Kappa free light chains is a valid tool in the diagnostics of MS: A large multicenter study.

OBJECTIVE: To validate kappa free light chain (KFLC) and lambda free light chain (LFLC) indices as a diagnostic biomarker in multiple sclerosis (MS). METHODS: We performed a multicenter study including 745 patients from 18 centers (219 controls and 526 clinically isolated syndrome (CIS)/MS patients) with a known oligoclonal IgG band (OCB) status. KFLC and LFLC were measured in paired cerebrospinal fluid (CSF) and serum samples. Gaussian mixture modeling was used to define a cut-off for KFLC and LFLC indexes. RESULTS: The cut-off for the KFLC index was 6.6 (95% confidence interval (CI) = 5.2-138.1). The cut-off for the LFLC index was 6.9 (95% CI = 4.5-22.2). For CIS/MS patients, sensitivity of the KFLC index (0.88; 95% CI = 0.85-0.90) was higher than OCB (0.82; 95%CI = 0.79-0.85; p < 0.001), but specificity (0.83; 95% CI = 0.78-0.88) was lower (OCB = 0.92; 95% CI = 0.89-0.96; p < 0.001). Both sensitivity and specificity for the LFLC index were lower than OCB. CONCLUSION: Compared with OCB, the KFLC index is more sensitive but less specific for diagnosing CIS/MS. Lacking an elevated KFLC index is more powerful for excluding MS compared with OCB but the latter is more important for ruling in a diagnosis of CIS/MS.

Does low socioeconomic status in early life protect against multiple sclerosis? A multinational, case-control study.

BACKGROUND AND PURPOSE: The findings from existing research on the association between socioeconomic status (SES) and multiple sclerosis (MS) are inconsistent. Most previous studies are limited to one country and do not adequately adjust for other risk factors for the disease. METHODS: The association between SES and MS was examined using data from the multinational Environmental Risk Factors in Multiple Sclerosis (EnvIMS) case-control study, comprising 2144 cases and 3859 controls from Norway, Canada and Italy. Multiple logistic regression was used to estimate the odds ratios and 95% confidence intervals for the association between early life SES, measured by parental educational level, and MS. Analyses were adjusted for age, sex, sunlight exposure, history of infectious mononucleosis, smoking, obesity and family size. RESULTS: Relative to those whose parents had primary school education or below, the adjusted odds ratio (95% confidence interval) for MS amongst individuals with university-educated parents, and the P value for trend across education levels, were 1.45 (1.03-2.05) in Canada (P for trend 0.030), 1.09 (0.85-1.39) in Norway (P for trend 0.395) and 0.65 (0.39-1.07) in Italy (P for trend 0.158). CONCLUSION: There is no consistent association between parental SES and MS risk in Norway, Canada and Italy, with a protective effect of low SES only found in Canada.

An overview of pregnancy-related issues in patients with multiple sclerosis.

Although pregnancy in women with multiple sclerosis (MS) is not generally considered high risk, there are some associated therapeutic challenges. The pregnancy-associated reduction in the relapse rate, especially in the third trimester, is followed by a sharp increase in the first few months postpartum. Nevertheless, retrospective evidence for pregnant women with and without MS followed for up to 10 years indicates that pregnancy has no perceptible effect on long-term disease course or disability progression. Likewise, MS has no apparent effects on the pregnancy course or fetal outcomes. All disease-modifying therapies (DMTs) have potential adverse effects on fertility and pregnancy outcomes, but the level of risk varies amongst agents. There is some support for continued use of interferon-ß and glatiramer acetate throughout pregnancy to reduce the risk of relapse. Use of DMTs during breastfeeding is best avoided if possible. Close evaluation of drug safety information is imperative when managing women with MS who are pregnant or wish to become pregnant. Decision-making should be a shared experience between patient and physician, and the approach must be individualized for each patient.

Guidance for the preparation of neurological management guidelines by EFNS scientific task forces - revised recommendations 2012.

This paper is meant to provide guidance to anyone wishing to write a neurological guideline for diagnosis or treatment, and is directed at the Scientist Panels and task forces of the European Federation of Neurological Societies (EFNS). It substitutes the previous guidance paper from 2004. It contains several new aspects: the guidance is now based on a change of the grading system for evidence and for the resulting recommendations, and has adopted The Grading of Recommendations, Assessment, Development and Evaluation system (GRADE). The process of grading the quality of evidence and strength of recommendations can now be improved and made more transparent. The task forces embarking on the development of a guideline must now make clearer and more transparent choices about outcomes considered most relevant when searching the literature and evaluating their findings. Thus, the outcomes chosen will be more critical, more patient-oriented and easier to translate into simple recommendations. This paper also provides updated practical recommendations for planning a guideline task force within the framework of the EFNS. Finally, this paper hopes to find the approval also by the relevant bodies of our future organization, the European Academy of Neurology.

Incidence of childhood and adolescence epilepsy: a community-based prospective study in the province of Ferrara and in Copparo, Italy, 1996-2005.

BACKGROUND: The annual incidence of childhood and adolescence epilepsy ranges from 41 to 97 diagnoses per 100,000 people in western Countries, with a reported decline over time. We aimed at studying the incidence of epilepsy in children and adolescents (1 month to 14 years) and its temporal trend in the province of Ferrara, northern Italy. METHODS: We implemented a community-based prospective multi-source registry. All children with newly diagnosed epilepsy in the period 1996-2005 were recorded. RESULTS: The incidence rate of newly diagnosed epilepsy in the considered age range was 57 per 100,000 person-years, (95% CI: 49.3-65.9), with a peak in the first year of life (109.4; 95% CI: 69.4-164.1), without differences between the two gender. The estimates were significantly lower than those observed previously (97.3; 95% CI: 81.9-115.7). CONCLUSIONS: Incidence rates for epilepsy in the Italian population aged 1 month to 14 years are in line with those of other European and Northern American Countries. The incidence of childhood epilepsy has declined over time in our area. A reduced impact of serious perinatal adverse events could partly explain the decline.

An extremes of outcome strategy provides evidence that multiple sclerosis severity is determined by alleles at the HLA-DRB1 locus.

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for variability in disease outcome. A cohort of sporadic MS cases (n = 163), taken from opposite extremes of the distribution of long-term outcome, was used to determine the role of the HLA-DRB1 locus on MS disease severity. Genotyping sets of benign and malignant MS patients showed that HLA-DRB1*01 was significantly underrepresented in malignant compared with benign cases. This allele appears to attenuate the progressive disability that characterizes MS in the long term. The observation was doubly replicated in (i) Sardinian benign and malignant patients and (ii) a cohort of affected sibling pairs discordant for HLA-DRB1*01. Among the latter, mean disability progression indices were significantly lower in those carrying the HLA-DRB1*01 allele compared with their disease-concordant siblings who did not. The findings were additionally supported by similar transmission distortion of HLA-DRB1*04 subtypes closely related to HLA-DRB1*01. The protective effect of HLA-DRB1*01 in sibling pairs may result from a specific epistatic interaction with the susceptibility allele HLA-DRB1*1501. A high-density (>700) SNP examination of the MHC region in the benign and malignant patients could not identify variants differing significantly between the two groups, suggesting that HLA-DRB1 may itself be the disease-modifying locus. We conclude that HLA-DRB1*01, previously implicated in disease resistance, acts as an independent modifier of disease progression. These results closely link susceptibility to long-term outcome in MS, suggesting that shared quantitative MHC-based mechanisms are common to both, emphasizing the central role of this region in pathogenesis.

Variation within the CLEC16A gene shows consistent disease association with both multiple sclerosis and type 1 diabetes in Sardinia.

Variation within intron 19 of the CLEC16A (KIAA0350) gene region was recently found to be unequivocally associated with type 1 diabetes (T1D) in genome-wide association (GWA) studies in Northern European populations. A variant in intron 22 that is nearly independent of the intron 19 variant showed suggestive evidence of association with multiple sclerosis (MS). Here, we genotyped the rs725613 polymorphism, representative of the earlier reported associations with T1D within CLEC16A, in 1037 T1D cases, 1498 MS cases and 1706 matched controls, all from the founder, autoimmunity-prone Sardinian population. In these Sardinian samples, allele A of rs725613 is positively associated not only with T1D (odds ratio=1.15, P one-tail=5.1 x 10(-3)) but also, and with a comparable effect size, with MS (odds ratio=1.21, P one-tail 6.7 x 10(-5)). Taken together these data provide evidence of joint disease association in T1D and MS within CLEC16A and underline a shared disease pathway.

Environmental risk factors in multiple sclerosis.

OBJECTIVES: Multiple sclerosis (MS) likely results from an interaction between genetic and exogenous factors. While genetics shapes the overall population MS susceptibility, observed epidemiological patterns strongly suggest a role for the environment in disease initiation and modulation. RESULTS: Findings from studies on seasonality in MS patients' birth, disease onset and exacerbations, as well as apparent temporal trends in incidence and gender ratio support an influential effect of viruses, metabolic and lifestyle factors on MS risk. Epstein-Barr virus, vitamin D status, and smoking are factors that may explain such epidemiological patterns. CONCLUSIONS: Further epidemiological investigations are encouraged and opportunities to use data from existing cohort studies as well as the design of new studies should be pursued. In particular, the development of new large multicentre population-based case-control studies which incorporate the study of the role of environment and genetics, including epigenetic mechanisms, in determining MS risk is proposed.

No effect of APOE and PVRL2 on the clinical outcome of multiple sclerosis.

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for its variability in disease outcome. Apolipoprotein E (APOE) is involved in neuronal remodelling and several studies have attempted to examine the effect of APOE on MS disease severity, but its function in modifying the course of MS is controversial. It has been suggested recently that PVRL2, not APOE, is the locus on chromosome 19 which influences clinical outcome of MS. A cohort of sporadic MS cases, taken from opposite extremes of the putative distribution of long-term outcome using the most stringent clinical criteria to date, was used to determine the role of APOE and PVRL2 on MS disease severity. The MS cases selected represent the prognostic best 5% (benign MS) and worst 5% (malignant MS) of cases in terms of clinical outcome assessed by the EDSS. Genotyping the two sets of MS patients (112 benign and 51 malignant) and a replication cohort from Sardinia provided no evidence to suggest that APOE or PVRL2 have any outcome modifying activity. We conclude that APOE and PVRL2 have little or no effect on the clinical outcome of MS.

The role of hereditary spastic paraplegia related genes in multiple sclerosis. A study of disease susceptibility and clinical outcome.

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for its variability in disease outcome. It has been observed that axonal loss in MS is significant and that irreversible clinical disability relates to such axonal loss. The clinical similarities between Hereditary Spastic Paraplegia (HSP) and progressive MS, along with their analogous profiles of axonal loss in the long tracts, make the genes known to cause HSP biologically relevant candidates for the study of clinical outcome in MS. A cohort of sporadic MS cases and a set of unaffected controls were used to determine the role of HSP genes on MS susceptibility and disease severity. The MS cases were taken from opposite extremes of the putative distribution of long-term outcome using the most stringent clinical criteria to date. Genotyping the two sets of MS patients and controls could not provide any evidence to suggest that genes involved in the pathogenesis of HSP (Paraplegin, NIPA1, KIF5A, HSPD1, Atlastin, Spartin, Spastin, PLP1, L1CAM, Maspardin and BSCL2) play a role in susceptibility to, or modifying the course of, MS, although small effects of these genes cannot be ruled out.

Seasonal fluctuation of multiple sclerosis births in Sardinia.

Study results from different geographical areas provide some circumstantial evidence that, when compared with the general population, people who later in life develop multiple sclerosis (MS) have a pattern of birth excess numbers in spring and late summer, which may disclose an association with MS-predisposing environmental agents. To identify the presence of season-related cluster of MS birth in Sardinia we have designed a case-control study in the province of Sassari, Northern Sardinia, insular Italy, an area at very-high and increasing risk for MS. Mean birth incidence rate of people with MS (810 cases) on a three-and six-months basis were compared with that of two control populations: the MS unaffected siblings (1069), sharing genetic material with patients, and a representative number of births (247,612) of the general population of the study area. We found that the birth in months peaking in spring significantly represents one risk factor for future MS development. This seasonal deviation of MS births reveals an intriguing epidemiological overlap with common environmental agents, which may open a new scenario of hypothetical explanations for environmental factors perhaps affecting the CNS at the crucial time of myelination or shaping the newborn immune system.

The epidemiology of multiple sclerosis in Europe.

Multiple sclerosis (MS) is a chronic and potentially highly disabling disorder with considerable social impact and economic consequences. It is the major cause of non-traumatic disability in young adults. The social costs associated with MS are high because of its long duration, the early loss of productivity, the need for assistance in activities of daily living and the use of immunomodulatory treatments and multidisciplinary health care. Available MS epidemiological estimates are aimed at providing a measure of the disease burden in Europe. The total estimated prevalence rate of MS for the past three decades is 83 per 100,000 with higher rates in northern countries and a female:male ratio around 2.0. Prevalence rates are higher for women for all countries considered. The highest prevalence rates have been estimated for the age group 35-64 years for both sexes and for all countries. The estimated European mean annual MS incidence rate is 4.3 cases per 100,000. The mean distribution by disease course and by disability is also reported. Despite the wealth of epidemiological data on MS, comparing epidemiological indices among European countries is a hard task and often leads only to approximate estimates. This represents a major methodological concern when evaluating the MS burden in Europe and when implementing specific cost-of-illness studies.

A genome screen for multiple sclerosis in Sardinian multiplex families.

The prevalence of multiple sclerosis in Sardinia is significantly higher than in neighbouring Mediterranean countries, suggesting that the isolated growth of the population has concentrated genetic factors which increase susceptibility to the disease. The distinct HLA association of multiple sclerosis in Sardinia supports this interpretation. We have performed a whole genome screen for linkage in 49 Sardinian multiplex families using 327 markers. Non parametric linkage analysis of these data reveal suggestive linkage in the region of Chr 1q31, Chr 10q23 and Chr 11p15.

Multiple sclerosis distribution in northern Sardinia: spatial cluster analysis of prevalence.

BACKGROUND: A heterogeneous geographic distribution of MS has been reported among different ethnic groups, and also within small communities. Epidemiologic studies conducted over the past two decades using repeated assessments clearly show that Sardinia is at high risk for MS, with a prevalence of 150 per 100,000 in 1997. OBJECTIVE: To present spatial analysis of the disease prevalence to disclose possible "hot" or "cold" spots of disease, further allowing correlations with risk factors. METHODS: A spatial analysis of the whole province of Sassari, in northern Sardinia, at a microgeographic level (i.e., in the 89 administrative communes and 6 linguistic areas) was conducted. Because of the small number of cases per commune and to overcome random variability, a hierarchical Bayesian approach was adopted. The distribution of prevalent cases by commune of residence on December 31, 1997 and from age 5 to 15 years was analyzed. RESULTS: A clustering pattern was found in the southwestern communes of the province based on geographic distribution by both prevalence and residence at age 5 to 15 years. A west-to-east gradient also was observed. CONCLUSIONS: This study highlights a hot spot of MS in the southwestern part of Sassari province, bordering with the commune of Macomer, where MS was once hypothesized as having occurred as an epidemic. Interestingly, these areas of MS clustering comprise the Common Logudorese linguistic domain. The Catalan area, linguistically and genetically distant from the remaining Sardinian domains, does not show such high estimates. Because MS is not a single-source infectious disease, this study may help test the hypothesis that a widely and evenly spread environmental (infectious?) agent may produce disease in subgroups of genetically more susceptible individuals in areas at higher inbreeding rates, wherein a disease mode of inheritance could be better investigated.

Multiple sclerosis-associated retrovirus and MS prognosis: an observational study.

MS-associated retrovirus (MSRV) in the CSF may have gliotoxic properties and could be associated with a more disabling MS. The authors tested this hypothesis in 15 untreated patients with MS: 6 MSRV- and 9 MSRV+ at the time of CSF withdrawal. After a 3-year mean follow-up, MSRV- patients showed a stable MS course, whereas MSRV+ patients had a progressive course (p = 0.01).

The increasing incidence and prevalence of MS in a Sardinian province.

OBJECTIVE: To verify incidence rates and their temporal trend in a homogeneous, ethnically, and genetically distinct population of central Sardinia (the Nuoro province). BACKGROUND: Intensive epidemiologic studies carried out in Sardinia since the 1970s have suggested that the prevalence and incidence of MS are much higher in this Mediterranean island compared with those found on mainland Italy. METHODS: The study area had a population of approximately 274, 000 people in the 1991 census. The authors adopted a complete enumerative approach by reviewing all possible sources of case collection available in the investigative area. RESULTS: Based on 469 MS patients, the mean annual incidence for 1955 to 1995 was 4.18 per 100,000 (or 4.3 per 100,000 if age- and sex-adjusted to the European population). The incidence, averaging 1.95 per 100,000 during 1955 to 1959, rose progressively over time, reaching rates of 6.6 in the quinquiennium 1985 to 1989 and 6.4 per 100,000 in 1990 to 1995. On December 31, 1994, the crude prevalence, based on 415 MS patients alive in the study area, was 151.9 per 100,000 (156.6 if adjusted to the European population). CONCLUSION: These incidence and prevalence rates are the highest to date that have been estimated for a large community in southern Europe, and they constitute some of the highest rates in the world. Based on other surveys, these results reinforce the position of Sardinia as a higher and rising prevalence area for MS compared with other Mediterranean populations. Genetic and social-historic data strengthen the hypothesis of the environmental role and genetic factors among Sardinians in determining the notable difference in MS frequency between Sardinians and other Mediterraneans.

Multiple sclerosis-associated retrovirus (MSRV) in Sardinian MS patients.

Blood and CSF of Sardinian patients with MS and neurologic control subjects were tested for MS-associated retrovirus (MSRV). CSF detection in MS was 50% at clinical onset, increasing with temporal disease progression, and 40% in control subjects. In blood, MSRV was detected in all MS patients, in most patients with inflammatory neurologic diseases, and rarely in healthy blood donors. MSRV may represent a marker of neurologic diseases of inflammatory origin.

Risperidone, neuroleptic malignant syndrome and probable dementia with Lewy bodies.

1. Conflicting reports are available regarding the sensitivity of patients with Dementia with Lewy bodies (DLB) to risperidone. 2. The authors studied a rare familial case of probable DLB, who developed a documented episode of neuroleptic malignant syndrome (NMS) following the exposure to risperidone. Previously, the patient had had an episode of NMS on trifluoperazine. 3. The discontinuance of risperidone, in combination with a mild increase of dopaminergic therapy, led to a complete recovery in few days. 4. In patients with DLB, a continued vigilance for extrapyramidal side effects, including NMS, would be advisable during the use of risperidone.

Which syringomyelia is truly associated with multiple sclerosis?

Necrosis of the spinal cord within multiple sclerosis (MS) lesions was suggested as a putative cause of syringomyelic cavity development in MS. A number of evidences suggest however that mechanisms other than necrosis are pathogenetically relevant for cavity formation, possibly depending on the atypical topographical distribution of the demyelinative lesion and on the increased cerebrospinal fluid pressure into the central canal below the compression. Not coincidentally, the hypothesis of post-necrotic and ex-vacuo mechanisms leading to cavitation derives from Japanese studies where MS is characterised by high tissue destructive capability and, besides its rarity, has many differences from the more common Western MS type and similarities with the acute disseminated encephalomyelitis (ADEM). Our opinion is that different MS types (Asian and Western) are accompanied by nonuniform mechanisms of syrinx formation and that the Asian MS type shares common, post-necrotic mechanisms with ADEM.

The vestibular system modulates masseter muscle activity.

The aim of this study was to investigate whether, and in what way, the vestibular input may influence the activity of the masseter muscles. The variations in the spontaneous electrical activity and the evoked responses in the masseter motor units to natural or electrical activation of the vestibular afferents were recorded in anesthetized guinea pigs. The effects of a unilateral lesion of the labyrinth on the firing rate of the masseter motor units were also studied. Results show that: 1) vestibular input elicited an excitatory tonic control on masseter muscle activity; 2) a faster labyrinthine control is driven to the contralateral than the homolateral masseter muscles; 3) vestibular macular input does exert an asymmetrical control on masseteric muscles of both sides, in relation to the head displacement in space. The latencies of responses recorded from the masseter motor units suggest that polysynaptic pathways are involved in connecting the vestibular system to the trigeminal complex. The possible anatomical substrates for this vestibulomasseteric reflex are discussed.