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.

Serum cholesterol levels and survival after rtPA treatment in acute stroke.

BACKGROUND: According to the reverse epidemiology hypothesis, high cholesterol levels might be protective and associated with greater survival rates under certain conditions. In stroke patients, a clear correlation between lipid levels and mortality after ischaemic and hemorrhagic strokes has been demonstrated. The aim of this study was to analyze the impact of lipid levels on 3-month mortality in patients with ischaemic stroke (IS) homogeneously treated with intravenous rtPA and admitted to a monitored acute stroke unit. METHODS: Retrospective analysis of a prospective cohort of 220 patients with an IS treated with rtPA within the first 4.5 h in a single tertiary hospital from January 2005 to August 2010. RESULTS: Mortality at 3 months was 15.0%. Univariate analysis showed that age, NIHSS at admission, heart failure, and atrial fibrillation were directly related to 3-month mortality; cholesterol, triglycerides, and low density lipoprotein were inversely associated. The death rate by cholesterol level was 5.5% for the highest tertile (>192 mg/dl), 13.7% for the middle (192-155 mg/dl), and 25.7% for the lowest (<155 mg/dl), P = 0.003. Multivariate analysis showed that amongst the lipid determinations, only cholesterol [OR: 0.985 (95% CI: 0.972-0.998), P = 0.021] was inversely associated with 3-month mortality. The 'protective' effect of cholesterol was independent of stroke severity and remained significant in non-lacunar strokes. CONCLUSIONS: Survival of stroke patients receiving current, most effective medical treatment is related to blood cholesterol levels, with an inverse relationship between cholesterol and mortality. The mechanism of this apparently paradoxical situation remains unexplained but merits further research.

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 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.

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.

Cladribine in aggressive forms of multiple sclerosis.

Cladribine (2-chlorodeoxyadenosine) is an immunosuppressant drug previously evaluated in multiple sclerosis (MS) with variable results. We report six patients with aggressive relapsing MS who despite a poor response to other therapies had a favourable clinical evolution after cladribine. Four women and two men with a rapid increase in the number and severity of relapses leading to increasing disability [mean Expanded Disability Status Scale (EDSS) 6.42, standard deviation +/- 0.58, mean relapse rate per year in the 2 years prior to study entry 2.67 +/- 0.75] were retrospectively evaluated. Brain magnetic resonance imaging (MRI) performed in five patients showed active disease with gadolinium-enhancing lesions. Cladribine was given at 0.07 mg/kg/day for five consecutive days once monthly with a total of 2- to 4-monthly courses. After 6 months, mean EDSS decreased to 3.75 +/- 1.64 and MRIs showed a decrease or suppression in the number of gadolinium-enhancing lesions. After 1 year from first dose, cladribine dosage was repeated in four patients because of recurrence of relapses with subsequent similar positive clinical results. In the follow-up period (49.33 +/- 39.66 months), the mean relapse rate decreased to 0.71 +/- 0.55 and no unexpected or serious adverse events were observed.

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).

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).

Narcolepsia e hipersomnia idiopática / No disponible

La narcolepsia es una enfermedad crónica relacionada con una hipofunción del sistema hipocretina (orexina) que se cree es secundaria a una pérdida de las neuronas hipotalámicas que la sintetizan. Clínicamente se manifiesta como somnolencia excesiva diurna, síntomasde disregulación del sueño REM (cataplejía, parálisis de sueño y alucinaciones hipnagógicas) y sueño nocturno fragmentado. La asociación de hipersomnia con cataplejía es altamente sugestiva de narcolepsia pero no ocurre en todos los pacientes, al igual que la presencia de tres o más inicios de sueño en REM en el Test de latenciasmúltiples de sueño (MSLT). Unos niveles bajos de hipocretina en el líquido cefaloraquídeo tienen una especificidad y sensibilidad elevadas y pueden ser de ayuda en el diagnóstico. El tratamiento es sintomático:la hipersomnolencia con estimulantes y la cataplejía conantidepresivos. Es posible que en los próximos años dispongamos de agonistas que permitan restaurar la función hipocre tinérgica de una manera práctica.La hipersomnia idiopática es una entidad de causa desconocida caracterizada por la presencia de somnolencia excesiva sin otros síntomas acompañantes y cuyo diagnóstico se realiza por exclusión de otras enfermedades que produzcan somnolencia. Su tratamientoes sintomático, con estimulantes

Narcolepsy is a chronic disease produced by a dysfunction of the hypocretine (orexin) system usually secondary to a loss of the hypothalamic hypocretinergic neurons. Clinically, patients show diurnal hypersomnia together with symptoms of REM sleep dysregulation (cataplexy, sleep paralysis and hypnagogic hallucinations) and fragmentation of nocturnal sleep. The association of hypersomnia with cataplexy is highly suggestive of narcolepsy, but it does not occur in every patient, similarly to what happens with the presence of three ormore sleep onset REM periods in the multiple sleep latency test (MSLT). Low levels of hypocretin in the cerebrospinal fluid have a high sensitivity and specificity for narcolepsy and can be helpful in the diagnosis. The treatment is symptomatic: hypersomnolence with stimulants and cataplexy with antidepressants. It is possible that in the near future hypocretine agonists will be available to treat the disease. Idiopathic hypersomnia is a disorder of unknown cause characterizedby hypersomnolence in the absence of other symptoms. It is diagnosed only after excluding other possible causes of hypersomnia. Treatment is also symptomatic, with stimulants

[Status cataplecticus induced by abrupt withdrawal of clomipramine]. / Estado de mal catapléjico inducido por la retirada brusca de clomipramina.

INTRODUCTION: Cataplexy is one of the main narcoleptic symptoms and is characterized by sudden loss of muscle tone triggered by emotional stimuli while consciousness is mantained. Clomipramine is an effective treatment of cataplexy. Cataplexy that occurs repeatedly for hours or days is referred to as status cataplecticus. PATIENTS: We report three adults with narcolepsy in whom cataplexy was chronically and effectively treated with clomipramine (75-150 mg/day). For diverse reasons, these three patients had an abrupt withdrawal of clomipramine, and after 2-9 days patients showed an invalidant status cataplecticus characterized by a marked increase of the frequency, duration and severity of their cataplectic attacks that were now elicited by mild emotional stimuli. After introduction of anticataplectic agents (clomipramine in two patients and fluoxetine in one patient), status cataplecticus was resolved in less than a week. CONCLUSION: In patients with narcolepsy, abrupt withdrawal of chronic treatment with clomipramine may be associated with status cataplecticus. This condition may be resolved with the reintroduction of anticataplectic agents.

Nonconvulsive status epilepticus associated with cephalosporins in patients with renal failure.

PURPOSE: Nonconvulsive status epilepticus is an unusual complication of cephalosporin therapy, with only a few isolated cases reported. SUBJECTS AND METHODS: We reviewed the clinical and electroencephalographic (EEG) characteristics of 10 patients with renal failure in whom developed alteration of consciousness without convulsions associated with continuous epileptiform EEG activity while being treated with cephalosporins. RESULTS: Nonconvulsive status epilepticus developed in 5 men and 5 women, with a mean (+/- SD) age of 69 +/- 14 years, while receiving intravenous cephalosporins (ceftriaxone, 2 patients; ceftazidime, 2; and cefepime, 6). All patients had renal failure; 1 also had hepatic failure. Patients presented with progressive disorientation or agitation, sometimes associated with mild facial or limb myoclonus, that had begun 1 to 10 days (mean, 5 +/- 2 days) after starting cephalosporin treatment. The EEG showed continuous or intermittent bursts of generalized, high-voltage, 1 to 2 Hz sharp wave activity or sharp and slow wave activity that resembled, but could be differentiated from, the triphasic waves seen in metabolic encephalopathies. Intravenous clonazepam suppressed the epileptiform activity completely in 5 patients and partially in the other 5. Cephalosporins were withdrawn, and antiepileptic therapy was started for all patients. All patients improved, 2 in less than 24 hours and the remainder within 2 to 7 days. CONCLUSIONS: Cephalosporins can cause nonconvulsive status epilepticus in patients with renal failure. The clinical picture is difficult to differentiate from a that of metabolic encephalopathy unless an EEG is obtained. Physicians should be aware of this potentially dangerous complication.