Maura Pugliatti

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.

Vascular Factors and Risk of Dementia: Design of the Three-City Study and Baseline Characteristics of the Study Population

Objective: To describe the baseline characteristics of the participants in the Three-City (3C) Study, a study aiming to evaluate the risk of dementia and cognitive impairment attributable to vascular factors. Methods: Between 1999 and 2001, 9,693 persons aged 65 years and over, noninstitutionalized, were recruited from the electoral rolls of three French cities, i.e. Bordeaux, Dijon and Montpellier. Health-related data were collected during face-to-face interviews using standardized questionnaires. The baseline examination included cognitive testing and diagnosis of dementia, and assessment of vascular risk factors, including blood pressure measurements, ultrasound examination of the carotid arteries, and measurement of biological parameters (glycemia, total, high-density lipoprotein and low-density lipoprotein cholesterol, triglycerides, creatinemia); 3,442 magnetic resonance imaging (MRI) examinations were performed in subjects aged 65–79. Measurements of ultrasound, blood, and MRI parameters were centralized. Two follow-up examinations (at 2 and 4 years) were planned. Results: After exclusion of the participants who had subsequently refused the medical interview, the 3C Study sample consisted of 3,649 men (39.3%) and 5,645 women, mean age 74.4 years, with a relatively high level of education and income. Forty-two percent of the participants reported to be followed up for hypertension, about one third for hypercholesterolemia, and 8% for diabetes; 65% had elevated blood pressure measures (systolic blood pressure ≧140 or diastolic blood pressure ≧90). The proportion of Mini-Mental State Examination scores below 24 was 7% and dementia was diagnosed in 2.2% of the participants. Conclusion: Distribution of baseline characteristics of the 3C Study participants suggests that this study will provide a unique opportunity to estimate the risk of dementia attributable to vascular factors.

The worldwide prevalence of multiple sclerosis

Despite the wealth of epidemiological data deriving from the systematic studies of multiple sclerosis (MS) that have been carried out for over 70 years, any attempt at redefining the pattern of MS geographic distribution is still a difficult task. In fact, comparing prevalence studies of different areas and at different times implies a number of problems: (a) the variability of the surveyed populations in terms of size, age structure, ethnic origin and composition [1]; (b) the difference when determining the numerator, i.e. the recognition of benign and very early cases [2]; (c) the extent to which complete case ascertainment is achieved based on geographic and time variables, access to medical care, local medical expertise, number of neurologists, availability of and accessibility to new diagnostic procedures, degree of public awareness about MS, and on the investigators’ zeal and resources [2,3]; (d) the use of different diagnostic criteria and the interobserver variability when applying them [1]. A description of MS geography worldwide is tentatively presented (for detailed references, see review by Rosati [4]).

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.

Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72

A large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72, a gene located on chromosome 9p21, has been recently reported to be responsible for ~40% of familial amyotrophic lateral sclerosis cases of European ancestry. The aim of the current article was to describe the phenotype of amyotrophic lateral sclerosis cases carrying the expansion by providing a detailed clinical description of affected cases from representative multi-generational kindreds, and by analysing the age of onset, gender ratio and survival in a large cohort of patients with familial amyotrophic lateral sclerosis. We collected DNA and analysed phenotype data for 141 index Italian familial amyotrophic lateral sclerosis cases (21 of Sardinian ancestry) and 41 German index familial amyotrophic lateral sclerosis cases. Pathogenic repeat expansions were detected in 45 (37.5%) patients from mainland Italy, 12 (57.1%) patients of Sardinian ancestry and nine (22.0%) of the 41 German index familial amyotrophic lateral sclerosis cases. The disease was maternally transmitted in 27 (49.1%) pedigrees and paternally transmitted in 28 (50.9%) pedigrees (P = non-significant). On average, children developed disease 7.0 years earlier than their parents [children: 55.8 years (standard deviation 7.9), parents: 62.8 (standard deviation 10.9); P = 0.003]. Parental phenotype influenced the type of clinical symptoms manifested by the child: of the 13 cases where the affected parent had an amyotrophic lateral sclerosis-frontotemporal dementia or frontotemporal dementia, the affected child also developed amyotrophic lateral sclerosis-frontotemporal dementia in nine cases. When compared with patients carrying mutations of other amyotrophic lateral sclerosis-related genes, those with C9ORF72 expansion had commonly a bulbar onset (42.2% compared with 25.0% among non-C9ORF72 expansion cases, P = 0.03) and cognitive impairment (46.7% compared with 9.1% among non-C9ORF72 expansion cases, P = 0.0001). Median survival from symptom onset among cases carrying C9ORF72 repeat expansion was 3.2 years lower than that of patients carrying TARDBP mutations (5.0 years; 95% confidence interval: 3.6-7.2) and longer than those with FUS mutations (1.9 years; 95% confidence interval: 1.7-2.1). We conclude that C9ORF72 hexanucleotide repeat expansions were the most frequent mutation in our large cohort of patients with familial amyotrophic lateral sclerosis of Italian, Sardinian and German ancestry. Together with mutation of SOD1, TARDBP and FUS, mutations of C9ORF72 account for ~60% of familial amyotrophic lateral sclerosis in Italy. Patients with C9ORF72 hexanucleotide repeat expansions present some phenotypic differences compared with patients with mutations of other genes or with unknown mutations, namely a high incidence of bulbar-onset disease and comorbidity with frontotemporal dementia. Their pedigrees typically display a high frequency of cases with pure frontotemporal dementia, widening the concept of familial amyotrophic lateral sclerosis.

Estimating the cost of epilepsy in Europe: a review with economic modeling.

Purpose: Based on available epidemiologic, health economic, and international population statistics literature, the cost of epilepsy in Europe was estimated.

Variants within the immunoregulatory CBLB gene are associated with Multiple Sclerosis

A genome-wide association scan of ∼6.6 million genotyped or imputed variants in 882 Sardinian individuals with multiple sclerosis (cases) and 872 controls suggested association of CBLB gene variants with disease, which was confirmed in 1,775 cases and 2,005 controls (rs9657904, overall P = 1.60 × 10−10, OR = 1.40). CBLB encodes a negative regulator of adaptive immune responses, and mice lacking the ortholog are prone to experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis.

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.

Multiple sclerosis epidemiology in Sardinia : evidence for a true increasing risk

Objectives– To update prevalence and incidence rates of MS among Sardinians. Materials and methods– The present work is a “spider” kind of population based survey, conducted over the interval 1968–97, on patients with MS (Poser criteria) living in the province of Sassari, Northern Sardinia (454,904 population). Results– A crude total prevalence rate of 144.4 per 100,000, an onset‐adjusted prevalence rate of 149.7 per 100,000 and an average annual incidence rate of 8.2 for the period 1993–7 were found. Conclusion– Repeated epidemiological assessments of MS in Sardinia over decades have shown that the island is at high risk for MS. The present work highlights that MS incidence in Sardinia has been increasing over time. Although a substantial and widely spread improvement in MS case ascertainment can be postulated as the reason for such observations, a comparison between our data and those recently reported from a more industrialized province in Northern Italy seems to prove an at least partially real increase in MS risk among Sardinians and favours the hypothesis of a MS “Sardinian focus” as related to its latitude.

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.