Ocrelizumab Alters Cytotoxic Lymphocyte Function While Reducing EBV-Specific CD8+ T-Cell Proliferation in Patients With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: The role of B cells in the pathogenic events leading to relapsing multiple sclerosis (R-MS) has only been recently elucidated. A pivotal step in defining this role has been provided by therapeutic efficacy of anti-CD20 monoclonal antibodies. Indeed, treatment with anti-CD20 can also alter number and function of other immune cells not directly expressing CD20 on their cell surface, whose activities can contribute to unknown aspects influencing therapeutic efficacy. We examined the phenotype and function of cytotoxic lymphocytes and Epstein-Barr virus (EBV)-specific immune responses in people with R-MS before and after ocrelizumab treatment. METHODS: In this prospective study, we collected blood samples from people with R-MS (n = 41) before and 6 and 12 months after initiating ocrelizumab to assess the immune phenotype and the indirect impact on cytotoxic functions of CD8+ T and NK cells. In addition, we evaluated the specific anti-EBV proliferative responses of both CD8+ T and NK lymphocytes as surrogate markers of anti-EBV activity. RESULTS: We observed that while ocrelizumab depleted circulating B cells, it also reduced the expression of activation and migratory markers on both CD8+ T and NK cells as well as their in vitro cytotoxic activity. A comparable pattern in the modulation of immune molecules by ocrelizumab was observed in cytotoxic cells even when patients with R-MS were divided into groups based on their prior disease-modifying treatment. These effects were accompanied by a significant and selective reduction of CD8+ T-cell proliferation in response to EBV antigenic peptides. DISCUSSION: Taken together, our findings suggest that ocrelizumab-while depleting B cells-affects the cytotoxic function of CD8+ and NK cells, whose reduced cross-activity against myelin antigens might also contribute to its therapeutic efficacy during MS.

MRI and steroid-responsive encephalopathy associated with autoimmune thyroiditis: first report of conus medullaris involvement and literature review of the known neuroimaging profiles.

BACKGROUND: Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT) is a rare but potentially reversible autoimmune encephalopathy. The most frequent neuroimaging correlates are normal brain MRI or non-specific white matter hyperintensities. METHODS: We present the first description of conus medullaris involvement, also providing an extensive review of MRI patterns described so far. RESULTS: Our results show that in less than 30% of cases, it is possible to find focal SREAT neuroanatomical correlates. Among these, T2w/FLAIR temporal hyperintensities are the most frequent, followed by basal ganglia/thalamic and brainstem involvement, respectively. CONCLUSIONS: Unfortunately, spinal cord investigation is an uncommon practice in the diagnostic approach of encephalopathies, thus neglecting potential pathological lesions of the medulla spinalis. In our opinion, the extension of the MRI study to the cervical, thoracic, and lumbosacral regions may allow finding new, and hopefully specific, anatomical correlates.

Emotional facial palsy: an unusual and rarely explored neurological sign.

The anatomy of the cortico-bulbar tract that drives voluntary movements of mimic muscles is well described. Some cases of facial palsy with inverse automatic-voluntary dissociation (emotional facial palsy; EFP) are reported in the literature. These cases suggested a completely independent path of the fibers whose lesion results in EFP. We aimed to review the clinical reports of EFP available in the literature to characterize the anatomical aspect of the fibers whose lesion results in the isolated impairment of spontaneous smiling. Cortico-pontine fibers that control spontaneous smiling arise from the medial surface of the prefrontal cortex and descend through the anterior limb of the internal capsule, thalamus, and brain steam, independently from those that control voluntary movement. The mesial temporal lobe, particularly the amygdala, plays a crucial role in the network driving emotionally evoked facial expressions. We would highlight the relevance of an unusual and rarely explored neurological sign that could be added to clinical examination in ruling out focal brain pathology, such as stroke, tumors, or multiple sclerosis.

Myasthenia gravis and telemedicine: a lesson from COVID-19 pandemic.

COVID-19 pandemic has induced an urgent reorganization of the healthcare system to ensure continuity of care for patients affected by chronic neurological diseases including myasthenia gravis (MG). Due to the fluctuating nature of the disease, early detection of disease worsening, adverse events, and possibly life-threatening complications is mandatory. This work analyzes the main unresolved issues in the management of the myasthenic patient, the possibilities offered so far by digital technologies, and proposes an online evaluation protocol based on 4 simple tests to improve MG management. Telemedicine and Digital Technology might help neurologists in the clinical decision-making process of MG management, avoiding unnecessary in presence consultations and allowing a rational use of the time and space reduced by the pandemic.

Exit Strategies in Natalizumab-Treated RRMS at High Risk of Progressive Multifocal Leukoencephalopathy: a Multicentre Comparison Study.

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.

MRI activity and extended interval of Natalizumab dosing regimen: a multicentre Italian study.

BACKGROUND: To minimize the risk of Progressive Multifocal Leukoencephalopathy and rebound in JCV-positive multiple sclerosis (MS) patients after 24 natalizumab doses, it has been proposed to extend the administrations interval. The objective is to evaluate the EID efficacy on MRI activity compared with the standard interval dosing (SID). METHODS: Observational, multicentre, retrospective cohort study, starting from the 24th natalizumab infusion to the loss of follow-up or 2 years after baseline. Three hundred and sixteen patients were enrolled. The median dose interval (MDI) following the 24th infusion was 5 weeks, with a bimodal distribution (modes at 4 and 6 weeks). Patients were grouped into 2 categories according to the mean number of weeks between doses: <5 weeks, SID; ≥5 weeks, EID. RESULTS: One hundred and eighty-seven patients were in the SID group (MDI = 4.5 weeks) and 129 in the EID group (MDI 6.1 weeks). The risk to develop active lesions on MRI is similar in SID and EID groups during the 6 and 12 months after the 24th natalizumab infusion, respectively 4.27% (95% CI:0.84-7.70) vs 4.71% (95% CI:0.16-9.25%) [p = 0.89] and 8.50% (95% CI:4.05-12.95) vs 6.55% (95% CI:2.11-11.00%) [p = 0.56]. The EID regimen does not appear to increase the occurrence of MRI activity during follow-up. CONCLUSION: There is no evidence of the reduced efficacy of natalizumab in an EID setting regarding the MRI activity. This observation supports the need for a bigger randomized study to assess the need to change the standard of the natalizumab dosing schedule, to better manage JCV-positive patients.

Atypical progressive multifocal leukoencephalopathy in a kidney transplant recipient with improving symptoms after immunocompetence recovery.

Progressive multifocal leukoencephalopathy (PML) is a viral infection due to John Cunningham Virus (JCV) resulting in progressive damage of brain white matter, mostly related to HIV infection or hemato-oncological malignancies. PML onset is usually multifocal with rapid neurological progression and poor prognosis. Here we report an atypical case of PML with monofocal onset and a good outcome in a 64-year-old man who received a kidney transplant for end-stage renal disease (ESRD). The applied antirejection immunosuppressive drug regimen included tacrolimus, prednisone and mycophenolic acid. Three years after the transplant, he complained of right-hand tremor and rapidly progressive right hemiparesis, with prominent involvement of the upper limb. Brain magnetic resonance imaging (MRI) showed a significant demyelinating area in the left frontal lobe, without mass effect and contrast enhancement. Real-time PCR analysis revealed the presence of JCV on cerebrospinal fluid. Consequent immunosuppressive drug suspension resulted in a global improvement of neurological symptoms and a favourable evolution of the neuroradiological findings. Subsequent eight-year follow-up MRI confirmed the stability of imaging findings over time. Therefore, early recognition of PML symptoms and MRI sign along with the rapid suspension of immunosuppressive drugs can modify the natural history of this disease after a kidney transplant.