Clinical baseline factors predict response to natalizumab: their usefulness in patient selection.

BACKGROUND: Optimal patient selection would improve the risk-benefit ratio of natalizumab treatment for relapsing-remitting multiple sclerosis (RR MS). Clinical features of subjects responding to natalizumab have not been univocally recognized. METHODS: Longitudinal data on RR MS patients treated with natalizumab in Liguria, Italy are reported. Predictors of relapse occurrence and disability improvement were analyzed with a logistic regression method in subjects treated for one year (N = 62). A new score, called "Better EDSS Trend (BET)", was devised to describe the impact of the treatment on disability. Changes in annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) after one and two years and proportion of disease-free patients were evaluated. RESULTS: Previous EDSS worsening plus ARR ≥ 2 increased the risk of relapse during the treatment [Odds Ratio (OR) 4.12, P = 0.04], but this was not associated with an increase in disability at one year. EDSS 3.0-3.5 or high disease activity were associated with neurological improvement in the first year of treatment (respectively OR 5.78, P = 0.05 and OR 4.80, P = 0.05). Positive BET score, i.e. improvement in the disability trend, was observed in 40.3% of patients, and correlated with high ARR in the year before treatment (OR 1.69, P = 0.03). CONCLUSION: Subjects with EDSS 3.0-3.5 and those with very active disease in the year before treatment are most likely to improve in neurological function under natalizumab. A relapse in the first year of treatment is associated to high pre-treatment disease activity; however, since the occurrence of a relapse did not have a negative impact on clinical improvement at one year, we suggest that it should not lead to treatment discontinuation. We propose BET as an additional endpoint of treatment response in MS.

Breakthrough SARS-CoV-2 infections after COVID-19 mRNA vaccination in MS patients on disease modifying therapies during the Delta and the Omicron waves in Italy.

BACKGROUND: In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in patients with MS (pwMS) under different DMTs and to identify correlates of reduced protection. METHODS: This is a prospective Italian multicenter cohort study, long-term clinical follow-up of the CovaXiMS (Covid-19 vaccine in Multiple Sclerosis) study. 1855 pwMS scheduled for SARS-CoV-2 mRNA vaccination were enrolled and followed up to a mean time of 10 months. The cumulative incidence of breakthrough Covid-19 cases in pwMS was calculated before and after December 2021, to separate the Delta from the Omicron waves and to account for the advent of the third vaccine dose. FINDINGS: 1705 pwMS received 2 m-RNA vaccine doses, 21/28 days apart. Of them, 1508 (88.5%) had blood assessment 4 weeks after the second vaccine dose and 1154/1266 (92%) received the third dose after a mean interval of 210 days (range 90-342 days) after the second dose. During follow-up, 131 breakthrough Covid-19 infections (33 during the Delta and 98 during the Omicron wave) were observed. The probability to be infected during the Delta wave was associated with SARS-CoV-2 antibody levels measured after 4 weeks from the second vaccine dose (HR=0.57, p < 0.001); the protective role of antibodies was preserved over the whole follow up (HR=0.57, 95%CI=0.43-0.75, p < 0.001), with a significant reduction (HR=1.40, 95%CI=1.01-1.94, p=0.04) for the Omicron cases. The third dose significantly reduced the risk of infection (HR=0.44, 95%CI=0.21-0.90,p=0.025) during the Omicron wave. INTERPRETATION: The risk of breakthrough SARS-CoV-2 infections is mainly associated with reduced levels of the virus-specific humoral immune response. FUNDING: Supported by FISM - Fondazione Italiana Sclerosi Multipla - cod. 2021/Special-Multi/001 and financed or co-financed with the '5 per mille' public funding.

Structural connectivity influences brain activation during PVSAT in Multiple Sclerosis.

To assess the influence of white matter pathology on cortical reorganization, we probed the fronto-parietal attention network in Multiple Sclerosis (MS) patients by combining the Paced Visual Serial Addition Test (PVSAT) with fMRI-guided fiber tractography (FT). During the PVSAT, the control subjects activated the left inferior parietal lobule, superior temporal gyrus, precuneus, precentral gyrus, and medial and middle frontal gyri; while the precuneus and the inferior parietal lobule gyrus bilaterally, the left precentral and angular gyri and the right superior parietal lobule were activated in the MS group. At fMRI-guided FT, the superior longitudinal fasciculus (SLF) was the main white matter tract connecting areas active during the PVSAT. We then identified two subgroups of MS patients according to the SLF mean Fractional Anisotropy, used as indicator of integrity. The activations of the MS patients with a less damaged tract were in the left hemisphere, similarly to controls; while the patients with a more damaged SLF showed bilateral cortical activations. The MS subgroups, however, did not differ in PVSAT performance. This approach could be useful to investigate the relationship between brain structural and functional plastic changes and to identify different MRI endophenotypes related to the same level of cognitive impairment.

Using STN DBS and medication reduction as a strategy to treat pathological gambling in Parkinson's disease.

We describe two patients with Parkinson's disease (PD) who developed clinical criteria of pathological gambling addiction in the setting of increased dopamine replacement therapy (levodopa and dopamine agonist medications). The second patient showed also signs of dopamine dysregulation syndrome, with an addiction to dopaminergic medication. Neither patients responded to the standard therapy for gambling behavior, but dramatically improved after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) and early postoperative withdrawal of dopaminergic therapy. The possible therapeutic role of subthalamic nucleus deep brain stimulation (STN-DBS) on such a disabling behavior needs to be investigated prospectively.

Cognitive recovery after delayed carbon monoxide encephalopathy.

We report on a patient with delayed carbon monoxide encephalopathy who presented with severe cognitive impairment associated with MRI findings of extensive demyelination of the cerebral white matter after a silent period of three weeks from acute intoxication. Despite the severe signs of structural and functional cerebral impairment in the sub-acute stage, the clinical course was favorable but for residual mild dysfunction of the frontal lobes.