Dietary Fatty Acids Directly Impact Central Nervous System Autoimmunity via the Small Intestine.

Growing empirical evidence suggests that nutrition and bacterial metabolites might impact the systemic immune response in the context of disease and autoimmunity. We report that long-chain fatty acids (LCFAs) enhanced differentiation and proliferation of T helper 1 (Th1) and/or Th17 cells and impaired their intestinal sequestration via p38-MAPK pathway. Alternatively, dietary short-chain FAs (SCFAs) expanded gut T regulatory (Treg) cells by suppression of the JNK1 and p38 pathway. We used experimental autoimmune encephalomyelitis (EAE) as a model of T cell-mediated autoimmunity to show that LCFAs consistently decreased SCFAs in the gut and exacerbated disease by expanding pathogenic Th1 and/or Th17 cell populations in the small intestine. Treatment with SCFAs ameliorated EAE and reduced axonal damage via long-lasting imprinting on lamina-propria-derived Treg cells. These data demonstrate a direct dietary impact on intestinal-specific, and subsequently central nervous system-specific, Th cell responses in autoimmunity, and thus might have therapeutic implications for autoimmune diseases such as multiple sclerosis.

Listeria rhombencephalitis mimicking a demyelinating event in an immunocompetent young patient.

BACKGROUND: Listeriosis caused by listeria monocytogenes (LM) is a potentially lethal foodborne infection of the central nervous system (CNS) and the third most common cause of bacterial meningitis. Foods most commonly implicated are soft cheeses, raw or ready-to-eat meat and pre-processed foods. The incubation time is between 11 and 70 days. Rarely LM rhombencephalitis (RE) can occur, which typically has a biphasic course with non- specific prodromal symptoms like fever, malaise, fatigue, headache, nausea and vomiting followed by cranial nerve palsies, ataxia and hemi- or tetraparesis. OBJECTIVE: To report a 31-year old immunocompetent female developing a severe abscessing RE caused by LM, which was initially assessed as a relapse after a clinically isolated syndrome (CIS). METHODS: Case report. RESULTS: Patients with CIS or multiple sclerosis, who present with brainstem symptoms should be evaluated carefully. The presence of clinical and paraclinical red flags in the diagnostic evaluation of a suspected CNS white matter disease should raise the awareness of clinicians for potential differential diagnoses.

Serum anti-Müllerian hormone levels in reproductive-age women with relapsing-remitting multiple sclerosis.

BACKGROUND: Fertility might be reduced in women with multiple sclerosis (MS), although only few studies exist and the underlying reasons are not well understood. Similar to other autoimmune diseases, a decreased ovarian reserve may contribute to impaired fertility in women with MS. Anti-Müllerian hormone (AMH) is an established marker of the ovarian reserve and an objective indicator of ovarian function, which is independent of the hypothalamus-pituitary-gonadal axis function. OBJECTIVE: The purpose of this study was to determine AMH levels in females with relapsing-remitting MS (RRMS) in combination with other reproduction and lifestyle factors. METHODS: A total of 76 reproductive-age females with RRMS and 58 healthy controls were included in this case control study. An enzymatically amplified two-site immunoassay was used to measure serum AMH level. RESULTS: Mean AMH level was significantly decreased in females with RRMS (p<0.04), and a higher proportion of females with RRMS showed very low AMH values (<0.4 ng/ml) compared to healthy controls (p<0.05). The majority of these women were currently without any disease modifying treatment. CONCLUSIONS: Our data contribute to our understanding of impaired fertility in women with MS. The unexpected finding that the majority of MS subjects with very low AMH levels were currently without medication requires further evaluation.

Modulation of autoimmune demyelination by laquinimod via induction of brain-derived neurotrophic factor.

Laquinimod is a promising, orally available compound that has been successfully evaluated in placebo-controlled phase II/III studies of relapsing-remitting multiple sclerosis (MS). Studies are ongoing to further define laquinimod's modulatory mechanisms. Analyses in the animal model of experimental autoimmune encephalomyelitis (EAE) demonstrate that laquinimod reduces infiltration of leukocytes into the central nervous system, induces a Th1 to Th2/3 shift, and suppresses Th17 responses. To evaluate the potential neuroprotective capacity of laquinimod via modulation of brain-derived neurotrophic factor (BDNF), we analyzed the expression of BDNF in blood samples from 203 MS patients treated with laquinimod. Furthermore, we investigated the effect of laquinimod in EAE using a conditional BDNF knockout strain lacking BDNF expression in myeloid cells and T cells (LLF mice). Treatment with laquinimod resulted in a significant and persistent increase in BDNF serum levels of MS patients when compared to baseline and placebo-treated patients. LLF mice treated with laquinimod display a more severe EAE disease course in comparison to wild-type mice. Furthermore, laquinimod-treated wild-type monocytes secreted an anti-inflammatory cytokine pattern in comparison to untreated wild-type monocytes and treated LLF monocytes. Adoptive transfer of laquinimod stimulated monocytes into mice with EAE ameliorated the disease course. Consistent with immunomodulatory properties, laquinimod skewed monocytes toward a regulatory phenotype and also acted via modulation of BDNF, which may contribute to neuroprotection in MS patients.

Natalizumab-associated reversible encephalopathy syndrome mimicking progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy is a rare but potentially lethal adverse event in natalizumab treated multiple sclerosis patients. We report on a 40-year old Caucasian man with typical relapsing progressive multiple sclerosis, who developed a reversible leukoencephalopathy syndrome after 43 natalizumab infusions mimicking progressive multifocal leukoencephalopathy. To our knowledge, this is the first case of its kind. Our case suggests that awareness ought to be sharpened for reversible leukoencephalopathy syndrome in the follow-up of natalizumab treated multiple sclerosis patients.

Constitutive activity of NF-kappa B in myeloid cells drives pathogenicity of monocytes and macrophages during autoimmune neuroinflammation.

The NF-κB/REL-family of transcription factors plays a central role in coordinating the expression of a wide variety of genes controlling immune responses including autoimmunity of the central nervous system (CNS). The inactive form of NF-κB consists of a heterodimer which is complexed with its inhibitor, IκB. Conditional knockout-mice for IκBα in myeloid cells (lysMCreIκBα(fl/fl)) have been generated and are characterized by a constitutive activation of NF-κB proteins allowing the study of this transcription factor in myelin-oligodendrocyte-glycoprotein induced experimental autoimmune encephalomyelitis (MOG-EAE), a well established experimental model for autoimmune demyelination of the CNS.In comparison to controls, lysMCreIκBα(fl/fl) mice developed a more severe clinical course of EAE. Upon histological analysis on day 15 p.i., there was an over two fold increased infiltration of T-cells and macrophages/microglia. In addition, lysMCreIκBα(fl/fl) mice displayed an increased expression of the NF-κB dependent factor inducible nitric oxide synthase in inflamed lesions. These changes in the CNS are associated with increased numbers of CD11b positive splenocytes and a higher expression of Ly6c on monocytes in the periphery. Well in accordance with these changes in the myeloid cell compartment, there was an increased production of the monocyte cytokines interleukin(IL)-12 p70, IL-6 and IL-1beta in splenocytes. In contrast, production of the T-cell associated cytokines interferon gamma (IFN-gamma) and IL-17 was not influenced.In summary, myeloid cell derived NF-κB plays a crucial role in autoimmune inflammation of the CNS and drives a pathogenic role of monocytes and macrophages independently from T-cells.

Components of acquisition-to-acquisition variance in continuous arterial spin labelling (CASL) imaging.

BACKGROUND: Images of perfusion estimates obtained with the continuous arterial spin labelling technique are characterized by variation between single acquisitions. Little is known about the spatial determinants of this variation during the acquisition process and their impact on voxel-by-voxel estimates of effects. RESULTS: We show here that the spatial patterns of covariance between voxels arising during the acquisition of these images uncover distinct mechanisms through which this variance arises: through variation in global perfusion levels; through the action of large vessels and other, less well characterized, large anatomical structures; and through the effect of noisy areas such as the edges of the brain. CONCLUSIONS: Knowledge of these covariance patterns is important to experimenters for a correct interpretation of findings, especially for studies where relatively few acquisitions are made.

Impact of aerobic exercise training on cognitive functions and affect associated to the COMT polymorphism in young adults.

Physical fitness can serve as a means to enhance cognitive functioning by modulating particular aspects of brain functioning. However, mechanisms underlying this modulating effect remain widely unresolved. To examine the impact and to clarify the mechanisms of physical fitness training in a young and healthy population, it was investigated whether an increase in fitness would result in improvements in executive control processes and positive and negative affect. Moreover, genotype of the Val158Met polymorphism in catechol-O-methyltransferase (COMT) as an index of relative central dopamine bioavailability was determined to elucidate dopamine tuning efficiency and its association with performance in the applied cognitive tasks. Seventy-five individuals participated and underwent an incremental fitness test to assess physical fitness. An exercising group subsequently engaged in a 17 weeks running training consisting of three running sessions at moderate to high, individually adjusted intensities. Associated with increased fitness improved cognitive flexibility and cognitive control were observed, whereas working memory remained unaffected. In runners, Val/Val participants improved cognitive performance to a greater extent compared to individuals carrying a Met allele. From the present results it is concluded that an increase in physical fitness provides a means to improve cognitive functioning via dopaminergic modulation.

Components of variance in brain perfusion and the design of studies of individual differences: the baseline study.

Simple baseline studies correlate average perfusion levels measured at rest with individual variables, or contrast subject groups as in case-control studies. In this methodological work, we summarize some formal properties of the design of these studies, and investigate the sources of variance that characterize data acquired with the arterial spin labeling technique, with the purpose of alerting users to the main sources of variation that determine background variance and affect the power of statistical tests. This design typology is characterized by two variance components: between acquisitions and between subjects. We show that variation between acquisitions is affected by the presence of large vessels and venous sinuses, with potential adverse effects especially in the temporal and insular regions, and provide maps of the number of acquisitions or subjects required to reach the desired estimate precision. Furthermore, we show that the largest source of variation between subjects is captured by global perfusion levels, and can in principle be removed by adjusting the data. Significance levels, however, are not always only improved by the adjustment procedure; we provide an example in the correlation with age, and attempt to explain the consequences of the adjustment with the help of a principal component analysis of the data. We also show the existence of variation between subjects in the perfusion in the territory of the posterior cerebral artery and in hemispheric asymmetry.

Effective immunosuppressant therapy with cyclophosphamide and corticosteroids in paraneoplastic cerebellar degeneration.

Paraneoplastic cerebellar degeneration (PCD) is a rare immune mediated phenomenon often associated with cancer of the ovarian. Hitherto, tumor dissection is the mainstay in therapy while immunomodulatory treatment regimes often fail. Here we report on an 86 year old female patient who developed a severe pancerebellar syndrome. Clinical course, onconeural (anti-Yo) antibodies and detection of ovarian cancer suggest the assumption of PCD as the most probable diagnosis. We initiated a high-dose course of corticosteroids followed by a single dose of cyclophosphamide (600 mg/day). Surprisingly patient's condition improved and stabilized within days subsequent to cyclophosphamide application. This case demonstrates the benefit of immunosuppressive therapy in an anti-Yo positive patient with severe PCD secondary to an ovarian cancer.

Antiepileptic activity of zonisamide on hippocampal CA3 neurons does not depend on carbonic anhydrase inhibition.

Zonisamide (ZNS) is an anticonvulsant drug known to affect various neuronal channels and transmitter systems. ZNS has also been reported to inhibit carbonic anhydrase activity and may thus influence neuronal activity via changes of pH. Therefore, we analyzed effects of ZNS in vitro using epileptic model systems which are sensitive to carbonic anhydrase inhibition and pH changes. Intracellular recordings from CA3 neurons (hippocampal slice, adult guinea pigs) were carried out under bicarbonate-buffered conditions. Epileptiform activity was induced by either 4-aminopyridine or theophylline. In parallel experiments, intracellular pH (pHi) was determined in the CA1 and CA3 subfields of 2',7-bis(2-carboxyethyl)-5(6)-carboxyfluorescin-acetoxymethyl ether (BCECF-AM) loaded slices. The ammonium prepulse method was used to test for effects of ZNS on pHi regulation. ZNS (50 microM) reversibly reduced the frequency of 4-AP induced epileptiform bursting and the number of action potentials per bursts but had no effect on input resistance and membrane potential. Theophylline-induced epileptiform bursting, although sensitive to hypercapnic acidosis, was not affected by ZNS. There was also no effect on steady-state pHi and pHi regulation of BCECF-AM loaded hippocampal tissue. Clinically relevant concentrations of ZNS strongly inhibit 4-AP induced epileptiform activity of hippocampal CA3 neurons in vitro, but this effect was unlikely based on carbonic anhydrase inhibition or changes of neuronal pHi.

Successful therapy with rituximab in three patients with probable neurosarcoidosis.

BACKGROUND: Neurosarcoidosis occurs in about 5-15% of patients with sarcoidosis. Therapy with corticosteroids is generally accepted as the first-line medication, followed by various immunomodulating and cytotoxic agents or combined therapy. However, some patients show an unsatisfactory outcome or have adverse events and require novel treatment strategies. METHODS: We describe three patients with systemic sarcoidosis and central nervous system involvement who received CD20-targeted B-cell depletion with rituximab. RESULTS: Treatment with rituximab was well tolerated and followed by marked remission in patients nonresponsive to other immunosuppressive agents. CONCLUSION: Rituximab may be used for patients with neurosarcoidosis who are nonresponsive to established treatment regimes.

Ovarian Reserve in Women With Neuromyelitis Optica Spectrum Disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is a neuroinflammatory disease. The majority of NMOSD patients is seropositive for aquaporin-4 (AQP4) antibodies. AQP4 is the main water channel protein in the central nervous system, but has also been identified in the female reproductive system. Fertility issues and ovarian reserve has not yet been studied in females with NMOSD. The purpose of this study was to measure serum Anti-Müllerian hormone (AMH) in females with NMOSD compared to healthy controls (HC), in combination with other lifestyle and reproduction parameters. AMH is independent from the menstrual cycle and a reliable indicator of both ovarian reserve and ovarian function. We included a total of 32 reproductive-age females, 18 HC and 14 with NMOSD. We used an enzymatically amplified two-site immunoassay to determine serum AMH level. In comparison to HC, mean AMH value was reduced in NMOSD. Apart from that significantly more women with NMOSD showed low AMH levels (< 0.8 ng/ml). Low AMH was associated with disease activity. In contrast, none of the immunotherapies for NMOSD, neither any reproductive life style parameter was associated with a decreased AMH. Our results contribute to understanding of hindered fertility in females with NMOSD and enables neurologists to better counsel female patients.

Severe spinal cord ischemia subsequent to fibrocartilaginous embolism.

Fibrocartilaginous embolism is a rare cause of spinal cord ischemia. Here we report the case of a young previously healthy man who noted sudden thoracic spinal belt-like pain after intensive physical effort. Following a free interval he developed paraplegia, complete sensory loss below Th(4) and inability to voluntarily purge bladder and bowel. Neuroimaging exposed an intramedullary longitudinal hyperintense signal from C(6) down to the conus in T2-weighted images, intersomatic disc collapses and vertebral body infarctions (C(5-7)/Th(8-10)). Other plausible diagnosis, e.g. spinal contusion, cord compression or acute onset transverse myelitis were excluded. Altogether, clinical presentation, neuroimaging and lack of evidence of other plausible diagnosis suggest fibrocartilaginous embolism as the most probable diagnosis.

Serotonin but not zonisamide inhibits theophylline-induced epileptiform activity in guinea pig hippocampal CA3 neurons.

To test the putative serotonin (5-HT)-like effect of zonisamide (ZNS) we employed xanthine-induced epileptiform activity in the hippocampus slice preparation from guinea pigs. In this model Na(+)- and T-type Ca(2+) channel blockers are hardly effective while 5-HT should be inhibitory. Bath application of 5-HT hyperpolarized neurons and abolished theophylline-induced epileptiform activity. In contrast, ZNS failed to alter epileptiform bursting. We conclude that 5-HT augmenting effects of ZNS are missing or are not sufficient to inhibit epileptiform activity in hippocampal slice preparations.

Treatment of multiple sclerosis during pregnancy - safety considerations.

INTRODUCTION: Women with multiple sclerosis (MS) are treated early in the disease course with disease modifying therapies (DMT). Updated information is needed on pregnancy outcomes of DMT-exposed pregnancies and the effect of the drug withdrawal on MS disease activity. Areas covered: In this review, we will cover the most important updated management strategies in planning a pregnancy when having MS. Expert opinion: MS itself does not increase the risk of adverse pregnancy outcomes and does not negatively influence the long-term course of the disease. As MS became a treatable disease, management of DMTs before, during and after pregnancy is important. This requires updated knowledge on safety of DMTs as well as data of the effect on disease activity after drug withdrawal. A special challenge is the handling of women with highly active MS, as pregnancy might not be powerful enough to suppress the risk of rebound relapses. Exclusive breastfeeding is an option for many women who want to do so, but in cases of high disease activity and those women who do not want to breastfeed, early reintroduction of MS therapies should be considered.

Laquinimod in the treatment of multiple sclerosis: a review of the data so far.

Laquinimod (ABR-215062) is a new orally available carboxamide derivative, which is currently developed for relapsing remitting (RR) and chronic progressive (CP) forms of multiple sclerosis (MS; RRMS or CPMS) as well as neurodegenerative diseases. Its mechanism of action may comprise immunomodulatory effects on T-cells, monocytes, and dendritic cells as well as neuroprotective effects with prominent actions on astrocytes. Laquinimod was tested in Phase II and III clinical trials in RRMS at different dosages ranging from 0.1 to 0.6 mg/day. The compound was well tolerated, yet at the dosages tested only led to moderate effects on the reduction of relapse rates as primary study endpoint in Phase III trials. In contrast, significant effects on brain atrophy and disease progression were observed. While there were no significant safety signals in the clinical trials, the Committee for Medicinal Products for Human Use (CHMP) refused marketing authorization for RRMS based on the assessment of the risk-benefit ratio with regard to data from animal studies. At present, the compound is further tested in RRMS as well as CPMS and Huntington's disease at different concentrations. Results from these trials will further inform about the clinical benefit of laquinimod in patient cohorts with a persisting, but still insufficiently met need for safe and at the same time effective oral compounds with neuroprotective effects.

Relevance of endoglin, IL-1α, IL-1ß and anti-ovarian antibodies in females with multiple sclerosis.

Few studies support the concept of reduced fertility in females with multiple sclerosis (MS). Recently we reported on reduced serum levels of Anti-Müllerian Hormone (AMH) in reproductive-age females with MS, suggestive of reduced ovarian reserve. The cause for this observation is not evident and remains speculative. The aim of the study is to examine possible immunological mechanisms interfering with fertility, as well as ovarian reserve that might affect the reproductive potential in women with MS. ELISA experiments were done to detect anti-ovarian antibodies (AOA), endoglin and interleukin (IL)-1α/-1ß in sera of 85 MS females, including 15 women with known low AMH level as a marker of ovarian reserve, compared to 63 healthy controls. Groups did not differ with respect to age, smoking habits, BMI, and use of oral contraceptives. MS females showed significantly increased endoglin values compared to healthy controls. Remarkable, the highest endoglin values were found in subjects with low AMH. AOA were neither detectable in MS patients nor control subjects. IL-1α and IL-1ß levels did not differ between groups. Our data established no relevance of IL-1α/-1ß or AOA in ovarian insufficiency/dysfunction but suggests the involvement of endoglin in RRMS.

The immunomodulatory effect of laquinimod in CNS autoimmunity is mediated by the aryl hydrocarbon receptor.

Though several functional properties of laquinimod have been identified, our understanding of the underlying mechanisms is still incomplete. Since the compound elicits similar immunomodulatory effects to ligands of the aryl hydrocarbon receptor (AhR), we compared the efficacy of laquinimod in experimental autoimmune encephalomyelitis (EAE)-afflicted wild-type and AhR-deficient mice. Laquinimod failed to ameliorate clinical symptoms and leukocyte infiltration in AhR-deficient mice; however, treatment exerted neuroprotection by elevation of brain-derived neurotrophic factor (BDNF) independent of genetic profile. Thus, our data identify the AhR pathway in these mutant mice as crucial for the immunomodulatory, but not neuroprotective, efficacy of laquinimod in EAE.