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Treatment with natalizumab once every 4 weeks is approved for patients with relapsing-remitting multiple sclerosis, but is associated with a risk of progressive multifocal leukoencephalopathy. Switching to extended-interval dosing is associated with lower progressive multifocal leukoencephalopathy risk, but the efficacy of this approach is unclear. We aimed to assess the safety and efficacy of natalizumab once every 6 weeks compared with once every 4 weeks in patients with relapsing-remitting multiple sclerosis. We did a randomised, controlled, open-label, phase 3b trial (NOVA) at 89 multiple sclerosis centres across 11 countries in the Americas, Europe, and Western Pacific. Included participants were aged 18–60 years with relapsing-remitting multiple sclerosis and had been treated with intravenous natalizumab 300 mg once every 4 weeks with no relapses for at least 12 months before randomisation, with no missed doses in the previous 3 months. Participants were randomly assigned (1:1), using a randomisation sequence generated by the study funder and contract personnel with interactive response technology, to switch to natalizumab once every 6 weeks or continue with once every 4 weeks. The centralised MRI reader, independent neurology evaluation committee, site examining neurologists, site backup examining neurologists, and site examining technicians were masked to study group assignments. The primary endpoint was the number of new or newly enlarging T2 hyperintense lesions at week 72, assessed in all participants who received at least one dose of assigned treatment and had at least one postbaseline MRI, relapse, or neurological examination or efficacy assessment. Missing primary endpoint data were handled under prespecified primary and secondary estimands: the primary estimand included all data, regardless of whether participants remained on the assigned treatment; the secondary estimand classed all data obtained after treatment discontinuation or study withdrawal as missing. Safety was assessed in all participants who received at least one dose of study treatment. Study enrolment is closed and an open-label extension study is ongoing. This study is registered with EudraCT, 2018-002145-11, and ClinicalTrials.gov, NCT03689972. Between Dec 26, 2018, and Aug 30, 2019, 605 patients were assessed for eligibility and 499 were enrolled and assigned to receive natalizumab once every 6 weeks (n=251) or once every 4 weeks (n=248). After prespecified adjustments for missing data, mean numbers of new or newly enlarging T2 hyperintense lesions at week 72 were 0·20 (95% CI 0·07–0·63) in the once every 6 weeks group and 0·05 (0·01–0·22) in the once every 4 weeks group (mean lesion ratio 4·24 [95% CI 0·86–20·85]; p=0·076) under the primary estimand, and 0·31 (95% CI 0·12–0·82) and 0·06 (0·01–0·31; mean lesion ratio 4·93 [95% CI 1·05–23·20]; p=0·044) under the secondary estimand. Two participants in the once every 6 weeks group with extreme new or newly enlarging T2 hyperintense lesion numbers (≥25) contributed most of the excess lesions. Adverse events occurred in 194 (78%) of 250 participants in the once every 6 weeks group and 190 (77%) of 247 in the once every 4 weeks group, and serious adverse events occurred in 17 (7%) and 17 (7%), respectively. No deaths were reported. There was one case of asymptomatic progressive multifocal leukoencephalopathy (without clinical signs) in the once every 6 weeks group, and no cases in the once every 4 weeks group; 6 months after diagnosis, the participant was without increased disability and remained classified as asymptomatic. We found a numerical difference in the mean number of new or newly enlarging T2 hyperintense lesions at week 72 between the once every 6 weeks and once every 4 weeks groups, which reached significance under the secondary estimand, but interpretation of statistical differences (or absence thereof) is limited because disease activity in the once every 4 weeks group was lower than expected. The safety profiles of natalizumab once every 6 weeks and once every 4 weeks were similar. Although this trial was not powered to assess differences in risk of progressive multifocal leukoencephalopathy, the occurrence of the (asymptomatic) case underscores the importance of monitoring and risk factor consideration in all patients receiving natalizumab. Biogen.

The main aim of the study is to evaluate the efficacy and safety profile of ocrelizumab (OCR), rituximab (RTX), and cladribine (CLA), employed as natalizumab (NTZ) exit strategies in relapsing–remitting multiple sclerosis (RRMS) patients at high-risk for progressive multifocal leukoencephalopathy (PML). This is a multicentre, retrospective, real-world study on consecutive RRMS patients from eleven tertiary Italian MS centres, who switched from NTZ to OCR, RTX, and CLA from January 1st, 2019, to December 31st, 2019. The primary study outcomes were the annualized relapse rate (ARR) and magnetic resonance imaging (MRI) outcome. Treatment effects were estimated by the inverse probability treatment weighting (IPTW), based on propensity-score (PS) approach. Additional endpoint included confirmed disability progression (CDP) as measured by Expanded Disability Status Scale and adverse events (AEs). Patients satisfying predefined inclusion and exclusion criteria were 120; 64 switched to OCR, 36 to RTX, and 20 to CLA. Patients from the 3 groups did not show differences for baseline characteristics, also after post hoc analysis. The IPTW PS-adjusted models revealed that patients on OCR had a lower risk for ARR than patients on CLA (ExpBOCR 0.485, CI 95% 0.264–0.893, p = 0.020). This result was confirmed also for 12-month MRI activity (ExpBOCR 0.248 CI 95% 0.065–0.948, p = 0.042). No differences were found in other pairwise comparisons (OCR vs RTX and RTX vs CLA) for the investigated outcomes. AEs were similar among the 3 groups. Anti-CD20 drugs were revealed to be effective and safe options as NTZ exit strategies. All investigated DMTs showed a good safety profile.

Objectives To compare brain MRI findings in progressive multifocal leukoencephalopathy (PML) associated to rituximab and natalizumab treatments and HIV infection. Materials and methods In this retrospective, multicentric study, we analyzed brain MRI exams from 72 patients diagnosed with definite PML: 32 after natalizumab treatment, 20 after rituximab treatment, and 20 HIV patients. We compared T2- or FLAIR-weighted images, diffusion-weighted images, T2*-weighted images, and contrast enhancement features, as well as lesion distribution, especially gray matter involvement. Results The three PML entities affect U-fibers associated with low signal intensities on T2*-weighted sequences. Natalizumab-associated PML showed a punctuate microcystic appearance in or in the vicinity of the main PML lesions, a potential involvement of the cortex, and contrast enhancement. HIV and rituximab-associated PML showed only mild contrast enhancement, punctuate appearance, and cortical involvement. The CD4/CD8 ratio showed a trend to be higher in the natalizumab group, possibly mirroring a more efficient immune response. Conclusion Imaging features of rituximab-associated PML are different from those of natalizumab-associated PML and are closer to those observed in HIV-associated PML. Key Points • Nowadays, PML is emerging as a complication of new effective therapies based on monoclonal antibodies. • Natalizumab-associated PML shows more inflammatory signs, a perivascular distribution “the milky way,” and more cortex involvement than rituximab- and HIV-associated PML. • MRI differences are probably related to higher levels of immunosuppression in HIV patients and those under rituximab therapy.

In this randomized trial involving patients with relapsing multiple sclerosis who had had relapses despite treatment with interferon, natalizumab in combination with interferon was more effective than interferon alone. After two years, the probability of sustained disability progression was 23 percent with combination treatment and 29 percent with interferon alone. Progressive multifocal leukoencephalopathy developed in two patients receiving combination treatment, and one of these two patients died of this serious complication of therapy. The adhesion molecule α 4 β 1 integrin is a key initiator of the inflammatory cascade involved in the pathogenesis of multiple sclerosis. 1 – 4 Natalizumab (Tysabri, Biogen Idec and Elan Pharmaceuticals) is the first α 4 integrin antagonist in a new class of selective adhesion-molecule inhibitors for the treatment of multiple sclerosis. Natalizumab binds to α 4 integrin on the surface of leukocytes, inhibiting their migration into the brain and thereby reducing inflammation. Current disease-modifying therapies for relapsing–remitting multiple sclerosis (interferon beta and glatiramer acetate) are only partially effective, 5 – 8 and most patients with multiple sclerosis have breakthrough disease activity . . .

Patients with active Crohn's disease who were randomly assigned to receive natalizumab did not have a significantly higher rate of initial response than those assigned to placebo (56 percent vs. 49 percent, P=0.05). Among patients with a response, those randomly assigned to continue natalizumab were more likely to have a sustained response than those assigned to placebo (61 percent vs. 28 percent, P<0.001). One patient treated with natalizumab died from progressive multifocal leukoencephalopathy associated with the JC virus, a human polyomavirus. Patients with active Crohn's disease who were randomly assigned to receive natalizumab did not have a significantly higher rate of initial response than those assigned to placebo (56 percent vs. 49 percent). The pathogenesis of Crohn's disease involves persistent recruitment of leukocytes into gut tissue, with resultant inflammation. Natalizumab (Tysabri, Elan Pharmaceuticals and Biogen Idec), a humanized IgG4 monoclonal antibody that blocks the adhesion and subsequent migration of leukocytes into the gut by binding α 4 integrin, is a member of a new class of molecules referred to as selective adhesion-molecule inhibitors. 1 Previous studies have suggested that natalizumab may be effective for the treatment of active Crohn's disease. 2 , 3 Furthermore, natalizumab has been shown to be effective in the treatment of multiple sclerosis, another chronic inflammatory disease. 4 , 5 Therefore, we conducted a . . .

Neurotoxicity associated with high-dose chemotherapy and whole brain radiotherapy (WBRT) is one of major complications for patients with central nervous system lymphoma (CNSL). Here we determined the incidence and risk factors of treatment-related leukoencephalopathy (tLE) in a clinical setting. We retrospectively reviewed clinical and radiological findings of 126 patients with  (CNSL) treated with high-dose methotrexate with or without intrathecal methotrexate administration (IT MTX) and response-adapted WBRT. During the whole observation period with a median of 38.7 months, tLE was found in 33 patients, most of them asymptomatic, with the median time to development 3.0 months, and the cumulative incidence reaching 29.2% (95% confidence interval, 20.6–38.2%) two years post chemotherapy. By multivariable analysis, IT MTX was identified as the only one significant risk factor (hazard ratio, 4.50; P  < 0.001), and the number of IT MTX was associated with the increased incidence and severity of tLE. These findings highlight the frequent neurological complications associated with CNS-directed therapy and confirm the neurotoxicity of IT MTX.

Purpose Metronidazole is a widely used antimicrobial and is generally well-tolerated, but its adverse effects can rarely manifest as ataxia, dysarthria, and encephalopathy. Rarely it can cause severe neurological toxicity in the form of Metronidazole-Induced Encephalopathy. Methods We report a 48-year-old female with acute cerebellar symptoms and altered sensorium following a 12-day course of Metronidazole. Results Magnetic Resonance Imaging (MRI) revealed unusual diffuse leukoencephalopathy involving the cerebellar, brainstem, and cerebral white matter with rapid clinical and radiological resolution occurred after discontinuation. Conclusions This case highlights the importance of early recognition of symptoms and immediate discontinuation of Metronidazole to prevent irreversible neurological sequelae, even in cases with limited exposure.

Daratumumab, a monoclonal antibody against CD38, is increasingly used in the treatment of multiple myeloma, other hematological malignancies and autoimmune diseases. Little is known about its CNS toxicity. We present a case of a patient with POEMS syndrome (syndrome of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) who developed an acute leukoencephalopathy shortly after initiation of therapy with daratumumab. Case report following the CARE case report guidelines. The patient presented with symptoms of headache and diffuse worsening of a pre-existing tetraparesis. MRI showed a rapidly progressive leukoencephalopathy. Extensive diagnostic evaluation revealed no specific cause, suggesting the leukoencephalopathy to be caused by daratumumab. Our report highlights a probably rare, but clinically significant adverse effect of daratumumab and underlines the necessity of raised vigilance for neurological side effects in patients treated with daratumumab.

More than a year after the start of the COVID-19 pandemic, long-term neurological manifestations of COVID-19 are increasingly being reported. The long-term sequelae of COVID-19-related leukoencephalopathy, however, remain unclear. Here, we present long-term neuroimaging follow-up in two cases of COVID-19-related leukoencephalopathy. The two cases demonstrate the utility of brain MRI for evaluating neurologic symptoms in critically ill patients with COVID-19, for diagnosis of underlying neural injury and prognostication of future recovery. The presence of leukoencephalopathy may result in chronic neurologic manifestations and may represent a poor prognosticator of neurologic recovery. The presence of leukoencephalomalacia on follow-up neuroimaging is potentially an indicator of irreversible white matter damage, which may be associated with more severe chronic deficits.

Oxycodone-induced leukoencephalopathy is a rare diagnosis that should be considered in unconscious patients with appropriate history. We describe a case of a 57-year-old unconscious woman who required intubation and did not respond to naloxone infusion. The unconsciousness was initially thought to be due to hypoxic brain injury. However, a further review of brain imaging showed characteristic features of oxycodone-induced leukoencephalopathy. We describe the pathological and radiological features of this condition, and provide a concise review of the limited literature on this condition. Accurate diagnosis of this condition will be valuable to clinicians and patients in terms of their medium-term and long-term prognosis, and potential for rehabilitation.