Nicola De Rossi

Natalizumab-related progressive multifocal leukoencephalopathy in multiple sclerosis: Findings from an Italian independent registry

Background The monoclonal antibody natalizumab (NTZ) is a highly effective treatment for patients with multiple sclerosis (MS). However, this drug is associated with increased risk of developing Progressive Multifocal Leukoencephalopathy (PML), an opportunistic infection of central nervous system (CNS) caused by the John Cunningham polyomavirus (JCV). Objective To describe the 12-month clinical course of 39 patients with MS (28 women, 11 men) who developed NTZ-related PML after a mean exposure of 39 infusions. Methods An Italian independent collaborative repository initiative collected and analyzed socio-demographic, clinical, magnetic resonance imaging (MRI) data and number of JCV-DNA copies detected on cerebrospinal fluid (CSF) samples of patients diagnosed as affected by NTZ-related PML. The evolution of disability, measured by the Expanded Disability Status Scale, was assessed at NTZ start, at PML diagnosis and after 2, 6 and 12 months from PML diagnosis. The effect of clinical and paraclinical characteristics at PML diagnosis on the final outcome was also investigated. Results Ten patients (25.6%) were diagnosed before 24 NTZ infusions. In six cases (15.4%) the PML suspect was made on the basis of highly suggestive MRI findings in absence of any detectable change of clinical conditions (asymptomatic PML). In patients with symptomatic PML, the diagnosis was quicker for those who presented with cognitive symptoms (n = 12) rather than for those with other neurological pictures (n = 21) (p = 0.003). Three patients (7.7%) died during the 12-month observation period, resulting in a survival rate of 92.3%. Asymptomatic PML, more localized brain involvement and gadolinium-enhancement detected at MRI, as well as lower viral load were associated with a better disability outcome (p-values<0.01). Conclusion Our findings support that early PML diagnosis, limited CNS involvement and initial signs of immune restoration are associated with a better outcome and higher survival rate, and confirm the utility of MRI as a surveillance tool for NTZ-treated patients.

Early erythropoietin influences both transfusion and ventilation need in very low birth weight infants.

Objective. The primary outcome measure of this study was the ability of rHuEPOα therapy to reduce transfusion needs, whereas secondary outcome measures were NICU-LOS and ventilation need. Methods. All babies with BW <1250 g and GA <30 were eligible. Thirty premature neonates were enrolled in the study (10 treated, 20 controls). rHuEPOα was administered as 300 IU/kg/dose 3 times/week subcutaneously. Iron, folic acid and Vitamin E supplementation were administered in both groups. Hematologic variables and blood sampling were recorded during the study. Results. In rHuEPO group, only four (40%) premature infants required a transfusion, averaging 0.4 ± 0.52 transfusions/pts. A total of 23 transfusions were administered to controls; 11 (55%) infants received one transfusion at least, 55% required multiple transfusions. The average number of transfusions/pts was statistically different (1.15 ± 1.46 vs. 0.4 ± 0.52; p = 0.02), as the cumulative number of transfused patients (55% vs. 40%; p<0.001). NICU stay was not statistically different, whereas ventilation-free days were increased in EPO group (p<0.05). Conclusions. R-Hu-EPO treatment in first post-natal weeks markedly enhanced erythropoiesis in severely premature infants compared with matched controls, with a significant impact on transfusion needs. EPO group experienced also a reduction of ventilation time and, possibly, a decreased occurrence of clinical BPD.

Clinical spectrum and IgG subclass analysis of anti-myelin oligodendrocyte glycoprotein antibody-associated syndromes: a multicenter study

Anti-myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) recently emerged as a potential biomarker in patients with inflammatory demyelinating diseases of the central nervous system. We here compare the clinical and laboratory findings observed in a cohort of MOG-Ab seropositive and seronegative cases and describe IgG subclass analysis results. Consecutive serum samples referred to Verona University Neuropathology Laboratory for aquaporin-4 (AQP4)-Ab and/or MOG-Ab testing were analysed between March 2014 and May 2017. The presence of AQP4-Ab was determined using a cell-based assay. A live cell immunofluorescence assay was used for the detection of MOG-IgG and IgG subclass analysis. Among 454 analysed samples, 29 were excluded due to AQP4-Ab positivity or to the final demonstration of a disorder not compatible with MOG-Ab. We obtained clinical data in 154 out of 425 cases. Of these, 22 subjects resulted MOG-Ab positive. MOG-Ab positive patients were mainly characterised by the involvement of the optic nerve and/or spinal cord. Half of the cases presented relapses and the recovery was usually partial. Brain MRI was heterogeneous while short lesions were the prevalent observation on spinal cord MRI. MOG-Ab titre usually decreased in non-relapsing cases. In all MOG-IgG positive cases, we observed IgG1 antibodies, which were predominant in most subjects. IgG2 (5/22), IgG3 (9/22) and IgG4 (3/22) antibodies were also detectable. We confirm that MOG-Ab-related syndromes have distinct features in the spectrum of demyelinating conditions, and we describe the possible role of the different IgG subclasses in this condition.

Early detection and favourable outcome of natalizumab-related progressive multifocal leukoencephalopathy (PML) in two multiple sclerosis patients.

A 42-year-old woman with RRMS and EDSS level of 7, previously treated with interferon (IFN)-b-1a and mitoxantrone, was started with natalizumab. JCV antibodies status test was not available at that time. After 31 infusions a routine MRI showed right parieto-occipital T2WI-hyperintense lesion with subcortical gadolinium (Gd) enhancement (Fig. 1), thus natalizumab treatment was immediately stopped. Right neglect, apraxia and alexia were present and EDSS increased to 8.5. CSF JCV-PCR performed at National Institute of Health Laboratory of Molecular Medicine and Neuroscience-Maryland, USA, (NINDS) was positive (24 DNA copies). She received only two of the seven scheduled PLEX cycles because of thrombosis on the site of venous catheterization. Oral prednisone (32.5 mg/day) was started and continued for the next 18 months. Cognitive functions gradually improved during 23-month follow-up as well as neurological examination (EDSS decreased to 7.5). Serial brain MRI scans showed stabilization of lesion size with progressive gadolinium enhancement disappearance (Fig. 2). Case 2

To do or not to do? Plasma exchange and timing of steroid administration in PML

To retrospectively analyze the effect of plasma exchange (PLEX; yes = PLEX+, no = PLEX–) and steroids administration timing (prophylactically [proST] or therapeutically [therST]) on the longitudinal clinical course of patients with natalizumab‐related progressive multifocal leukoencephalopathy (PML) and full‐blown immune reconstitution inflammatory syndrome (PML‐IRIS).

Is maraviroc useful in multiple sclerosis patients with natalizumab-related progressive multifocal leukoencephalopathy?

BACKGROUND Despite the recent advances in the understanding of natalizumab (NTZ) related progressive multifocal leukoencephalopathy (PML) and its associated immune reconstitution inflammatory syndrome (PML-IRIS), the therapeutic options are still under investigated. In this context, the beneficial use of maraviroc is still an anecdotal observation. OBJECTIVE To evaluate the impact of maraviroc in modifying the course of PML preventing IRIS or blunting IRIS manifestations. METHODS Three patients with NTZ PML included in the Italian dataset of PML were treated with maraviroc. Their longitudinal clinical and radiological course was described in detail. RESULTS The three patients were characterized by a steady clinical worsening not controlled by maraviroc. All the three patients manifested PML-IRIS, which emerged, respectively, at 62, 64 and 90days post NTZ withdrawal. This is in accordance with the data of the Italian dataset. Clinical and radiological stabilization of PML-IRIS occurred only after corticosteroids administration. CONCLUSION In these three cases, maraviroc did not show any clear effect in modulating the clinical course of PML preventing IRIS. Moreover, once PML-IRIS emerged, the clinical stabilization was achieved only with the use of corticosteroids. Thus, the use of maraviroc should be regarded with extreme caution due the potential adverse events associated with its use.

Association Between BKPyV Serotype I Antibody Level and Natalizumab-Associated Progressive Multifocal Leukoencephalopathy

To determine the association between BK polyomavirus (BKPyV) types 1 and 4 capsid antibody and natalizumab-associated progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS), serum samples were obtained from 10 natalizumab-associated PML cases and 130 control MS patients treated with natalizumab, and 82 control MS patients never exposed to natalizumab. In a sex- and age-adjusted regression model, BKPyV serotype 1 antibody levels were significantly higher in natalizumab-treated controls (p = 0.009) compared with cases, and were higher in controls never treated with natalizumab compared with cases, but the difference did not reach statistical significance (p = 0.158). There was no association between BKPyV serotype 4 antibody and PML. We hypothesize that a robust immune response to BKPyV may be protective against the development of PML.

Divergent Trends of Anti-JCPyV Serum Reactivity and Neutralizing Activity in Multiple Sclerosis (MS) Patients during Treatment with Natalizumab

The association between natalizumab and progressive multifocal leukoencephalopathy (PML) is established, but a reliable clinical risk stratification flow-chart is lacking. New risk factors are needed, such as the possible role of the anti-JC polyomavirus (JCPyV) neutralizing antibody. In this pilot study, we analyzed this parameter during natalizumab treatment. Sequential sera of 38 multiple sclerosis patients during their first year of natalizumab treatment were collected, and grouped according to the number of infusions. For 11 patients, samples were also available after 24 infusions (T24), when progressive multifocal leukoencephalopathy (PML) risk is higher. The reactivity against VP1, the main JCPyV surface protein, and the anti-JCPyV neutralizing activity were evaluated. During the first year, a lack of correlation between anti-JCPyV antibody response and its neutralizing activity was observed: a significant decrease in anti-JCPyV antibody response was observed (p = 0.0039), not paralleled by a similar trend in the total anti-JCPyV neutralizing activity (p = 0.2239). This lack of correlation was even more evident at T24 when, notwithstanding a significant increase in the anti-JCPyV response (p = 0.0097), a further decrease of the neutralizing activity was observed (p = 0.0062). This is the first study evidencing, prospectively, the lack of correlation between the anti-JCPyV antibody response and its neutralizing activity during natalizumab treatment.

The still under-investigated role of cognitive deficits in PML diagnosis

BackgroundDespite cognitive deficits frequently represent the first clinical manifestations of Progressive Multifocal Leukoencephalopathy (PML) in Natalizumab-treated MS patients, the importance of cognitive deficits in PML diagnosis is still under-investigated. The aim of the current study is to investigate the cognitive deficits at PML diagnosis in a group of Italian patients with PML.MethodsThirty-four PML patients were included in the study. The demographic and clinical data, the lesion load and localization, and the longitudinal clinical course was compared between patients with (n = 13) and without (n = 15) cognitive deficit upon PML suspicion (the remaining six patients were asymptomatic). Clinical presentation of cognitive symptoms was described in detail.ResultAfter symptoms detection, the time to diagnosis resulted to be shorter for patients presenting with cognitive than for patients with non cognitive onset (p = 0.03). Within patients with cognitive onset, six patients were presenting with language and/or reading difficulties (46.15%); five patients with memory difficulties (38.4%); three patients with apraxia (23.1%); two patients with disorientation (15.3%); two patients with neglect (15.3%); one patients with object agnosia (7.7%), one patient with perseveration (7.7%) and one patient with dementia (7.7%). Frontal lesions were less frequent (p = 0.03), whereas temporal lesions were slightly more frequent (p = 0.06) in patients with cognitive deficits. The longitudinal PML course seemed to be more severe in cognitive than in non cognitive patients (F = 2.73, p = 0.03), but differences disappeared (F = 1.24, p = 0.29) when balancing for the incidence of immune reconstitution syndrome and for other treatments for PML (steroids, plasma exchange (PLEX) and other therapies (Mefloquine, Mirtazapine, Maraviroc).ConclusionCognitive deficits at PML onset manifest with symptoms which are absolutely rare in MS. Their appearance in MS patients should strongly suggest PML. Clinicians should be sensitive to the importance of formal neuropsychological evaluation, with particular focus on executive function, which are not easily detected without a formal assessment.

Natalizumab to Fingolimod Switching in Multiple Sclerosis: Results from a “Real Word” Retrospective Analysis

Fingolimod is an alternative for patients with multiple sclerosis who discontinue natalizumab because of leukoencephalopathy risk. However, the interruption of natalizumab might cause disease reactivation. We aimed to describe the disease course of patients switching to fingolimod after treatment with natalizumab or β-interferon, in a real-world setting, through a retrospective analysis of data in patients with multiple sclerosis that receiving fingolimod at a single centre in Italy. Ninety patients were divided into two groups: patients switching to fingolimod from natalizumab (n = 43, Group 1), and treatment naive (n=5) plus patients switching from β-interferon (n = 42) (Group 2). In Group 1, the mean annualised relapse rate significantly increased from 0.36 at natalizumab discontinuation to 0.80 after natalizumab washout and 1.12 after the first 3 months of fingolimod, decreasing thereafter to 0.49 by the end of followup. In Group 2, the relapse rate significantly decreased from 1.16 to 0.47 at the end of follow-up. Relapses during natalizumab washout predicted increased disease activity during the first 3 months of fingolimod (p = 0.043). We conclude that fingolimod has a delayed effect in patients switching from natalizumab versus treatment-naive patients or those switching from β-interferon. Worsening of disease activity during the washout period may be predictive of treatment failure.