Rheumatoid meningitis: a case series report and review of modern therapeutic schemes and outcome.

INTRODUCTION: Rheumatoid meningitis (RM) is an extremely rare extra-articular complication of rheumatoid arthritis (RA), with approximately 165 cases reported world-wide. RM exhibits a broad range of symptoms, with stroke-like episodes and seizures being the most common manifestations. The primary differential diagnoses include vascular and infectious diseases. The influence of immunomodulatory medications on the pathophysiology of RM remains unclear. There are no consensus guidelines on therapeutic regimen. METHODS: We present four patients with prior history of RA that developed different neurological syndromes in correlation to radiological leptomeningitis. Clinical presentations, comorbid conditions, supplementary diagnostic assessments, treatments, and prognosis are provided. A literature review of recent immunosuppressive management in RM patients was performed. RESULTS: Three patients presented to hospital with recurrent focal seizures. Only two suffered meningism, reporting headache and fever. Magnetic resonance imaging (MRI) showed different grades of leptomeningitis across all cases. Notably, three cases demonstrated bilateral involvement extending to the pachymeninges. Two patients exhibited pronounced CSF mononuclear inflammation while extended microbiological evaluations yielded negative results. Two patients required biopsy for confirmation. The initiation of immunosuppressive therapy marked a turning point for three patients who previously exhibited progressive deterioration. Mortality was absent in all cases. CONCLUSIONS: Our experience remarks the elusive nature of RM. Rigorous exclusionary diagnostics are imperative to differentiate RM from mimicking conditions. Clinical manifestations oscillate between transient episodes and progressive neurological impairments, punctuated by frequent epileptic seizures. In scenarios where clinical worsening persists or where clinical and radiological evaluations are inconclusive, aggressive immunosuppressive therapy is recommended.

Teriflunomide and Epstein-Barr virus in a Spanish multiple sclerosis cohort: in vivo antiviral activity and clinical response.

Background: Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) have been associated with multiple sclerosis (MS). Teriflunomide is an oral disease-modifying therapy approved for treatment of relapsing forms of MS. In the preclinical Theiler's murine encephalitis virus model of MS, the drug demonstrated an increased rate of viral clearance versus the vehicle placebo. Furthermore, teriflunomide inhibits lytic EBV infection in vitro. Objective: 1. To evaluate the humoral response against EBV and HHV-6 prior to teriflunomide treatment and 6 months later. 2. To correlate the variation in the humoral response against EBV and HHV-6 with the clinical and radiological response after 24 months of treatment with teriflunomide. 3. To analyze the utility of different demographic, clinical, radiological, and environmental data to identify early biomarkers of response to teriflunomide. Methods: A total of 101 MS patients (62 women; mean age: 43.4 years) with one serum prior to teriflunomide onset and another serum sample 6 months later were recruited. A total of 80 had been treated for at least 24 months, 13 had stopped teriflunomide before 24 months, and 8 were currently under teriflunomide therapy but with less than 24 months of follow-up. We analyzed the levels of the viral antibodies titers abovementioned in serum samples with ELISA commercial kits, and the levels of serum neurofilament light chain (Nf-L). Results: Antiviral antibody titers decreased for EBNA-1 IgG (74.3%), VCA IgG (69%), HHV-6 IgG (60.4%), and HHV-6 IgM (73.3%) after 6 months of teriflunomide. VCA IgG titers at baseline correlated with Nf-L levels measured at the same time (r = 0.221; p = 0.028) and 6 months later (r = 0.240; p = 0.017). We found that higher EBNA-1 titers (p = 0.001) and a higher age (p = 0.04) at baseline were associated with NEDA-3 conditions. Thus, 77.8% of patients with EBNA-1 >23.0 AU and >42.8 years (P50 values) were NEDA-3. Conclusion: Treatment with teriflunomide was associated with a reduction of the levels of IgG antibody titers against EBV and HHV-6. Furthermore, higher EBNA-1 IgG titers prior to teriflunomide initiation were associated with a better clinical response.

Evolution of antibody titres against Epstein-Barr virus and human herpesvirus 6A/B and expression of multiple sclerosis-associated retrovirus in the serum of pregnant multiple sclerosis patients.

Epstein-Barr virus (EBV), human herpesvirus 6A/B (HHV-6A/B) and multiple sclerosis (MS)-associated retrovirus (MSRV) have been described as possible MS triggers. We analysed antibody titres against EBV and HHV-6, and MSRV envelope (env) mRNA expression, in the serum of pregnant multiple sclerosis patients (P-MS) to study their possible link to the clinical activity of MS during pregnancy and postpartum and their possible role as relapse predictors. For that purpose, serum samples were collected from 71 pregnant women (50 pregnant MS and 21 pregnant healthy controls-P-HC) during pregnancy and postpartum. Relating to antibody titres, IgM antibody titres against HHV-6A/B were significantly higher in P-MS than in P-HC both in each pregnancy trimester and in the postpartum period. Moreover, IgM antibody titres against HHV-6A/B were higher in P-MS who suffered a relapse during the postpartum. Regarding MSRV env mRNA expression, the prevalence in the first trimester of pregnancy was significantly higher in P-MS who suffered relapses during pregnancy. Summing it up, high IgM antibody titres against HHV-6A/B and MSRV env mRNA expression during the first trimester of pregnancy could act as relapse predictors for the gestation/postpartum periods.

Cytokine profile during pregnancy predicts relapses during pregnancy and postpartum in multiple sclerosis.

OBJECTIVE: To explore the serum cytokine profile associated with disease activity during pregnancy and postpartum in MS, and to assess any potential biomarkers predicting the occurrence of relapses during this period. METHODS: We included 53 MS pregnant women recruited between 2007 and 2018. Interferon-gamma, Tumor necrosis factor-alpha, interleukin-17, granulocyte/macrophage-colony stimulating factor, Activin-A, interleukin-10, and programmed-death-ligand-1 (PD-L1) were measured quarterly in serum by ELISA. RESULTS: Seventeen patients (32%) experienced relapses during pregnancy or puerperium and 37(68%) did not. We did not found differences in clinical characteristics or treatment status between the two groups. However, relapsing patients showed at the first trimester of pregnancy considerably lower levels of serum Activin-A (336.4 pg/dl [289.6-491.7], median [IQR] vs. 760.0 pg/dl [493.2-1108.0],p = .003), which correlated positively with serum PD-L1 (r = 0.53,p = .0005) and IL-10 (r = 0.43,p = .004) values. Activin-A levels lower than 515 pg/ml at the first trimester identified patients with high probability of relapsing during pregnancy and postpartum (OR = 13.75, CI: 2.5-76.8, p = .001). CONCLUSIONS: MS patients with no relapses during pregnancy and puerperium showed an early triggering of a tolerogenic innate immune response evidenced by high serum Activin-A concentrations during the first trimester of pregnancy. Thus, serum Activin-A can be a useful biomarker to predict clinical activity during this period.

Differential Expression of SMAD Genes and S1PR1 on Circulating CD4+ T Cells in Multiple Sclerosis and Crohn's Disease.

The Th17 immune response plays a key role in autoimmune diseases such as multiple sclerosis (MS) and inflammatory bowel disease (IBD). Expression of Th17-related genes in inflamed tissues has been reported in autoimmune diseases. However, values are frequently obtained using invasive methods. We aimed to identify biomarkers of MS in an accessible sample, such as blood, by quantifying the relative expression of 91 Th17-related genes in CD4+ T lymphocytes from patients with MS during a relapse or during a remitting phase. We also compared our findings with those of healthy controls. After confirmation in a validation cohort, expression of SMAD7 and S1PR1 mRNAs was decreased in remitting disease (-2.3-fold and -1.3-fold, respectively) and relapsing disease (-2.2-fold and -1.3-fold, respectively). No differential expression was observed for other SMAD7-related genes, namely, SMAD2, SMAD3, and SMAD4. Under-regulation of SMAD7 and S1PR1 was also observed in another autoimmune disease, Crohn's disease (CD) (-4.6-fold, -1.6-fold, respectively), suggesting the presence of common markers for autoimmune diseases. In addition, expression of TNF, SMAD2, SMAD3, and SMAD4 were also decreased in CD (-2.2-fold, -1.4-fold, -1.6-fold, and -1.6-fold, respectively). Our study suggests that expression of SMAD7 and S1PR1 mRNA in blood samples are markers for MS and CD, and TNF, SMAD2, SMAD3, and SMAD4 for CD. These genes could prove useful as markers of autoimmune diseases, thus obviating the need for invasive methods.

Palatal and Oromandibular Tremor Secondary to Degenerative Olivary Hypertrophy After Ependymoma Surgery.

Palatal tremor (PT) is a rare movement disorder that involves pharynx, tongue, and other facial muscles. Symptomatic PT is due to lesions on the dentate-rubro-olivary pathways. We present an illustrative case of PT due to degenerative olivary hypertrophy after ependymoma surgery.

Anti-JC virus seroprevalence in a Spanish multiple sclerosis cohort: JC virus seroprevalence in Spain.

OBJECTIVE: To estimate the seroprevalence of anti-JCV antibodies, seroconverting rates and evolution of antibody levels in a multiple sclerosis (MS) Spanish cohort. METHODS: Multicenter, retrospective cross-sectional and longitudinal study. The JCV seroprevalence was analyzed in 711 MS patients by using 1st (STRATIFY-1) and 2nd generation (STRATIFY-2) two-step ELISA over 2.65 (±0.97) years. Seroconversion rate was obtained over 2 samples from 314 patients, and index stability from 301 patients with 3 or more samples available. The effect of each ELISA generation, demographics, clinical characteristics and therapy on seroprevalence was assessed by logistic regression. RESULTS: The overall anti-JCV seroprevalence was 55.3% (51.6-58.9), similar across regions (p=0.073). It increased with age (p<0.000) and when STRATIFY-2 was used (60.5%, p=0.001). Neither sex nor immunosuppressive therapy had any influence. Yearly seroconversion rate was 7% (considering only STRATIFY-2). Serological changes were observed in 24/301 patients, 5.7% initially seropositive reverted to seronegative and 7% initially seronegative changed to seropositive and again to seronegative, all these cases had initial index values around the assay's cut-off. CONCLUSIONS: JCV seroprevalence in Spanish MS patients was similar to that reported in other European populations. Changes in serostatus are not infrequent and should be considered in clinical decisions.

Anteromedial thigh perforator flap to cover the inguinal region in a crossover femorofemoral bypass.

We report the case of a 48-year-old male with an exposition of a femorofemoral crossover bypass in the inguinal region and superficial femoral occlusion. This was successfully treated using an anteromedial thigh (AMT) pedicled flap based on the perforator vessel of the descending branch of the lateral circumflex femoral artery. Our report focuses on: i) considering the AMT flap as a safe and easy option to cover the inguinal region in cases of bypass exposure; ii) describing the attachment of this flap to the deep femoral artery in a patient with superficial femoral occlusion, in spite of some literature controversy.

Splanchnic Th(2) and Th(1) cytokine redistribution in microsurgical cholestatic rats.

BACKGROUND: Long-term extrahepatic cholestasis in the rat induces ductular proliferation and fibrosis in the liver, portal hypertension, splenomegaly, portosystemic collateral circulation, and ascites. These splanchnic alterations could have an inflammatory pathophysiology. MATERIAL AND METHODS: We measured serum levels of hepatobiliary injury markers and the acute phase proteins, alpha-1-major acid protein (alpha(1)-MAP) and alpha-1-acid glycoprotein (alpha(1)-GPA) in rats 6 wk after microsurgical extrahepatic cholestasis. We also assayed Th(1) (TNF-alpha and IL-1beta) and Th(2) (IL-4 and IL-10) cytokine levels in the liver, ileum, spleen, and mesenteric lymph complex by enzyme-linked immunosorbent assay (ELISA) techniques. Liver fibrosis was measured by Sirius red stain and by using an image system computer-assisted method and mast cell liver infiltration by Giemsa stain. RESULTS: The cholestatic rats showed an increase (P<0.001) in serum levels of bile acids, total and direct bilirubin, AST, ALT, AST/ALT index, gamma-GT, alkaline phosphatase, alpha(1)- MAP, alpha(1)-GPA, and LDH (P<0.05) in relation to sham-operated rats. TNF-alpha, IL-1beta, IL-4, and IL-10 increased in the ileum (P<0.01) and mesenteric lymph complex (P<0.001), and decreased in the liver (P<0.001). A marked bile proliferation associated with fibrosis (P<0.001) and mast cell infiltration was also shown in the liver of cholestatic rats. CONCLUSION: The splanchnic redistribution of cytokines, with an increase of Th(1) and Th(2) production in the small bowel and in the mesenteric lymph complex, supports the key role of inflammatory mechanisms in rats with secondary biliary fibrosis.

Experimental obstructive cholestasis: the wound-like inflammatory liver response.

Obstructive cholestasis causes hepatic cirrhosis and portal hypertension. The pathophysiological mechanisms involved in the development of liver disease are multiple and linked. We propose grouping these mechanisms according to the three phenotypes mainly expressed in the interstitial space in order to integrate them.Experimental extrahepatic cholestasis is the model most frequently used to study obstructive cholestasis. The early liver interstitial alterations described in these experimental models would produce an ischemia/reperfusion phenotype with oxidative and nitrosative stress. Then, the hyperexpression of a leukocytic phenotype, in which Kupffer cells and neutrophils participate, would induce enzymatic stress. And finally, an angiogenic phenotype, responsible for peribiliary plexus development with sinusoidal arterialization, occurs. In addition, an intense cholangiocyte proliferation, which acquires neuroendocrine abilities, stands out. This histopathological finding is also associated with fibrosis.It is proposed that the sequence of these inflammatory phenotypes, perhaps with a trophic meaning, ultimately produces a benign tumoral biliary process - although it poses severe hepatocytic insufficiency. Moreover, the persistence of this benign tumor disease would induce a higher degree of dedifferentiation and autonomy and, therefore, its malign degeneration.

An accurate and easy procedure to obtain isothermal Kováts retention indices in gas chromatography.

Isothermal Kováts retention indices may be used in GC for identification purposes, but they are also useful in characterisation of stationary phases and for studying structural and physico-chemical properties of both the analyte and the stationary phase. They are currently reported as whole numbers with an accuracy of one index unit for non-polar stationary phases. The method recommended for their calculation uses a linear regression model, although non-linear models have also been applied with good results. In both cases, a computer programme and the retention times of a series of n-alkanes that elute correctly and resolved from the other compounds are needed, conditions which cannot always be fulfilled. However, it is possible to calculate retention indices with an accuracy of 0.1 retention index units (0.2 units for packed columns) with the help of only three n-alkanes using just a pocket calculator or a computer spreadsheet. The main requirement is that at least one of the n-alkanes has a retention index differing by no more than one hundred retention index units from that of the analyte being investigated. Examples are given for different stationary phases.

Improving the accuracy of Kováts' retention indices in isothermal gas chromatography.

Isothermal Kováts' retention indices are currently reported as whole numbers, and are frequently deduced from a linear least mean squares fitting of the logarithms of adjusted retention times of a number of n-alkanes versus carbon number, following an iterative method that minimises errors. The currently accepted accuracy is about one retention index unit for apolar stationary phases, and lower for polar stationary phases. This paper presents results that show how the accuracy of the retention index may be safely reported to one-tenth of a retention index unit by the use of a non-linear equation, with present day gas chromatographs without electronic flow controllers. Results are presented that prove the correctness of the retention indices found for several substances on one particular capillary column. Hints on the minimum retention times needed to achieve the 0.1 retention index accuracy are mentioned, for retention times recorded in minutes and in seconds. According to results of this paper, two chromatograms, run under the appropriate conditions, are sufficient to obtain the desired accuracy. The method proposed in this paper does not require knowledge of the hold-up time of the chromatogram.