Abstract We report the case of a woman with natalizumab-treated Multiple Sclerosis (MS) that developed progressive multifocal leukoencephalopathy (PML) with atypical MRI features at early onset. This ...case shows that PML can have variable radiological patterns in natalizumab-treated MS patients thus expanding the possible MRI patterns at onset in these patients.
Disability accrual in multiple sclerosis may occur as relapse-associated worsening or progression independent of relapse activity. The role of progression independent of relapse activity in early MS ...is yet to be established. The objective of this multicentre, observational, retrospective cohort study was to investigate the contribution of relapse-associated worsening and progression independent of relapse activity to confirmed disability accumulation in patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis, assessed within one year from onset and with follow-up >/= 5 years (n = 5169). Data were extracted from the Italian Multiple Sclerosis Register. Confirmed disability accumulation was defined by an increase in Expanded Disability Status Scale score confirmed at 6 months, and classified per temporal association with relapses. Factors associated with progression independent of relapse activity and relapse-associated worsening were assessed using multivariable Cox regression models. Over a follow-up period of 11.5 ± 5.5 years, progression independent of relapse activity occurred in 1427 (27.6%) and relapse-associated worsening in 922 (17.8%) patients. Progression independent of relapse activity was associated with older age at baseline (HR = 1.19; 95CI 1.13-1.25, p < 0.001), having a relapsing-remitting course at baseline (HR = 1.44; 95CI 1.28-1.61, p < 0.001), longer disease duration at baseline (HR = 1.56; 95%CI 1.28-1.90, p < 0.001), lower Expanded Disability Status Scale at baseline (HR = 0.92; 95CI 0.88-0.96, p < 0.001), lower number of relapses before the event (HR = 0.76; 95CI 0.73-0.80, p < 0.001). Relapse-associated worsening was associated with younger age at baseline (HR = 0.87; 95CI 0.81-0.93, p < 0.001), having a relapsing-remitting course at baseline (HR = 1.55; 95CI 1.35-1.79, p < 0.001), lower Expanded Disability Status Scale at baseline (HR = 0.94; 95CI 0.89-0.99, p = 0.017), higher number of relapses before the event (HR = 1.04; 95CI 1.01-1.07, p < 0.001). Longer exposure to disease modifying drugs was associated with a lower risk of both progression independent of relapse activity and relapse-associated worsening (p < 0.001). This study provides evidence that in early relapsing-onset multiple sclerosis cohort, progression independent of relapse activity was an important contributor to confirmed disability accumulation. Our findings indicate that insidious progression appears even in the earliest phases of the disease, suggesting that inflammation and neurodegeneration can represent a single disease continuum, in which age is one of the main determinants of disease phenomenology.
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.
Background
Active relapsing–remitting (RR) and secondary progressive (SP) multiple sclerosis (MS) are currently defined as “relapsing MS” (RMS). The aim of this cross-sectional study was to assess ...drivers of treatment switches due to clinical relapses in a population of RMS patients collected in the Italian MS and Related Disorders Register (I-MS&RD).
Methods
RRMS and SPMS patients with at least one relapse in a time window of 2 years before of data extraction were defined as RMS. Factors associated with disease-modifying therapy (DMT) switching due to clinical activity were assessed through multivariable logistic regression models in which treatment exposure was included as the last recorded DMT and the last DMT’s class moderate-efficacy (ME), high-efficacy (HE) DMTs and anti-CD20 drugs.
Results
A cohort of 4739 RMS patients (4161 RRMS, 578 SPMS) was extracted from the I-MS&RD. A total of 2694 patients switching DMTs due to relapses were identified. Switchers were significantly (
p
< 0.0001) younger, less disabled, more frequently affected by an RR disease course in comparison to non-switcher patients. The multivariable logistic regression models showed that Alemtuzumab (OR 0.08, 95% CI 0.02–0.37), Natalizumab (0.48, 0.30–0.76), Ocrelizumab (0.1, 0.02–0.45) and Rituximab (0.23, 0.06–0.82) exposure was a protective factor against treatment switch due to relapses. Moreover, the use of HE DMTs (0.43, 0.31–0.59), especially anti-CD20 drugs (0.14, 0.05–0.37), resulted to be a protective factor against treatment switch due to relapses in comparison with ME DMTs.
Conclusions
More than 50% of RMS switched therapy due to disease activity. HE DMTs, especially anti-CD20 drugs, significantly reduce the risk of treatment switch.
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.
Objectives: This study was aimed at investigating the frequency of the visual phenomenon of palinopsia (visual perseveration) in patients with migraine.
Methods: We interviewed 63 patients with ...migraine with aura (MwA), 137 patients with migraine without aura (MwoA) and 226 sex-age-matched healthy control subjects using an ad hoc structured interview/questionnaire. The interview was divided into four classes of variables for statistical testing.
Results: Palinopsia occurred in 19/200 patients (9.5%); of them 10/63 had MwA and 9/137 MwoA (14.2% vs 6.6%, chi = 9.7, degrees of freedom = 1, p = 0.002). Patients with palinopsia had a significantly lower migraine attack frequency than those without this visual phenomenon (4.3 ± 0.3 vs 14.4 ± 0.2, z = 7.1, p < 0.0001). No healthy control subjects complained of palinopsia according to the structured interview/questionnaire.
Discussion: Palinopsia is probably under-diagnosed in patients with migraine. Further investigations are needed to assess whether migraineurs are particularly susceptible to the development of recurrent episodes of visual perseveration.
The trisomy of the short arm of chromosome 10 is a rare condition. The phenotypic expression of this genetic aberration is characterised by growth and mental retardation with several neurological ...signs. We report the neurophysiological findings in a newborn affected by 10p chromosome trisomy who developed seizures. Serial EEGs showed a progressive reduction in burst-suppression activity and a slow rhythmic basal activity. At 1 year of age the recording showed for the first time spikes of high amplitude (up to 800 μV) in bilateral frontal regions. These findings could be related to an asymmetrical cerebral maturation in the context of perinatal sufferance and brain malformation due to the genetic aberration.
Background
Nucleoside reverse transcriptase inhibitors (NRTIs) disrupt neuronal mitochondrial DNA synthesis, resulting in antiretroviral toxic neuropathy (ATN). Acetyl‐l‐carnitine (ALCAR) enhances ...neurotrophic support of sensory neurones, potentially providing symptom relief and nerve regeneration.
Objective
The objective of the study was to assess the safety and efficacy compared to placebo of intramuscular ALCAR in HIV‐positive patients with symptomatic distal symmetrical polyneuropathy.
Methods
Ninety patients were enrolled and randomized to receive ALCAR 500 mg twice a day (bid); n=43 or placebo (n=47) intramuscularly twice daily for 14 days followed by 42 days of oral ALCAR 1000 mg bid. Assessment of pain was obtained using the Visual Analogue Scale (VAS), Total Symptom Score (TSS), Clinical Global Impression of Change, McGill Pain Questionnaire (MPQ), and the need for rescue analgesics.
Results
There was no statistically significant difference in changes in VAS over 14 days between groups for the intent‐to‐treat (ITT) population, but for the efficacy‐evaluable (EE) population ALCAR treatment produced a significantly greater reduction in pain compared with placebo (P=0.022). The proportion of patients with an improvement in TSS over 14 days was greater in the ALCAR group compared with the placebo group, but the differences were not statistically significant. During the open‐label phase, patients experienced an improvement in pain, as measured by the VAS, TSS and McGill Pain Questionnaire.
Conclusion
ALCAR, administered twice a day intramuscularly to HIV‐1‐infected patients with symptomatic ATN, significantly reduced weekly mean pain ratings on the VAS compared with placebo. Treatment with oral ALCAR improved symptoms for the patient group as a whole. Intramuscular and oral ALCAR was generally safe and well tolerated.
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