Cristina Montomoli

QT interval prolongation related to psychoactive drug treatment: a comparison of monotherapy versus polytherapy

BackgroundSeveral antipsychotic agents are known to prolong the QT interval in a dose dependent manner. Corrected QT interval (QTc) exceeding a threshold value of 450 ms may be associated with an increased risk of life threatening arrhythmias. Antipsychotic agents are often given in combination with other psychotropic drugs, such as antidepressants, that may also contribute to QT prolongation. This observational study compares the effects observed on QT interval between antipsychotic monotherapy and psychoactive polytherapy, which included an additional antidepressant or lithium treatment.MethodWe examined two groups of hospitalized women with Schizophrenia, Bipolar Disorder and Schizoaffective Disorder in a naturalistic setting. Group 1 was composed of nineteen hospitalized women treated with antipsychotic monotherapy (either haloperidol, olanzapine, risperidone or clozapine) and Group 2 was composed of nineteen hospitalized women treated with an antipsychotic (either haloperidol, olanzapine, risperidone or quetiapine) with an additional antidepressant (citalopram, escitalopram, sertraline, paroxetine, fluvoxamine, mirtazapine, venlafaxine or clomipramine) or lithium. An Electrocardiogram (ECG) was carried out before the beginning of the treatment for both groups and at a second time after four days of therapy at full dosage, when blood was also drawn for determination of serum levels of the antipsychotic.Statistical analysis included repeated measures ANOVA, Fisher Exact Test and Indipendent T Test.ResultsMean QTc intervals significantly increased in Group 2 (24 ± 21 ms) however this was not the case in Group 1 (-1 ± 30 ms) (Repeated measures ANOVA p < 0,01). Furthermore we found a significant difference in the number of patients who exceeded the threshold of borderline QTc interval value (450 ms) between the two groups, with seven patients in Group 2 (38%) compared to one patient in Group 1 (7%) (Fisher Exact Text, p < 0,05).ConclusionsNo significant prolongation of the QT interval was found following monotherapy with an antipsychotic agent, while combination of these drugs with antidepressants caused a significant QT prolongation. Careful monitoring of the QT interval is suggested in patients taking a combined treatment of antipsychotic and antidepressant agents.

Epidemiology of multiple sclerosis in south-western Sardinia

Background: Sardinia is a known high-risk area for multiple sclerosis (MS), but no data for south-western Sardinia (SWS) are available. SWS has a genetically homogeneous population, apart from St Peter Island, and represents a peculiar environment related to the industrial, mineralogical and military economy. Objective: To estimate prevalence and incidence and to evaluate temporal trends and geographical distribution of MS in SWS. Methods: MS prevalence was evaluated on 31 December 2007 and crude mean annual incidence rate was defined between 2003 and 2007. Temporal trend in MS incidence was assessed using the Armitage test. To identify MS clusters, Standard Morbidity Ratio (SMR) was calculated for each village and geographical distribution prevalence by means of a Bayesian hierarchical model. Results: Total crude prevalence rate was 210.4 (95% CI 186.3–234.5): 280.3 (95% CI 241.4–319.3) for females, 138 (95% CI 110.1–165.8) for males. The crude mean annual incidence rate was 9.7/100,000 (95% CI 3.4–13.2): 4.7/100,000 (95% CI 2.4–17.0) and 14.6/100,000 (95% CI 11.8–34.8) for males and females respectively. MS incidence has increased over the last 50 years. Cluster analysis showed an SMR of 0.2 (95% CI 0.05–0.68, p = 0.002) on the island of San Pietro, and 2.0 (95% CI 1.35–2.95, p = 0.001) in Domusnovas. Spatial distribution of MS was confirmed by Bayesian geographical analysis. Conclusions: Our data confirm Sardinia as a high-risk area for MS and support the relevance of genetic factors in MS, as evidenced in St Peter Island. However, we found an unexpectedly high MS prevalence in one village, in particular in males, suggesting an environmental influence on MS occurrence.

An electrophysiological approach to the diagnosis of neurogenic dysphagia: implications for botulinum toxin treatment

Objectives: Botulinum toxin (BTX) injection into the cricopharyngeal (CP) muscle has been proposed for the treatment of neurogenic dysphagia due to CP hyperactivity. The aim was to determine whether an electrophysiological method exploring oropharyngeal swallowing could guide treatment and discriminate responders from non-responders, based on the association of CP dysfunction with other electrophysiological abnormalities of swallowing. Methods: Patients with different neurological disorders were examined: Parkinson disease, progressive supranuclear palsy, multiple system atrophy-Parkinson variant, multiple system atrophy cerebellar variant, stroke, multiple sclerosis and ataxia telangiectasia. All patients presented with clinical dysphagia, and with complete absence of CP muscle inhibition during the hypopharyngeal phase of swallowing. Each patient underwent clinical and electrophysiological investigations before and after treatment with BTX into the CP muscle of one side (15 units of Botox). Clinical and electrophysiological procedures were performed in a blind manner by two different investigators. The following electrophysiological measures were analysed: (1) duration of EMG activity of suprahyoid/submental muscles (SHEMG-D); (2) duration of laryngopharyngeal mechanogram (LPM-D); (3) duration of the inhibition of the CP muscle EMG activity (CPEMG-ID); and (4) interval between onset of EMG activity of suprahyoid/submental muscles and onset of laryngopharyngeal mechanogram (I-SHEMG-LPM). Results: Two months after treatment, 50% of patients showed a significant improvement. Patients with prolonged or reduced SHEMG-D values and prolonged I-SHEMG-LPM values did not respond to BTX. Therefore, values for which BTX had no effect (warning values) were identified. Conclusions: This electrophysiological method can recognise swallowing abnormalities which may affect the outcome of the therapeutic approach to dysphagia with BTX treatment.

The Sardinian IDDM study : 1. Epidemiology and geographical distribution of IDDM in Sardinia during 1989 to 1994

Summary Analysis of the geographical variation of risk for a disease is a key issue in descriptive epidemiology and may provide useful suggestions for planning further studies to identify the underlying causes. We adopted a Bayesian approach to investigate the geographical distribution of insulin-dependent diabetes mellitus (IDDM) incidence rate across Sardinia. Data on incidence of IDDM in children aged under 15 years (619 IDDM cases) in Sardinia was obtained by the Sardinian Eurodiab ACE register. The overall completeness of ascertainment was: 91.3 %. The average yearly standardized incidence rate for the years 1989–1994 was 33.24 per 100 000 (95 % C. I. 30.60, 35.88), which is the second highest in Europe after Finland. Sex and age-specific risks were higher in males than in females. Considering the variation of IDDM risk according to the age at diagnosis, the risk profile increased up to the 13th year of age for both sexes, being steeper in males. The degree of geographical variation in IDDM risk was small with a slight difference between the highest and the lowest standardized rate across the map. Indeed, even the municipalities at lowest risk in Sardinia showed a risk higher than most European countries. The Sardinian population is genetically atypical, characterized by genetic homogeneity and marked susceptibility to autoimmune diseases. Our finding of a small geographical variation within the island coupled with a marked temporal trend previously observed in data on military conscripts could be interpreted as evidence of a relatively recent environmental aetiological factor that was uniformly distributed across the island and had its effect in a genetically predisposed population. [Diabetologia (1998) 41: 221–227]

Early prediction of the long term evolution of multiple sclerosis: the Bayesian Risk Estimate for Multiple Sclerosis (BREMS) score

Aim: To propose a simple tool for early prediction of unfavourable long term evolution of multiple sclerosis (MS). Methods: A Bayesian model allowed us to calculate, within the first year of disease and for each patient, the Bayesian Risk Estimate for MS (BREMS) score that represents the risk of reaching secondary progression (SP). Results: The median BREMS scores were higher in 158 patients who reached SP within 10 years compared with 1087 progression free patients (0.69 vs 0.30; p<0.0001). The BREMS value was related to SP risk in the whole cohort (p<0.0001) and in the subgroup of 535 patients who had never been treated with immune therapies, thus reasonably representing the natural history of the disease (p<0.000001). Conclusions: The BREMS score may be useful both to identify patients who are candidates for early or for more aggressive therapies and to improve the design and analysis of clinical therapeutic trials and of observational studies.

Association between the ancestral haplotype HLA A30B18DR3 and multiple sclerosis in Central Sardinia

Association and linkage studies have established the importance of the major histocompatibility complex (MHC) in the susceptibility for multiple sclerosis (MS). We carried out a case‐control study to investigate the ancestral haplotype A30B18DR3 and MS in the Nuoro population of Sardinia, which is isolated and genetically distinct from other populations in the Mediterranean basin and characterized by genetic homogeneity, high level of inbreeding, low migration, high prevalence of MS, high frequency of the relevant haplotype, and high past malaria prevalence. Cases and controls were serologically typed for the currently recognized HLA‐A, B, and DR antigens. We used a log‐linear approach to fit a wide class of models. We tested our hypothesis comparing different models via a likelihood ratio test. We overcame the complication due to unknown gametic phase using expectation‐maximization (EM) algorithm as the estimation method. We estimated confidence intervals for odds ratio by using a profile likelihood approach. We found that: (1) the ancestral haplotype A30B18DR3 was associated to MS after allowing for a possible stratification in cases and controls; (2) DR3 allele was conditional independent on disease status, given A30B18 haplotype; (3) there was a tendency for ORs for the high‐risk haplotypes to be higher in the high malaria strata; however, this indication did not achieve statistical significance (P = 0.11). Genet. Epidemiol. 20:271–283, 2001.

Estrogen receptor α and APOEɛ4 polymorphisms interact to increase risk for sporadic AD in Italian females

Alzheimers disease (AD) is a progressive neurodegenerative disease that affects both sexes, with a higher prevalence in women. Declining estrogen levels after menopause may render estrogen target neurons in the brain more susceptible to age or disease‐related processes such as AD. To investigate the role of two single nucleotide polymorphisms in the first intron of the ER‐α gene, denominated PvuII and XbaI, and their interaction with the known AD susceptibility gene APOE, we examined 131 patients with sporadic AD and 109 healthy control subjects. In multinomial logistic regression analysis, a significantly increased risk of sporadic AD because of interaction between the ER‐α p allele and APOE ɛ4 allele was observed in women, taking subjects who had neither the p allele nor ɛ4 as reference [odds ratio (OR) 7.24; 95% CI, 2.22–23.60]. For women carrying the ER‐α x allele together with APOE ɛ4, the risk of sporadic AD was similarly elevated (OR 8.33; 95% CI, 1.73–40.06). The data suggest that the p and x alleles of polymorphic ER‐α gene interact synergistically with the APOE ɛ4 allele to increase the risk of AD in women but not in men in this Italian cohort.

Usefulness of BFB/EMG in facial palsy rehabilitation

Objective. To analyze and to compare the recovery and the development of synkinesis in patients with idiopathic facial palsy (Bells palsy) following treatment with two methods of rehabilitation, kinesitherapy (KT) and biofeedback/EMG (BFB/EMG). Study design. Retrospective cases – series review. Methods. Seventy-four patients with Bell’ palsy were clinically evaluated within 1 month from onset of palsy and at 12 months after palsy (House scale and synkinesis evaluation). Electromyography (EMG) and Electroneurography (ENG) were performed about 4 weeks after palsy to better evaluate functional abnormalities due to facial nerve lesion. The patients followed two different protocols for rehabilitation: the first 32 patients were treated with therapeutic exercises performed by therapists (KT group), the latter 42 patients were treated using BFB/EMG methods (BFB group) with inhibition of synkinetic movement as the primary goal. Results. KT and BFB patients were evaluated for clinical and neurophysiological characteristics before rehabilitative treatment. BFB patients showed better clinical recovery and minor synkinesis than KT patients. Conclusions. BFB/EMG seems to be more useful than KT in Bells palsy treatment. This could be due to the fact that BFB/EMG gives more accurate information than KT on muscle activation with better modulation in voluntary recruitment of motor unit.

Melanoma in multiple sclerosis treated with natalizumab: causal association or coincidence?

We report a relapsing—remitting multiple sclerosis patient who received monthly intravenous natalizumab. After the fifth dose, the patient had a change in a long-standing mole. Ten months later, the mole became ulcerative and was ablated. Histological examination identified a spreading melanoma reaching the lower dermis (Clark level IV). Considering that at the moment the incidence of melanoma is estimable as about 5 per 100,000 multiple sclerosis person-years treated with natalizumab, and that, in the general population, the incidence of melanoma per 100,000 person-years is more than 10, we may speculate that the occurrence of melanoma during natalizumab treatment in multiple sclerosis is purely a coincidence.

Familial Migraine With Aura: Association Study With 5-HT1B/1D, 5-HT2C, and hSERT Polymorphisms

Background.—The serotonergic system has a significant role in the pathophysiology and pharmacology of migraine.