Abstract

The insertion of additional 168 base pair containing seven octapeptide repeats in the prion protein (PrP) gene region spanning residues 51-91 is associated with inherited prion disease. In 2008, we reported the clinical features of a novel de novo seven-octapeptide repeat insertion (7-OPRI) mutation coupled with codon 129 methionine (M) homozygosity in the PrP gene of a 19-year-old man presenting with psychosis and atypical dementia, and 16-year survival. Here, we describe the histopathological and PrP molecular properties in the autopsied brain of this patient. Histopathological examination revealed widespread brain atrophy, focal spongiform degeneration (SD), cortical PrP plaques, and elongated PrP formations in the cerebellum. Overall, these histopathological features resemble those described in a Belgian pedigree with 7-OPRI mutation except for the presence of PrP plaques in our case, which are morphologically different from the multicore plaques described in some OPRI mutations and in Gerstmann-Sträussler-Scheinker (GSS) syndrome. The comparative characterization of the detergent-soluble and detergent-insoluble PrP in our patient and in sporadic Creutzfeldt-Jakob disease (CJD) revealed distinct molecular signatures. Proteinase K digestion of the pathogenic, disease-associated PrP (PrPD) revealed PrPD type 1 in the cerebral cortex and mixed PrPD types 1 and 2 in the cerebellum. Altogether, the present study outlines the importance of assessing the phenotypical and PrP biochemical properties of these rare conditions, thereby widening the spectrum of the phenotypic heterogeneity of the 7-OPRI insertion mutations. Further studies are needed to determine whether distinct conformers of PrPD are associated with two major clinico-histopathological phenotypes in prion disease with 7-OPRI.

Keywords: Prion protein (PrP); conformation; genetic; histopathology; insertion mutation.

Abstract

A large body of evidence suggests that, besides their cholesterol-lowering effect, statins exert anti-inflammatory action. Consequently, statins may have therapeutic potential in immune-mediated disorders such as multiple sclerosis. Our objectives were to determine safety, tolerability and efficacy of low-dose atorvastatin plus high-dose interferon beta-1a in multiple sclerosis patients responding poorly to interferon beta-1a alone. Relapsing-remitting multiple sclerosis patients, aged 18-50 years, with contrast-enhanced lesions or relapses while on therapy with interferon beta-1a 44 microg (three times weekly) for 12 months, were randomized to combination therapy (interferon + atorvastatin 20 mg per day; group A) or interferon alone (group B) for 24 months. Patients underwent blood analysis and clinical assessment with the Expanded Disability Status Scale every 3 months, and brain gadolinium-enhanced magnetic resonance imaging at screening, and 12 and 24 months thereafter. Primary outcome measure was contrast-enhanced lesion number. Secondary outcome measures were number of relapses, EDSS variation and safety laboratory data. Forty-five patients were randomized to group A (n = 21) or B (n = 24). At 24 months, group A had significantly fewer contrast-enhanced lesions versus baseline (p = 0.007) and significantly fewer relapses versus the two pre-randomization years (p < 0.001). At survival analysis, the risk for a 1-point EDSS increase was slightly higher in group B than in group A (p = 0.053). Low-dose atorvastatin may be beneficial, as add-on therapy, in poor responders to high-dose interferon beta-1a alone.

Abstract

Background: The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) is the most widely used in clinical practice and the least time-consuming battery to estimate cognitive function in adults with Multiple Sclerosis (MS), while it has been included in few studies on young MS, also because of the absence of normative values.

Objective: The aim of this study is to evaluate the impact of age, sex and education on BICAMS scores in a young adolescent population.

Methods: We administered the BICAMS to 169, 11-to-18-year-old, healthy subjects. Linear regression models were used to assess the impact of age, sex, and education on sub-test scores. When statistically significant (p < 0.05), we used the regression coefficient to correct the raw scores.

Results: younger age was associated with worse performance on SDMT (β = 1.76; p < 0.05), CVLT-II (β = 3.33; p < 0.05) and BVMT-R (β = 0.62; p < 0.05). Female sex was associated SDMT (β = 2.75 (p < 0.05) and CVLT-II (β = 2.51 (p < 0.05). Educational attainment was associated with better performance on SDMT (β = 1.79 (p = < 0.05) and BVMT-R (β = 0.61; p < 0.05). Cut-off points were suggested at the 5th lowest percentile.

Conclusion: Age, sex, and education must be accounted for when applying the BICAMS to young population. Its use in everyday assessment of patients with Pediatric Onset Multiple Sclerosis (POMS) could help to compare and combine data across centers, identifying patients requiring a comprehensive evaluation and ad hoc cognitive stimulation programs.

Keywords: BICAMS; Cognition; Cognitive; Multiple sclerosis; Pediatric.

Abstract

Background: The increase in disease-modifying drugs (DMDs) allows individualization of treatment in relapsing multiple sclerosis (RMS); however, the long-term impact of different treatment sequences is not well established. This is particularly relevant for MS patients who may need to postpone more aggressive DMD strategies.

Objective: To evaluate different therapeutic strategies and their long-term outcomes, measured as relapses and confirmed disability progression (CDP), in MS 'real-world' settings.

Methods: Multicentre, observational, retrospectively acquired cohort study evaluating the long-term impact of different treatment strategies on disability outcomes in patients with RMS in the Italian MS Register.

Results: We evaluated 1152 RMS-naïve patients after propensity-score adjustment. Patients included were receiving: interferon beta-1a (IFN-β1a) 44 µg switching to fingolimod (FTY; IFN-switchers; n = 97); FTY only (FTY-stayers; n = 157); IFN-β1a only (IFN-stayers; n = 849). CDP and relapses did not differ between FTY-stayers and IFN-switchers [HR (95% CI) 0.99 (0.48-2.04), p = 0.98 and 0.81 (0.42-1.58), p = 0.55, respectively]. However, IFN-stayers showed increased risk of relapses compared with FTY-stayers [HR (95% CI) 1.46 (1.00-2.12), p = 0.05].

Conclusion: The ideal treatment option for MS is becoming increasingly complex, with the need to balance benefit and risks. Our results suggest that starting with FTY affects the long-term disease outcome similarly to escalating from IFN-β1a to FTY.

Keywords: EDSS score; Interferons; Long-term outcomes; Multiple sclerosis; Real-world setting; Treatment sequences.

Abstract

Frontotemporal lobar degeneration (FTLD) is a group of neurodegenerative diseases displaying high clinical, pathologic, and genetic heterogeneity. Several autosomal dominant progranulin (GRN) mutations have been reported, accounting for 5%-10% of FTLD cases worldwide. In this study, we described the clinical characteristics of 7 Italian patients, 5 with a diagnosis of frontotemporal dementia behavioral variant and 2 of corticobasal syndrome (CBS), carrying the GRN deletion g.101349_101355delCTGCTGT, resulting in the C157KfsX97 null mutation, and hypothesized the existence of a founder effect by means of haplotype sharing analysis. We performed plasma progranulin dosage, GRN gene sequencing, and haplotype sharing study, analyzing 10 short tandem repeat markers, spanning a region of 11.08 Mb flanking GRN on chromosome 17q21. We observed shared alleles among 6 patients for 8 consecutive short tandem repeat markers spanning a 7.29 Mb region. Therefore, also with this particular mutation, the elevated clinical variability described among GRN-mutated FTLD cases is confirmed. Moreover, this is the first study reporting the likely existence of a founder effect for C157KfsX97 mutation in Southern Italy.

Keywords: Corticobasal syndrome; Founder effect; Frontotemporal lobar degeneration; GRN; Mutation; Progranulin protein.

Abstract

Introduction: Delta-δ-tetrahydrocannabinol and cannabidiol (THC:CBD) oromucosal spray is used as an add-on therapy option for moderate to severe multiple sclerosis (MS) spasticity resistant to other medications. Aims of this study were to provide real-life data on long-term clinical outcomes in a large population of Italian patients treated with THC:CBD and to evaluate predictors of THC:CBD therapy continuation.

Materials and methods: This prospective observational multicentre Italian study screened all patients with MS consecutively included in the Agenzia Italiana del Farmaco e-registry at the start of THC:CBD treatment (baseline), after 4 weeks (T1), 12±3 weeks (T2), 24±3 weeks (T3), 48±3 weeks (T4) and 72±3 weeks (T5) from baseline.

Results: A total of 1845 patients were recruited from 32 MS Italian centres. At T1, 1502 (81.4%) of patients reached a Numerical Rating Scale (NRS) improvement of ≥20%, with an NRS reduction of 26.9% at T1 and of 34.4% at T5. At T5, 725 patients (48.3% of 1502) discontinued treatment with highest discontinuation rate at T2 and T3. Daily number of puffs was generally stable through the observation period. The multivariate analysis showed that higher NRS scores at baseline (OR 2.28, 95% CI 1.15 to 6.36, p<0.01) and higher differences of NRS between T0 and T1 (OR 2.11, 95% CI 1.08 to 8.26, p<0.05) were associated with an increased probability to continue therapy after 18 months.

Discussion: THC:CBD effects were sustained for 18 months with a relatively stable number of puffs per day. About 50% of patients abandoned THC:CBD therapy for loss of efficacy or adverse events.

Abstract

Background and objectives: Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive disorder caused by pathogenic variants in the ABCC6 gene. The phenotypic spectrum of PXE is highly variable and includes principally three major features: skin lesions, eye and vascular manifestations, while brain manifestations are less common. To date about 400 different PXE associated variants in ABCC6 gene are described without any evident genotype-phenotype correlation. Herein, we report the clinical and molecular findings of a large PXE family with clinical and genetic intra-familial variability with significant cerebrovascular involvement.

Methods: The analysis of the ABCC6 gene was performed in the proband and her familiars for the definition of genetic background. Then, in order to determine why some affected individuals had more prominent brain involvement, we investigated classic thrombophilic gene variants.

Results: Molecular findings disclosed two different ABCC6 mutations, i.e., the recurrent p.(Arg518Gln) and the novel p.(Val1285Met) missense substitution responsible of a pseudo-dominant inheritance. The study of thrombophilic gene variants revealed the presence of 4G/4G SERPINE1 genotype in the proband and in her father, which both developed ischemic stroke. The proband carried also the C677T variant the MTHFR gene.

Conclusion: We argue, for the first time, that the 4G/4G SERPINE1 genotype could represent an additional risk factor in PXE for developing ischemic stroke, which adds up to the already known predisposing conditions. Therapeutic implications are discussed, we also advise that PXE patients should be adequately screened for cerebral vasculopathy, even more if familial history is suggestive of brain complications.

Keywords: 4G/5G; MTHFR C677T; PAI-1; Pseudoxanthoma elasticum; SERPINE1; Stroke; Thrombophilia.

Abstract

Background and aims: No consensus exists on how aggressively to treat relapsing-remitting multiple sclerosis (RRMS) nor on the timing of the treatment. The objective of this study was to evaluate disability trajectories in RRMS patients treated with an early intensive treatment (EIT) or with a moderate-efficacy treatment followed by escalation to higher-efficacy disease modifying therapy (ESC).

Methods: RRMS patients with ⩾5-year follow-up and ⩾3 visits after disease modifying therapy (DMT) start were selected from the Italian MS Registry. EIT group included patients who received as first DMT fingolimod, natalizumab, mitoxantrone, alemtuzumab, ocrelizumab, cladribine. ESC group patients received the high efficacy DMT after ⩾1 year of glatiramer acetate, interferons, azathioprine, teriflunomide or dimethylfumarate treatment. Patients were 1:1 propensity score (PS) matched for characteristics at the first DMT. The disability trajectories were evaluated by applying a longitudinal model for repeated measures. The effect of early versus late start of high-efficacy DMT was assessed by the mean annual Expanded Disability Status Scale (EDSS) changes compared with baseline values (delta-EDSS) in EIT and ESC groups.

Results: The study cohort included 2702 RRMS patients. The PS matching procedure produced 363 pairs, followed for a median (interquartile range) of 8.5 (6.5-11.7) years. Mean annual delta-EDSS values were all significantly (p < 0.02) higher in the ESC group compared with the EIT group. In particular, the mean delta-EDSS differences between the two groups tended to increase from 0.1 (0.01-0.19, p = 0.03) at 1 year to 0.30 (0.07-0.53, p = 0.009) at 5 years and to 0.67 (0.31-1.03, p = 0.0003) at 10 years.

Conclusion: Our results indicate that EIT strategy is more effective than ESC strategy in controlling disability progression over time.

Keywords: big data; disability trajectories; disease registry; multiple sclerosis.

Abstract

Background: Natalizumab (NTZ) is an effective treatment for relapsing-remitting multiple sclerosis (RRMS). However, patients and physicians may consider discontinuing NTZ therapy due to safety or efficacy issues. The aim of our study was to evaluate the NTZ discontinuation rate and reasons of discontinuation in a large Italian population of RRMS patients.

Materials and methods: The data were extracted from the Italian MS registry in May 2018 and were collected from 51,845 patients in 69 Italian multiple sclerosis centers. MS patients with at least one NTZ infusion in the period between June 1st 2012 to May 15th 2018 were included. Discontinuation rates at each time point were calculated. Reasons for NTZ discontinuation were classified as "lack of efficacy", "progressive multifocal leukoencephalopathy (PML) risk" or "other".

Results: Out of 51,845, 5151 patients, 3019 (58.6%) females, with a mean age of 43.6 ± 10.1 years (median 40), were analyzed. Out of 2037 (39.5%) who discontinued NTZ, a significantly higher percentage suspended NTZ because of PML risk compared to lack of efficacy [1682 (32.7% of 5151) vs 221 (4.3%), p < 0.001]; other reasons were identified for 99 (1.9%) patients. Patients discontinuing treatment were older, had longer disease duration and worse EDSS at the time of NTZ initiation and at last follow-up on NTZ treatment. The JCV index and EDSS at baseline were predictors for stopping therapy (HR 2.94, 95% CI 1.22-4.75; p = 0.02; HR 1.36, 95% CI 1.18-5.41; p = 0.04).

Conclusions: Roughly 60% of MS patients stayed on NTZ treatment during the observation period. For those patients in whom NTZ discontinuation was required, it was mainly due to PML concerns.

Keywords: Discontinuation rate; Multiple sclerosis; Natalizumab; Reasons for discontinuation.

Abstract

Background and aim: Disease-modifying therapies (DMTs) used in multiple sclerosis (MS) have distinct safety profiles. In this paper, we report preliminary results of an on-going pharmacovigilance project (the FASM study).

Results: Neurologists working at involved multiple sclerosis centers collected 272 Individual Case Safety Reports (ICSRs). Adverse drug reactions (ADRs) mainly occurred in adult patients and in a higher percentage of women compared to men. No difference was found in ADRs distribution by seriousness. The outcome was reported as favorable in 61% of ICSRs. Out of 272 ICSRs, almost 53% reported dimethyl fumarate, fingolimod and IFN beta 1a as suspected. These medications were commonly associated to the occurrence of ADRs related hematological, gastrointestinal, general, infective or cancer disorders. The median time to event (days) was 177 for dimethyl fumarate, 1058 for fingolimod and 413 for IFN beta 1a. The median time to event for the remaining suspected drugs was 226.

Conclusion: We believe that our results, together with those that will be presented at the end of the study, may bring new knowledge concerning the safety profile of DMTs and their proper use. This will provide the opportunity to draw new recommendations both for neurologists and patients.

Keywords: FASM study; adverse drugs reactions; disease-modifying therapies; multiple sclerosis; pharmacovigilance project; safety.