproteinase-1 ratio. The results suggested that MMPs released in the CSF may be involved in the pathogenesis of neuro-BD by promoting local damage, similarly as suspected in other inflammatory diseases.

The presentation of headache in neuro-Behçet's disease: a case-series.

INTRODUCTION: Behçet's disease (BD) is a chronic, relapsing, multisystemic, inflammatory disorder with unknown etiology. Neurological involvement is observed in about 5% of the patients with BD and headache is a frequently reported symptom with or without neurological involvement. In this case-series, we aim to demonstrate the secondary headaches associated with neuro-Behçet's disease in consecutive BD patients who had been referred for neurologic evaluation. METHODS: The case-series included 17 patients (11 males [65%]), mean age 41 +/- 11.4, who met the criteria for BD established by the International Study Group for BD and developed headache during the disease course. RESULTS: Seventeen BD patients were identified, the neurologic presentations included in parenchymal involvement 12 (70%), extraparenchymal involvement/venous thrombosis in 5 (30%), seizure disorder in 2 (12%), and psychiatric problems/depression or anxiety in 5 (30%) patients, respectively. The characteristics of the headache according to the patients' reports included subacute, moderate to severe headache with unilateral localization and throbbing quality accompanied by nausea, vomiting, and aggravation upon awakening. CONCLUSION: Because neurological involvement is one of the most devastating aspects of BD, the need to treat neurological involvement as early as possible, the possible role of headache onset as an early indicator for neurological involvement in this relatively uncommon disease should be kept in mind.

Two Japanese cases of anti-MOG antibody-associated encephalitis that mimicked neuro-Behçet's disease.

Recently, we documented two Japanese cases of myelin-oligodendrocyte glycoprotein (MOG) antibody-associated relapsing encephalitis among patients who had been diagnosed with probable neuro-Behçet's disease (NBD). They presented partial systemic BD symptoms, brainstem lesions, and the human leukocyte antigen (HLA) B51 allele and responded well to steroid therapy. Our cases suggest that we need to differentiate anti-MOG antibody-associated encephalitis from probable NBD because both disorders can present with brainstem or cerebral lesions, CSF pleocytosis, and elevated levels of CSF IL-6 and respond to steroid treatment. Furthermore, oral ulceration, skin lesions, and HLA-B51 might be observed nonspecifically in patients with anti-MOG antibody-associated encephalitis.

Decreased Level of IL-37 Correlates Negatively with Inflammatory Cytokines in Cerebrospinal Fluid of Patients with Neuro-Behcet's Disease.

BACKGROUND: Behçet's disease (BD) is a systemic inflammatory disease with a chronic, relapsing-remitting course of unknown etiology. Neuro-Behcet's disease (NBD) induces serious CNS complications and is known to be the main cause of long-term morbidity and mortality. IL-37 is a natural suppressor of innate inflammation which its role in NBD has not been fully understood. OBJECTIVE: To determine the expression of IL-37 in cerebrospinal fluid (CSF) and its relationship with other inflammatory cytokines. METHODS: Level of IL-37, IL-6, IL-17, IL-21, TSLP and TGF-ß were measured in CSF of 22 patients with NBD and 12 non-inflammatory neurological disease (NIND) and 10 headache attributed to Behçet's disease (HaBD) by enzyme-linked immunosorbent assay (ELISA). In addition, IL-37 mRNA relative expression was detected by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: CSF level and mRNA expression of IL-37 were elevated in NBD patients compared to those in NIND and HaBD patients. Levels of IL-6, IL-17, IL-21 and TSLP were found to be increased in NBD patients and were inversely associated with IL-37 level. Moreover, TGF-ß level in CSF of NBD patients was positively correlated with IL-37 levels. IL-37 increased significantly after treatment and in remission group, but TGF-ß was only increased in treatment group. CONCLUSION: IL-37 expression increased in NBD patients, and correlated with disease activity. Our data conclude that IL-37 could be a disease marker in NBD, however it requires further studies.

Interleukin-6 in neuro-Behçet's disease: association with disease subsets and long-term outcome.

Increased cerebrospinal fluid (CSF) IL-6 has been reported in patients with Behçet's disease (BD) and neurological involvement. To elucidate the value of IL-6 as a marker of disease activity, serum and CSF IL-6 levels of 68 BD patients with acute (26) or chronic progressive (14) parenchymal involvement (pNB), dural sinus thrombosis (10), ischemic stroke (5) or headache (13) were measured by ELISA. Samples from multiple sclerosis, subacute sclerosing panencephalitis, and noninflammatory neurological disorders were used as controls. CSF but not serum samples of neuro-BD patients with acute pNB displayed significantly increased IL-6 levels as compared to other groups. Chronic progressive pNB patients also showed increased CSF IL-6 levels, albeit less prominent. Patients with increased CSF IL-6 levels were more likely to have increased CSF cell counts and total protein levels and these three parameters were correlated with long-term (3 years) disease outcome. In four chronic progressive patients, IL-6 was elevated despite otherwise normal CSF. CSF IL-6 seems to be a marker of disease activity and long-term outcome for pNB along with CSF cell count and protein levels. CSF IL-6 could be used in chronic progressive patients who have normal CSF cell, or protein levels to detect disease activity.

Multiple ring enhancing brain lesions on computed tomography: an Indian perspective.

BACKGROUND: Multiple enhancing computed tomography (CT) brain lesions are common neuroimaging abnormalities in India. Several published case reports suggest that multiple enhancing lesions of the brain can occur with a wide variety of infective and non-infective etiologies. METHODS: In this prospective follow up study, 110 consecutive patients with two or more than two enhancing brain lesions were subjected to a clinical evaluation and a battery of common investigative tests. RESULTS: Infective pathologies were the most common etiology for multiple enhancing lesions of the brain. Tuberculosis was the commonest infective pathology, followed by neurocysticercosis. Neoplastic diseases were common non-infective causes. In majority, brain lesions were metastatic manifestation of a systemic neoplastic disorder. Lung carcinoma was the commonest primary malignancy. One patient each had multiple brain abscesses, Behcet's syndrome and systemic lupus erythematosus. Among 4 human immunodeficiency virus-infected patients, one had toxoplasmosis and two patients were diagnosed to have cryptococcal meningitis. In 45 patients, after initial work up, etiological diagnosis could not be ascertained. These undiagnosed patients were empirically treated with antituberculous drugs and corticosteroids. Six undiagnosed patients showed pulmonary metastasis on repeat X-ray chest. In 10 patients CT lesions completely disappeared. In 5 patients number of CT lesions decreased. Six patients died. However, in majority of the undiagnosed patients follow up CT scans of brain remained unaltered. CONCLUSION: A large number of infectious and non-infectious diseases can cause multiple enhancing lesions of the brain. The work up of these patients should include clinical evaluation, imaging and a battery of laboratory tests. The specific diagnosis may remain a challenge in several cases.

[A case of chronic progressive neuro-Behçet disease with extensive cerebral atrophy and elevated CSF IL-6 activity treated with infliximab].

A 43-year-old man without a previous episode of uveitis presented with slowly progressive neurological symptoms that appeared within the past year such as dysarthria, ataxic gait, and behavioral changes. Brain MRI findings showed atrophic lesions in the brainstem and cerebellum. Because these clinical symptoms and abnormal MRI findings indicated spinocerebellar degeneration as the initial diagnosis, he was admitted to our hospital. On admission, we noticed that he had non-neurological manifestations of Behçet disease, such as stomatitis, genital ulcers, and folliculitis. HLA-B51 was positive. He also showed pleocytosis (29 cells/mm3, predominantly mononuclear cells) and elevated cerebrospinal fluid (CSF) IL-6 levels (213 pg/ml), hence he was diagnosed with chronic progressive neuro-Behçet disease (CPNBD). The therapeutic effect of a high-dose intravenous methylprednisolone pulse (1,000 mg/day for 3 days) and methotrexate (maximum dosage, 16 mg/week) was poor against both neurological symptoms and CSF findings. Intravenous infliximab therapy (5 mg/kg, 2 weeks) dramatically decreased CSF IL-6 levels (13 pg/ml) but clinical symptoms remained unchanged. MRI findings of extensive cerebral atrophy and increased CSF IL-6 levels at the pretreatment time point reflected irreversible neurological involvement in CPNBD. For cases with progressive psychiatric symptoms and cerebellar ataxia in the early stage of the disease, skin manifestations should be examined immediately, CSF IL-6 levels measured, and immunosuppressive therapy initiated before CPNBD progresses to brainstem atrophy.

CSF flow patterns in the brain in patients with neuro-Behçet disease and Behçet disease.

OBJECTIVE: In the etiopathogenesis of Behcet disease (BD) and Neuro-Behcet disease (NBD), vascular eclipse occurs in both the arteries and veins. The disease affects all vascular structures. The present study evaluates the use of Phase Contrast (PC) Cerebral Spinal Fluid (CSF) Flow Magnetic Resonance Imaging (MRI), a non-invasive technique for measuring CSF dynamics, for determining the level of aqueducts that are influenced in BD and NBD. PATIENTS AND METHODS: The quantitative evaluation of CSF flow in BD and NBD was performed using images obtained at the level of the cerebral aqueduct on the semi-axial plane. The PC-MRI angiography technique was used. RESULTS: There is no distinctive difference between BD and NBD that can be distinguished by the aqueduct diameters of both conditions. A clear increase in aqueduct diameter occurred BD and NBD group when compared to the control group. While there were no differences found between the BD group and the control group regarding peak velocity, average velocity, forward flow, reverse flow, net forward flow, and flow, there were distinctive increases in these various factors in the NBD group. CONCLUSIONS: Using the non-invasive PC-MRI technique, this study found that in BD and NBD patients, changes occurred in CSF flow figures. Increases in CSF parameters were also observed in NBD patients, a finding which may be helpful for future distinction between BD and NBD during diagnosis.

Discrepancies of NKT cells expression in peripheral blood and in cerebrospinal fluid from Behçet's disease.

The precise role of natural killer T (NKT) cells in the pathogenesis of Behçet's disease (BD) remains unknown. The frequency, cytokine profile and heterogeneity of NKT cells were studied in peripheral blood mononuclear cells (PBMC) from 42BD patients and in cerebrospinal fluid (CSF) samples from 9 neuro-BD patients. Flow cytometry revealed a decreased frequency of NKT cells in PBMC from BD patients (median: 0.06%; range: 0%-0.3%) when compared to healthy controls (median: 0.23%; range: 0.1%-0.7%; P<0.01). NKT cells were biased toward a Th(1)-like phenotype, with a significant decrease of IL-4/IFN-gamma ratio in BD (median: 0.049; range: 0.01-0.13) vs. healthy controls (median: 0.82; range: 0.4-1.33; P<0.01). NKT cells were increased in CSF-BD samples (median: 0.18%; range: 0.1%-0.4%), when compared to CSF-NIND patients (median: 0.05%; range: 0.01%-0.09%; P<0.01). Based on the reactivity of PBMC-derived NKT cells toward alpha-galactosylceramide (alpha-GalCer), 80% of BD patients were non-responsive. At the opposite, the reactivity of NKT cells in CSF from BD patients was not impaired. BD-CSF NKT cells exhibited an increased expression of IFN-gamma-producing cells, demonstrating that CSF-NKT cells were functional, and biased toward a Th(1)-like phenotype. These data suggest that functional NKT cells are recruited into BD inflammatory sites contributing to BD pathogenesis.

Seven-year follow-up of neurologic involvement in Behçet syndrome.

OBJECTIVE: To determine the long-term prognosis of neurologic involvement in Behçet syndrome. DESIGN: Forty-six patients with Behçet syndrome, who had been the subjects of a previous report with short-term follow-up, were reexamined 7 years later; 42 of them could be reexamined neurologically. Neuropsychological testing, magnetic resonance imaging, electromyography, and evoked potential studies were performed when available. RESULTS: Of the 27 patients who had had headaches without any neurologic symptoms or signs previously, 2 had developed an acute neurologic attack. In addition, 7 patients in this group showed minor abnormalities on neurologic examination and/or other laboratory investigations, without history of any attacks. Among the previous neuro-Behçet group (n = 15), as defined by the presence of neurologic signs or symptoms, other than headache, 7 had a stationary course, while 8 had been progressive. Three of the latter group had died. Patients with progressive course had had abnormal cerebrospinal fluid findings at the time of the previous report, whereas patients with a stationary course had not. CONCLUSIONS: Silent neurologic involvement may occur in Behçet syndrome. Patients should undergo periodic neurologic evaluation. The long-term prognosis in neuro-Behçet syndrome does not seem to be as favorable as we observed in short-term follow-up. Cerebrospinal fluid findings may predict prognosis.

Humoral and cellular immunologic study of cerebrospinal fluid in a patient with Behçet encephalitis.

To study the immunopathogenesis of neuro-Behçet syndrome, we performed serial cerebrospinal fluid (CSF) examinations in a patient with Behçet's syndrome and involvement of the central nervous system. Before and after immunosuppressive treatment, we measured the CSF indexes of immunoglobulins (Ig), and the third (C3) and the fourth (C4) component of complement, and quantified immune complexes and lymphocyte subsets in CSF and peripheral blood. During active encephalitis, humoral abnormalities were intrathecal production of IgM and, to a lesser degree, IgG and IgA, presence of immune complexes in CSF but not in peripheral blood, intrathecal C3 production, and elevated CSF C3 and C4 concentrations; lymphocyte subset analysis showed an increased CSF CD8+ T-cell percentage, in combination with slightly increased PB CD3+ and CD8+ T-cell subsets. After effective immunosuppressive treatment, humoral and cellular CSF values were normal. We conclude that intrathecally produced immunoglobulins, immune complexes, and C3 as well as CD8+ T cells are likely to participate in the development of Behçet encephalitis.