Low 25-hydroxyvitamin D, but not the bioavailable fraction of 25-hydroxyvitamin D, is a risk factor for multiple sclerosis.

BACKGROUND AND PURPOSE: Low 25-hydroxyvitamin D [25(OH)D] levels correlate with higher disease activity in patients with multiple sclerosis (MS). However, it is not clear whether low 25(OH)D levels directly contribute to increased disease activity or merely represent a consequence of reduced endogenous vitamin D synthesis in more disabled MS patients. Furthermore, recent data suggest that bioavailable vitamin D, which also integrates the levels of vitamin D binding proteins and albumin, could be a biologically more relevant parameter than 25(OH)D. METHODS: Measured de-seasonalized 25(OH)D3 and vitamin D binding protein and calculated bioavailable and free vitamin D were compared in the baseline serum samples of 76 patients with clinically isolated syndrome enrolled in a longitudinal observational study and in 76 age- and sex-matched healthy controls (HC). RESULTS: 25(OH)D3 levels were lower in patients with clinically isolated syndrome (P = 0.002) than in HC, and more patients (8/76, 10.5%) than HC (1/76, 1.3%) had 25(OH)D3 levels <25 nmol/l (P = 0.03). In contrast, levels of 25(OH)D2, vitamin D binding protein and calculated levels of free and bioavailable vitamin D did not differ between the two groups. CONCLUSIONS: Lower 25(OH)D3 levels already in the earliest phase of disease and in clinically hardly affected patients suggest that low 25(OH)D3 levels are rather a risk factor for than a consequence of MS. Nevertheless, because bioavailable vitamin D levels did not differ between the two groups, the mechanism underlying the association of 25(OH)D3 and MS does not appear to be related to reduced bioavailability of vitamin D.

Severe cognitive impairment associated with intrathecal antibodies to the NR1 subunit of the N-methyl-D-aspartate receptor in a patient with multiple sclerosis.

IMPORTANCE: Some patients with multiple sclerosis (MS) can either present with or develop severe cognitive impairment during the course of their disease. However, the mechanisms underlying severe cognitive dysfunction in MS are not well understood. OBSERVATIONS: We report on a woman who was diagnosed as having MS at age 33 years and who after giving birth at age 37 years developed cognitive impairment with severe memory dysfunction as the leading symptom. Treatment with different immunotherapies, including cyclophosphamide and natalizumab, did not improve her cognitive deficits, necessitating admission to a nursing home at age 39 years. During a thorough reevaluation at age 43 years, analysis of current and stored cerebrospinal fluid and serum samples demonstrated an intrathecal synthesis of IgG antibodies to the NR1 subunit of the N-methyl-D-aspartate receptor, that is, the characteristic laboratory finding of anti-N-methyl-D-aspartate receptor encephalitis. Although the patient initially stabilized under therapy with corticosteroids, plasma exchange, and mitoxantrone, severe cognitive impairment persisted and she eventually died from the sequelae of her disease. CONCLUSIONS AND RELEVANCE: This report suggests that the occasional occurrence of severe cognitive impairment in patients with MS may, in some cases, be related to a superimposed antibody-mediated autoimmune encephalitis.

Multiple sclerosis: modulation of toll-like receptor (TLR) expression by interferon-ß includes upregulation of TLR7 in plasmacytoid dendritic cells.

Interferon-ß is an established treatment for patients with multiple sclerosis (MS) but its mechanisms of action are not well understood. Viral infections are a known trigger of MS relapses. Toll-like receptors (TLRs) are key components of the innate immune system, which sense conserved structures of viruses and other pathogens. Effects of interferon-ß on mRNA levels of all known human TLRs (TLR1-10) and the TLR adaptor molecule MyD88 were analyzed in peripheral blood mononuclear cells (PBMCs) of healthy donors by quantitative real-time PCR and by transcriptome analysis in PBMCs of 25 interferon-ß-treated patients with relapsing-remitting MS. Regulation of TLR protein expression by interferon-ß was investigated by flow cytometry of leukocyte subsets of healthy subjects and of untreated, interferon-ß-, or glatiramer acetate-treated patients with MS. Interferon-ß specifically upregulated mRNA expression of TLR3, TLR7, and MyD88 and downregulated TLR9 mRNA in PBMCs of healthy donors as well as in PBMCs of patients with MS. Plasmacytoid dendritic cells (pDCs) were identified as the major cell type responding to interferon-ß with increased expression of TLR7 and MyD88 protein. In line with this, expression of TLR7 protein was increased in pDCs of interferon-ß-treated, but not untreated or glatiramer acetate-treated patients with MS. Interferon-ß-induced upregulation of TLR7 in pDCs is of functional relevance since pre-treatment of PBMCs with interferon-ß resulted in a strongly increased production of interferon-α upon stimulation with the TLR7 agonist loxoribine. Flow cytometry confirmed pDCs as the cellular source of interferon-α production induced by activation of TLR7. Thus, upregulation of TLR7 in pDCs and a consequently increased activation of pDCs by TLR7 ligands represents a novel immunoregulatory mechanism of interferon-ß. We hypothesize that this mechanism could contribute to a reduction of virus-triggered relapses in patients with MS.

Retinal ganglion cell and inner plexiform layer thinning in clinically isolated syndrome.

BACKGROUND: Axonal and neuronal damage are widely accepted as key events in the disease course of multiple sclerosis. However, it has been unclear to date at which stage in disease evolution neurodegeneration begins and whether neuronal damage can occur even in the absence of acute inflammatory attacks. OBJECTIVE: To characterize inner retinal layer changes in patients with clinically isolated syndrome (CIS). METHOD: 45 patients with CIS and age- and sex-matched healthy controls were investigated using spectral domain optical coherence tomography. Patients' eyes were stratified into the following categories according to history of optic neuritis (ON): eyes with clinically-diagnosed ON (CIS-ON), eyes with suspected subclinical ON (CIS-SON) as indicated by a visual evoked potential latency of >115 ms and eyes unaffected by ON (CIS-NON). RESULTS: CIS-NON eyes showed significant reduction of ganglion cell- and inner plexiform layer and a topography similar to that of CIS-ON eyes. Seven eyes were characterized as CIS-SON and likewise showed significant retinal layer thinning. The most pronounced thinning was present in CIS-ON eyes. CONCLUSION: Our findings indicate that retinal pathology does occur already in CIS. Intraretinal layer segmentation may be an easily applicable, non-invasive method for early detection of retinal pathology in patients unaffected by ON.

Systemic sclerosis without antinuclear antibodies or Raynaud's phenomenon: a multicentre study in the prospective EULAR Scleroderma Trials and Research (EUSTAR) database.

OBJECTIVE: To assess patients with SSc who present without circulating ANAs or RP. METHODS: Five thousand three hundred and ninety patients who fulfilled the ACR criteria for SSc and were enrolled in the EULAR Scleroderma Trials and Research (EUSTAR) database were screened for the absence of both RP and circulating ANA. To differentiate SSc from its mimics, additional information was gathered using a standardized questionnaire. RESULTS: Five thousand three hundred and seventy-eight (99.8%) of the 5390 SSc patients in the EUSTAR database had either detectable ANA or a history of RP. Twelve (0.2%) patients lacked both circulating ANA and RP. Details of the medical history could be obtained for seven patients. Three cases were compatible with ANA-negative and RP-negative SSc and were not typical of any known SSc mimic. Four patients had a malignancy: two had breast cancer, one had multiple myeloma with possible scleromyxoedema and one had bladder carcinoma. There was no temporal relationship between the onset of skin fibrosis and that of the tumour. Although no patient with confirmed nephrogenic systemic fibrosis was identified among the cases of ANA-negative and RP-negative SSc, the presentation of one patient could be compatible with that of nephrogenic systemic fibrosis other than for the absence of chronic kidney disease or of known prior gadolinium exposure. CONCLUSION: We have identified a very small subgroup of SSc patients who lack both circulating ANA and RP, none of whom fulfils the diagnostic criteria for any known SSc mimic. Prospective studies are needed to elucidate the clinical presentation, evolution and outcome of such patients.

Six-minute walk distance as a marker for disability and complaints in patients with systemic sclerosis.

OBJECTIVES: The role of the six-minute walk distance (6MWD), measured by a six-minute walk test (6MWT), in the assessment of systemic sclerosis (SSc) patients remains to be evaluated. Here, we have analysed whether 6MWD is associated with clinical parameters obtained by an extended standardised assessment of SSc patients. METHODS: In 101 consecutive SSc patients, 6MWD was correlated with disease activity, Scleroderma Health Assessment Questionnaire (SHAQ) score, nutrition status, age, ESR, haemoglobin values, and several lung function parameters. RESULTS: Of the 101 SSc patients, 6 patients were excluded because of diseases that could influence the result of the 6MWT, such as asthma, COPD or peripheral vascular disease. In the remaining 95 patients the median 6MWD was 491.0 m (range 86.0-664.5 m). 6MWD weakly-to-moderately correlated with predicted FVC, FEV1, TLC, DLCO and nutrition status. Moderate negative correlations were found for the SHAQ score and disease activity, weaker correlations for age and BMI. Exclusion of patients with musculoskeletal limitations revealed similar results. Training status of the patients did not affect 6MWD. Multivariate analyses revealed SHAQ score and predicted DLCO values as the best parameters predicting 6MWD. Optimal 6MWD cut-off values for the presence of PAH, predicted FVC values <80%, and dyspnea NYHA III/IV were between 465 m and 480 m. CONCLUSIONS: 6MWD is a surrogate marker for disability and complaints in SSc patients. Therefore, 6MWT could provide a valuable outcome parameter although it lacks organ specificity.

Neuroimaging by 320-row CT: is there a diagnostic benefit or is it just another scanner? A retrospective evaluation of 60 consecutive acute neurological patients.

320-row CT enables dynamic CT angiography (4D CTA) of the entire intracranial circulation and whole-brain perfusion imaging (CTP). Sixty acute patients with neurological symptoms underwent various 320-row CT-specific protocols, including combined 4D CTA and CTP. Clinical and neuroradiological records were assessed for presumptive diagnoses, final diagnoses, supplementary and follow-up imaging studies. Additional diagnostic benefits delivered by 320-row CT were noted. Out of 60 procedures, 59 were accomplished successfully. Ischemia (n = 19), intracerebral hemorrhage (n = 7) and transient ischemic attacks (n = 10) were the major final diagnoses. Except one small cortical and two small subcortical infarctions all ischemias were diagnosed. All hemorrhages were diagnosed together with their underlying vascular pathology in five atypical cases. In conclusion, 320-row CT is a technically robust procedure being suitable for comprehensive neuroimaging of acute patients. It can provide dynamic angiographic and perfusion data of the whole brain and can deliver additional diagnostic information not available by standard CT.