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.

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.

[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.

Quantitative analysis of brainstem atrophy on magnetic resonance imaging in chronic progressive neuro-Behçet's disease.

OBJECTIVES: To examine whether quantitative analysis of the brainstem areas on magnetic resonance imaging (MRI) scans is useful for diagnosis as well as evaluation of disease activity in chronic progressive neuro-Behçet's disease (CPNB). METHODS: MRI scans in patients with acute neuro-Behçet's disease (ANB) (n = 10), CPNB (n = 10), Behçet's disease with neurological manifestations non-attributable to NB (non-NB) (n = 8), and control patients with non-inflammatory neurological diseases (NID) (n = 10) were studied. The areas of midbrain tegmentum and pons were measured on mid-sagittal sections of T1-weighted images of MRI using software NIH Image J ver.1.45. RESULTS: The areas of midbrain tegmentum as well as those of pons were significantly decreased in CPNB compared with those in the other three groups. On receiver operating characteristic (ROC) analysis, the sensitivity and specificity of the areas of brainstem combining midbrain tegmentum and pons for diagnosis of CPNB against non-CPNB (ANB+non-NB) were 80.0% and 94.4%, respectively, at cut-off value of 614.9 mm(2). Brainstem atrophy progressed most markedly during the first 2 years during the course of CPNB. Moreover, the progression rate of atrophy was closely correlated with the elevation of cerebrospinal fluid interleukin-6. CONCLUSION: These results indicate that quantitative analysis of the brainstem areas on MRI scans is effective for diagnosis as well as for evaluation of the disease activity in CPNB. Moreover, it is suggested that an appropriate therapeutic intervention to reduce CSF IL-6 would be required as early as possible upon diagnosis of CPNB.

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.

VEGF and mRNA VEGF expression in CSF from Behçet's disease with neurological involvement.

Vascular endothelial growth factor (VEGF) stimulates angiogenesis, but is also pro-inflammatory and plays an important role in the development of neurological disease, where it can have both attenuating and exacerbating effects. Several studies have indicated that VEGF-A (VEGF) may play a role in the pathogenesis of neurological inflammatory diseases. To assess the role of VEGF in patients with Behçet's disease with neurological involvement, VEGF was measured in the cerebrospinal fluid (CSF) of 32 patients compared to a group of 12 patients with noninflammatory neurological diseases (NIND) and 14 patients with multiple sclerosis (MS). We have also studied the expression of mRNA-VEGF (VEGF-A) in CSF and in peripheral blood mononuclear cells. The mean VEGF(CSF) was significantly increased in neuro-BD and MS patients compared to NIND patients. There was an association between neuro-BD-VEGF(CSF), and leukocyte count. A significant correlation was also observed between neuro-BD-VEGF(CSF) and CSF(%CD4) cells. As a measure of the integrity of the blood-brain barrier Q(albumin) was found correlated to VEGF(CSF). VEGF mRNA was significantly increased in neuro-BD patients compared to NIND patients. These results indicate that, VEGF may be associated with the increased percentages of CD4 cell subpopulation. The role of VEGF is within the inflammatory cascade in the mediation of blood-brain barrier disruption and not specific to Behçet's.

CSF levels of cytokines in neuro-Behçet's disease.

BACKGROUND: Neurological manifestations of Behçet's disease (neuro-Behçet's disease) present in 5-30% of patients. Although cytokines play a pivotal role in pathogenesis of Behçet's disease, published studies about the cerebrospinal fluid (CSF) levels of cytokines in neuro-Behçet's disease are scanty. METHODS: Nine patients with active parenchymal, one patient with non-parenchymal neuro-Behçet's disease, six patients with headache attributed to Behçet's disease, 13 patients with viral meningitis, and 19 healthy controls were recruited. Interleukin 6, 8, 10, tumor necrotic factor-alpha, and interferon-gamma were measured in the CSF using enzyme-linked immunosorbent assay method. RESULTS: Patients with viral meningitis had significantly higher levels of all investigated cytokines except for interferon-gamma in comparison with the patients with parenchymal neuro-Behçet's disease, headache attributed to Behçet's disease and controls (P values <0.05). CSF interleukin 6 was significantly higher in patients with parenchymal neuro-Behçet's disease in comparison with the controls (P=0.025). CSF levels of investigated cytokines had no significant difference between patients with headache attributed to Behçet's disease and controls (P values >0.05). Patients with headache attributed to BD and patients with parenchymal NBD had no significant difference in measured cytokines (P values >0.05). CONCLUSION: In contrast to some previous studies, our investigation showed loss of analogy between CSF cytokine profiles of patients with parenchymal neuro-Behçet's disease and viral meningitis. Also we postulated a crucial role for interleukin 6 in immunopathogenesis of neuro-Behçet's disease.

Successful treatment for sympathetic storms in a patient with neuro-Behçet's disease.

Sympathetic storms (SyS) are characterized by hyperactivity of autonomic functions, resulting in episodes of hyperthermia, hypertension, tachycardia, and hyperhidrosis. We show here a patient with neuro-Behçet's disease (NBD) complicated by SyS. Although SyS is well known to occur with brain tumors, trauma, and hydrocephalus, this is the first report to show that SyS is a manifestation of central nervous system involvement in a patient with NBD. High concentrations of norepinephrine (NE) and IL-8 in cerebrospinal fluid reflected the activity of SyS. The patient's symptoms showed almost complete improvement after treatment with corticosteroids and intravenous cyclophosphamide. Also, the concentrations of NE and IL-8 were decreased to normal levels. An awareness of the potential for SyS and adequate immunosuppressant therapy are of importance when dealing with patients with NBD.

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 pediatric patient with neuro-Behçet's disease.

Behçet's disease is rare in childhood. We describe a 10-year-old boy with neuro-Behçet's disease (NB) who presented with fever, headache, vertigo, and hearing loss. An examination of the cerebrospinal fluid (CSF) revealed pleocytosis as well as elevated protein and interleukin (IL)-6 levels. Brain magnetic resonance imaging (MRI) showed hyperintensity of the right thalamus and midbrain on T2-WI, and gadolinium (Gd) enhancement of left acoustic nerve origin. HLA-B51 was positive. Prednisolone combined with methotrexate resulted in a complete remission. Brain MRI and the CSF IL-6 level were useful for the diagnosis and monitoring of this pediatric patient with NB.

Neuro-Behçet: report of three clinically distinct cases

We report three patients who collectively have very representative clinical forms of neuro-Behçet and different neurological findings. The first case, male, 49 years old, presents symptoms similar to multiple sclerosis. The second case, male 15 years old, presents with parenchymatous compromise and an association with antiphospholipid antibody. And the third case, female 25 years old, presents an acute meningitis. Neuro-Behçet must always be included as a differential diagnosis of neurological disorders that have any difficulties in establishing a definite diagnosis

Cerebrospinal fluid interleukin-6 in progressive Neuro-Behçet's syndrome.

Central nervous system (CNS) involvement in Behçet's disease, usually called neuro-Behçet's syndrome (NB), is one of the most serious complications of the disease. The present study examined cerebrospinal fluid (CSF) interleukin-6 (IL-6) activity in patients with NB to explore its relevance to the progressive CNS disease. Paired CSF and serum specimens were obtained from 11 patients who were diagnosed as having progressive NB based on careful clinical observation and from 11 patients with active Behçet's disease but lacking progressive CNS disease. IL-6 levels in the CSF and sera were determined using IL-6-dependent murine hybridoma MH60.BSF2 cells. All 11 patients with progressive NB showed marked elevation of CSF IL-6 activity [0.18-3.90 U/ml, 1.19 +/- 1.18 (mean +/- SD), normal range, <0.010 U/ml]. In contrast, only 5 of the 11 control patients showed very modest CSF IL-6 activity below 0.10 U/ml, and CSF IL-6 was not detected in the other 6 patients. There was no difference in the serum IL-6 activities of patients with progressive NB and control patients. There was no significant correlation of CSF IL-6 activity with serum IL-6 activity, CSF cell counts, CSF total protein levels, or the CSF/serum albumin quotient. These results indicate that persistent chronic CNS inflammation, as evidenced by the enhanced production of IL-6 within the CNS, plays an important role in the pathogenesis of progressive neuropsychiatric manifestations in Behcet's disease.

Phenotype and functional profile of T cells expressing gamma delta receptor from patients with active Behçet's disease.

OBJECTIVE: Our aim was to investigate the TCR gamma delta+ subset in Behçet's disease (BD) inflammatory sites, which better reflects changes associated with the pathologic process than peripheral blood. METHODS: Forty-five patients with active BD, 10 patients with recurrent aphthous ulcers, 12 patients with rheumatoid arthritis, 5 patients with noninflammatory neurologic diseases and 15 healthy individuals were studied. Three monoclonal antibodies TCR delta 1, BB3, and A13 were used to assess the percentage of TCR gamma delta+ in peripheral blood mononuclear cells (PBMC), in bronchoalveolar lavage and cerebrospinal fluid (CSF). CD11a/CD18 was used to study adhesion molecules. TCR gamma delta+ cells isolated by immunomagnetic separation were tested for cytolytic activity against K562 target cells after interleukin 2 stimulation. RESULTS: The PBMC TCR gamma delta BB3+ subset was significantly increased in BD. In BD inflammatory sites, TCR gamma delta+ cells were also present, composed mainly of A13+ cells from these sites also expressed CD11a marker. TCR gamma delta+ cells from inflammatory sites displayed a higher cytotoxic activity than controls, mediated by the A13+ subset. CONCLUSION: The accumulation of cytotoxic TCR gamma delta+ cells at the sites of inflammation suggests their involvement in the local injury process.

Anticardiolipin antibodies and interleukin-6 in cerebrospinal fluid and blood of Chinese patients with neuro-Behçet's syndrome.

Anticardiolipin antibodies of the IgG, IgM and IgA isotypes and soluble IL-6 were measured in paired serum and cerebrospinal fluid samples from five patients with neuro-Behçet's syndrome. Another five patients with non-inflammatory neurological diseases were also studied as a control group. Anticardiolipin antibodies, especially the IgM isotype, and IL-6 were highly elevated in the cerebrospinal fluid of patients with neuro-Behçet's. Levels of both IgM isotype anticardiolipin antibodies and IL-6 in the cerebrospinal fluid dropped after disease activity subsided. These results suggest that the increase in IgM isotype anticardiolipin antibodies and IL-6 in cerebrospinal fluid may be involved in the immune response of neuro-Behçet's within the central nervous system. Serial measurements of IgM isotype anticardiolipin antibodies and IL-6 in the cerebrospinal fluid may be useful in evaluating disease activity in neuro-Behçet's.

[Leukotrienes and neurological diseases]. / Leukotrienler ve nörolojik hastaliklar.

Assessment of Leukotriene C4 (LTC4) activity in the serum and cerebrospinal fluid (CSF) specimens of patients with multiple sclerosis (MS), Parkinson's disease, amyotrophic lateral sclerosis (ALS), Myasthenia gravis (MG), Behçet's disease and neuro-Behçet, as well as in normal controls were carried out in order to determine its role in the pathogenesis of neurologic disorders. LTC4 levels were found to be elevated in MS and Behçet patient in comparison with controls. Augmentation of LTC4 levels underlines the fact that leukotrienes may be held responsible the pathogenesis of these disorders.

A clinical comparative study of multiple sclerosis and neuro-Behçet's syndrome.

Clinical comparisons were made between Japanese patients with multiple sclerosis (66 cases) and neuro-Behçet's syndrome (23 cases). Those with neuro-Behçet showed marked male predominance, while those with multiple sclerosis showed slight female preponderance. Both showed encephalomyelopathy disseminated in time and space. Patients with multiple sclerosis, however, showed a more polyphasic course, whilst those with neuro-Behçet showed a more progressive one. In multiple sclerosis optic neuritis, acute transverse myelitis, painful tonic seizures, mental disturbance and internuclear ophthalmoplegia were common. On the other hand, in neuro-Behçet the main neurological manifestation was progressive pseudobulbar palsy. Serum and CSF showed more inflammatory changes in neuro-Behçet than in multiple sclerosis. Clinical estimation suggested that in multiple sclerosis the main lesions were in the optic nerve, tegmentum of the brain stem and spinal cord, whereas in neuro-Behçet they were in the basal parts of the brain stem.