Low cytomegalovirus seroprevalence in early multiple sclerosis: a case for the 'hygiene hypothesis'?

BACKGROUND AND PURPOSE: Cytomegalovirus (CMV) infection has recently been associated with a lower multiple sclerosis (MS) susceptibility, although it remains controversial whether it has a protective role or is merely an epiphenomenon related to westernization and early-life viral infections. We aimed to evaluate whether CMV serostatus may differ in patients with early MS as compared with patients with non-early MS, analyzing the putative association of this virus with MS clinical course and humoral immune responses against other herpesviruses. METHODS: Multicentric analysis was undertaken of 310 patients with MS (early MS, disease duration ≤5 years, n = 127) and controls (n = 155), evaluating specific humoral responses to CMV, Epstein-Barr virus and human herpesvirus-6, as well as T-cell and natural killer (NK)-cell immunophenotypes. RESULTS: Cytomegalovirus seroprevalence in early MS was lower than in non-early MS or controls (P < 0.01), being independently associated with disease duration (odds ratio, 1.04; 95% confidence interval, 1.01-1.08, P < 0.05). CMV+ patients with MS displayed increased proportions of differentiated T-cells (CD27-CD28-, CD57+, LILRB1+) and NKG2C+ NK-cells, which were associated with a lower disability in early MS (P < 0.05). CMV+ patients with early MS had an age-related decline in serum anti-EBNA-1 antibodies (P < 0.01), but no CMV-related differences in anti-human herpesvirus-6 humoral responses. CONCLUSIONS: Low CMV seroprevalence was observed in patients with early MS. Modification of MS risk attributed to CMV might be related to the induction of differentiated T-cell and NK-cell subsets and/or modulation of Epstein-Barr virus-specific immune responses at early stages of the disease.

Leucoencefalopatía multifocal progresiva en un paciente inmunocompetente / Progressive multifocal leukoencephalopathy in an immunocompetent patient

No disponible

Anorgasmia masculina como síntoma inicial de mielitis transversa / Male anorgasmia as initial symptom of transverse myelitis

No disponible

Natural killer cell phenotype and clinical response to interferon-beta therapy in multiple sclerosis.

CD56(bright) NK cells, which may play a role in immunoregulation, are expanded in multiple sclerosis (MS) patients treated with immunomodulatory therapies such as daclizumab and interferon-beta (IFNß). Yet, whether this NK cell subset is directly involved in the therapeutic effect is unknown. As NK receptor (NKR) expression by subsets of NK cells and CD8+ T lymphocytes is related to MS clinical course, we addressed whether CD56(bright) NK cells and NKR in IFNß-treated MS patients differ according to the clinical response. IFNß was associated to lower LILRB1+ and KIR+NK cells, and higher NKG2A+NK cell proportions, an immunophenotypic pattern mainly found in responders. After IFNß treatment, a CD56(bright) NK cell expansion was significantly related to a positive clinical response. Our results reveal that IFNß may promote in responders changes in the NK cell immunophenotype, corresponding to the profile found at early maturation stages of this lymphocyte lineage.

Natural killer receptors distribution in multiple sclerosis: Relation to clinical course and interferon-beta therapy.

NK cell receptors (NKR) are expressed in subsets of NK and CD8+ T cells, lymphocytes involved in multiple sclerosis (MS) pathogenesis. Clinical implications of NKR expression in MS are unknown. Here, we show that the proportions of CD8+ T cells displaying LILRB1, an inhibitory NKR expressed at late stages of T cell differentiation, were directly related with age and MS duration, and inversely with the immunomodulatory therapy-dependent increase of CD56(bright) NK cells. Similar associations were found for KIR+ and CD56+ CD8+ T cells, whereas no age-related NKR distribution was perceived in controls. Moreover, active MS had lower LILRB1+ NK cells, and IFN-ß-treated patients exhibited a phenotypic profile related to shorter disease evolution. Progressive accumulation of terminally differentiated T lymphocytes and experienced NK cells in MS, presumably stimulated in response to a persistent challenge and modulated by IFN-ß therapy, may support the analysis of NKR distribution as new biomarkers.

[Multiple sclerosis epidemiological situation update: pertinence and set-up of a population based registry of new cases in Catalonia]. / Situación epidemiológica actual de la esclerosis múltiple: pertinencia y puesta en marcha de un registro poblacional de nuevos casos en Cataluña.

INTRODUCTION: The first epidemiological studies on multiple sclerosis (MS) around the world pictured a north to south latitudinal gradient that led to the first genetic and environmental pathogenic hypothesis. MS incidence seems to be increasing during the past 20 years based on recent data from prospective studies performed in Europe, America and Asia. This phenomenon could be explained by a better case ascertainment as well as a change in causal factors. The few prospective studies in our area together with the increase in the disease in other regions, justifies an epidemiological MS project in order to describe the incidence and temporal trends of MS. DEVELOPMENT: A prospective multicenter MS registry has been established according to the actual requirements of an epidemiological surveillance system. Case definition is based on the fulfillment of the McDonald diagnostic criteria. The registry setting is the geographical area of Cataluna (northeastern Spain), using a wide network of hospitals specialized in MS management. CONCLUSION: Recent epidemiological studies have described an increase in MS incidence. In order to contrast this finding in our area, we consider appropriate to set up a population based registry.

Situación epidemiológica actual de la esclerosis múltiple: pertinencia y puesta en marcha de un registro poblacional de nuevos casos en Cataluña / Multiple sclerosis epidemiological situation update: pertinence and set-up of a population based registry of new cases in Catalonia

Introducción. Los primeros estudios epidemiológicos de esclerosis múltiple (EM) de ámbito mundial caracterizaron un patrón geográfico latitudinal, con prevalencias más altas en las zonas más alejadas del ecuador. A raíz de esta distribución, se plantearon hipótesis causales de índole genética y ambiental. Según los datos de estudios prospectivos desarrollados en diversas regiones de Europa, América y Asia, la incidencia de la enfermedad ha aumentado a lo largo de los últimos 30 años, lo cual podría indicar una mejor detección de casos o un cambio en los factores causales subyacentes. Los escasos estudios prospectivos disponibles en nuestro entorno y el aumento de la enfermedad descrito en otras regiones justifican la pertinencia de un proyecto epidemiológico dirigido a conocer las tasas de incidencia y la tendencia temporal de EM. Desarrollo. De acuerdo con los requisitos actuales de un sistema de vigilancia epidemiológica, se ha establecido un registro prospectivo de carácter multicéntrico. Para la definición de nuevo diagnóstico se emplean los criterios establecidos por McDonald. El ámbito de aplicación es el territorio de Cataluña, a través una red de hospitales de referencia especializados en el manejo de EM, que notifican la información mediante un aplicativo informático conectado a internet. Conclusiones. Los estudios epidemiológicos de la EM de las últimas décadas han descrito un incremento de su incidencia. Para dimensionar este fenómeno en nuestro ámbito, creemos pertinente la puesta en marcha de un registro poblacional de la enfermedad en Cataluña (AU)

Introduction. The first epidemiological studies on multiple sclerosis (MS) around the world pictured a north to south latitudinal gradient that led to the first genetic and environmental pathogenic hypothesis. MS incidence seems to be increasing during the past 20 years based on recent data from prospective studies performed in Europe, America and Asia. This phenomenon could be explained by a better case ascertainment as well as a change in causal factors. The few prospective studies in our area together with the increase in the disease in other regions, justifies an epidemiological MS project in order to describe the incidence and temporal trends of MS. Development. A prospective multicenter MS registry has been established according to the actual requirements of an epidemiological surveillance system. Case definition is based on the fulfillment of the McDonald diagnostic criteria. The registry setting is the geographical area of Cataluña (northeastern Spain), using a wide network of hospitals specialized in MS management. Conclusion. Recent epidemiological studies have described an increase in MS incidence. In order to contrast this finding in our area, we consider appropriate to set up a population based registry (AU)

Multiple sclerosis associates with LILRA3 deletion in Spanish patients.

The genetic susceptibility to multiple sclerosis (MS) is only partially explained, and it shows geographic variations. We analyse here two series of Spanish patients and healthy controls and show that relapsing MS (R-MS) is associated with a gene deletion affecting the hypothetically soluble leukocyte immunoglobulin (Ig)-like receptor A3 (LILRA3, 19q13.4), in agreement with an earlier finding in German patients. Our study points to a gene-dose-dependent, protective role for LILRA3, the deletion of which synergizes with HLA-DRB1(*)1501 to increase the risk of R-MS. We also investigated whether the risk of suffering R-MS might be influenced by the genotypic diversity of killer-cell Ig-like receptors (KIRs), located only approximately 400 kb telomeric to LILRA3, and implicated in autoimmunity and defence against viruses. The relationship of LILRA3 deletion with R-MS is not secondary to linkage disequilibrium with a KIR gene, but we cannot exclude some contributions of KIR to the genetic susceptibility to R-MS.

Manometric correlations of anorectal dysfunction and biofeedback outcome in patients with multiple sclerosis.

OBJECTIVE: To evaluate clinical and manometric characteristics of multiple sclerosis (MS) patients with anorectal dysfunction (ARD) and their influence on biofeedback outcome. PATIENTS AND METHODS: Patients were clinically and manometrically studied and compared with controls. Patients were subsequently offered to initiate biofeedback manoeuvres to improve ARD. RESULTS: Fifty-two patients with ARD, 39 women, mean age 44.96 +/- 9.26 years, mean Expanded Disability Status Scale 4.13 +/- 1.72, were evaluated. Thirty-one patients had relapsing-remitting (RR), 16 secondary progressive and five primary progressive MS. ARD complaints were constipation (67.3%), double ARD (23.1%) and isolated incontinence (9.6%). The manometric study showed significant differences in patients compared with controls in maximal contraction pressures (98.1 +/- 44.2 mm Hg versus 152.05 +/- 66.9 mm Hg, P < 0.001) and anal inhibitory reflex threshold (92.9 +/- 63.4 mL versus 40.45 +/- 11.3 mL, P < 0.001). Maximal pressure was lower in progressive forms compared with RR forms (83.1 +/- 36.2 mm Hg versus 108.2 +/- 46.7 mm Hg, P < 0.05) in relation to higher disability. Patients with paradoxical contraction (PC) (35 patients, 67.3%) showed more manometric disturbances. From a total of 18 patients performing biofeedback, those reporting some improvement (six complete, two partial) had milder manometric abnormalities. CONCLUSIONS: The most frequent manometric abnormalities in our MS patients with ARD were alterations of maximal pressures, anal inhibitory reflex and PC. Biofeedback could be more useful in patients with lower disability and manometric alterations.

Clustering of vascular risk factors and in-hospital death after acute ischemic stroke.

OBJECTIVE: to evaluate the influence of clustering of vascular risk factors (VRF) on in-hospital mortality in patients with acute ischemic stroke (AIS) developing a risk score for mortality prediction. METHODS: clinical data from 1527 patients admitted to hospital with a first-ever AIS were prospectively evaluated from 1997 to 2005 assessing the presence of six VRF: diabetes, hypertension, hyperlipidemia, ischemic heart disease, atrial fibrillation and peripheral arterial disease. A composite vascular risk score (VRS) was created using five risk factors. Hyperlipidemia was excluded from the score due to its protective impact on mortality. Two modified VRS models were created and assessed for their accuracy as predictors for in-hospital mortality based on the odds ratio for each VRF obtained in the univariate analysis. RESULTS: 197 patients (12.9 %) died during the acute hospitalization period. Stroke severity increased with each additional VRF (p = 0.002). Cox proportional hazards model adjusted for confounders showed an association between the composite VRS and in-hospital mortality (p = 0.045). According to the clustering of VRS, the risk for in-hospital death increased from 1.951 (95 % CI 1.041-3.665) for patients having one VRS to 2.343 (95% CI 1.081-5.076) for those having a VRS > or = 4. ROC curves showed that the modified VRS model based on a given value of one for each accumulated VRF, including the absence of hyperlipidemia, had the highest predictive capability for in-hospital mortality (p < 0.0001). CONCLUSIONS: the presence of multiple VRF in patients with acute ischemic stroke increases the stroke severity and the risk of in-hospital death.

Prevalence of autoimmune thyroid disorders in a Spanish multiple sclerosis cohort.

The aim of the study was to determine the prevalence of thyroid autoimmune disorders in a cohort of untreated multiple sclerosis (MS) patients and compare it with a stratified sample of an adult population. We prospectively studied 93 untreated MS patients. The control group included 401 healthy subjects selected by stratified sampling in a non-iodine-deficient area. Antithyroid antibodies (ATA) (antibodies against peroxidase and thyroglobulin) were considered positive at titres > or =149 IU/ml. Antibodies were positive in 11 MS patients (11.8%; 95% CI 5.3-18.4%). This prevalence was five times higher (P = 0.0001) when compared with that in the control population. We found six cases with subclinical hypothyroidism (6.45%; 95% CI 11.4-1.5) in contrast to 2.24% in the control group. Comparing MS with positive and negative ATA, there was a non-significant, slightly higher frequency of low Expanded Disability Status Scale (EDSS) score in the ATA-positive group (81% vs. 73.2%). One year after start of interferon (IFN) treatment, only one patient developed subclinical thyroid dysfunction. MS patients have a higher prevalence of ATA compared with the general population. An initial ATA and thyroid-stimulating hormone (TSH) determination is recommended in all MS patients. A periodic assessment of thyroid function during IFN treatment only seems to be justified in those cases where positive ATA or dysfunction is present before treatment.

Periodic hyperthermia and abnormal circadian temperature rhythm in a patient with multiple sclerosis.

Disturbances of the central thermoregulation in patients with multiple sclerosis (MS) are not often reported. We describe a 45-year old patient with a 13-year history of MS, who developed a clinical picture of recurrent hyperthermia. MRI showed a bilateral involvement of the hypothalamus in the setting of diffuse white matter disease. Serial body temperature measurement for five consecutive months disclosed an inversion of the circadian temperature rhythm. The clinical presentation and MRI findings suggested abnormalities of the central thermal control in relation to MS widespread involvement of the central nervous system (CNS).

Anorectal dysfunction in multiple sclerosis.

OBJECTIVE: To ascertain the prevalence of anorectal dysfunction (ARD) in patients with multiple sclerosis (MS) and its relationship with MS clinical characteristics. METHODS: Prospective transversal study in 193 patients with MS. All patients fulfilled a protocol that included: demographic variables, clinical characteristics of MS and the presence of ARD and urinary dysfunction (UD). RESULTS: One hundred and ninety-three patients: 66.8% women, an average age of 42.8 (12.1) years; 67.8% of patients had relapsing remitting MS, 21.2% a secondary progressive and 10.9% a primary progressive form. The average duration of MS was 10.7 (9.4) years and the EDSS 2.8 (2.3). ARD was present in 93 patients (48.2%), and UD in 50.2%. ARD associated to UD was present in 35.7% of cases. The univariate study revealed that patients with ARD were older (P <0.001), had greater disability (P <0.0001), longer disease duration (P <0.001) and a greater association with UD (P<0.0001). ARD was more frequent in progressive forms (P<0.0001). The logistic regression analysis showed that female sex (P = 0.015), EDSS (P = 0.002) and UD (P = 0.003) were independent factors related to ARD. CONCLUSION: ARD is a highly prevalent disorder in MS. Female sex, EDSS and UD are independent predictors of ARD development.

No association of the Val66Met polymorphism of brain-derived neurotrophic factor (BDNF) to multiple sclerosis.

Brain-derived neurotrophic factor (BDNF), a neurotrophin produced by neurons and immune cells, promotes neuronal survival and repair during development and after CNS injury. The BDNF-Val66Met polymorphism is functional and induces abnormal intracellular trafficking and decreased BDNF release. Therefore, we investigated the impact of the BDNF-Val66Met polymorphism on the susceptibility and clinical course in a case-control study of 224 multiple sclerosis (MS) Spanish patients and 177 healthy controls. We found no evidence for association to susceptibility or severity of the disease in our population. Moreover, we did not observe, in a subgroup of 12 MS patients, that the methionine substitution at position 66 in the prodomain had negative impact in the capacity to produce BDNF by peripheral blood mononuclear cells (PBMC).

Serum lipid levels and in-hospital mortality in patients with intracerebral hemorrhage.

OBJECTIVE: To test the hypothesis that low serum cholesterol and low serum triglyceride levels at admission are related to an increase of in-hospital mortality in patients with first-ever supratentorial spontaneous intracerebral hemorrhage (ICH). METHODS: The authors obtained the serum cholesterol and triglyceride levels during the first 48 hours after first-ever ICH in 184 patients. They analyzed the impact of serum cholesterol and triglyceride concentrations on the in-hospital mortality after adjustment for possible confounding variables according to the results of the univariate analysis (age, hemorrhage volume, intraventricular extension, glycemia, serum albumin, and Glasgow Coma Scale score at admission) using the Cox proportional hazards model. They also analyzed the survival curves according to the cholesterol and triglyceride quartiles. RESULTS: Low serum cholesterol (p = 0.002; hazard ratio [HR] 0.988 [95% CI 0.979 to 0.997] mg/dL) and low serum triglyceride (p = 0.011; HR 0.986 [95% CI 0.976 to 0.997] mg/dL) concentrations were independently associated with increased in-hospital mortality after ICH. Analyzed by quartiles, the HR of in-hospital mortality was 3.136 (95% CI 0.833 to 11.087) for patients in the lowest cholesterol quartile (< 166 mg/dL) and 3.484 (95% CI 1.088 to 11.155) for patients in the lowest triglyceride quartile (< 74 mg/dL). CONCLUSIONS: Low serum cholesterol and triglyceride levels obtained during the first hours after intracerebral hemorrhage (ICH) are strong independent predictors of in-hospital mortality in patients with spontaneous supratentorial ICH.

[Crossed aphasia: description of a case]. / Afasia cruzada: descripción de un caso.

We describe a new case of crossed aphasia in a right-handed patient with a right hemispheric lesion. A right-handed man, 76 year-old, developed a sudden left hemiparesis with sensitive impairment and mutism. He has neither family history of left handeness or ambidexterity or vascular risk factors. CT cerebral scan showed a large infarct of the middle cerebral artery on the right side, with haemorrhagic suffusion. Cerebral MRI and EEG-cartography confirmed the indemnity of the left hemisphere. Aphasia studies confirmed a mutism with spared verbal comprehension, but alexia was present. A year later, left hemiparesis was recovered but aphasia remained. Crossed aphasia is rarely seen. It is caused by a right hemispheric lesion in right-handed subjects. Fluency is most commonly impaired. At onset, mutism is the common symptom, which evolves to expressive aphasia. Several hypothesis have been raised about the possible mechanisms involved. The few number of PET or SPECT studies performed in these patients have disclosed extensive areas of hypometabolism in the right hemisphere, that exceed the size of the image observed with CT scan or MRI.