Effects of immunomodulatory treatment with subcutaneous interferon beta-1a on cognitive decline in mildly disabled patients with relapsing-remitting multiple sclerosis.

The objective of this study was to assess the effects of subcutaneous (sc) interferon beta-1a (IFNbeta-1a) on cognition in mildly disabled patients with relapsing-remitting multiple sclerosis (RRMS). Patients aged 18-50 years with RRMS (McDonald criteria; Expanded Disability Status Scale score

The interleukin-1 cluster gene region is associated with multiple sclerosis in an Italian Caucasian population.

BACKGROUND: Polymorphisms of the interleukin-1 (IL-1) gene family have been proposed as potential variants for different diseases including multiple sclerosis (MS). With respect to MS, IL-1 beta (-511 C/T; rs16944), IL-1 beta (+3954 C/T; rs1143634), IL-1 alpha (-889 C/T; rs1800587), IL-1 alpha (+4845 G/T; rs17561), and the variable number of tandem repeats in intron 2 of the IL-1 receptor antagonist (IL-1RN) gene polymorphisms have been studied in different ethnic groups, leading to conflicting results. METHODS: This study investigates the association between IL-1 genes and MS by means of 70 markers spanning the 1.1 Mb region where the IL-1 genes map and exploring both the linkage disequilibrium (LD) and the haplotype structure in a case-control design including 410 subjects (160 patients and 250 controls). RESULTS: From allelic/genotypic tests, significant association was found for several polymorphisms including the IL-1 beta (-511 C/T) variant (P-adjusted = 4.5 x 10(-4)) and some polymorphisms around the IL-1RN gene. The 'block-step' pattern obtained from both the LD map and pairwise analysis identifies four LD regions. Region 1 showed a significant association with MS for the global test (P < 0.0001) and haplotypes containing the IL-1 beta (-511 C/T) variant still demonstrate highly significant association with disease (P-value range: 9.9 x 10(-5) to 0.02). CONCLUSIONS: Our findings support the existence of a causative variant for MS within this candidate region in a representative Italian Caucasian population and, in particular, the role of the IL-1 beta (-511 C/T) variant warrants further investigation.

Multiple sclerosis in the province of Ferrara : evidence for an increasing trend.

BACKGROUND: Epidemiological studies on the distribution of multiple sclerosis (MS) conducted in the Mediterranean area in the last two decades have disclosed a significant increase in frequency of the disease, indicating caution when a latitude-related model of MS is accepted. Previous descriptive surveys in the province of Ferrara, northern Italy, carried out by our own epidemiological research group, have established that this area is at high risk for MS. OBJECTIVE: To confirm the above assumption and to update MS frequency estimates in this area. DESIGN AND SETTING: We conducted a community-based intensive prevalence and incidence study, by adopting a complete enumeration approach. RESULTS: On December 31, 2004, 423 patients (300 women and 123 men) suffering from definite or probable MS (Poser's criteria) living in the province of Ferrara, yielded a crude prevalence rate of 120.93 (95 % CI, 110.05-134.23) per 100,000, 164.26 for women and 73.59 for men. The average incidence from 1990 to 2003 was 4.35 per 100,000 (95 % CI, 3.77-4.99), 5.91 for women and 2.63 for men. The incidence rate,which was relatively stable during the previous 25 years (1965-1989) with a mean rate of 2.3 per 100,000, increased to a value of 3.39 per 100,000 in the period 1990-1994, 4.09 per 100,000 in the period 1995-1999 and 3.84 per 100,000 in the period 2000-2003. CONCLUSIONS: These results confirm that in Ferrara MS occurs more frequently than suggested by the geographic- related distribution model and, based on other recent national surveys, support the view that northern Italy is a high-risk area for the disease. The marked increase in MS prevalence rate, in comparison with previous investigations, is in part due to the increasing survival of patients as a result of improved supportive care and the accumulation of new incidence cases owing to the reduction in diagnostic latency for better quality of neurological diagnostic procedures. The incidence in the province of Ferrara was found to slowly change with an incremental trend,which cannot only be attributed to improvements in diagnostic ability. Environmental risk factors in genetically predisposed people over time could be considered.

Botulinum toxin treatment in the facial muscles of humans: evidence of an action in untreated near muscles by peripheral local diffusion.

In a population of subjects with blepharospasm and facial hemispasm treated for the first time with botulinum toxin type A (BT) in the orbicularis oculi muscle, we performed an electrophysiologic study (compound muscle action potential and motor evoked potential) to assess whether BT effect could be detected in near untreated muscles (orbicularis oris and masseter). There was a significant BT action in nearly untreated muscles with different peripheral innervation that can be explained by local diffusion of the drug.

Epidemiological study of myasthenia gravis in the province of Ferrara, Italy.

The only prevalence rate of myasthenia gravis (MG) so far estimated in Italy by an epidemiological study carried out in Pavia, North Italy, indicates a prevalence quite similar to that observed in other countries. The purpose of the survey was to verify the frequency of the disease in a geographically well-defined and previously surveyed community. On the basis of 39 cases, on 31 December 1987 the prevalence per million was 105.3 (102.3 if standardized for the Italian population). This is the highest prevalence figure yet found, indicating a value similar to that established in Northern Europe. According to Kurtzke this high prevalence rate reflects the high standard of the local public health service, which permitted a more intensive search for affected subjects.

Systemic lupus erythematosus presenting with neurological disorders.

Six patients are described who developed a wide variety of neurological manifestations heralding systemic lupus erythematosus (SLE), which included epileptic seizures, stroke, peripheral polyradiculoneuropathy similar to Guillain-Barré syndrome, transverse myelopathy and multifocal disorders with remitting course mimicking multiple sclerosis. The peculiarity of these cases was that the neurological disorders remained the only manifestations of SLE for many years and the nervous system appeared to be the main target even after the development of systemic SLE. In five patients the prognosis was favourable and corticosteroid treatment led to prolonged remission.

T-cell phenotypic profiles in the cerebrospinal fluid and peripheral blood of multiple sclerosis patients.

Thirty-nine patients with clinically definite multiple sclerosis (MS) entered the study. Of 28 subjects with a relapsing-remitting course, 19 were classified in acute relapse, 9 in remission; 11 patients had a progressive course without remissions. Furthermore, 6 subjects with inflammatory neurological disease (IND), and 10 with non-inflammatory and non-neoplastic neurological disease (NIND) were investigated. We simultaneously studied cerebrospinal fluid (CSF) and peripheral blood (PB) T-, B- and NK-cell subsets, as defined by following monoclonal antibodies: anti-CD3, -CD4, -CD8, -CD19, -CD16, -HLA-DR and -IL-2-R. We found a significant increase of CD4+ T-cells compared with controls in CSF, with respect to PB, of MS patients, particularly in acute relapse. An increase of HLA-DR+ cell percentages in the CSF than in the PB in all MS groups, especially in attacks of MS but also in remission, was also observed, with a positive correlation between CD4+ T-cell and DR+ cell percentages both in the CSF as well as in the PB of relapsing MS patients. These findings, together with the increase of IL-2-R+ cells in the PB, particularly in relapsing MS, give further support for the presence of a systemic T-cell activation in MS.

Neurological involvement in primary Sjögren's syndrome: clinical and instrumental evaluation in a cohort of Italian patients.

To evaluate nervous system involvement in a cohort of Italian patients with primary Sjögren's syndrome (pSS), 87 unselected patients (83 female, and four male) observed consecutively at our institution over a period of 5 years were screened by clinical and instrumental (MRI, SPECT, electrophysiological testing, CSF analysis) investigations for peripheral and central neurological abnormalities. Seroimmunological parameters and extraglandular features other than neurological manifestations were also evaluated. Seven patients had central nervous system (CNS) disease (8%), mostly non-focal dysfunction, and 12 had peripheral nervous system (PNS) disease (13.8%), mostly mild or severe sensory or sensory-motor polyneuropathies. One patient had concomitant CNS and PNS involvement. Compared with CNS disease, PNS involvement occurred in older patients (> 50 years), independent of the disease duration. Patients with and without neurological abnormalities did not differ for seroimmunological parameters (including antiphospholipid antibodies) or extraglandular manifestations. From a statistical point of view, the only relevant finding was the detection of a slight increase in serum IgA and IgM levels (p < 0.05) in patients with an intact nervous system. Neurological involvement in pSS, be it central or peripheral, is not a rare finding. A careful clinical neurological evaluation, combined with a multiplicity of instrumental investigations, is recommended in the global assessment of pSS patients.

Cognitive impairment and its relation with disease measures in mildly disabled patients with relapsing-remitting multiple sclerosis: baseline results from the Cognitive Impairment in Multiple Sclerosis (COGIMUS) study.

BACKGROUND: Cognitive impairment is a common symptom of multiple sclerosis (MS), but the association between cognitive impairment and magnetic resonance imaging (MRI) disease measures in patients with relapsing-remitting (RR) MS is unclear. OBJECTIVES: To study the prevalence of cognitive impairment and its relation with MRI disease measures in mildly disabled patients with RRMS. METHODS: Patients aged 18-50 years with RRMS (McDonald criteria) and an Expanded Disability Status Scale (EDSS) score or=3 cognitive tests) was present in approximately 20% of all patients and in the subgroup who underwent MRI. T2 hyperintense and T1 hypointense lesion volumes were significantly higher in patients with cognitive impairment (defined as impaired performance on at least three tests of the Rao's battery) than those without. EDSS score was also significantly higher in cognitively impaired than in cognitively preserved patients. Disease duration, depression, and years in formal education did not differ significantly between cognitively impaired and cognitively preserved patients. T2 lesion volume, performance intelligence quotient, and age were significant predictors of cognitive impairment in this population. Weak correlations were found between performance on individual cognitive tests and specific MRI measures, with T1 and T2 lesion volumes correlating with performance on most cognitive tests. CONCLUSIONS: Cognitive impairment occurs in approximately one-fifth of mildly disabled patients with MS and is associated with specific MRI disease measures. Assessment of cognitive function at diagnosis could facilitate the identification of patients who may benefit from therapeutic intervention with disease-modifying therapies to prevent further lesion development.

Cryoglobulinemic neuropathy related to hepatitis C virus infection. Clinical, laboratory and neurophysiological study.

Peripheral neuropathy is frequently reported in mixed cryoglobulinemia. As a close relationship has been established between mixed cryoglobulinemia and hepatitis C virus (HCV), the clinical, neurophysiological, and serologic findings of five patients affected by neuropathy, cryoglobulinemia and HCV infection were investigated. HCV infection was ascertained by the presence in the serum of anti-HCV antibodies detected by enzyme-linked immunosorbent assay(ELISA), and of HCV RNA assessed by polymerase chain reaction (PCR). Initial symptoms included paresthesias and painful dysesthesias in the legs. Later on, the patients developed a mainly asymmetric axonal polyneuropathy or a multifocal neuropathy associated with signs of systemic vasculitis. In this case series we report the short-term prognosis, as well as the response to interferon (IFN) alpha and conventional treatment. The presence of HCV RNA supports the hypothesis that a persistent HCV infection might be involved in the pathogenesis of mixed cryoglobulinemia and cryoglobulinemia-associated disorders.

Stiff person syndrome does not always occur with maternal passive transfer of GAD65 antibodies.

The authors report the presence of high titer antibodies to glutamic acid decarboxylase (anti-GAD65) until age 24 months in two asymptomatic newborns of a woman with stiff-person syndrome (SPS). No signs of SPS were detectable in the two children at ages 6 and 8 years. This observation indicates that other cofactors are involved in the pathogenesis of SPS.

Comparative study on the prevalence of myasthenia gravis in the provinces of Bologna and Ferrara, Italy.

This cooperative study was performed in the provinces of Bologna and Ferrara to estimate the prevalence rate of Myasthenia Gravis (MG). Two independent groups used the same case collection method and diagnostic criteria. The study was performed from January 1, 1987 to March 1, 1988. Cases were collected through: 1) review of clinical files from neurology clinics in Bologna and Ferrara, and from the main North-Italian centers for MG (neurology clinics of Milan and Turin; thoracic surgery unit, Turin); 2) thoracic surgery and intensive care units in Bologna and Ferrara; 3) physicians prescribing anticholinesterase drugs. Prevalence rates of generalized MG per million population were 60.9 in the city and 41.0 in the remaining province for Bologna and 118.9 in the city and 87.9 in the remaining province for Ferrara. The difference in prevalence rates between the two areas was statistically significant. Our survey shows that prevalence studies on MG may be biased by factors that cannot be controlled and that most previous studies have probably underestimated the prevalence of MG.

Human herpesvirus 6 infects the central nervous system of multiple sclerosis patients in the early stages of the disease.

The presence and the replicative state of human herpesvirus 6 (HHV-6) were evaluated in clinical samples from multiple sclerosis (MS) patients at the first time of MS diagnosis. HHV-6 variant B was present in peripheral blood mononuclear cells of 5/32 (15%) patients, but persisted with a latent infection. Viral sequences were present also in cerebrospinal fluid (CSF), both free in the liquid (7/32, 22%) and latent in the cellular fraction (3/32, 9%), as shown by analysis of viral transcription. In these cases, variant A was detected. HHV-6 DNA sequences present in the CSF were associated to mature viral particles. In fact, in vitro infectious assays of CSF showed the presence of replication-competent virions. These results show that about 20% of MS patients have active foci of HHV-6 variant A infection in the early stages of the disease and suggest that viral replication takes place within the central nervous system.

Epidemiology of Parkinson's disease in Italy. A descriptive survey in the U.S.L. of Cento, province of Ferrara, Emilia-Romagna.

In order to verify the epidemiology of Parkinson's disease in northern-Italy, we carried out a descriptive study in the Local Health Service No. 30 of Cento, Emilia-Romagna. Based on 73 accepted cases, the prevalence rate on December 31, 1987, was 190.3 per 100,000 population. No significant difference was reported between the two sexes. The highest rates were observed in the age groups over 60 years. Our data indicate that the risk of Parkinson's disease in northern-Italy is similar to that observed in other Caucasian populations.

Environmental risk factors and multiple sclerosis: a community-based, case-control study in the province of Ferrara, Italy.

The frequency of multiple sclerosis (MS) in Italy and in other areas of the world seems to have increased over time, suggesting that some environmental factors operate in its etiology. We performed a retrospective, community-based case-control study on MS in order to verify the etiologic role of selected environmental factors. We found an association between MS and higher educational level, employment in public administration, past history of allergies, and infection at an early age with measles, rubella and whooping cough. Our data seem to confirm that exogenous factors play a role in the etiology of MS although some confounding variables could have accounted for the associations.

Dietary habits and multiple sclerosis. A retrospective study in Ferrara, Italy.

In a retrospective case-control study of multiple sclerosis (MS), set up with the aim of verifying the role of environmental factors in pathogenesis, we included a section on dietary habits. We compared the frequency and pattern of food consumption by cases and controls. We found an association between. MS and high consumption of bread and "pasta", butter and lard, legume soup, horse flesh, coffee and tea in the period from infancy to adolescence. A different pattern of consumption of eggs, wine and mineral water between cases and controls was found during adulthood. Our results support, at least partially, the data already reported in the international literature on an association between certain dietary factors and MS. Some foods consumed at certain "critical" ages could play a causal role in the onset of MS.

Immunogenetic heterogeneity and associated autoimmune disorders in myasthenia gravis: a population-based survey in the province of Ferrara, northern Italy.

INTRODUCTION: The well-established relationship between myasthenia gravis (MG) and HLA antigens varies among different ethnic groups. In Caucasians B8 and/or DR3 alleles have been found associated with young MG women without thymoma and with high titres of acetylcholine-receptor antibody (AChR Ab). An increased frequency of haplotype HLA-A3, B7 and/or DR2 has been observed in older MG patients with low AChR Ab levels. So far, there is no convincing evidence for an association between a specific haplotype HLA and ocular MG or MG with thymoma. MG subjects often show other concurrent autoimmune disorders suggesting a more general inherited predisposition to autoimmunity. We performed a community-based study to verify the HLA-A, B, C, DR and DQ profile on ethnically homogeneous MG patients and with the aim to estimate the frequency of concurrent autoimmune diseases and to compare HLA phenotypes to autoimmune status in different MG patients groups. METHODS: Forty-seven patients, living in the province of Ferrara, were followed-up in our neurologic department and typed for HLA Antigens. In addition a set of immunological laboratory tests was performed. RESULTS: We found a trend towards an increased B8 and DR3 frequencies in total affected population; an association between B8 allele and early onset of generalized MG sustained by thymic hyperplasia. The DR3 allele is statistically associated with the presence of additional autoimmune disorders. CONCLUSIONS: Our data support the hypothesis of a genetically-based heterogeneity of the disease and show an increased prevalence of associate autoimmune conditions in MG patients.