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Purpose: To determine the relationship between the neurogenic bladder symptoms score (NBSS) and urodynamic examination in patients affected by multiple sclerosis (MS) and related lower urinary tract dysfunction (LUTD). Methods: We recruited 122 consecutive patients with MS in remission and LUTD from January 2011 to September 2013 who underwent their first urodynamic examination. Neurological impairment was assessed using the Expanded Disability Status Scale (EDSS) and bladder symptoms were studied with the NBSS. Results: Median NBSS was 20.0 (interquartile range, 12.75–31.0). Neurogenic detrusor overactivity (NDO) was discovered in 69 patients (56.6%). The concordance between patients with NDO and maximum detrusor pressure during involuntary detrusor contraction (PdetmaxIDC)≥20.0 cm H2O was 0.89 (κ-Cohen; P

Cognitive impairment (CIm) is a frequent finding in multiple sclerosis (MS) affecting up to 65% of patients. The aim of this study was to evaluate the prevalence and incidence of CIm in a population-based cohort of MS patients identified in the city of Catania from 1995 to 2004. One-hundred and twenty-five patients experiencing the onset of MS during 1995-2004 were enrolled. Cognitive performance was assessed through the Brief Repeatable Battery (BRB) of neuropsychological tests and the Stroop word-color task (ST). CIm was defined as the failure on at least three tests involving at least two different domains. Patients without CIm at baseline were followed up after over 3 years. The most impaired tests were the Symbol Digit Modalities Test (36%) and the Paced Auditory Serial Addition Test 3 (35%). At baseline the prevalence of CIm was 44% (95% CI 35.2-53.1). An almost sixfold increased risk of developing CIm was found among MS patients aged 40 and above at the time of the NPS examination (OR 5.84; 95% CI 2.57-13.2; p value0.0001) and a threefold increased risk for patients with an EDSS score3 (OR 3.51; 95% CI 1.30-9.46, p value 0.01). At the follow-up out of the 70 MS patients without CIm at baseline evaluation, 26 (37.1 %) developed CIm. The total person-years at risk was 269 person-years giving an incidence rate of CIm of 96.6/1,000 person-year (95% CI 57.3-128.7). The overall prevalence of CIm in MS is 44% and the incidence after 4 years is 37.1%. CIm affects more frequently patients older than 40 years and with a higher EDSS score.

The experience of persons with multiple sclerosis (MS) and their caregivers is usually investigated in terms of emotional distress and health-related quality of life, while well-being indicators remain largely underexplored. In addition, findings are often interpreted from the clinical perspective, neglecting socio-cultural aspects that may crucially contribute to individuals' functioning. At the methodological level, most studies rely on scaled instruments, not allowing participants to freely express their needs and resources. Based on the bio-psycho-social perspective endorsed by the International Classification of Functioning, well-being indicators were investigated among 62 persons with MS (PwMS), their 62 caregivers and two control groups, matched by age and gender. Participants completed the Positive Affect Negative Affect Schedule (PANAS), the Satisfaction with Life Scale (SWLS), and the Eudaimonic and Hedonic Happiness Investigation instrument (EHHI). EHHI provides information on participants' happiness, goals and meanings through scaled and open-ended questions, contextualized within major life domains. No relevant differences emerged among PwMS and caregivers, compared with the respective control groups, as concerns life domains associated with happiness, goals and meaning. Participants across groups prominently mentioned family, highlighting its intrinsic value and its relevance as a sharing context; health did not represent a major theme for PwMS; community, society and religion/spirituality issues were substantially neglected by all participants. PwMS and caregivers reported lower levels of positive affect than their control groups, while no substantial differences emerged for negative affect, happiness and meaningfulness levels in life and across most domains. Results suggest that the experience of MS is associated with well-being in relevant life domains, such as family and close relationships. Although PwMS and caregivers identified a lower number of goals and meaning-related opportunities compared to control groups, they showed a positive adjustment to disease through the development of personal and family resources. These assets are often undervalued by health professionals and social institutions, while they could be fruitfully exploited through the active involvement of PwMS and their families as expert and exemplary informants in initiatives aimed at promoting the well-being of individuals and communities.

Over the last 20 years, the treatment landscape of relapsing-remitting multiple sclerosis (RRMS) has impressively changed and new oral first-line agents have been licensed. Indeed, from a complete lack of any treatment, neurologists have gone to drugs that are increasingly effective but which are associated with significant risks that can affect the survival of their patients. Neurologist specialised in the treatment of MS have to expand their medical skills and become familiar with haematological, cardiac, hepatic, renal and endocrine adverse events which were reported with the use of newer treatments now available. Neurologists must also become aware of the risk of opportunistic infections …

In the last 30 years the introduction of VATS in the surgical practice made possible to perform a wide range of thoracic operations including thymectomy. We describe our single incision video-assisted transcervical thymectomy (VATT) for non-thymomatous myasthenia gravis and/or small (

Background: Patients with paediatric-onset multiple sclerosis (POMS) could be at an increased risk for cognitive impairment (CI), given the potential harmful effects of disease activity in neurodevelopment. However, there is scarce information on their long-term cognitive outcomes. Objective: To compare the prevalence and profile of CI between adults with a history of POMS and those with classic, adult-onset multiple sclerosis (AOMS). Methods: Cognitive performance was assessed through the Brief Repeatable Battery (BRB) and the Stroop Test in consecutive patients referred to six Italian MS centres. CI was defined as impairment in ⩾2 cognitive domains. Results: In all, 119 patients with POMS and 712 with AOMS were included in this analysis. The prevalence of CI was 48.0% in AOMS, 44.5% in POMS; with similar neuropsychological profile between the two groups. However, when adjusting for current age, we found a significantly increased risk for CI (odds ratio (OR) = 1.71; p = 0.02) and for impairment in information processing speed (OR = 1.86; p Conclusion: Patients with a history of POMS appear to be at higher risk of physical and cognitive disability than AOMS patients, after correcting for age effects, with particular involvement of information processing speed.

Background Multiple sclerosis (MS) is a chronic neurological disease impacting patients’ health-related quality of life (HRQoL). Since MS specific HRQoL questionnaire are often time consuming; thus, simple, feasible and ease administering instruments are needed to assess MS HRQoL in clinical practice and clinical trials. Hence, aim of our study was to investigated the HRQoL in a large cohort of MS patients using the Coop/Wonca charts. Methods This was multicenter, independent, non-sponsored, observational study, including patients from 40 Italian MS centers. Inclusion criteria were Expanded Disability Status Scale score between 1.0 and 5.5; stable disease at enrolment. HRQoL was assessed, using six Coop/Wonca charts for physical fitness, feelings, daily activities, social activities, changes in health, health condition, and the Composites Scores of Multiple Sclerosis Quality of Life-54 (MSQoL-54), physical health composite summary (PHCS) and the mental health composite summary (MHCS). Results Out of 648, 593 relapsing-remitting MS patients, 415 (70%) women, mean age years, 417 (70%) were finally enrolled. We found a inter-rater agreement of 0.8, ranging from 0.64 to 0.91, as expressed by the alpha coefficient. Intra-rater agreement was 0.82, ranging from 0.78 to 0.96. Coop/Wonca charts were scored with a Likert method from one to five (corresponding to best and worst HRQoL respectively). According to this scoring, study population was stratified into three categories (score 1–2 corresponding to better HRQoL; score 3 corresponding to neutral profile; score 4–5 corresponding to worse HRQoL). Coop/Wonca charts resulted significantly correlated with PHCS and with MHCS.

Besides the impact of disease per se, the use of immunomodulatory therapies in adolescents with relapsing-remitting multiple sclerosis (RRMS) may have an effect on quality of life (QL). The FUTURE (Quality of liFe in adolescent sUbjecTs affected by mUltiple sclerosis treated with immunomodulatoRy agEnt using self-injecting device) study was designed to evaluate the changes in QL of Italian adolescents with RRMS receiving treatment with IFN-β1a (Rebif; 22 μg), administered subcutaneously three times weekly using the RebiSmart™ electronic autoinjection device over a 52-week period. Fifty adolescents with RRMS were enrolled and 40 completed the study. Changes from baseline to end of treatment (EoT) in adolescent self-reported and parent-reported QL were assessed using the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (PedsQL), which has been validated for use in pediatric MS and for which an Italian version is available. The adolescent self-reported total PedsQL4.0 score and all of its subscales tended to increase from baseline to EoT, the only exception being “Emotional functioning.” In parent-reported measures, the total PedsQL4.0 score increased significantly from baseline to EoT (+ 5.27 points, p = 0.041). Significant increases were also evident for parent-reported “Psychosocial health summary score” (+ 5.90 points; p = 0.015) and “School functioning” (+ 7.84 points; p = 0.029). Our results indicate that adolescents with RRMS using the electronic injection device RebiSmart™ for self-administration of Rebif® can experience long-term improvements in QL.

Multiple sclerosis (MS) is a demyelinating and neurodegenerative disease of the central nervous system (CNS), most probably autoimmune in origin, usually occurring in young adults with a female/male prevalence of approximately 3:1. Women with MS in the reproductive age may face challenging issues in reconciling the desire for parenthood with their condition, owing to the possible influence both on the ongoing or planned treatment with the possible consequences on the disease course and on the potential negative effects of treatments on foetal and pregnancy outcomes. At MS diagnosis, timely counselling should promote informed parenthood, while disease evolution should be assessed before making therapeutic decisions. Current guidelines advise the discontinuation of any treatment during pregnancy, with possible exceptions for some treatments in patients with very active disease. Relapses decline during pregnancy but are more frequent during puerperium, when MS therapy should be promptly resumed in most of the cases. First-line immunomodulatory agents, such as interferon-β (IFN-β) and glatiramer acetate (GA), significantly reduce the post-partum risk of relapse. Due to substantial evidence of safety with the use of GA during pregnancy, a recent change in European marketing authorization removed the pregnancy contraindication for GA. This paper reports a consensus of Italian experts involved in MS management, including neurologists, gynaecologists and psychologists. This consensus, based on a review of the available scientific evidence, promoted an interdisciplinary approach to the management of pregnancy in MS women.

Background Epidemiologic studies have raised the possibility that some pesticide compounds induce the neurodegenerative disease amyotrophic lateral sclerosis (ALS), though the available evidence is not entirely consistent. Methods We conducted a population-based case-control study in two Italian populations to assess the extent to which residence in the vicinity of agricultural crops associated with the application of neurotoxic pesticides is a risk factor for ALS, using crop acreage in proximity to the residence as an index of exposure. Results Based on 703 cases and 2737 controls, we computed an ALS odds ratio of 0.92 (95% confidence interval 0.78-1.09) for those in proximity to agricultural land. Results were not substantially different when using alternative exposure categories or when analyzing specific crop types, with the exception of a higher risk related to exposure to citrus orchards and olive groves in Southern Italy, though based on few exposed subjects (N = 89 and 8, respectively). There was little evidence of any dose-response relation between crop proximity and ALS risk, and using long-term residence instead of current residence did not substantially change our estimates. Conclusions Though our index of exposure is indirect and subject to considerable misclassification, our results offer little support for the hypothesis that neurotoxic pesticide exposure increases ALS risk.

Sexual dysfunction (SD) is prevalent in multiple sclerosis (MS) patients and affects quality of life. Furthermore, lower urinary tract dysfunction (LUTD) is common in MS patients.This study aims to evaluate the relationship between SD, neurological disability, depression, anxiety, and urodynamic alterations in patients with MS and LUTD.From January 2011 to September 2013, 135 consecutive patients with MS in remission phase and LUTD underwent first urodynamic examination, according to the International Continence Society criteria. Depression and anxiety were evaluated with the Hamilton Depression Scale (HAM-D) and the Hamilton Anxiety Scale (HAM-A), neurological impairment was assessed using the Expanded Disability Status Scale (EDSS), and SD was investigated with the Female Sexual Function Index (FSFI) or the International Index of Erectile Function (IIEF-15).Multivariate logistic regression analyses were carried out to identify variables for predicting female sexual dysfunction (FSD) (FSFI 26.55), male SD (IIEF-15 60), or moderate-severe erectile dysfunction (IIEF-EF ≤ 16), after adjusting for confounding factors.Total IIEF-15 and all subdomains (all P 0.01), total FSFI, FSFI-arousal, FSFI-lubrication, and FSFI-orgasm (all P 0.05) were lower in subjects with EDSS ≥ 4.5. We found inverse relationship between IIEF-15 and relative subdomains with EDSS (all P 0.01) and between FSFI and relative subdomains with EDSS (all P 0.01), HAM-D (all P 0.01), and HAM-A (all P 0.01). Continuous EDSS (odds ratio [OR] = 1.54; P = 0.03) and categorical EDSS (≥4.5) (OR = 6.0; P = 0.03), HAM-D (OR = 4.74; P = 0.03), and HAM-A (OR = 4.10; P = 0.02) were significantly associated with FSD (FSFI 26.55). Detrusor overactivity (DO) was an independent predictor of moderate-severe ED (IIEF-EF ≤ 16) (OR = 2.03; P 0.01), and of FSD (OR = 9.73; P = 0.04).Neurological disability, depression and DO are significantly predictive of SD in MS patients, irrespective of gender. An EDSS ≥ 4.5 may significantly predict the presence of SD.

Abnormalities in the gray matter (GM) of the brain parenchyma are present early in the course of multiple sclerosis.To quantify white matter (WM) and subcortical deep GM (SDGM) alterations in patients with clinically isolated syndrome (CIS) using diffusion tensor imaging (DTI).45 CIS patients and 52 healthy controls (HC) were scanned on 3T MRI. Mean diffusivity (MD) and fractional anisotropy (FA) were calculated, in addition to the estimation of structural brain volume and lesion measurements.FA was significantly lower in CIS patients in the whole brain (p0.001), total SDGM (p0.001), normal appearing (NA) GM (p=0.016), thalamus (p=0.029) putamen (p=0.036), caudate (p=0.041) and accumbens nuclei (p=0.041) compared to HC. No DTI MD or volumetric differences were detected in the brain parenchyma between CIS and HC groups. Normalized lateral ventricular volume was higher in CIS patients compared to HC (p=0.033). A significant association was detected between the increased T2 lesion number and volume and decreased FA of the NAWM (p=0.036), but not with FA of NAGM or SDGM structures.Diffuse DTI alterations of GM structures, not associated with lesion formation, are present in CIS patients.

Background: Individuals with multiple sclerosis (MS) spasticity present with a range of symptoms and disability levels that are frequently challenging to manage. Summary: Clinical case reviews in treatment-resistant MS spasticity were presented in five country-specific sessions conducted in parallel at the MS Experts Summit. Attendees at the Norwegian session discussed early response to new treatments for severe spasticity and highlighted the importance of titrating THC:CBD oromucosal spray (Sativex®) when adding it to baclofen. The French group focussed on MS symptoms and patient characteristics that interact with spasticity and agreed on a list of minimum ratings for diagnosis of MS spasticity symptoms. Attendees at the Spanish session concurred that THC:CBD oromucosal spray is effective and well tolerated as add-on therapy in treatment-resistant MS spasticity, particularly for pain, spasms and gait disturbances. The Italian group discussed the use of add-on THC:CBD oromucosal spray and other possible combination therapies for treatment-resistant MS spasticity. Attendees at the German session highlighted the need to address trigger factors for MS spasticity to reduce the potential for impact on activities of daily living (ADL) and quality of life (QoL). Three innovative studies of MS spasticity from the poster session were selected for closer review. The MOVE 1 EU epidemiological study indicated that, across western Europe, patients with MS spasticity continue to have unmet management needs. A literature review demonstrated that symptomatic relief of MS spasticity in patients who respond to THC:CBD oromucosal spray translates into sustainable improvements in ADL and QoL. Enriched-design studies of medications targeting the endocannabinoid system require careful interpretation due to possible pharmacodynamic ‘priming', i.e. carry-over effects of successful active treatment during the enrichment phase. Key Messages: Sharing experiences of clinical practice, including experience with the use of THC:CBD oromucosal spray, may be useful to overcome some of the challenges in the overall management of patients with moderate to severe treatment-resistant MS spasticity.

The above article was published online with an error in author name’s affiliation. The Author Claudia Niccolai has changed her affiliation to IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.

In the original article, Maria Pia Amato’s second affiliation was not included. The second affiliation is IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy. The correct affiliation is presented here.

The Brief Repeatable Battery (BRB) of Neuropsychological Tests is one of the most widely used instruments to assess cognitive functioning in multiple sclerosis patients. However, to date, normative data for the Italian population are available only for the version A, which limits the use of the battery in longitudinal evaluations. We administered the BRB version B to 132 healthy subjects to obtain normative values taking into account the influences of demographic factors on the test scores and calculating corrections for these relevant factors (age, gender and education). Higher age and educational level were associated with better performance on all the tests. The World List Generation was also influenced by gender, since women performed better than men. Moreover, some tests of the version B seem to be easier than those of version A. Our data can improve the applicability of the BRB for both clinical and research purposes in longitudinal assessments.

Background: There is limited and inconsistent information on the clinical determinants of cognitive impairment (CI) in multiple sclerosis (MS). Objective: The aim of this study was to compare the prevalence and profile of CI across MS disease subtypes and assess its clinical determinants. Methods: Cognitive performance was assessed through the Brief Repeatable Battery and the Stroop test in consecutive patients with MS referred to six Italian centers. CI was defined as impairment in ⩾ 2 cognitive domains. Results: A total of 1040 patients were included, 167 with clinically isolated syndrome (CIS), 759 with relapsing remitting (RR), 74 with secondary progressive (SP), and 40 with primary progressive (PP) disease course. The overall prevalence of CI was 46.3%; 34.5% in CIS, 44.5% in RR, 79.4% in SP, and 91.3% in PP. The severity of impairment and the number of involved domains were significantly higher in SP and primary progressive multiple sclerosis (PPMS) than in CIS and RR. In multivariable logistic regression analysis, the presence of CI was significantly associated with higher Expanded Disability Status Scale (EDSS) and older age. Conclusion: CI is present in all MS subtypes since the clinical onset and its frequency is increased in the progressive forms, but these differences seem to be more associated with patient age and physical disability than to disease subtype per se.

Background Depression occurs in about 50% of patients with multiple sclerosis. The aims of this study was to investigate the prevalence of depressive symptoms in a multicenter MS population using the Beck Depression Inventory II (BDI II) and to identify possible correlations between the BDI II score and demographic and clinical variables. Methods Data were collected in a multi-center, cross-sectional study over a period of six months in six MS centers in Italy using BDI II. Results 1,011 MS patients participated in the study. 676 subjects were female, with a mean age of 34 years (SD 10.8), mean EDSS of 3.3 (0–8.5) and mean disease duration of 10.3 years (range 1–50 years). 668 (%) subjects scored lower than 14 on the BDI II and 343 (33.9%) scored greater than 14 (14 cut-off score). For patients with BDI>14 multivariate analysis showed a significant difference between EDSS and disease course. BDI II scores for subjects with secondary progressive (SP) MS were significantly different from primary progressive (PP) patients (p < 0.001) but similar to relapsing-remitting (RR) patients. Considering subjects with moderate to severe depressive symptoms (BDI II score from 20–63), in relation to disease course, 11.7% (83/710) had RR MS, 40.7% (96/236) SP and 13.6% (6/44) PP. Conclusions Using the BDI II, 30% of the current sample had depressive symptoms. BDI II score correlates with disability and disease course, particularly in subjects with SP MS. The BDI II scale can be a useful tool in clinical practice to screen depressive symptoms in people with MS.

In this issue of Neurology ®, Bove et al.1 address whether hormone replacement therapy in the early menopausal years may be associated with better quality of life in women with multiple sclerosis (MS). There may be worsening of disabilities during menopause in women with MS,2 and functional networks of working memory circuitry are influenced by menopausal status.3 Estrogen replacement therapy administered after surgical menopause has shown beneficial effects on verbal memory,4 and a window of opportunity of estrogen treatment for neuroprotection has been proposed.5 In this retrospective analysis of data acquired from the Nurse's Healthy Study including 248 MS cases, the authors determined whether hormone use for at least 12 months was associated with better scores on the 10-item physical functioning assessment (PF10) subscale of the 36-Item Short Form Health Survey (quality of life). Surveys completed between 3 and 10 years after the final menstrual period were assessed (147 MS cases). They found that there was an association between better PF10 scores and estrogen use (mainly Premarin use; Pfizer, New York, NY). Also, duration of hormone treatment was associated with higher PF10 scores. An association between better PF10 scores and hormone use in women without MS was not found, suggesting that hormone treatment may uniquely benefit physical functioning in women with MS.

In 1993, the first disease-modifying therapy (DMT) specifically for relapsing-remitting multiple sclerosis (RRMS) was introduced, and an untreatable disease became treatable. The US Food and Drug Administration now has approved 14 DMTs in 8 classes with different mechanisms of action, administration routes, and side effects.1 This therapeutic palette allows neurologists to control RRMS in most patients.

Performing a therapeutic switch in MS is still a matter of debate. Objective of our study is to compare switching to another first-line therapy with switching to a second-line therapy in persons with relapsing-remitting multiple sclerosis (pwRRMS). A retrospective analysis of data prospectively collected was performed. PwRRMS experiencing on-treatment disease activity were included. No clinical relapse, no sustained disability progression by the Expanded Disability Status Scale (EDSS), and no radiological activity (new T2 and/or gadolinium-enhanced brain lesions) were used as indicators of no disease activity (NEDA 3). Time to reach the first relapse after switch and time to reach an EDSS of 4.0 were also evaluated. Ninety-one pwRRMS were enrolled. Forty-eight (52.7 %) were on lateral switch, and 43 (47.3 %) on escalation switch. At baseline, the two groups differed for T2 and T1 brain lesions number (higher in the escalation group, p

Background: In Italy, all prescriptions for THC:CBD oromucosal spray for treatment of multiple sclerosis (MS) spasticity are linked to the official Agenzia Italiana del Farmaco (AIFA) web-based registry, which tracks the effectiveness and tolerability of medications in a prospective and observational manner. Methods: AIFA e-registry data for THC:CBD oromucosal spray collected between January 2014 and February 2015 for 1,534 patients from 30 large Italian specialized MS centres were compiled. Patients had a long disease history (17.6 ± 8.6 years) and significant impairment (mean Expanded Disability Status Scale score 6.4 ± 1.2). MS spasticity was evaluated using the 0-10 numerical rating scale (NRS). Results: After the first month titration and trial period, 61.9% of patients achieved sufficient improvement in spasticity (≥20% NRS) to qualify for continued treatment. After 6 months, clinically meaningful ≥30% NRS improvement was recorded in 40.2% of patients continuing with treatment. Spasticity-associated symptoms such as cramps and nocturnal spasms improved in most responding patients. Mean reported doses of THC:CBD oromucosal spray (6.2-6.7 sprays/day) were lower than those reported in clinical trials. Adverse events (mainly mild to moderate) were reported by 15% of patients; no new safety concerns beyond the approved label were identified. Conclusion: The results of the AIFA e-registry analysis align with those of other THC:CBD observational projects and reaffirm the characteristics of this therapeutic option in the management of treatment-resistant MS spasticity, a frequently overlooked symptom.

Cognitive-motor interference refers to dual-tasking (DT) interference (DTi) occurring when the simultaneous performance of a cognitive and a motor task leads to a percentage change in one or both tasks. Several theories exist to explain DTi in humans: the capacity-sharing, the bottleneck and the cross-talk theories. Numerous studies investigating whether a specific brain locus is associated with cognitive-motor DTi have been conducted, but not systematically reviewed. We aimed to review the evidences on brain activity associated with the cognitive-motor DT, in order to better understand the neurological basis of the CMi. Results were reported according to the technique used to assess brain activity. Twenty-three articles met the inclusion criteria. Out of them, nine studies used functional magnetic resonance imaging to show an additive, under-additive, over- additive, or a mixed activation pattern of the brain. Seven studies used near-infrared spectroscopy, and seven neurophysiological instruments. Yet a specific DT locus in the brain cannot be concluded from the overall current literature. Future studies are warranted to overcome the shortcomings identified.

Introduction: Multiple sclerosis (MS) is a chronic inflammatory central nervous system disease that causes disabling physical symptoms, involving different functional domains. Because MS can be unpredictable, devising a treatment approach can be challenging. There are no tests that can reliably predict whether a specific medication will work well or poorly for any patient.Areas covered: In this review we will focus on the recommendations and decisions in MS management, considering how much far we are from a concept of personalized therapy. Personalized medicine is a medical approach that separates patients into different groups with medical decisions, practices, interventions tailored to the individual patient.Expert commentary: A personalized approach in MS therapy should be based on several factors, including: recent MS activity (in terms of severity and recovery); severity of lesion damage on magnetic resonance imaging; patients’ preferences regarding type of therapy and adverse side effects of...

Rituximab (RTX) efficacy in NMO is suggested by several case series. No consensus exists on optimal dosing strategies. At present the treatment schedules more frequently used are 375 mg/m2/week iv for 4 weeks (RTX-A) and 1000 mg iv twice, 2 weeks apart (RTX-B). Aim of this study is to confirm RTX efficacy and safety in the treatment of NMO and to evaluate whether a most favourable dosage regimen exists. Data on RTX-treated NMO patients were collected from 13 Italian Hospitals. 73 patients (64 F), were enlisted. RTX-A was administered in 42/73 patients, RTX-B in 31/73. Median follow-up was 27 months (range 7-106). Mean relapse rate in the previous year before RTX start was 2.2 +/- 1.3 for RTX-A and 2.3 +/- 1.2 for RTX-B. ARR in the first year of treatment was 0.8 +/- 0.9 for RTX-A and 0.2 +/- 0.4 for RTX-B, in the second year of treatment was 0.9 +/- 1.5 for RTX-A and 0.4 +/- 0.8 for RTX-B patients (p = 0.001 for the first year, ns (0.09) for the second year). RTX-B was more effective in delaying the occurrence of a relapse (HR 2.2 (95 % IC 1.08-4.53) p = 0.02). Adverse events were described in 19/73 patients (mainly urinary tract and respiratory infections, and infusion reactions). Two deaths were reported in severely disabled patients. Though with the limitations of an observational study, our data support RTX efficacy in NMO and suggest that high dose pulses might be more effective than a more fractioned dose.

Purpose: Individualized quality of life (QoL) measures differ from traditional inventories in that QoL domains/weights are not predetermined, but identified by the individual. We assessed practicability of the Schedule for the Evaluation of Individual QoL-Direct Weighting (SEIQoL-DW) interview in severely affected multiple sclerosis (MS) patients; the key QoL dimensions identified; and the correlation of the SEIQoL-DW index score with standard patient-reported outcome measures (PROMs). Methods: Participants were people with severe MS who performed the baseline visit of the PeNSAMI trial (ISRCTN73082124). The SEIQoL-DW was administered at the patient’s home by a trained examiner. Patients then received the following PROMs: the Core-Palliative care Outcome Scale (Core-POS), the Palliative care Outcome Scale-Symptoms-MS (POS-S-MS), the European Quality of Life Five Dimensions-3L (EQ-5D-3L), and the Hospital Anxiety and Depression Scale (HADS). Results: Of 59 enrolled patients, 11 (19 %) did not receive the SEIQoL-DW (and the other PROMs) because of severe cognitive compromise or inability to communicate. SEIQoL-DW administration was completed and deemed valid in all 48 cases (mean age 60 years, 58 % women, median Expanded Disability Status Scale score 8.5). Mean SEIQoL-DW index score was 59.1 (SD 25.5). The most commonly nominated SEIQoL-DW areas were family (94 % of the patients), relationships, and leisure activities (both 65 %). Core-POS and POS-S-MS contained 70 % of the SEIQoL-DW-nominated areas. Nevertheless, correlations between SEIQoL-DW index, Core-POS, and POS-S-MS (and the other PROMs) were negligible. Conclusions: Individualized QoL can be assessed in severely affected MS patients, providing information that is not tracked by the standard inventories Core-POS, POS-S-MS, EQ-5D-3L, and HADS.

Patient autonomy is a concept that implies variable degrees of patient participation in different aspects of health and healthcare, including the choice of therapy. This study, conducted in patients with multiple sclerosis (MS), examined several factors in relation to the patient's role in the therapeutic decision-making process. One hundred newly diagnosed patients with MS attending their first ever specialist consultation at the MS center of Catania, Italy, were consecutively enrolled in a single-center, open, observational study. Clinical and demographic data were collected as part of this routine first consultation. Through administration of the Control Preferences Scale, we ascertained the patients' willingness to participate in the decision-making process on their first-line treatment, classifying them, on the basis of their attitude, as passive, collaborative or active. Of 100 patients with MS, 40 had a passive attitude, while 35 were willing to collaborate and 25 wanted to play an active role in the decision-making process. The patients showing an active attitude had a significantly higher Expanded Disability Status Scale score and a significantly higher number of relapses (p

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection of the central nervous system caused by the John Cunningham virus (JCV) that has been associated with therapeutic immunosuppression in patients with multiple sclerosis (MS). So far, more than 600 cases of PML have been reported in association with natalizumab administration. There have also been confirmed cases of PML in individuals who received fingolimod and dimethyl fumarate without previous natalizumab treatment. The new licensed disease-modifying therapies for MS carry the risk of immunosuppressant and so of JCV reactivation. Various factors have been identified with increased risk of developing PML, including a positive JCV serology, natalizumab administration for >2 years, and prior use of immunosuppressive agents. Clinicians can employ such tools for patients’ risk stratification, but the incidence of PML among patients receiving natalizumab therapy has not changed. In this review we outline the current state of understanding of PML pathogenesis and patients’ risk stratification. The landscape of MS is dramatically changing and knowledge of the side effects of the licensed therapies is imperative to enable optimal decision making.

Though recent progress in multiple sclerosis (MS) treatment is remarkable, numerous unmet needs remain to be addressed often inducing patients to look for complementary and alternative medicines (CAM), especially herbal remedies (HR). HR use, scarcely investigated in MS, may cause adverse reactions (AR) and interfere with conventional treatment. We performed a survey aimed at evaluating use and attitudes towards HR and factor associated to HR use. Other CAM use and attitudes have been investigated as well. Multiple-choice questionnaires were distributed to MS out patients attending 14 Italian referral Centers. Multivariable logistic regression was used to identify HR use determinants. Present/past HR use for either MS or other diseases was reported in 35.6 % of 2419 cases (95 % CI 36.0-40.0 %). CAM use was reported in 42.5 % of cases. Independent predictors of HR use were represented by higher education, geographic area, dissatisfaction with conventional treatment of diseases other than MS and benefit perception from CAM use. Both HR and CAM use were not always disclosed to the healthcare professional. In conclusion, HR and other CAM appear to be popular among MS patients. The involvement of the healthcare professionals appears to be scarce with potential risk of AR or interference with conventional treatments.

Introduction: Multiple Sclerosis is the leading cause of no traumatic disability in young people. Nowadays, neurorehabilitation is commonly prescribed in patients with MS, but there are still some issues to be explored further. In this review, we discuss the following topics: 1) the neuroscientific basis of neurorehabilitation in multiple sclerosis; 2) what would be the ideal set of rehabilitative treatment: inpatients, outpatient or home-based therapy? Methods: A systematic search was made, using combination of the following terms: rehabilitation, multiple sclerosis, disability, plasticity, motor learning, cognitive rehabilitation, quality of life. Results: A growing amount of evidence suggest that motor and cognitive rehabilitation may enhance functional and structural brain plasticity in patients with multiple sclerosis. Improvement of function seems to be correlated with functional Magnetic Resonance Imaging changes in brain. Moreover, several studies show the effectiveness of cognitive rehabilitation to improve some domains of neuropsychological functions, such as attention, information processing and executive functions. Regarding the rehabilitative setting, it should be chosen taking into account the personal needs of each patient. All the studies, performed in different setting, demonstrated the effectiveness of rehabilitation in Persons affected by multiple sclerosis. Conclusion: Rehabilitation is effective in mitigating disability and improving QoL in persons with MS. Setting for rehabilitation treatment should be chosen taking into account many personal needs and desires of each patient.

Patti F, Nicoletti A, Pappalardo A, Castiglione A, Lo Fermo S, Messina S, D’Amico E, Cimino V, Zappia M. Frequency and severity of headache is worsened by Interferon-β therapy in patients with multiple sclerosis. Acta Neurol Scand: 2012: 125: 91–95. © 2011 John Wiley & Sons A/S. Background – The relationship between multiple sclerosis (MS) and headache (HA) is not well known. It was reported that interferon-beta (IFNβ) could induce or worsen HA. Objective – To evaluate the impact of IFNβ treatment on HA and the relationship between HA and the various commercial preparations of IFNβ in mildly disabled patients with MS. Methods – A specific questionnaire was administered to 357 relapsing-remitting MS patients. Characteristics of HAs were considered, including the temporal relationships with IFNβ administration. Results – One hundred and seventeen patients were treated with weekly intramuscular injections of interferon IFNβ-1a (Avonex®), 84 with subcutaneous injections of IFNβ-1b (Betaferon®) every other day, 48 and 108 with three times weekly subcutaneous injections of IFNβ-1a (Rebif®) 22 mcg or IFNβ-1a (Rebif®) 44 mcg, respectively. Three hundred and fourteen patients were affected by HA, and among them, 219 patients suffered of pre-existing HA. In this latter group, 121 subjects (55%) noted a worsening of their HA after starting IFNβ therapy; this was more frequently reported by patients treated with Avonex® and Rebif® 44. Ninety-five patients experienced new HA. Conclusion – IFNβ treatment could worsen HA in patients with pre-existing HA or cause the appearance of new HA. Among different IFNβ preparations, Rebif® 44 and Avonex® seemed to be more cephalalgic than the other drugs.

Background: Most disease-modifying therapies (DMTs) for multiple sclerosis (MS) are self-injectable medications that must be taken on an ongoing basis to reduce disease activity. Thus, adherence to therapy becomes an important challenge that must be addressed to maximize benefits of therapy. This study evaluated rates of adherence to prescribed treatment and explored factors affecting adherence amongst patients with relapsing-remitting MS. Methods: This was an observational, multicenter, multinational, phase 4 study. Patients and physicians received paper questionnaires regarding adherence to DMTs approved at the time of the study, including intramuscular interferon beta-1a (IFNβ-1a), subcutaneous IFNβ-1a, IFNβ-1b, and glatiramer acetate. Quality of life and cognition data also were collected. Multivariate analysis was conducted to identify factors associated with adherence to long-term DMTs. Results: Two thousand six hundred and forty-eight patients were studied, revealing an average treatment duration of 31 months. Seventy-five percent of patients (n = 1923) were adherent to therapy. The most common reasons for non-adherence were forgetting to administer the injection (50.2%) and other injection-related reasons (32.0%). Adherent patients reported better quality of life (P

Background and Objective: The objective of this study was to determine the prevalence and incidence of multiple sclerosis (MS) and its temporal profiles from 1975 to 2005 in the city of Catania. Methods: The incidence of MS from 1975 to 31 December 1999 had been previously investigated by the same group. The frequency of MS in the community of Catania from 1 January 2000 to 31 December 2004 was studied in a population of 313,110 inhabitants (2001 census). All patients who satisfied Poser’s criteria were considered as prevalent and incident cases. Results: Three hundred and ninety-eight patients with MS who had experienced the clinical onset of the disease before 31 December 2004 were found in a population of 313,110 inhabitants. The prevalence rate was 127.1/100,000 [95% confidence interval (CI) 115.1–140.4]. From 2000 to 2004, 108 patients with MS had clinical onset of the disease . The mean annual incidence was 7.0/100,000 (95% CI 5.7–13.7) and was higher in women (8.4/100,000; 95% CI 6.4–10.5) than in men (5.3/100,000; 95% CI 3.7–7.2). The mean length of time between the date of clinical onset and the date of the diagnosis was 1.4 ± 1.7 years. During the last 30 years the incidence of MS in this population increased from 1.3/100,000 during the first quinquennium (1975–9) to 7.0/100,000 during 2000–4. Conclusions: Incidence rates have further increased in this population, suggesting that the risk of MS is still increasing.

Annunziata P, De Santi L, Di Rezze S, Millefiorini E, Capello E, Mancardi G, De Riz M, Scarpini E, Vecchio R, Patti F. Clinical features of Sjogren’s syndrome in patients with multiple sclerosis. Acta Neurol Scand: 2011: 124: 109–114. © 2010 John Wiley & Sons A/S. Objectives – To assess the frequency of clinical features of Sjogren’s syndrome (SS) in patients with multiple sclerosis (MS) receiving treatment with disease-modifying drugs (DMDs) or naive to treatment and the possible association with clinical, cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) parameters. Methods – A multicentre cross-sectional observational study was designed, based on a structured neurologist-administered questionnaire to 440 patients. Results – Twenty-eight of 230 (12%) patients receiving treatment with DMDs (DMDs+) and 14 of 210 (6.6%) treatment-naive patients (DMDs−) showed clinical features of SS. Four primary SS were diagnosed, two of which were DMDs+ and two were DMDs−. Sicca symptoms were significantly associated with higher EDSS scores (P = 0.018), a low frequency of gadolinium-enhanced MRI-positive lesions (P = 0.018) and cerebral disturbances (P = 0.001). Conclusions – Screening for the clinical features of SS should be performed in patients with MS both receiving treatment with immunomodulatory drugs and without therapy.

Psychiatric disturbances may occur at the onset of multiple sclerosis. However, information on their outcome is lacking. Our objective was to document the characteristics of psychiatric symptoms at presentation of multiple sclerosis and to define the long-term evolution of psychiatric disturbances in these patients. Based on a clinical record analysis of patients with defined multiple sclerosis diagnosis and coming under the care of a university multiple sclerosis centre within the period 1997—2007, patients with both psychiatric and neurological symptoms at presentation were identified. Clinical data at onset and at last follow-up were considered. Among 682 evaluated patients, psychiatric disturbances were associated with multiple sclerosis onset in 16 cases (2.3%). Most patients (56%) presented with a mood disorder with clinical characteristics of a major depressive-like episode, five (32%) had psychotic symptoms. Initial psychiatric disturbances improved later than neurological symptoms, or never fully recovered, regardless of the concomitant use of psychotropic medications. In most of the subjects psychiatric disturbances tended to remain over the follow-up period and at last visit, after a mean follow-up of 7.6 years (±2.3), 14 subjects (87%) had a supplementary diagnosis of psychiatric illness. Psychiatric symptoms at onset of multiple sclerosis may be indicators of possible maintenance of psychiatric morbidity in a sizeable proportion of patients.

Importance Chronic cerebrospinal venous insufficiency (CCSVI) is characterized by restricted venous outflow from the brain and spinal cord. Whether this condition is associated with multiple sclerosis (MS) and whether venous percutaneous transluminal angioplasty (PTA) is beneficial in persons with MS and CCSVI is controversial. Objective To determine the efficacy and safety of venous PTA in patients with MS and CCSVI. Design, Setting, and Participants We analyzed 177 patients with relapsing-remitting MS; 62 were ineligible, including 47 (26.6%) who did not have CCSVI on color Doppler ultrasonography screening. A total of 115 patients were recruited in the study timeframe. All patients underwent a randomized, double-blind, sham-controlled, parallel-group trial in 6 MS centers in Italy. The trial began in August 2012 and concluded in March 2016; data were analyzed from April 2016 to September 2016. The analysis was intention to treat. Interventions Patients were randomly allocated (2:1) to either venous PTA or catheter venography without venous angioplasty (sham). Main Outcomes and Measures Two primary end points were assessed at 12 months: (1) a composite functional measure (ie, walking control, balance, manual dexterity, postvoid residual urine volume, and visual acuity) and (2) a measure of new combined brain lesions on magnetic resonance imaging, including the proportion of lesion-free patients. Combined lesions included T1 gadolinium-enhancing lesions plus new or enlarged T2 lesions. Results Of the included 115 patients with relapsing-remitting MS, 76 were allocated to the PTA group (45 female [59%]; mean [SD] age, 40.0 [10.3] years) and 39 to the sham group (29 female [74%]; mean [SD] age, 37.5 [10.6] years); 112 (97.4%) completed follow-up. No serious adverse events occurred. Flow restoration was achieved in 38 of 71 patients (54%) in the PTA group. The functional composite measure did not differ between the PTA and sham groups (41.7% vs 48.7%; odds ratio, 0.75; 95% CI, 0.34-1.68;P = .49). The mean (SD) number of combined lesions on magnetic resonance imaging at 6 to 12 months were 0.47 (1.19) in the PTA group vs 1.27 (2.65) in the sham group (mean ratio, 0.37; 95% CI, 0.15-0.91;P = .03: adjustedP = .09) and were 1.40 (4.21) in the PTA group vs 1.95 (3.73) in the sham group at 0 to 12 months (mean ratio, 0.72; 95% CI, 0.32-1.63;P = .45; adjustedP = .45). At follow-up after 6 to 12 months, 58 of 70 patients (83%) in the PTA group and 22 of 33 (67%) in the sham group were free of new lesions on magnetic resonance imaging (odds ratio, 2.64; 95% CI, 1.11-6.28;P = .03; adjustedP = .09). At 0 to 12 months, 46 of 73 patients (63.0%) in the PTA group and 18 of 37 (49%) in the sham group were free of new lesions on magnetic resonance imaging (odds ratio, 1.80; 95% CI, 0.81-4.01;P = .15; adjustedP = .30). Conclusion and Relevance Venous PTA has proven to be a safe but largely ineffective technique; the treatment cannot be recommended in patients with MS. Trial Registration clinicaltrials.gov Identifier:NCT01371760

Background and purpose: Multiple sclerosis (MS) patients are often emotionally disturbed. We investigated anger in these patients in relation to demographic, clinical, and mood characteristics. Patients and methods: About 195 cognitively unimpaired MS patients (150 relapsing–remitting and 45 progressive) were evaluated with the State Trait Anger Expression Inventory, the Chicago Multiscale Depression Inventory, and the State Trait Anxiety Inventory. The patients’ anger score distribution was compared with that of the normal Italian population. Correlation coefficients among scale scores were calculated and mean anger scores were compared across different groups of patients by analysis of variance. Results: Of the five different aspects of anger, levels of withheld and controlled Anger were respectively higher and lower than what is expected in the normal population. Although anger was correlated with anxiety and depression, it was largely independent from these mood conditions. Mean anger severity scores were not strongly influenced by individual demographic characteristics and were not higher in more severe patients. Conclusions: The presence of an altered pattern of anger, unrelated to the clinical severity of MS, suggests that anger is not an emotional reaction to disease stress. An alteration of anger mechanisms might be a direct consequence of the demyelination of the connections among the amygdale, the basal ganglia and the medial prefrontal cortex.

Objective: Recent findings support greater efficacy of early vs. delayed interferon beta (IFN) treatment in patients with a first clinical event suggestive of multiple sclerosis (MS). We aimed to evaluate the effectiveness of early IFN treatment in definite relapsing-remitting MS (RRMS) and to assess the optimal time to initiate IFN treatment with regard to the greatest benefits on disability progression. Methods: A cohort of 2,570 IFN-treated RRMS patients was prospectively followed for up to 7 years in 15 Italian MS Centers. A Cox proportional hazards regression model adjusted for propensity score (PS) quintiles was used to assess differences between groups of patients with early vs. delayed IFN treatment on risk of reaching a 1-point progression in the Expanded Disability Status Scale (EDSS) score, and the EDSS 4.0 and 6.0 milestones. A set of PS-adjusted Cox hazards regression models were calculated according to different times of treatment initiation (within 1 year up to within 5 years from disease onset). A sensitivity analysis was performed to assess the robustness of findings. Results: The lowest hazard ratios (HRs) for the three PS quintiles–adjusted models were obtained by a cutoff of treatment initiation within 1 year from disease onset. Early treatment significantly reduced the risk of reaching a 1-point progression in EDSS score (HR 0.63; 95% CI 0.48 – 0.85; p 0.002), and the EDSS 4.0 milestone (HR 0.56; 95% CI 0.36 – 0.90; p 0.015). Sensitivity analysis showed the bound of significance for unmeasured confounders. Interpretation: Greater benefits on disability progression may be obtained by an early IFN treatment in RRMS. Ann Neurol 2009;66:513–520

Introduction: Drug rash with eosinophilia and systemic signs (DRESS) syndrome is defined by the triad of fever, dermatitis, and internal organ involvement, characteristically occurring with a delay of 3 to 8 weeks after the initiation of treatment with the associated drug. We describe a case of DRESS syndrome in a patient with multiple sclerosis (MS), characterized by a very high eosinophilia and cholestatic hepatitis. Case summary: A 44-year-old white woman with primary progressive MS receiving a multidrug of PO baclofen 75 mg/d, PO piracetam 3 g/d, and IV mitoxantrone 10 mg administered once a month presented to the Multiple Sclerosis Center, University of Catania, Catania, Italy. Eight weeks after the introduction of the latter 2 drugs, the patient had clinical and histological signs of severe cholestatic syndrome followed by hypereosinophilia. All treatments were stopped on admission. Laboratory tests (serologic viral markers, autoantibody pattern antinuclear autoantibodies, antismooth muscle autoantibodies, antimitochondrial autoantibodies, antineutrophil-cytoplasmic autoantibodies, antiliver-kidney-microsomes), abdomen ultrasound, and magnetic resonance cholangiopancreatography did not reveal a cause of the cholestatic syndrome. A liver biopsy was performed because of the persistence of the clinical signs. A Naranjo rating of 4 suggested that mitoxantrone was possibly associated with the occurrence of DRESS. Six months after the first symptoms of DRESS appeared, laboratory tests were normal. Although there are few diagnostic methods for confirming an adverse drug hypersensitivity reaction, a skin prick test suggested a marked positivity for mitoxantrone at all concentrations (100%, 50%, 10%). During the first 72 hours, reaction was characterized by skin edema, erythema, and itchiness in the site of inoculation of the drug. The local reaction started to regress after 72 hours, with a complete restitution ad integrum in 6 days. A blue discoloration of skin remained for an additional 13 days. Conclusion: We report a case of DRESS syndrome possibly associated with mitoxantrone in a patient with MS.

We carried out a population-based case-control study to evaluate the association between multiple sclerosis (MS) and headache. We had previously determined the incidence of MS during 1990-1999 in Catania, Sicily, identifying 155 incident MS patients; these subjects underwent a telephone interview using a standardized questionnaire for headache. Diagnosis and classification of headaches were made according to International Headache Society criteria (1988). A control group was selected from the general population through random digit dialling. One hundred and one (65.2±) MS patients, of the 155 identified, and 101 controls were screened for headaches. Fifty-eight (57.4±) MS patients and 38 (37.2±) controls fulfilled the diagnostic criteria of headache. A significant association between MS and headache was found with an adjusted odds ratio, estimated by logistic regression, of 2.18 (95± confidence interval 1.27, 3.93). Frequency of headaches in our MS population is higher than in the general population, supporting the hypothesis of a possible association between these two conditions.

There exist controversial and discrepant results on the risk of spontaneous abortions and teratogenesis induced by interferon treatment in people with MS.Aim of this study is to evaluate risks of the administration of INFbeta related not only to the foetus, but also to children development up to 12-months developmental milestones.The study design is retrospective with a follow-up of babies until 18-months of their life. Thirty-eight women out of 240 with MS followed-up at Clinic MS Center of the University Hospital of Catania, Italy became pregnant in the period june 1997-may 2006. Patients were grouped into three arms: in utero exposed to INFbeta, never treated and patients who discontinued INFbeta before starting conception. Pregnancy outcomes, birth weight, 12-month developmental milestones were collected with an ad hoc questionnaire.Newborns of in utero exposed to INFbeta patients were little smaller for birth weight (3079.6 +/- 313.3 g), but not statistically significant, if compared with the other groups. Developmental milestones appeared within the normal range in all groups.Our results were particularly favourable on pregnancy outcomes, because we observed only a smaller birth weight which was not detrimental for the further development of children. We believe that INFbeta therapy might not be considered to be a reason for interruption of an intact pregnancy once the drug has been discontinued until delivery.

Background and purpose Trace elements (TEs) may play a role in the pathogenesis of amyotrophic lateral sclerosis (ALS) and volcanic degassing is the major natural source of TEs. Mount Etna, in the province of Catania, is the largest active volcano in Europe. Our aim was to assess the incidence of ALS in the province of Catania during 2005–2010 and its spatial distribution with respect to volcanic gas deposition. Methods Cases from all neurological centres of the province of Catania and of the boundary provinces were retrospectively collected. Patients who had onset during 2005–2010 and fulfilled the El Escorial revised diagnostic criteria were included. The incidence of ALS was estimated for the entire province and separately for the population living on the eastern and western flank of Mount Etna, respectively, the most and least exposed areas to volcanogenic TEs, considered as a possible risk factor for ALS. Results One hundred and twenty-six (57 men) ALS patients were enrolled. The mean annual crude incidence rate was 2.0/100 000 person-years (95% confidence interval 1.7–2.4). A higher incidence rate was found in the population living on the eastern flank compared to the western flank (2.4/100 000 and 0.9/100 000 respectively) with a relative risk of 2.75 (95% confidence interval 1.64–4.89; P < 0.001). Conclusions The incidence of ALS in the province of Catania is close to those reported worldwide. The incidence was higher amongst the population living on the eastern flank of Mount Etna, which could be interpreted as a possible role of volcanogenic TEs. Further research on TEs and genetic factors is necessary to support this assumption.