Natalizumab-associated Progressive Multifocal Leukoencephalopathy Research Articles

Severe early natalizumab-associated PML in MS: Effective control of PML-IRIS with maraviroc.

Severe early natalizumab-associated PML in MS: Effective control of PML-IRIS with maraviroc.

Natalizumab-associated progressive multifocal leukoencephalopathy is not preceded by elevated drug concentrations

Background: In recent years, a small but increasing number of neurologists choose to extend dose intervals of natalizumab with the aim of reducing the risk of progressive multifocal leukoencephalopathy (PML). This idea is based on the hypothesis that high drug concentrations increase the risk of PML. Objective: We investigated the relation between longitudinal natalizumab concentrations in patients who developed PML and patients who did not develop PML. Methods: In a prospective observational cohort study of 219 patients with relapsing–remitting multiple sclerosis treated with natalizumab, serum samples were taken every 12 weeks prior to natalizumab infusion. In this cohort, 5 patients developed PML and were matched with 10 patients from the cohort who did not develop PML. Natalizumab concentrations were measured in available samples, and the longitudinal results were compared between the two patient groups. Results: Mean natalizumab concentrations in the five patients developing PML was 18.9 µg/mL (standard deviation (SD): ±13.4) versus 23.8 µg/mL (SD: ±11.5) of the control patients. Furthermore, we did not observe a clear rise in concentration levels in patients subsequently developing PML. Conclusion: Our results provide preliminary evidence that contradicts the hypothesis that exposure to elevated concentrations of natalizumab is a relevant risk factor of developing PML.

Commentary on “Successful pregnancy after natalizumab-associated progressive multifocal leukoencephalopathy in a patient with multiple sclerosis”

Commentary on “Successful pregnancy after natalizumab-associated progressive multifocal leukoencephalopathy in a patient with multiple sclerosis”

Predictors of Response to Multiple Sclerosis Therapeutics in Individual Patients.

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system. Several disease-modifying therapies have been shown to ameliorate the disease course; however, the individual treatment response and the occurrence of adverse events remain highly unpredictable. In the last 2 decades, a multitude of studies have aimed to identify biomarkers that enable treatment allocation in the individual patient or subgroup of patients with regard to treatment efficacy and safety profile. Following a PubMed database search, we provide an overview on what is presently known about body fluid markers for the prediction of response to the currently approved MS therapeutics. We also discuss the potential use of biomarkers with regard to drug-induced adverse events. To date, only a few molecules have been introduced in clinical routine: anti-drug antibodies against interferon (IFN)-β and natalizumab that are associated with abolished drug levels and treatment failure; anti-JC virus (JCV) antibody index that allows risk stratification for the development of progressive multifocal leukoencephalopathy (PML), a rare but severe adverse event during natalizumab treatment; and serostatus of varicella zoster virus as screening examination prior to fingolimod therapy to prevent the infection. A few candidate biomarkers still need closer examination, such as type I IFN signature and T-helper cell (Th)-17 reactivity for prediction of IFN-β treatment response, L-selectin expression for prediction of natalizumab-associated PML, interleukin (IL)-21 levels for prediction of secondary autoimmunity after exposure to alemtuzumab, lymphocyte count with regard to PML risk while receiving dimethyl fumarate or N-terminal-pro-B-type natriuretic peptide (NT-proBNP) for monitoring of cardiac side effects during mitoxantrone therapy.

Predictors of severity and functional outcome in natalizumab-associated progressive multifocal leukoencephalopathy

Objective: Progressive multifocal leukoencephalopathy (PML) is an emerging complication of immunosuppressive therapies, especially natalizumab in multiple sclerosis (MS). Factors associated with functional outcome of natalizumab-associated PML (natalizumab-PML) have not been sufficiently described. Methods: We retrospectively analyzed medical records of all patients with natalizumab-PML (n = 32) treated in our hospital since 2009. Disability measured by Expanded Disability Status Scale (EDSS) at two different time points (highest available EDSS during PML and last available EDSS after PML diagnosis) served as functional outcome parameters. Clinical, laboratory, and imaging data were analyzed for association with functional outcome by applying Spearman’s rho and multivariate regression analysis. Results: In all, 31/32 patients survived PML. A poor functional outcome was associated with higher age, higher initial John Cunningham virus (JCV) copy number in cerebrospinal fluid (CSF), and more extensive PML lesions on initial magnetic resonance imaging (MRI). No association between functional outcome and the duration of natalizumab therapy or a delayed PML diagnosis was observed. Conclusion: This study will be useful for neurological practice to estimate functional outcome or disease severity of natalizumab-PML in primary care settings.

MRI criteria differentiating asymptomatic PML from new MS lesions during natalizumab pharmacovigilance

ObjectiveDifferentiation between progressive multifocal leukoencephalopathy (PML) and new multiple sclerosis (MS) lesions on brain MRI during natalizumab pharmacovigilance in the absence of clinical signs and symptoms is challenging but is...

Treatment of Progressive Multifocal Leukoencephalopathy With Mirtazapine.

Progressive multifocal leukoencephalopathy (PML) is a rare, JC-virus-mediated, demyelinating disease with a high mortality rate. As no recommended treatment exists, mirtazapine, a potential blocker of virus entry into cells, has been empirically used. We analysed existing data on mirtazapine's efficacy to treat PML by systematically reviewing the literature since 2005, when it was first used. Searches in PubMed, EBSCO, SCOPUS and Google Scholar between January 2005 and December 2015, identified five cohort studies and 74 case reports.No statistically significant effect of mirtazapine on PML outcome was observed in the cohort studies. From studying thecase reports, mortality rate for PML was associated with the underlying circumstances, such as an older age, the use of an immunosuppressant, orPML occurring in patients with a haematological malignancy or a transplant. Except for natalizumab-associated PML, we did not highlight any potential benefit of mirtazapine on disease outcomes. Further interventional studies are needed to confirm that 5-HT2AR inhibition is relevant to treat PML.

A box of chocolates.

The articles in this issue of Neurology® Neuroimmunology & Neuroinflammation cover a broad range of topics, including new insights into the pathogenesis of natalizumab-associated progressive multifocal leukoencephalopathy (PML), important observations on antibody testing in neuromyelitis optica spectrum disorders (NMOSD), and a study related to degenerative dementia. However, all the articles are of interest. Like the famous box of chocolates anecdote from the movie Forrest Gump , you never know what you are going to get, but you know it will be enjoyable.

Erratum to: Reassessing the risk of natalizumab-associated PML

Erratum to: Reassessing the risk of natalizumab-associated PML

High cumulative JC virus seroconversion rate during long-term use of natalizumab.

John Cunningham virus (JCV) seropositivity is a risk factor for the development of natalizumab-associated progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients. When JCV seronegative patients seroconvert, their risk of developing PML increases. Limited longitudinal data exist about the seroconversion rate amongst natalizumab-treated relapsing-remitting MS (RRMS) patients. Our objective was to evaluate the seroconversion rate in a large Dutch cohort of natalizumab-treated RRMS patients. Seroconversion was defined as at least two consecutive seropositive serum samples (or cessation of therapy after a single seropositive sample because of seropositivity) after initial seronegative testing. In our study of 179 patients for whom longitudinal blood samples were available over a long period (median 4.2 years), anti-JCV antibody indices were measured in 933 available samples. Eighty-six patients (48.0%) tested seronegative initially. Of these 86 seronegative patients, 23 patients (26.7%) seroconverted during follow-up. The annualized seroconversion rate was 7.1%. Seroconversion occurred between 9 and 90 months (median 43 months) of treatment. The rate of seroconversion was independent of follow-up duration. No significant increase was seen in the anti-JCV antibody index in the non-converting patients during the follow-up. The annualized seroconversion rate of 7.1% in patients using natalizumab, cumulatively leading to more than 25% of seronegative patients becoming seropositive in 4 years, is of clinical relevance and should be taken into account in the risk assessment when considering the start of natalizumab therapy.

Reassessing the risk of natalizumab-associated PML.

The risk algorithm for natalizumab-associated PML was first established in 2012 using the observations that JC virus antibody status, prolonged duration of natalizumab therapy (>2years), and prior exposure to immunosuppressive therapy increased the risk for the disease. Prior to the publication of Biogen's algorithm, a risk algorithm was created by Fox and Rudick using an Excel spreadsheet in order to address the concerns of their patients. Applying the most recently available data regarding natalizumab-associated PML, the risk assessments for PML were recalculated. The current numbers indicate substantially higher risks for PML in 2015 than in 2012. Our calculations suggest that an individual having all three risk factors has an approximately 1 in 44 chance of developing PML.

Concomitant granule cell neuronopathy in patients with natalizumab-associated PML.

Granule cell neuronopathy (GCN) is a rare JC virus infection of the cerebellar granule cell neurons in immunocompromised patients. On brain imaging, GCN is characterized by cerebellar atrophy which can be accompanied by infratentorial white matter lesions. The objective of this study is to investigate the prevalence of MRI findings suggestive of GCN in a large natalizumab-associated progressive multifocal leukoencephalopathy (PML) cohort. MRI scans from before, at the time of, and during follow-up after diagnosis of PML in 44 natalizumab-treated MS patients, and a control group of 25 natalizumab-treated non-PML MS patients were retrospectively reviewed for imaging findings suggestive of GCN. To assess and quantify the degree of cerebellar atrophy, we used a 4 grade rating scale. Three patients in the PML group showed imaging findings suggestive of GCN and none in the control group. In two of these PML patients, cerebellar atrophy progressed from grade 0 at the time of diagnosis of isolated supratentorial PML to grade 1 and 2 after 2.5 and 3 months, respectively, in the absence of infratentorial white mater lesions. The third patient had grade 1 cerebellar atrophy before diagnosis of infra- and supratentorial PML, and showed progression of cerebellar atrophy to grade 2 in the 3 months following PML diagnosis. None of the other eight patients with infratentorial PML lesions developed cerebellar atrophy suggestive of GCN. Three cases with imaging findings suggestive of GCN were detected among 44 natalizumab-associated PML patients. GCN may, therefore, be more common than previously considered in natalizumab-associated PML patients.

Longitudinal analyses of anti-JCV antibody index for risk assessment of progressive multifocal leukoencephalopathy.

Risk assessment for natalizumab-associated progressive multifocal leukoencephalopathy (Nat-PML) comprises the anti-JC virus (JCV) antibody index (AI). The anti-JCV AI was longitudinally determined in a natalizumab-treated MS cohort (Nat-MS, n = 468) and samples of Nat-PML patients (n = 15). In Nat-MS, the median AI was 0.8 (25th to 75th percentile, 0.2–2.8) with an intra-individual coefficient of variation (CV) of 9.8% (4.8–17.6). Patients with an AI ≤ 0.9 exhibited higher CV. The AI was higher (3.4 (3.1–3.6)) in samples before Nat-PML diagnosis than in seropositive Nat-MS (2.4 (1.0–3.4), n = 298, p = 0.010). AIs ≥ 3.0 were associated with a 14.5-fold (95% CI 2.3–90.4) increased PML risk (p = 0.002). Groups with an AI below 1.5 exhibit higher variability or even serostatus fluctuation. AI dynamics require further investigation.

Use of interleukin-2 for management of natalizumab-associated progressive multifocal leukoencephalopathy: case report and review of literature.

A 51-year-old woman with relapsing-remitting multiple sclerosis (RRMS) and 3-year history of natalizumab use developed expressive aphasia. A brain magnetic resonance image (MRI) showed left frontotemporal and right parietal lesion with mild contrast enhancement and cerebrospinal fluid (CSF) was positive for John Cunningham virus (JCV) by polymerase chain reaction (PCR). The patient received five cycles of plasmapheresis followed by intravenous immunoglobulin. Despite this intervention, her speech deteriorated and she developed right hemiparesis. Upon referral to our institution, CSF quantitative JCV PCR was notable for 834 copies/ml. The patient was given an initial dose of 50,000 units of interleukin-2 (IL-2) subcutaneously (SQ) followed by 1 million units IL-2 SQ daily. Due to concern for immune reconstitution inflammatory syndrome (IRIS), the patient also received intravenous methylprednisone weekly. The regimen was tolerated well by the patient with no severe adverse effects. Clinically, the patient showed some improvement, and became more responsive and regained right lower extremity antigravity strength. After 12 weeks of IL-2 therapy, JCV quantitative PCR was notable for 31 copies/ml and the patient was more responsive. Due to persistence of JCV, IL-2 therapy was changed to mefloquine. At follow up after 6 months, the patient showed no clinical deterioration.

Central Nervous System Infections With Immunomodulatory Therapies

Serious central nervous system infections may occur in the setting of immunomodulatory drug use. It is important for neurologists to be aware of the incidence, diagnosis, management, and treatment of these infections. Infectious disease has long been recognized as a complication of broad immunosuppression. However, the frequency with which infectious disease is observed appears to be lower and the spectrum of infectious complications narrower with immunomodulatory drugs, a class of agents having a more restricted effect on the immune system. An increasingly broad spectrum of immunomodulating agents has been used in the treatment of neurologic disorders, particularly in the management of multiple sclerosis. The recognition of progressive multifocal leukoencephalopathy (PML) in association with the use of natalizumab, an α4β1 integrin inhibitor used in the treatment of multiple sclerosis, heralded concerns about infections associated with the use of immunomodulatory therapy. While the observation of PML with natalizumab remains the most striking example to date, other immunomodulatory treatments may also be associated with an increased risk of PML. Furthermore, other infectious diseases, including herpes simplex virus, varicella-zoster virus, and tuberculosis, are also associated with the use of immunomodulatory agents. The use of screening tests, careful monitoring, and immunization and the initiation of prophylactic treatment to address potential infectious complications associated with use of immunomodulatory therapies is evolving; at the same time, the armamentarium of neuroimmunodulatory therapies continues to expand. A comprehensive understanding of natalizumab-associated PML is illustrative of the potential pathogenic effects of immunomodulatory agents that lead to infectious complications, as well as the recognition and potential treatment strategies of these complications. The current knowledge of immunotherapy-associated PML incidence, clinical and radiographic features, and management are discussed in detail in this article. Increased risk of herpetic and other infectious complications has also been encountered with immunomodulation. Strategies in relation to minimizing risk and decreasing chances of encountering infectious complications associated with the use of such therapies, including those related to PML, tuberculosis, herpes simplex virus, and varicella-zoster virus, are highlighted.

7T MRI in natalizumab-associated PML and ongoing MS disease activity: A case study.

Objective:To assess the ability of ultra-high-field MRI to distinguish early progressive multifocal leukoencephalopathy (PML) from multiple sclerosis (MS) lesions in a rare case of simultaneous presentation of natalizumab–associated PML and ongoing MS activity.Methods:Advanced neuroimaging including 1.5T, 3T, and 7T MRI with a spatial resolution of up to 0.08 mm3 was performed.Results:7T MRI differentiated between PML-related and MS-related brain damage in vivo. Ring-enhancing MS plaques displayed a central vein, whereas confluent PML lesions were preceded by punctate or milky way–like T2 lesions.Conclusions:Given the importance of early diagnosis of treatment-associated PML, future systematic studies are warranted to assess the value of highly resolving MRI in differentiating between early PML- and MS-induced brain parenchymal lesions.

MRI characteristics of early PML-IRIS after natalizumab treatment in patients with MS

ObjectiveThe early detection of MRI findings suggestive of immune reconstitution inflammatory syndrome (IRIS) in natalizumab-associated progressive multifocal leukoencephalopathy (PML) is of crucial clinical relevance in terms of treatment decision-making and...

Brain Magnetic Susceptibility Changes in Patients with Natalizumab-Associated Progressive Multifocal Leukoencephalopathy.

We investigated the brain magnetic susceptibility changes induced by natalizumab-associated progressive multifocal leukoencephalopathy. We retrospectively included 12 patients with natalizumab-progressive multifocal leukoencephalopathy, 5 with progressive multifocal leukoencephalopathy from other causes, and 55 patients with MS without progressive multifocal leukoencephalopathy for comparison. MR imaging examinations included T2* or SWI sequences in patients with progressive multifocal leukoencephalopathy (86 examinations) and SWI in all patients with MS without progressive multifocal leukoencephalopathy. Signal abnormalities on T2* and SWI were defined as low signal intensity within the cortex and/or U-fibers and the basal ganglia. We observed T2* or SWI signal abnormalities at the chronic stage in all patients with progressive multifocal leukoencephalopathy, whereas no area of low SWI signal intensity was detected in patients without progressive multifocal leukoencephalopathy. Among the 8 patients with asymptomatic natalizumab-progressive multifocal leukoencephalopathy, susceptibility changes were observed in 6 (75%). The basal ganglia adjacent to progressive multifocal leukoencephalopathy lesions systematically appeared hypointense by using T2* and/or SWI. Brain magnetic susceptibility changes may be explained by the increased iron deposition and constitute a useful tool for the diagnosis of progressive multifocal leukoencephalopathy.

P4. Contrast-enhancing lesions within the spinal chord help to identify IRIS in patients with natalizumab-PML

Most, if not all patients with natalizumab-associated progressive multifocal leukoencephalopathy (PML) who are treated by plasma exchange (PLEX) develop an immune reconstitution inflammatory syndrome (IRIS), which often leads to severe tissue destruction within the brain. While steroids can efficiently treat IRIS, they worsen PML and a reliable and prompt diagnosis of IRIS in natalizumab-PML patients is thus critical. We report on a patient with supratentorial manifestations of natalizumab-PML who developed difficulties urination three weeks after PLEX and corresponding new gadolinium-enhancing lesions within the spinal chord. Cerebral MRI confirmed the diagnosis of IRIS. Therefore, detection of contrast-enhancing lesions within the spinal chord may help to identify IRIS in patients with natalizumab-PML.

Neuropathology of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy

The pathological findings of natalizumab-associated progressive multifocal leukoencephalopathy (PML) are reviewed. In addition to the classical pathology of PML including the presence of enlarged abnormal astrocytes, intranuclear inclusions mainly found within large swollen oligodendrocytes and abundant myelin-laden macrophages/microglia, massive perivascular and parenchymal mononuclear cell infiltration was observed. The latter pathologic picture is that of immune reconstitution inflammatory syndrome (IRIS), and most of these infiltrating cells are CD8-positive T cells. Because IRIS inevitably occurs after the cessation of natalizumab therapy due to the development of PML and subsequent plasma exchange, most of the published pathologic pictures of natalizumab-associated PML patients were a mixture of PML and PML-IRIS. PML-IRIS is also characterized by fewer oligodendroglial viral inclusions and fewer cells that are immunoreactive against anti-JCV antibodies. These findings suggest the effective removal of JCV after the return of normal immune-surveillance in the central nervous system, but clinicians should be aware that JCV elimination is not complete under the IRIS condition, and the immunosuppressive therapy against IRIS should be carefully performed. Mononuclear cell infiltration in natalizumab-associated PML-IRIS patients was much more prominent than that in HIV-associated PML-IRIS patients, reflecting the retained, even enhanced, systemic immunities in patients treated by natalizumab.