Ilaria Casetta

Restless legs syndrome and pregnancy

Objective: To perform a large and detailed epidemiologic study on restless legs syndrome (RLS) during pregnancy and the puerperium. Methods: A structured clinical interview, assessing symptoms since the beginning of pregnancy, was performed to a population of 642 pregnant women at the time of delivery and at follow-up evaluation (1, 3, and 6 months after delivery). Main hematologic tests were also evaluated. A woman was considered affected if she met the International RLS Study Group criteria for RLS diagnosis. Results: Twenty-six percent of women were affected by RLS during their pregnancy. The disease was strongly related to the third trimester of pregnancy and tended to disappear reaching the time of delivery. Affected women presented lower values of hemoglobin and mean corpuscular volume compared with healthy subjects (both groups received the same supplemental iron and folate therapy). Conclusions: Pregnancy is associated with transient restless legs syndrome.

Incidence and Prognosis of Stroke in the Belluno Province, Italy First-Year Results of a Community-Based Study

BACKGROUND AND PURPOSE We sought to register the incidence rate, risk factors, and case-fatality rate of all the new cases of first-ever-in-a-lifetime stroke in the province of Beluno, Italy. This study aimed to provide an epidemiological survey of cerebrovascular disease that could supply investigative objectives and support information for regional healthcare facilities planning. METHODS We undertook a prospective population-based study in the territory of the 1st, 2nd, 3rd, and 4th local health units in the province of Belluno, an area located in northeast Italy (population, 211 389). RESULTS In the first year of the study (June 1, 1992, to May 31, 1993), 474 cases of first-ever stroke were registered. The crude annual incidence rate was 2.24/1000 (2.01/1000 for men and 2.45/1000 for women). After adjustment to the European population, the incidence rate for first stroke was 1.70/1000 per year. The pathological diagnosis was confirmed by a CT scan in 89.5% of cases. Cerebral infarction accounted for 319 cases, while 93 patients suffered a primary intracerebral hemorrhage, 12 patients a subarachnoid hemorrhage, and 50 patients a stroke of unknown origin. The overall 30-day case-fatality rate was 33%, and the mortality within the first week from stroke onset was 23%. The recurrence rate after 1 month was 1.9%. After 1 month, 46% of our patients were functionally independent in activities of daily living. CONCLUSIONS Our first-year results confirm the fairly high risk for stroke in central and northern Italy and support European findings regarding risk factors for stroke.

Cerebrospinal fluid and serum levels and intrathecal production of active matrix metalloproteinase-9 (MMP-9) as markers of disease activity in patients with multiple sclerosis.

In this study, we employed a sensitive activity assay system to measure cerebrospinal fluid (CSF) and serum levels of active matrix metalloproteinase-9 (MMP-9) in 37 relapsing-remitting (RR), 15 secondary progressive (SP) and nine primary progressive (PP) multiple sclerosis (MS) patients, grouped according to clinical and magnetic resonance imaging (MRI) evidence of disease activity. We also studied, as neurological controls, 48 patients with other inflammatory neurological disorders (OIND) and 48 with non-inflammatory neurological disorders (NIND). To assess active MMP-9/TIMP-1 circuit, CSF and serum levels of MMP-9 tissue inhibitor TIMP-1 were quantified by ELISA in the same patient population. CSF mean levels of active MMP-9, CSF active MMP-9/TIMP-1 ratios and intrathecal active MMP-9 synthesis, as indicated by specific index, were more elevated in MS than in NIND (P <0.05, <0.02 and <0.02, respectively), serum active MMP-9/TIMP-1 ratio was higher in MS (P<0.01) and OIND (P<0.02) than in NIND, and serum TIMP-1 concentrations were lower in MS than in NIND (P<0.05). More importantly, serum active MMP-9 mean levels, serum active MMP-9/TIMP-1 ratio and intrathecal production of active MMP-9 were increased in MS patients with clinical (P<0.001, <0.001 and <0.05, respectively) and MRI (P<0.001, <0.001 and <0.02, respectively) disease activity, whereas CSF mean concentrations of active MMP-9 and CSF active MMP-9/TIMP-1 ratio were enhanced only in MS patients with MRI evidence of disease activity (P<0.02 and <0.01, respectively). Altogether, these findings suggest that a shift in MMP-9/TIMP-1 balance towards proteolytic activity of MMP-9 could be relevant in MS immune dysregulation. In addition, our results indicate that CSF and serum levels of active MMP-9 may represent a potential surrogate biomarker for monitoring MS disease activity. In particular, serum active MMP-9/TIMP-1 ratio seems to be a very appropriate indicator of ongoing MS inflammation, since it is easily measurable.

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.

A2A adenosine receptor overexpression and functionality, as well as TNF-α levels, correlate with motor symptoms in Parkinson’s disease

The antagonistic interaction between adenosine and dopamine receptors could have important pathophysiological and therapeutic implications in Parkinsons disease (PD). The primary aim of this study was to investigate the expression, affinity, and density of A1, A2A, A2B, and A3 adenosine receptors (ARs) and D2 dopamine receptors (D2Rs) in PD. An increase in A2AAR density in putamen was found. The presence and functionality of ARs in human lymphocyte and neutrophil membranes from patients with PD revealed a specific A2AAR alteration compared with healthy subjects. A statistically significant linear correlation among the A2AAR density, functionality, or tumor necrosis factor‐α (TNF‐α) levels and Unified Parkinsons Disease Rating Scale (UPDRS) motor score was reported. Adenosine concentration and TNF‐α levels were increased in plasma of patients with PD. In rat adrenal pheochromocytoma (PC12) cells, a widely useful model, adenosine antagonists decreased dopamine uptake, and an opposite effect was mediated by A2A agonists. This is the first report showing the presence of an A2AAR alteration in putamen in PD that mirrors a similar up‐regulation in human peripheral blood cells. Moreover, the correlation found between A2AAR density or A2A agonist potency and UPDRS motor score highlights the central role of A2AARs in the pharmacological treatment of PD.—Varani, K., Vincenzi, F., Tosi, A., Gessi, S., Casetta, I., Granieri, G., Fazio, P., Leung, E., MacLennan, S., Granieri, E., Borea, P. A. A2A adenosine receptor overexpression and functionality, as well as TNF‐α levels, correlate with motor symptoms in Parkinsons disease. FASEB J. 24, 587–598 (2010). www.fasebj.org

A prospective study on the predictive value of CSF oligoclonal bands and MRI in acute isolated neurological syndromes for subsequent progression to multiple sclerosis.

A prospective study in patients with a clinical acute isolated brainstem or spinal cord disorder was undertaken. The aim was to evaluate the predictive value of IgG intrathecal synthesis (through the detection of oligoclonal bands in CSF) and MRI lesions at presentation, for the subsequent progression to multiple sclerosis. Forty four patients took part in this study: 22 had a brainstem disorder and 22 a spinal cord disorder. After a mean period of 26 (SD 22) months, 30 patients (68.2%) developed clinically definite multiple sclerosis. The remaining 14 patients were followed up for more than seven years. Twenty six (59.1%) patients had oligoclonal bands in CSF, with a sensitivity of 80.0%, specificity of 85.7%, and a predictive value of 92.2%. Magnetic resonance imaging showed disseminated white matter lesions in 22 patients (50.0%), with a sensitivity of 60.0%, a specificity of 71.4%, and a predictive value of 81.7%. The difference between patients with multiple sclerosis and patients without the disease was statistically significant for the findings of an IgG intrathecal synthesis (P < 0.001). It was only borderline for the MRI findings (P = 0.052). Thus the detection of an intrathecal synthesis at presentation seemed to be a better prognostic indicator of the progression to multiple sclerosis in patients affected by acute isolated brainstem or spinal cord syndromes.

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.

Early predictors of intractability in childhood epilepsy: a community‐based case–control study in Copparo, Italy

Objectives – To identify early predictors of intractability in childhood and adolescence epilepsy. Materials and methods – We carried out a community‐based case–control study using the incidence cohort of epileptic patients living in the district of Copparo, in the province of Ferrara, Italy. The comparative study was performed in 31 cases and 95 controls. Cases were patients who averaged at least 1 unprovoked seizure per month during an observational period of at least 2 years. Controls were subjects having achieved remission for at least 5 years regardless of current therapy. Results – Onset at age <1 year, remote symptomatic etiology and high frequency of seizures before therapy were found to be independent early predictors of intractability. Conclusion – Our study suggested that the risk of developing intractable epilepsy may, to some extent, be predicted at the time of initial diagnosis in children with early‐onset epilepsy of remote symptomatic etiology, especially if seizure propensity is initially high.

25-Hydroxyvitamin D in cerebrospinal fluid during relapse and remission of multiple sclerosis

Hypovitaminosis D may play a role in multiple sclerosis (MS), but little is known about intrathecal vitamin D. 25-Hydroxyvitamin D was measured in cerebrospinal fluid and sera from 36 patients with relapsing-remitting MS, 20 patients with other inflammatory neurological diseases and 18 patients with non-inflammatory neurological diseases with liquid chromatography-mass spectrometry. There were no significant differences in cerebrospinal fluid concentrations of 25-hydroxyvitamin D, but the cerebrospinal fluid:serum ratio was significantly lower in MS compared with other inflammatory neurological diseases (p=0.0012) and non-inflammatory neurological diseases (p=0.041) patients. The concentrations of 25-hydroxyvitamin D in cerebrospinal fluid and serum were positively correlated and their ratio was similar to that of albumin. Neither the concentrations of 25-hydroxyvitamin D in cerebrospinal fluid or serum nor their ratio were associated with the presence of relapses or gadolinium-enhanced lesions. These results do not support that 25-hydroxyvitamin D is actively transported to the cerebrospinal fluid, or that the cerebrospinal fluid or serum levels or their ratio exert a major impact on MS activity.

Transient RLS during pregnancy is a risk factor for the chronic idiopathic form

Objective: Pregnancy is a risk factor for transient restless legs syndrome, which usually recovers during the postdelivery period. The goal of the present survey is to investigate whether restless legs syndrome during pregnancy represents a risk factor for later development of restless legs syndrome. Methods: A long-term follow-up study, planned as an extension of a previous survey on restless legs syndrome during pregnancy, was carried out. After a mean interval of 6.5 years, 207 parous women were contacted again to compare the incidence of restless legs syndrome among subjects who never experienced the symptoms with those who reported restless legs syndrome during the previously investigated pregnancy. Results: Seventy-four women who experienced restless legs syndrome during previous pregnancy, and 133 who did not, were included in the study. The incidence of restless legs syndrome was 56% person/year in women who experienced the transient pregnancy restless legs syndrome form, and 12.6% person/year in subjects who did not, with a significant 4-fold increased risk of developing chronic restless legs syndrome in women who presented restless legs in the previous pregnancy. Considering further new pregnancies during the follow-up period, the restless legs symptoms reappeared in 58% of the cases, while they emerged for the first time in only 3% of women who had never experienced restless legs syndrome. Conclusions: The transient pregnancy restless legs syndrome form is a significant risk factor for the development of a future chronic idiopathic restless legs syndrome form, and for a new transient symptomatology in a future pregnancy.