Novel findings in a Swedish primary familial brain calcification cohort.

INTRODUCTION: Brain calcifications are frequent findings on imaging. In a small proportion of cases, these calcifications are associated with pathogenic gene variants, hence termed primary familial brain calcification (PFBC). The clinical penetrance is incomplete and phenotypic variability is substantial. This paper aims to characterize a Swedish PFBC cohort including 25 patients: 20 from seven families and five sporadic cases. METHODS: Longitudinal clinical assessment and CT imaging were conducted, abnormalities were assessed using the total calcification score (TCS). Genetic analyses, including a panel of six known PFBC genes, were performed in all index and sporadic cases. Additionally, three patients carrying a novel pathogenic copy number variant in SLC20A2 had their cerebrospinal fluid phosphate (CSF-Pi) levels measured. RESULTS: Among the 25 patients, the majority (76%) displayed varying symptoms during the initial assessment including motor (60%), psychiatric (40%), and/or cognitive abnormalities (24%). Clinical progression was observed in most patients (78.6%), but there was no significant difference in calcification between the first and second scans, with mean scores of 27.3 and 32.8, respectively. In three families and two sporadic cases, pathogenic genetic variants were identified, including a novel finding, in the SLC20A2 gene. In the three tested patients, the CSF-Pi levels were normal. CONCLUSIONS: This report demonstrates the variable expressivity seen in PFBC and includes a novel pathogenic variant in the SLC20A2 gene. In four families and three sporadic cases, no pathogenic variants were found, suggesting that new PFBC genes remain to be discovered.

Safety and efficacy of rituximab versus dimethyl fumarate in patients with relapsing-remitting multiple sclerosis or clinically isolated syndrome in Sweden: a rater-blinded, phase 3, randomised controlled trial.

BACKGROUND: B-cell depleting therapies are highly efficacious in relapsing-remitting multiple sclerosis but one such therapy, rituximab, is not approved for multiple sclerosis and no phase 3 trial data are available. We therefore examined the safety and efficacy of rituximab compared with dimethyl fumarate in patients with relapsing-remitting multiple sclerosis to obtain data that might allow inclusion of rituximab in treatment guidelines. METHODS: RIFUND-MS was a multicentre, rater-blinded, active-comparator, phase 3, randomised controlled trial done at 17 Swedish university and community hospitals. Key inclusion criteria for participants were: age 18-50 years; relapsing-remitting multiple sclerosis or clinically isolated syndrome according to prevailing McDonald criteria; 10 years or less since diagnosis; untreated or only exposed to interferons or glatiramer acetate; and with clinical or neuroradiological disease activity in the past year. Patients were automatically randomly assigned (1:1) by the treating physician using a randomisation module in the Swedish multiple sclerosis registry, without stratification, to oral dimethyl fumarate 240 mg twice daily or to intravenous rituximab 1000 mg followed by 500 mg every 6 months. Relapse evaluation, Expanded Disability Status Scale rating, and assessment of MRI scans were done by examining physicians and radiologists masked to treatment allocation. The primary outcome was the proportion of patients with at least one relapse (defined as subacute onset of new or worsening neurological symptoms compatible with multiple sclerosis with a duration of more than 24 h and preceded by at least 30 days of clinical stability), assessed in an intention-to-treat analysis using log-binomial regression with robust standard errors. This trial is registered at ClinicalTrials.gov, NCT02746744. FINDINGS: Between July 1, 2016, and Dec 18, 2018, 322 patients were screened for eligibility, 200 of whom were randomly assigned to a treatment group (100 assigned to rituximab and 100 assigned to dimethyl fumarate). The last patient completed 24-month follow-up on April 21, 2021. 98 patients in the rituximab group and 97 patients in the dimethyl fumarate group were eligible for the primary outcome analysis. Three (3%) patients in the rituximab group and 16 (16%) patients in the dimethyl fumarate group had a protocol-defined relapse during the trial, corresponding to a risk ratio of 0·19 (95% CI 0·06-0·62; p=0·0060). Infusion reactions (105 events [40·9 per 100 patient-years]) in the rituximab group and gastrointestinal reactions (65 events [47·4 per 100 patient-years]) and flush (65 events [47·4 per 100 patient-years]) in the dimethyl fumarate group were the most prevalent adverse events. There were no safety concerns. INTERPRETATION: RIFUND-MS provides evidence that rituximab given as 1000 mg followed by 500 mg every 6 months is superior to dimethyl fumarate in preventing relapses over 24 months in patients with early relapsing-remitting multiple sclerosis. Health economic and long-term safety studies of rituximab in patients with multiple sclerosis are needed. FUNDING: Swedish Research Council.

Efficacy and tolerability of levetiracetam during 1-year follow-up in patients with refractory epilepsy.

PROBLEM: Levetiracetam (LEV) is a new antiepileptic drug shown to be effective for the treatment of partial seizures in pivotal clinical trials. We investigated the long-term efficacy and tolerability of LEV as add-on therapy, regardless of seizure type, especially in persons who would not be eligible for clinical trials due to factors such as mental retardation and concomitant psychiatric disorders. METHODS: Ninety-eight patients participated and were followed for 1 year. Demographic data, seizure frequency, and side effects were recorded at baseline and during the 1-year follow-up. The first 35 patients were given LEV at a starting dose of 500 mg b.i.d. with weekly increments of 1000 mg (fast titration). The other patients were given LEV with a starting dose of 250 mg b.i.d. with weekly increments of 250 mg (slow titration). RESULTS: Fourteen patients were completely seizure free after titration to effective dose and 57 were responders with >50% seizure reduction for the first year. In the group with generalized seizures, 1 out of 19 became seizure free, but 8 patients had >50% decrease. Average dose at 1 year was 1900 mg (+/-900). Seventeen of 38 discontinuations were due to adverse effects and 21 were due to lack of efficacy. With fast titration, 15 out of 35 (43%) experienced tiredness during the first 12 weeks, and with slower titration 20 of 63 (32%) experienced tiredness. The difference was not statistically significant. Four out of the five patients who discontinued due to behavioral adverse events (mainly irritability) previously had behavioral problems and/or mental retardation. One patient discontinued due to psychosis. CONCLUSIONS: Levetiracetam appears to be well tolerated in patients with severe epilepsy and shows efficacy in a long-term follow-up. Behavioral adverse events were noted in a small number of patients and occurred mainly in patients who had a history of behavioral disturbance or were mentally retarded. These data from an open population are consistent with the findings of clinical trials.