Background
The Work Ability in Natalizumab-Treated MS Patients (WANT) study assessed work ability, quality of life, and cognitive processing speed during natalizumab treatment.
Methods
WANT was a ...1-year, prospective, multicenter observational study conducted in Italy. Inclusion criteria included relapsing-remitting multiple sclerosis (MS), natalizumab treatment, full-time worker status, and loss of working hours due to MS as measured by the Work Productivity and Activity Impairment Questionnaire for MS (WPAI:MS). The primary endpoint was change in WPAI:MS domain scores after 1 year on natalizumab. Secondary endpoints included change in annualized relapse rate (ARR), Multiple Sclerosis Impact Scale (MSIS-29) score, and Symbol Digit Modalities Test (SDMT) score.
Results
At enrollment, the 91 patients had a mean age of 38.3 (standard deviation SD, 9.0) years and a mean ARR of 1.5 (SD, 0.8). After 1 year, improvements were observed in all WPAI:MS domains, with significant reductions in Absenteeism (−4.2 SD, 26.0,
p
= 0.0190) and Work Productivity Loss (−7.2 SD, 28.6;
p
= 0.0456). These changes were accompanied by a low ARR (0.1), and 87.9% of patients were relapse free. Significant improvement was observed in MSIS-29 physical and psychological domains (reductions of 2.8 SD, 11.6;
p
= 0.0295 and 6.3 SD, 15.6;
p
= 0.0007, respectively) and SDMT score (increase of 2.4 SD, 7.9;
p
= 0.0006). Adverse events were reported in 32 of 104 patients (30.8%).
Conclusions
The reductions in Absenteeism and Work Productivity Loss and the improved physical and psychological functioning reported after 1 year of natalizumab treatment in real-world settings extend our understanding of natalizumab’s effects on patient-centric and health economics outcomes.
•ECTS is associated with various degrees of neuropsychological impairment.•Our review aimed to clarify and synthesize the available literature regarding executive function (EF) profile of children ...with ECTS within a comprehensive theoretical framework and the clinical variables’ impact on these abilities.•Results confirmed the presence of a specific impairment in two abilities: inhibitory control and cognitive flexibility.•The early detection of children with ECTS at risk of developing neuropsychological impairment could activate interventions and prevent worse school achievement, social functioning, and a poor quality of life.
Self-limited Epilepsy with Centrotemporal Spikes (ECTS) is a self-limiting childhood epilepsy with an overall good prognosis. The neurocognitive profile of ECTS shows various degrees of neuropsychological impairment, with speech impairment and executive dysfunction being the most prominent. This review aimed to clarify the executive function (EF) profile of children with ECTS and the clinical variables’ impact on these abilities. We conducted a systematic review of the relevant literature for articles published up to January 2021. Demographic and clinical characteristics were abstracted from the original records. EF tasks used in the studies were classified according to Diamond’s model, which identified four components: working memory, inhibitory control, cognitive flexibility, and higher order EFs. Twenty-three studies were included. Among the included records, 14 studies examined working memory, 15 inhibitory control, 15 flexibility, 4 higher order EFs, and 2 general EFs. Results confirmed the presence of a specific impairment in two abilities: inhibitory control and cognitive flexibility. This review confirms the need to assess each EF both in verbal and visual-spatial tasks. The early detection of children with ECTS at risk of developing neuropsychological impairment could activate interventions and prevent worse school achievement, social functioning, and a poor quality of life.
Systematic review registration: PROSPERO: CRD42021245959.
Although specific neuropsychological deficits have been recognized during the active phase of epilepsy with centrotemporal spikes (ECTS), the natural cognitive and neuropsychological history after ...remission has not been elucidated so far. We evaluated the natural cognitive and neuropsychological outcomes five years after disease remission and investigated possible predictors of long-term outcome among socio-demographic and electro-clinical variables. We performed an observational cross-sectional study. Electro-clinical characteristics during the active phase of epilepsy, as well as antiepileptic treatment and premorbid neurodevelopmental concerns were reviewed for 70 patients. At least five years after epilepsy remission, all patients were contacted, and 46 completed a structured questionnaire about patients’ current education and academic skills, general health, and parents’ socio-economic status. Among them, 23 patients underwent an ad hoc cognitive and neuropsychological protocol and emotional-behavioral assessment. Chi-square tests and t-tests were carried out to define the role of putative predictors of neuropsychological outcomes. Mean cognitive and neuropsychological performances appeared to be overall adequate, except for the dictation. Positive family history for epilepsy (p = 0.01769) and familial socioeconomic status (mother’s schooling (p = 0.04169), father’s schooling (p = 0.01939), mother’s income (p = 0.0262), father’s income (p = 0.01331)) were identified as predictors of outcomes. Our data suggest that ECTS with typical electro-clinical features depicts an overall preserved cognitive and neuropsychological long-term outcome. We suggest particular attention should be paid to patients with socio-economic disadvantage and familial history of epilepsy, as they may experience worse neurocognitive post-morbid performances.
gene has been known to be the cause of "hyperphosphatasia, mental retardation syndrome-3" (HPMRS3). To date, 14 pathogenic variants in
have been identified as the cause of this syndrome in 24 ...patients described in single-case reports or small clinical series with pan-ethnic distribution. We aim to present a pediatric
-mutated case, intending to further expand the clinical phenotype of the syndrome and to report our experience on a therapeutic approach to drug-resistant epilepsy.We present the clinical, neuroradiological, and genetic characterization of a Caucasian pediatric subject with biallelic pathogenic variants in the
gene revealed by next generation sequencing analysis.We identified a subject who presented with global developmental delay and visual impairment. Brain magnetic resonance imaging showed mild hypoplasia of the inferior cerebellar vermis and corpus callosum and mild white matter reduction. Laboratory investigations detected an increase in alkaline phosphatase. At the age of 13 months, he began to present epileptic focal seizures with impaired awareness, which did not respond to various antiseizure medications. Electroencephalogram (EEG) showed progressive background activity disorganization and multifocal epileptic abnormalities. Treatment with high-dose pyridoxine showed partial benefit, but the persistence of seizures and the lack of EEG amelioration prompted us to introduce ketogenic diet treatment.Our case provides a further phenotypical expansion of HPMRS3 to include developmental and epileptic encephalopathy. Due to the limited number of patients reported so far, the full delineation of the clinical spectrum of HPMRS3 and indications for precision medicine would benefit from the description of new cases and their follow-up evaluations.
Purpose
Obstructive sleep apnea (OSA) is the most prevalent sleep-related breathing disorder, with a negative impact on cardiovascular health. Different OSA symptoms and treatment response in males ...and females have been reported. The aim of this study was to investigate inflammatory markers in patients with OSA and the relationship of those markers to disease severity in male and female subjects.
Methods
We considered consecutive subjects referred to the outpatient Sleep Disorder Service of the Respiratory Medicine Department, San Marino Hospital. We included patients with a diagnosis of moderate or severe OSAS and an age range of 45–80 years. Concomitant inflammatory conditions were an exclusion criterion. A polygraphic study and a blood draw for inflammatory markers were performed for each subject.
Results
Of 110 subjects, 59 were males. Severe OSA affected 72 subjects. We analyzed data through a 4-level categorical variable according to sex and OSA severity (moderate OSA, males; severe OSA, males; moderate OSA, females; severe OSA, females), which showed significant differences for interleukin-6 (IL-6) and C-reactive protein (CRP) levels. A significant difference in IL-6 levels with a significant ascending trend (
p
= 0.045) from females with moderate OSAS to males with severe OSAS emerged in our pairwise comparison for estimated marginal means. Also, a significant trend (
p
= 0.0001) for CRP levels from males with moderate OSAS to females with severe OSAS was shown.
Conclusions
OSA and inflammation are interconnected, and both are associated with vascular diseases. Sex-related differences in OSA phenotypes may help the clinicians aim for a more personalized approach.
Background and purpose
Tumefactive multiple sclerosis (TuMS) (i.e., MS onset presenting with tumefactive demyelinating lesions TDLs) is a diagnostic and therapeutic challenge. We performed a ...multicentre retrospective study to describe the clinical characteristics and the prognostic factors of TuMS.
Methods
One hundred two TuMS patients were included in this retrospective study. Demographic, clinical, magnetic resonance imaging (MRI), laboratory data and treatment choices were collected.
Results
TuMS was found to affect women more than men (female:male: 2.4), with a young adulthood onset (median age: 29.5 years, range: 11–68 years, interquartile range IQR: 38 years). At onset, 52% of TuMS patients presented with the involvement of more than one functional system and 24.5% of them with multiple TDLs. TDLs most frequently presented with an infiltrative MRI pattern (38.7%). Cerebrospinal fluid immunoglobulin G oligoclonal bands were often demonstrated (76.6%). In 25.3% of the cases, more than one acute‐phase treatment was administered, and almost one‐half of the patients (46.6%) were treated with high‐efficacy treatments. After a median follow‐up of 2.3 years (range: 0.1–10.7 years, IQR: 3.4 years), the median Expanded Disability Status Scale (EDSS) score was 1.5 (range: 0–7, IQR: 2). Independent risk factors for reaching an EDSS score ≥3 were a higher age at onset (odds ratio OR: 1.08, 95% confidence interval CI: 1.03–1.14, p < 0.01), a higher number of TDLs (OR: 1.67, 95% CI: 1.02–2.74, p < 0.05) and the presence of infiltrative TDLs (OR: 3.34, 95% CI: 1.18–9.5, p < 0.001) at baseline.
Conclusions
The management of TuMS might be challenging because of its peculiar characteristics. Large prospective studies could help to define the clinical characteristics and the best treatment algorithms for people with TuMS.
Multiple sclerosis (MS) presenting at onset with tumefactive demyelinating lesions (shown here, a representative magnetic resonance image) should be considered a part of the MS spectrum, but with its own peculiar features. Among them, tumefactive MS frequently has a multifocal clinical onset, which often requires acute‐phase retreatments. The recurrence of further tumefactive lesions is rare, and the median 2‐year Expanded Disability Status Scale score is 1.5, though patients were frequently treated with high‐efficacy drugs, a therapeutic choice that may have influenced the disease course. Among tumefactive MS‐specific prognostic factors, tumefactive lesions, with an infiltrative magnetic resonance imaging pattern at onset, are associated with worse disability outcomes.
We investigated the occurrence and relative contribution of relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) to confirmed disability accrual (CDA) and ...transition to secondary progression (SP) in relapsing multiple sclerosis (MS).
Relapsing-onset MS patients with follow-up > / = 5 years (16,130) were extracted from the Italian MS Registry. CDA was a 6-month confirmed increase in Expanded Disability Status Scale (EDSS) score. Sustained disability accumulation (SDA) was a CDA with no EDSS improvement in all subsequent visits. Predictors of PIRA and RAW and the association between final EDSS score and type of CDA were assessed using logistic multivariable regression and multivariable ordinal regression models, respectively.
Over 11.8 ± 5.4 years, 16,731 CDA events occurred in 8998 (55.8%) patients. PIRA (12,175) accounted for 72.3% of CDA. SDA occurred in 8912 (73.2%) PIRA and 2583 (56.7%) RAW (p < 0.001). 4453 (27.6%) patients transitioned to SPMS, 4010 (73.2%) out of 5476 patients with sustained PIRA and 443 (24.8%) out of 1790 patients with non-sustained PIRA. In the multivariable ordinal regression analysis, higher final EDSS score was associated with PIRA (estimated coefficient 0.349, 95% CI 0.120-0.577, p = 0.003).
In this real-world relapsing-onset MS cohort, PIRA was the main driver of disability accumulation and was associated with higher disability in the long term. Sustained PIRA was linked to transition to SP and could represent a more accurate PIRA definition and a criterion to mark the putative onset of the progressive phase.
In multiple sclerosis (MS), MRI markers can measure the potential neuroprotective effects of fingolimod beyond its anti-inflammatory activity. In this study we aimed to comprehensively explore, in ...the real-word setting, whether fingolimod not only reduces clinical/MRI inflammatory activity, but also influences the progression of irreversible focal and whole brain damage in relapsing-remitting RR MS patients.BACKGROUND AND OBJECTIVESIn multiple sclerosis (MS), MRI markers can measure the potential neuroprotective effects of fingolimod beyond its anti-inflammatory activity. In this study we aimed to comprehensively explore, in the real-word setting, whether fingolimod not only reduces clinical/MRI inflammatory activity, but also influences the progression of irreversible focal and whole brain damage in relapsing-remitting RR MS patients.The "EVOLUTION" study, a 24-month observational, prospective, single-arm, multicenter study, enrolled 261 RRMS patients who started fingolimod at 32 Italian MS centers and underwent biannual neurological assessments and annual MRI evaluations. Study outcomes included the proportions of evaluable RRMS patients achieving at 24 months: (1) no new/enlarging T2-hyperintense white matter (WM) lesions and/or clinical relapses; (2) a modified classification of "No Evidence of Disease Activity 4" ("modified NEDA-4") defined as no new/enlarging T2-hyperintense WM lesions, clinical relapses, and 6-month confirmed disability progression, and a yearly percentage lateral ventricular volume change on T2-FLAIR images < 2%; (3) less than 40% of active lesions at baseline and month 12 evolving to permanent black holes (PBHs).METHODSThe "EVOLUTION" study, a 24-month observational, prospective, single-arm, multicenter study, enrolled 261 RRMS patients who started fingolimod at 32 Italian MS centers and underwent biannual neurological assessments and annual MRI evaluations. Study outcomes included the proportions of evaluable RRMS patients achieving at 24 months: (1) no new/enlarging T2-hyperintense white matter (WM) lesions and/or clinical relapses; (2) a modified classification of "No Evidence of Disease Activity 4" ("modified NEDA-4") defined as no new/enlarging T2-hyperintense WM lesions, clinical relapses, and 6-month confirmed disability progression, and a yearly percentage lateral ventricular volume change on T2-FLAIR images < 2%; (3) less than 40% of active lesions at baseline and month 12 evolving to permanent black holes (PBHs).At month 24, 76/160 (47.5%; 95% confidence interval CI = 39.8%;55.2%) RRMS patients had no clinical/MRI activity. Thirty-nine of 170 RRMS patients (22.9%; 95% CI = 16.6%;29.3%) achieved "modified NEDA-4" status. Forty-four of 72 RRMS patients (61.1%; 95% CI = 49.8%;72.4%) had less than 40% of active WM lesions evolving to PBHs. The study confirmed the established safety and tolerability profile of fingolimod.RESULTSAt month 24, 76/160 (47.5%; 95% confidence interval CI = 39.8%;55.2%) RRMS patients had no clinical/MRI activity. Thirty-nine of 170 RRMS patients (22.9%; 95% CI = 16.6%;29.3%) achieved "modified NEDA-4" status. Forty-four of 72 RRMS patients (61.1%; 95% CI = 49.8%;72.4%) had less than 40% of active WM lesions evolving to PBHs. The study confirmed the established safety and tolerability profile of fingolimod.By comparing our results with those from the literature, the EVOLUTION study seems to indicate a neuroprotective effect of fingolimod, limiting inflammatory activity, brain atrophy and PBH development.DISCUSSIONBy comparing our results with those from the literature, the EVOLUTION study seems to indicate a neuroprotective effect of fingolimod, limiting inflammatory activity, brain atrophy and PBH development.
Although up to 20% of patients with multiple sclerosis (MS) experience onset before 18 years of age, it has been suggested that people with pediatric-onset MS (POMS) are protected against disability ...because of greater capacity for repair.
To assess the incidence of and factors associated with progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW) in POMS compared with typical adult-onset MS (AOMS) and late-onset MS (LOMS).
This cohort study on prospectively acquired data from the Italian MS Register was performed from June 1, 2000, to September 30, 2021. At the time of data extraction, longitudinal data from 73 564 patients from 120 MS centers were available in the register.
The main outcomes included age-related cumulative incidence and adjusted hazard ratios (HRs) for PIRA and RAW and associated factors.
Clinical and magnetic resonance imaging features, time receiving disease-modifying therapy (DMT), and time to first DMT.
After applying the inclusion and exclusion criteria, the study assessed 16 130 patients with MS (median IQR age at onset, 28.7 22.8-36.2 years; 68.3% female). Compared with AOMS and LOMS, patients with POMS had less disability, exhibited more active disease, and were exposed to DMT for a longer period. A first 48-week-confirmed PIRA occurred in 7176 patients (44.5%): 558 patients with POMS (40.4%), 6258 patients with AOMS (44.3%), and 360 patients with LOMS (56.8%) (P < .001). Factors associated with PIRA were older age at onset (AOMS vs POMS HR, 1.42; 95% CI, 1.30-1.55; LOMS vs POMS HR, 2.98; 95% CI, 2.60-3.41; P < .001), longer disease duration (HR, 1.04; 95% CI, 1.04-1.05; P < .001), and shorter DMT exposure (HR, 0.69; 95% CI, 0.64-0.74; P < .001). The incidence of PIRA was 1.3% at 20 years of age, but it rapidly increased approximately 7 times between 21 and 30 years of age (9.0%) and nearly doubled for each age decade from 40 to 70 years (21.6% at 40 years, 39.0% at 50 years, 61.0% at 60 years, and 78.7% at 70 years). The cumulative incidence of RAW events followed a similar trend from 20 to 60 years (0.5% at 20 years, 3.5% at 30 years, 7.8% at 40 years, 14.4% at 50 years, and 24.1% at 60 years); no further increase was found at 70 years (27.7%). Delayed DMT initiation was associated with higher risk of PIRA (HR, 1.16; 95% CI, 1.00-1.34; P = .04) and RAW (HR, 1.75; 95% CI, 1.28-2.39; P = .001).
PIRA can occur at any age, and although pediatric onset is not fully protective against progression, this study's findings suggest that patients with pediatric onset are less likely to exhibit PIRA over a decade of follow-up. However, these data also reinforce the benefit for DMT initiation in patients with POMS, as treatment was associated with reduced occurrence of both PIRA and RAW regardless of age at onset.
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