Broader anti-EBV TCR repertoire in multiple sclerosis: disease specificity and treatment modulation.

Epstein-Barr virus (EBV) infection has long been associated with the development of multiple sclerosis (MS). MS patients have elevated titers of EBV-specific antibodies in serum and show signs of CNS damage only after EBV infection. Regarding CD8+ T-cells, an elevated but ineffective response to EBV was suggested in MS patients, who present with a broader MHC-I-restricted EBV-specific T-cell receptor beta chain (TRB) repertoire compared to controls. It is not known whether this altered EBV response could be subject to dynamic changes, e.g., by approved MS therapies, and whether it is specific for MS. 1317 peripheral blood TRB repertoire samples of healthy donors (n=409), patients with MS (n=710) before and after treatment, patients with neuromyelitis optica spectrum disorder (n=87), myelin-oligodendrocyte-glycoprotein antibody-associated disease (n=64) and Susac's syndrome (n=47) were analyzed. Apart from MS, none of the evaluated diseases presented with a broader anti-EBV TRB repertoire. In MS patients undergoing autologous hematopoietic stem-cell transplantation, EBV reactivation coincided with elevated MHC-I-restricted EBV-specific TRB sequence matches. Therapy with ocrelizumab, teriflunomide or dimethyl fumarate reduced EBV-specific, but not CMV-specific MHC-I-restricted TRB sequence matches. Together, this data suggests that the aberrant MHC-I-restricted T-cell response directed against EBV is specific to MS with regard to NMO, MOGAD and Susac's Syndrome and that it is specifically modified by MS treatments interfering with EBV host cells or activated lymphocytes.

Factors associated with depressive mood at the onset of multiple sclerosis - an analysis of 781 patients of the German NationMS cohort.

Background: Depression has a major impact on the disease burden of multiple sclerosis (MS). Analyses of overlapping MS and depression risk factors [smoking, vitamin D (25-OH-VD) and Epstein-Barr virus (EBV) infection] and sex, age, disease characteristics and neuroimaging features associated with depressive symptoms in early MS are scarce. Objectives: To assess an association of MS risk factors with depressive symptoms within the German NationMS cohort. Design: Cross-sectional analysis within a multicenter observational study. Methods: Baseline data of n = 781 adults with newly diagnosed clinically isolated syndrome or relapsing-remitting MS qualified for analysis. Global and region-specific magnetic resonance imaging (MRI)-volumetry parameters were available for n = 327 patients. Association of demographic factors, MS characteristics and risk factors [sex, age, smoking, disease course, presence of current relapse, expanded disability status scale (EDSS) score, fatigue (fatigue scale motor cognition), 25-OH-VD serum concentration, EBV nuclear antigen-1 IgG (EBNA1-IgG) serum levels] and depressive symptoms (Beck Depression Inventory-II, BDI-II) was tested as a primary outcome by multivariable linear regression. Non-parametric correlation and group comparison were performed for associations of MRI parameters and depressive symptoms. Results: Mean age was 34.3 years (95% confidence interval: 33.6-35.0). The female-to-male ratio was 2.3:1. At least minimal depressive symptoms (BDI-II > 8) were present in n = 256 (32.8%), 25-OH-VD deficiency (<20 ng/ml) in n = 398 (51.0%), n = 246 (31.5%) participants were smokers. Presence of current relapse [coefficient (c) = 1.48, p = 0.016], more severe fatigue (c = 0.26, p < 0.0001), lower 25-OH-VD (c = -0.03, p = 0.034) and smoking (c = 0.35, p = 0.008) were associated with higher BDI-II scores. Sex, age, disease course, EDSS, month of visit, EBNA1-IgG levels and brain volumes at baseline were not. Conclusion: Depressive symptoms need to be assessed in early MS. Patients during relapse seem especially vulnerable to depressive symptoms. Contributing factors such as fatigue, vitamin D deficiency and smoking, could specifically be targeted in future interventions and should be investigated in prospective studies.

The relevance of NMDA receptor antibody-specific index for diagnosis and prognosis in patients with anti-NMDA receptor encephalitis.

The clinical implications of the presence of anti-N-methyl-D-aspartate receptor (NMDAR)-specific intrathecal immunoglobulin G synthesis and whether it determines the diagnosis of anti-NMDAR encephalitis have not been thoroughly investigated yet. Thus, the aim of this study was to investigate whether the detection of intrathecal anti-NMDAR-specific IgG synthesis contributes to the diagnostic confirmation of anti-NMDAR encephalitis, to disease severity, and to prognosis in patients with positive serum anti-NMDAR-IgG. In this study, patients with detectable anti-NMDAR IgG in serum and/or cerebrospinal fluid (CSF) were included and separated into two groups that either met the 2016 criteria by Graus et al. of definite anti-NMDAR encephalitis (n = 27) or did not (n = 15). In a total, of 80 paired CSF/serum samples, antibody titers were titrated manually and end-point titer levels were carefully determined in a blinded manner to the subgroup attribution. The disease course was assessed via the modified Rankin Scale (mRS) and prognosis was estimated by the anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score. With respect to whether the diagnostic Graus criteria for definite anti-NMDAR encephalitis were fulfilled, a significantly unequal distribution of intrathecal anti-NMDAR antibody-specific synthesis could be shown with a high negative predictive value in case of a negative anti-NMDAR antibody-specific index (NMDAR AI, p = .008. OR = 23.9, sensitivity = 1.0, specificity = 0.4, negative predictive value = 1). A weak correlation was found between the CSF antibody titer and mRS value at the time of sample collection (rs = .37, p = .008, 95% CI [.09, .59]). During the disease course a higher delta-mRS value formed of the mRS at initial presentation minus that at the last recorded presentation correlated with a higher NMDAR AI at first lumbar puncture (rs = - .56, p = .017, 95% CI [- .83, - .11]). No association with the prognostic NEOS score was found. In conclusion, a negative antibody-specific index for anti-NMDAR IgG antibodies has a highly negative predictive value for the diagnosis of anti-NMDAR encephalitis. Yet, a positive NMDAR AI alone does not allow the diagnosis of anti-NMDAR encephalitis.

Association of obesity with disease outcome in multiple sclerosis.

BACKGROUND: Obesity reportedly increases the risk for developing multiple sclerosis (MS), but little is known about its association with disability accumulation. METHODS: This nationwide longitudinal cohort study included 1066 individuals with newly diagnosed MS from the German National MS cohort. Expanded Disability Status Scale (EDSS) scores, relapse rates, MRI findings and choice of immunotherapy were compared at baseline and at years 2, 4 and 6 between obese (body mass index, BMI ≥30 kg/m2) and non-obese (BMI <30 kg/m2) patients and correlated with individual BMI values. RESULTS: Presence of obesity at disease onset was associated with higher disability at baseline and at 2, 4 and 6 years of follow-up (p<0.001). Median time to reach EDSS 3 was 0.99 years for patients with BMI ≥30 kg/m2 and 1.46 years for non-obese patients. Risk to reach EDSS 3 over 6 years was significantly increased in patients with BMI ≥30 kg/m2 compared with patients with BMI <30 kg/m2 after adjustment for sex, age, smoking (HR 1.87; 95% CI 1.3 to 2.6; log-rank test p<0.001) and independent of disease-modifying therapies. Obesity was not significantly associated with higher relapse rates, increased number of contrast-enhancing MRI lesions or higher MRI T2 lesion burden over 6 years of follow-up. CONCLUSIONS: Obesity in newly diagnosed patients with MS is associated with higher disease severity and poorer outcome. Obesity management could improve clinical outcome of MS.

Stem Cell Therapy in Neuroimmunological Diseases and Its Potential Neuroimmunological Complications.

Background: Since the 1990s, transplantations of hematopoietic and mesenchymal stem cells (HSCT and MSCT) and dendritic cell (DCT) have been investigated for the treatment of neurological autoimmune disorders (NADs). With the growing number of transplanted patients, awareness of neuroimmunolgical complications has increased. Therefore, an overview of SCT for the most common NADs and reports of secondary immunity after SCT is provided. Methods: For this narrative review, a literature search of the PubMed database was performed. A total of 86 articles reporting on different SCTs in NADs and 61 articles dealing with immune-mediated neurological complications after SCT were included. For multiple sclerosis (MS), only registered trials and phase I/II or II studies were considered, whereas all available articles on other disorders were included. The different transplantation procedures and efficacy and safety data are presented. Results: In MS patients, beneficial effects of HSCT, MSCT, and DCT with a decrease in disability and stabilization of disease activity have been reported. These effects were also shown in other NADs mainly in case reports. In seven of 132 reported patients with immune-mediated neurological complications, the outcome was fatal. Conclusions: Phase III trials are ongoing for MS, but the role of SCT in other NADs is currently limited to refractory patients due to occasional serious complications.

Severe allo-immune antibody-associated peripheral and central nervous system diseases after allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a curative treatment for hematologic malignancies. Acute and chronic graft-versus-host disease (GvHD) are the major immune-mediated complications after alloHSCT. However, there is controversy whether neurologic complications after alloHSCT might represent manifestations of GvHD. We report three patients who acquired distinct, severe immune-mediated peripheral or central nervous system diseases after alloHSCT without other, concomitant GvHD manifestations. One patient had been diagnosed with B-cell chronic lymphocytic leukemia and two patients with high risk myelodysplastic syndrome. Patient #1 presented as LGI1- and GAD-IgG positive immune-mediated encephalitis, patient #2 was diagnosed with MOG-IgG positive encephalomyelitis, and patient #3 had chronic inflammatory polyneuropathy associated with SSA(Ro)-IgG positive Sjögren's syndrome. 100% donor chimerism was detectable in the peripheral blood in all three. The specific antibodies were undetectable in donors' and patients' blood before alloHSCT suggesting that the antibodies had arisen from the transplanted donor immune system. Early intensive immunotherapy led to improvement of clinical symptoms and stability of the neurological disease, however, at the cost of losing the graft-versus-malignancy effect in one patient. In conclusion, we provide evidence of isolated, severe allo-immune diseases of the peripheral and central nervous system as complications of alloHSCT ("neuro-GvHD"). Interdisciplinary surveillance and thorough diagnostic work-up are needed for early diagnosis and treatment of neuro-immunologic complications after alloHSCT to improve the otherwise poor outcome.

MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 3: Brainstem involvement - frequency, presentation and outcome.

BACKGROUND: Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) are present in a subset of aquaporin-4 (AQP4)-IgG-negative patients with optic neuritis (ON) and/or myelitis. Little is known so far about brainstem involvement in MOG-IgG-positive patients. OBJECTIVE: To investigate the frequency, clinical and paraclinical features, course, outcome, and prognostic implications of brainstem involvement in MOG-IgG-positive ON and/or myelitis. METHODS: Retrospective case study. RESULTS: Among 50 patients with MOG-IgG-positive ON and/or myelitis, 15 (30 %) with a history of brainstem encephalitis were identified. All were negative for AQP4-IgG. Symptoms included respiratory insufficiency, intractable nausea and vomiting (INV), dysarthria, dysphagia, impaired cough reflex, oculomotor nerve palsy and diplopia, nystagmus, internuclear ophthalmoplegia (INO), facial nerve paresis, trigeminal hypesthesia/dysesthesia, vertigo, hearing loss, balance difficulties, and gait and limb ataxia; brainstem involvement was asymptomatic in three cases. Brainstem inflammation was already present at or very shortly after disease onset in 7/15 (47 %) patients. 16/21 (76.2 %) brainstem attacks were accompanied by acute myelitis and/or ON. Lesions were located in the pons (11/13), medulla oblongata (8/14), mesencephalon (cerebral peduncles; 2/14), and cerebellar peduncles (5/14), were adjacent to the fourth ventricle in 2/12, and periaqueductal in 1/12; some had concomitant diencephalic (2/13) or cerebellar lesions (1/14). MRI or laboratory signs of blood-brain barrier damage were present in 5/12. Cerebrospinal fluid pleocytosis was found in 11/14 cases, with neutrophils in 7/11 (3-34 % of all CSF white blood cells), and oligoclonal bands in 4/14. Attacks were preceded by acute infection or vaccination in 5/15 (33.3 %). A history of teratoma was noted in one case. The disease followed a relapsing course in 13/15 (87 %); the brainstem was involved more than once in 6. Immunosuppression was not always effective in preventing relapses. Interferon-beta was followed by new attacks in two patients. While one patient died from central hypoventilation, partial or complete recovery was achieved in the remainder following treatment with high-dose steroids and/or plasma exchange. Brainstem involvement was associated with a more aggressive general disease course (higher relapse rate, more myelitis attacks, more frequently supratentorial brain lesions, worse EDSS at last follow-up). CONCLUSIONS: Brainstem involvement is present in around one third of MOG-IgG-positive patients with ON and/or myelitis. Clinical manifestations are diverse and may include symptoms typically seen in AQP4-IgG-positive neuromyelitis optica, such as INV and respiratory insufficiency, or in multiple sclerosis, such as INO. As MOG-IgG-positive brainstem encephalitis may take a serious or even fatal course, particular attention should be paid to signs or symptoms of additional brainstem involvement in patients presenting with MOG-IgG-positive ON and/or myelitis.

Effect of FTY720-phosphate on the expression of inflammation-associated molecules in astrocytes in vitro.

FTY720 is a new oral immunomodulatory therapy for the treatment of multiple sclerosis (MS). There is strong evidence that FTY720 has direct effects on brain resident cells such as astrocytes acting via sphingosine­1­phosphate (S1P) receptors. In the present study, the mRNA expression of S1P receptors as well as selected cytokines, chemokines and growth factors were investigated in primary murine astrocytes under inflammatory conditions in the presence or absence of the phosphorylated form of FTY720 (FTY720­P). Following stimulation with either the pro­inflammatory cytokine tumor necrosis factor­α (TNF­α) or with bacterial lipopolysaccharide, there was an increased expression of the receptors S1P1 and S1P3, the cytokines and chemokines interleukin (IL)­1ß, chemokine (C­C­motif) ligand 2 (CCL­2), CCL­20 and chemokine (C­X­C­motif) ligand 12 as well as the growth factors insulin­like growth factor­1, ciliary neurotrophic factor and glial cell line­derived neurotrophic factor (GDNF). FTY720­P led to an increased expression of IL­1ß and GDNF at distinct time points following co­stimulation with TNF­α compared with TNF­α treatment alone. However, the presence of FTY720­P did not have any further significant effects on the expression of S1P receptors, cytokines or growth factors, suggesting that the regulation of these target genes in astrocytes is not likely to be a major mechanism underlying the effect of FTY720­P in diseases such as MS.

Importance of follow-up cerebrospinal fluid analysis in cryptococcal meningoencephalitis.

Cryptococcal meningoencephalitis represents a serious infection of the central nervous system, where reliable prognostic factors during the disease course are needed. Twenty-one patients diagnosed with cryptococcal meningoencephalitis in a German university hospital from 1999 to 2013 were analysed retrospectively. CSF parameters were analysed prior to therapy and during antifungal treatment and were compared between patients who survived or deceased. Fifteen patients clinically improved after antifungal therapy, while six patients died. No differences were observed between the outcome groups for the CSF parameters cell count, lactate, total protein, and CSF-serum albumin quotients (QAlb). Follow-up examinations of serum cryptococcal antigen titer and CSF cell count have shown that these parameters cannot be used to monitor the efficacy of antifungal therapy as well. In contrast, the course of QAlb during therapy was indicative for the outcome as a possible prognostic marker. In patients with clinical improvement QAlb values were falling under therapy, while rising QAlb values were found in patients with fatal outcome indicating a continuing dysfunction of the blood-CSF barrier. In conclusion, our results indicate that, among the various CSF parameters, the course of QAlb presents a promising marker that might be used to monitor the efficacy of antifungal therapy.

Anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis show distinct patterns of brain glucose metabolism in 18F-fluoro-2-deoxy-d-glucose positron emission tomography.

BACKGROUND: Pathogenic autoantibodies targeting the recently identified leucine rich glioma inactivated 1 protein and the subunit 1 of the N-methyl-D-aspartate receptor induce autoimmune encephalitis. A comparison of brain metabolic patterns in 18F-fluoro-2-deoxy-d-glucose positron emission tomography of anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis patients has not been performed yet and shall be helpful in differentiating these two most common forms of autoimmune encephalitis. METHODS: The brain 18F-fluoro-2-deoxy-d-glucose uptake from whole-body positron emission tomography of six anti-N-methyl-D-aspartate receptor encephalitis patients and four patients with anti-leucine rich glioma inactivated 1 protein encephalitis admitted to Hannover Medical School between 2008 and 2012 was retrospectively analyzed and compared to matched controls. RESULTS: Group analysis of anti-N-methyl-D-aspartate encephalitis patients demonstrated regionally limited hypermetabolism in frontotemporal areas contrasting an extensive hypometabolism in parietal lobes, whereas the anti-leucine rich glioma inactivated 1 protein syndrome was characterized by hypermetabolism in cerebellar, basal ganglia, occipital and precentral areas and minor frontomesial hypometabolism. CONCLUSIONS: This retrospective 18F-fluoro-2-deoxy-d-glucose positron emission tomography study provides novel evidence for distinct brain metabolic patterns in patients with anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis.

Ovarectomy despite Negative Imaging in Anti-NMDA Receptor Encephalitis: Effective Even Late.

Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune antibody-mediated neuropsychiatric disorder. The disorder is known to be associated with ovarian teratoma and predominantly affects young women. Here, we report the case of a 34-year-old woman with anti-NMDAR encephalitis, in which detailed investigations gave no specific hint for an ovarian teratoma. Despite this, and due to a continuous severe clinical syndrome, an ovarectomy was performed and histological examination revealed an occult teratoma. The ovarectomy led to a remarkable improvement even with a long term intensive care treatment for 11 months. The most important lesson to be learned from this instructive case is that even though none of the investigations was indicative for an ovarian teratoma, including an explorative laparoscopy with biopsy, there still may be an occult ovarian teratoma. This shows that tumour search and diagnosis are extremely important in patients presenting with anti-NMDAR encephalitis, and a laparotomy and ovarectomy is justified. Furthermore, removal of the teratoma even 11 months after a very severe course is still therapeutically effective.

Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: A multicentre study of 175 patients.

BACKGROUND: The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity. OBJECTIVE: To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus. METHODS: Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%). RESULTS: Seropositive patients were found to be predominantly female (p < 0.0003), to more often have signs of co-existing autoimmunity (p < 0.00001), and to experience more severe clinical attacks. A visual acuity of ≤ 0.1 during acute optic neuritis (ON) attacks was more frequent among seropositives (p < 0.002). Similarly, motor symptoms were more common in seropositive patients, the median Medical Research Council scale (MRC) grade worse, and MRC grades ≤ 2 more frequent, in particular if patients met the 2006 revised criteria (p < 0.005, p < 0.006 and p < 0.01, respectively), the total spinal cord lesion load was higher (p < 0.006), and lesions ≥ 6 vertebral segments as well as entire spinal cord involvement more frequent (p < 0.003 and p < 0.043). By contrast, bilateral ON at onset was more common in seronegatives (p < 0.007), as was simultaneous ON and myelitis (p < 0.001); accordingly, the time to diagnosis of NMO was shorter in the seronegative group (p < 0.029). The course of disease was more often monophasic in seronegatives (p < 0.008). Seropositives and seronegatives did not differ significantly with regard to age at onset, time to relapse, annualized relapse rates, outcome from relapse (complete, partial, no recovery), annualized EDSS increase, mortality rate, supratentorial brain lesions, brainstem lesions, history of carcinoma, frequency of preceding infections, oligoclonal bands, or CSF pleocytosis. Both the time to relapse and the time to diagnosis was longer if the disease started with ON (p < 0.002 and p < 0.013). Motor symptoms or tetraparesis at first myelitis and > 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome. CONCLUSION: This study provides an overview of the clinical and paraclinical features of NMOSD in Caucasians and demonstrates a number of distinct disease characteristics in seropositive and seronegative patients.

Glatiramer acetate increases phagocytic activity of human monocytes in vitro and in multiple sclerosis patients.

Beside its effects on T cells, a direct influence on cells of the myelo-monocytic lineage by GA becomes evident. Recently, we demonstrated that GA drives microglia to adopt properties of type II antigen presenting cells (APC) and increases their phagocytic activity. In the present work, we focused on human blood monocytes in order to examine whether GA may increase phagocytic activity in vivo and to evaluate the molecular mechanisms explaining this new discovered mode of action. Peripheral blood mononuclear cells (PBMC) were obtained using a Biocoll-Isopaque gradient and monocytes were subsequently isolated by using CD14 MicroBeads. Phagocytic activity was determined by flow cytometric measurement of the ingestion of fluorescent beads. Flow cytometry was also used to assess monocytic differentiation and expression of phagocytic receptors. Monocytes of GA treated MS patients exhibited a significantly higher phagocytic activity than those of healthy controls or non-treated MS patients. In vitro, a significant phagocytic response was already detectable after 1 h of GA treatment at the concentrations of 62.5 and 125 µg/ml. A significant increase at all concentrations of GA was observed after 3 h and 24 h, respectively. Only monocytes co-expressing CD16, particularly CD14(++)CD16(+) cells, were observed to phagocytose. Treatment of monocytes with IL-10 and supernatants from GA-treated monocytes did not alter phagocytosis. We observed a decrease in CD11c expression by GA while no changes were found in the expression of CD11b, CD36, CD51/61, CD91, TIM-3, and CD206. In our blocking assays, treatment with anti-CD14, anti-CD16, anti-TIM3, anti-CD210, and particularly anti-CD36 antibodies led to a decrease in phagocytosis. Our results demonstrate a new mechanism of action of GA treatment that augments phagocytic activity of human monocytes in vivo and in vitro. This activity seems to arise from the CD14(++)CD16(+) monocyte subset.

Longitudinal extensive transverse myelitis--it's not all neuromyelitis optica.

Longitudinal extensive transverse myelitis (LETM) is defined as a spinal cord lesion that extends over three or more vertebrae, as seen on MRI of the spine. The clinical presentation of a patient with LETM is often dramatic and can consist of paraparesis or tetraparesis, sensory disturbances, and gait, bladder, bowel and/or sexual dysfunction. LETM is a characteristic feature of neuromyelitis optica, but such spinal lesions can also occur in various other autoimmune and inflammatory diseases that involve the CNS--such as multiple sclerosis, sarcoidosis or Sjögren syndrome--or in infectious diseases with CNS involvement. Patients with a neoplastic disorder or traumatic spinal cord injury can also present with longitudinal spinal lesions. In this Review, the signs and symptoms that suggest various etiologies and differential diagnoses of LETM are described, and illustrated by educational case studies. The best therapeutic options for patients with each diagnosis are also discussed.

Clinical approach to optic neuritis: pitfalls, red flags and differential diagnosis.

Demyelinating optic neuritis (ON) is the most common cause of optic neuropathy typically presenting with a subacute painful visual loss. In 20% of patients with multiple sclerosis (MS), ON is the presenting symptom and half of the patients with isolated ON develop MS within 15 years. The diagnosis of ON plays an important role in neurological practice. A correct and early diagnosis is necessary to ensure optimal further investigations and treatment. Other causes of optic neuropathies such as connective tissue disorders, infectious diseases, tumours or ischaemic neuropathies are less frequent but clinical and therapeutic management can differ dramatically. We present five patients admitted to our hospital with suspected demyelinating ON, but the clinical work up revealed different causes of optic neuropathy. We discuss the differential diagnosis of ON and clinical red flags that require careful diagnostic assessment of other diseases. A workflow for the diagnosis of optic neuropathies is presented.

CCL5 induces a pro-inflammatory profile in microglia in vitro.

The chemokine receptors CCR1, CCR2, CCR3, CCR5, and CXCR2 have been found to be expressed on microglia in many neurodegenerative diseases, such as multiple sclerosis and Alzheimer's disease. There is emerging evidence that chemokines, besides chemoattraction, might directly modulate reactive profiles of microglia. To address this hypothesis we have investigated the effects of CCL2, CCL3, CCL5, and CXCL1 on cytokine and growth factor production, NO synthesis, and phagocytosis in non-stimulated and lipopolysaccharide-stimulated primary rat microglia. The respective receptors CCR1, CCR5, and CXCR2 were shown to be functionally expressed on microglia. All tested chemokines stimulated chemotaxis whereas only CCL5 increased NO secretion and attenuated IL-10 as well as IGF-1 production in activated microglia. Based on these findings we propose that besides its chemoattractant function CCL5 has a modulatory effect on activated microglia.

Specific immune intervention with monoclonal antibodies for the treatment of multiple sclerosis.

Multiple sclerosis (MS) is considered to be an autoimmune disease leading to inflammatory demyelination and axonal damage in the central nervous system (CNS). Current treatments involve non-specific immunosuppression and immunomodulation. The development of monoclonal antibodies for therapeutic use allows targeting of specific immune mechanisms. Natalizumab, a monoclonal antibody directed against alpha4beta1 integrin that plays a crucial role in the transmigration of immune cells across the blood-brain-barrier, has been licensed for relapsing-remitting (RR) MS in 2006. Rituximab, directed against CD20 expressed on pre B-cells and B-cells has been tested successfully in a phase II trial and suggests that several B-cell dependent mechanisms may be relevant to the mode of action. Alemtuzumab, targeting CD52 expressed on T-cells, B-cells, monocytes and macrophages, has also shown to be effective in early RRMS and phase III trials are currently ongoing. Daclizumab binds to CD25, the alpha chain of the interleukin (IL)-2 receptor, and is also being tested for RRMS. Beside the clinical data the results from these clinical trials give also new insights into the pathogenesis of MS. We critically discuss the potential but also the pitfalls and potential hazards of these new therapeutic strategies.

Meningeal carcinomatosis from penile squamous cell carcinoma.

We report herein a clinical case of a patient with meningeal carcinomatosis from penile squamous cell carcinoma. A 68-year-old man presented with mental changes, headaches, and unstable gait. Examinations revealed brain metastases and infiltration of the leptomeninges and subarachnoid space by carcinoma cells. Only 11 months earlier the patient had been diagnosed with penile squamous cell carcinoma of poor differentiation and had underwent subtotal penectomy and adjuvant chemotherapy and radiation. Infiltration of the central nervous system with penile cancer is extremely rare, and only five cases with brain metastases have been described to date. This is the first report of a patient with penile cancer spread to the leptomeninges.

Fluorodeoxyglucose positron emission tomography (FDG-PET) is useful in the diagnosis of neurosarcoidosis.

A 45-year-old man presented with a progressive transverse spinal cord syndrome. MRI scanning revealed bitemporal and multiple spinal lesions with significant enhancement after gadolinium administration mimicking an acute disseminated encephalomyelitis. CSF analyses showed a lymphocytic pleocytosis. After treatment with high dose steroids clinical improvement was observed with a secondary decline shortly thereafter. MRI rescanning showed no remarkable alterations of the lesions. Further diagnostic work-up included a fluorodeoxyglucose positron emission tomography (FDG-PET) of the whole body to search for occult inflammation or neoplasia. The FDG-PET showed hypermetabolic foci corresponding to the lesions on MRI and additionally increased uptake in mediastinal and pulmonary hilar lymph nodes. A mediastinal lymph node was biopsied. Pathology was consistent with the diagnosis of sarcoidosis. The usual diagnostical tools to evaluate a sarcoidosis, such as serum angiotensin converting enzyme (ACE) and computed tomography of the chest were performed initially and revealed no pathological results. Therefore, in this case FDG-PET was crucial for the diagnostic work-up leading to an accessible inflammatory lesion outside the CNS for biopsy and the final diagnosis of sarcoidosis.

Chronic toxic demyelination in the central nervous system leads to axonal damage despite remyelination.

The majority of multiple sclerosis lesions fail to remyelinate after chronic demyelinating episodes resulting in neurologic disability. In the current study, chronic demyelination was investigated by using the cuprizone model, a toxic demyelination model. C57BL/6 mice were administered a 0.2% cuprizone diet up to 16 weeks to induce chronic demyelination. For comparison, another group was maintained only for 6 weeks on cuprizone to model acute demyelination. Both groups were analysed regarding the remyelination process after withdrawal of the toxin. Reexpression of myelin proteins after chronic demyelination was reduced by a factor of two as judged by LFB and myelin protein stainings compared to acute demyelination after 2 weeks on remyelination. During chronic demyelination mature oligodendrocytes (Nogo-A positive cells) were severely depleted by 90% compared to age matched controls. Nevertheless, extensive remyelination occurred after withdrawal of cuprizone and was nearly complete after 12 weeks. There was only minimal acute axonal damage as judged by APP staining, with the course of APP positive axons correlating with macrophage/microglia accumulation. Chronic axonal damage detected by SMI-32 positive staining was only seen after chronic demyelination and was still observable during the whole remyelination period. These data suggest that two pattern of axonal injury occur in the cuprizone model.