Natalizumab-associated Progressive Multifocal Leukoencephalopathy Research Articles

Successful epilepsy surgery in two cases with multiple sclerosis.

Brain surgery is the only curative treatment for people with focal epilepsy, but it is unclear whether this induces active disease in multiple sclerosis (MS). This creates a barrier to evaluate MS patients for epilepsy surgery. We present two cases of successful epilepsy surgery in patients with pharmacoresistant epilepsy and stable MS and give an overview of the existing literature. (1) a 28-year-old woman with seizures arising from a right basal temporo-occipital ganglioglioma was seizure-free after surgery, without MS relapse but with one new MS lesion postsurgically. (2) a 46-year-old woman with seizures arising from a natalizumab-associated progressive multifocal leukoencephalopathy (PML) lesion in the right frontal lobe was seizure-free after surgery preceded by extraoperative subdural electrocorticography, with new subclinical MS lesions. We are the first to report brain surgery in a PML survivor. Both patients stabilized radiologically after initiating second-line therapies. Successful epilepsy surgery can substantially increase the quality of life in patients with pharmacoresistant epilepsy and MS. With increasing survival rates of brain tumors and PML, the risk-benefit ratio of epilepsy surgery compared to a potential MS relapse after surgery becomes critically important. Shared decision-making is valuable for balancing the risks related to both diseases.

Long-term outcome of natalizumab-associated progressive multifocal leukoencephalopathy in Austria: a nationwide retrospective study

Background/objectiveThe use of natalizumab (NAT) in multiple sclerosis (MS) may be complicated by progressive multifocal leukoencephalopathy (PML), a rare and life-threatening opportunistic brain infection. We aimed to analyze the course of MS after PML recovery together with the long-term outcome of NAT-associated PML (NAT-PML) in Austria.MethodsRetrospective study based on identification of cases in the nationwide Austrian MS treatment registry (AMSTR) and MS centers with review of patient records. The expanded disability status scale (EDSS) was used to measure neurological disability and outcome.ResultsAs of December 2022, we identified 15 NAT-PML cases in Austria; only 20% occurred after 2016, when increased vigilance commenced. Two patients did not survive acute PML, and an additional patient died five years later, yielding a mortality rate of 20%. Seizures occurred exclusively in patients with pronounced EDSS increase. Gadolinium (Gd)-enhancement on brain magnetic resonance imaging (MRI) on PML suspicion was associated with minor changes of post-PML neurological disability. Long-term follow-up of up to 132 months (median 76 months) was available in 11/15. The overall median EDSS increased from 3.5 at pre-PML to 6.5 at the last assessment. Regarding inflammatory MS-related disease activity during the observation period, one single individual experienced an MS relapse and another patient had two Gd-enhancing brain lesions. Three patients converted to progressive MS within three years from PML and the EDSS further increased in 6/11.ConclusionsThe number of NAT-PML cases is decreasing over time. While many patients accumulated severe persistent neurological deficits compared to pre-PML, inflammatory MS-related disease activity after PML recovery was rare.

Retrospective comparison clinical presentation and outcome of Natalizumab and Fingolimod-associated PML (P7-3.004)

Retrospective comparison clinical presentation and outcome of Natalizumab and Fingolimod-associated PML (P7-3.004)

Differential diagnosis of immune reconstitution inflammatory syndrome and progressive multifocal leukoencephalopathy after natalizumab withdrawal

The appearance of new foci on MRI, the increase in neurological deficits, including the appearance of cognitive disorders and disturbances in the level of consciousness in patients with multiple sclerosis during the «washing period» when transferring from natalizumab (NZ) to another drug, may be due to both progressive multifocal leukoencephalopathy (PML) and exacerbation of the disease in the absence of therapy. Discontinuation of NS is fraught not only with a resumption, but with an increase in disease activity, the development of an immune reconstitution inflammatory syndrome (IRIS) due to the opening of the blood-brain barrier. Often, the processes of differential diagnosis of IRIS and natalizumab-associated PML are complex and require the use of additional methods of examination and monitoring of the dynamics of the patient's condition. However, the severity of the condition and the severity of the consequences caused by incorrect therapeutic tactics significantly reduce the time for diagnosis and require an immediate decision. The difficulties of differential diagnosis of IRIS and PML are reflected in the clinical case.

A case of natalizumab‐associated progressive multifocal leukoencephalopathy followed by immune reconstitution inflammatory syndrome with difficulty in the timing of immunotherapy

AbstractBackgroundDetails regarding the clinical course of natalizumab‐associated progressive multifocal leukoencephalopathy (NAT‐PML) have not been reported in Japanese patients. We experienced a Japanese NAT‐PML case and report it for the purpose of clarifying the challenge it posed in medical treatment.Case PresentationHerein, we describe a 58‐y‐old multiple sclerosis patient who had NAT‐PML with immune reconstitution inflammatory syndrome (IRIS). Before NAT‐PML developed, the patient's Expanded Disability Status Scale (EDSS) score was 5.5. She received natalizumab (300 mg) every 3–7 w, and her EDSS score had not changed for 9.1 y. The John Cunningham virus (JCV) index was 0.43 before NAT‐PML developed. She developed a gait disturbance when NAT‐PML emerged. Natalizumab was administered a total of 108 times. The patient was diagnosed with probable NAT‐PML on the basis of punctate lesions on T2‐weighted imaging and a JCV‐PCR result of 29 copies/ml from cerebrospinal fluid (CSF) testing. Intravenous methylprednisolone (IVMP) was initiated when the contrast‐enhanced lesion was first detected, but the NAT‐PML lesion was rather enlarged despite the temporary disappearance of the contrast‐enhanced lesion. An obvious increase in the IgG index and a slight increase in the CSF cell count were recognized at the time the immunological response was activated. Three cycles of a 3‐d course of IVMP were administered every 2 w for IRIS, and the patient's worst EDSS score was 9.5.ConclusionTreatment sequencing should be executed before the onset of NAT‐PML. Changes in CSF cell count and IgG index may be useful for treatment decision; further research is needed.

021 Determinants of natalizumab-associated PML outcomes

IntroductionNatalizumab treatment is associated with risk of progressive multifocal leukoencephalopa- thy (PML). Following PML diagnosis, plasma exchange (PLEX) may be used to enable rapid natalizumab clearance. This analysis explores the impact of PLEX and patient characteristics on natalizumab-associated PML outcomes.MethodsPatients with multiple sclerosis, natalizumab-associated PML, and PLEX treatment status as of September 2018 were included (PLEX+, n=616; PLEX−, n=109). The primary outcome was 2-year survival after PML diagnosis. Kaplan-Meier estimates of cumulative survival for patients with/without PLEX were stratified by log JC virus (JCV) viral copy number (VCN) at PML diagnosis. Hazard ratios for survival were based on a Cox proportional hazards model.ResultsThe cumulative probability of 2-year survival for PLEX+ vs PLEX− patients was 88.2% vs. 89.3% (P=0.857) with log VCN ≤5, 73.8% vs. 89.3% (P=0.097) with log VCN >5 to ≤7, and 68.2% vs. 78.9% (P=0.435) with log VCN >7. Improved survival was associated with younger age, asymptomatic presentation, localized PML lesions, and lower log JCV VCN.ConclusionsPLEX had no significant effect on survival rates. Numerically worse 2-year survival probabilities were observed with PLEX regardless of PML presentation, suggesting PLEX is not effective for improving post-PML outcomes.SupportBiogen. Disclosures: Included on the poster.g.giovannoni@qmul.ac.uk

Erratum: Heltberg et al., "Biophysical Modeling of Dopaminergic Denervation Landscapes in the Striatum Reveals New Therapeutic Strategy".

<h3>Objectives</h3> Neurosarcoidosis is a rare disorder with diverse clinical manifestations and a wide range of radiological features on MRI that make diagnosis challenging. Here we present a case of neurosarcoidosis with perivascular punctate enhancement on brain and spine MRI. Differential diagnosis of this characteristic radiological pattern are discussed. <h3>Case</h3> A 43 year old man presented with progressive cognitive decline and severe fatigue. Brain MRI demonstrated confluent white matter changes with punctate, perivascular gadolinium enhancement. Spine MRI showed increased signal intensity with punctate enhancement. A brain biopsy revealed a non-caseating granulomatous process related to blood vessels and the Virchow-Robin space, without necrosis, vascular destruction or any signs of vasculitis. Systemic sarcoidosis was excluded. Cyclophosphamide with steroids was effective. <h3>Conclusions</h3> Perivascular punctate enhancement on MRI has been described in a number of neurological conditions including chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS), isolated angiitis of the CNS, lymphoma, multiple sclerosis and natalizumab-associated progressive multifocal leukoencephalopathy. Although rare, it can also be observed in patients with neurosarcoidosis. Recognition of punctuate enhancement on brain or spine MRI should expedite further investigations and include work up for this condition. This case emphasises the inclusion of neurosarcoidosis in the differential diagnosis of perivascular punctate enhancement on brain and spine MRI. Enhancement is caused by perivascular granulomata and although rare, cerebrovascular sarcoidosis is a recognised entity.

Wearing-off symptoms during standard and extended natalizumab dosing intervals: Experiences from the COVID-19 pandemic

Natalizumab effectively prevents disease activity in relapsing-remitting multiple sclerosis, but many treated patients report subjective wearing-off symptoms at the end of the 4-week interval between infusions. Extended interval dosing (EID) is a promising strategy to mitigate the risk of natalizumab-associated progressive multifocal leukoencephalopathy, but it is unknown whether EID affects wearing-off symptoms. In this observational study, we evaluated if prevalence or intensity of wearing-off symptoms changed when natalizumab dosing intervals were extended from 4 to 6 weeks in 30 treated patients during the outbreak of COVID-19 in Norway. New or increased wearing-off symptoms during EID were reported by 50%. Symptom increase was more frequent among patients with pre-existing wearing-off symptoms during standard dosing compared to patients without such pre-existing symptoms [p = 0.0005]. Our observations support the need to study the effect of EID on wearing-off symptoms in randomized controlled trials.

TSPO PET imaging of natalizumab-associated progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a severe infection of the CNS caused by the polyomavirus JC that can occur in multiple sclerosis patients treated with natalizumab. Clinical management of patients with natalizumab-associated PML is challenging not least because current imaging tools for the early detection, longitudinal monitoring and differential diagnosis of PML lesions are limited. Here we evaluate whether translocator protein (TSPO) PET imaging can be applied to monitor the inflammatory activity of PML lesions over time and differentiate them from multiple sclerosis lesions. For this monocentre pilot study we followed eight patients with natalizumab-associated PML with PET imaging using the TSPO radioligand 18F-GE-180 combined with frequent 3 T MRI. In addition we compared TSPO PET signals in PML lesions with the signal pattern of multiple sclerosis lesions from 17 independent multiple sclerosis patients. We evaluated the standardized uptake value ratio as well as the morphometry of the TSPO uptake for putative PML and multiple sclerosis lesions areas compared to a radiologically unaffected pseudo-reference region in the cerebrum. Furthermore, TSPO expression in situ was immunohistochemically verified by determining the density and cellular identity of TSPO-expressing cells in brain sections from four patients with early natalizumab-associated PML as well as five patients with other forms of PML and six patients with inflammatory demyelinating CNS lesions (clinically isolated syndrome/multiple sclerosis). Histological analysis revealed a reticular accumulation of TSPO expressing phagocytes in PML lesions, while such phagocytes showed a more homogeneous distribution in putative multiple sclerosis lesions. TSPO PET imaging showed an enhanced tracer uptake in natalizumab-associated PML lesions that was present from the early to the chronic stages (up to 52 months after PML diagnosis). While gadolinium enhancement on MRI rapidly declined to baseline levels, TSPO tracer uptake followed a slow one phase decay curve. A TSPO-based 3D diagnostic matrix taking into account the uptake levels as well as the shape and texture of the TSPO signal differentiated >96% of PML and multiple sclerosis lesions. Indeed, treatment with rituximab after natalizumab-associated PML in three patients did not affect tracer uptake in the assigned PML lesions but reverted tracer uptake to baseline in the assigned active multiple sclerosis lesions. Taken together our study suggests that TSPO PET imaging can reveal CNS inflammation in natalizumab-associated PML. TSPO PET may facilitate longitudinal monitoring of disease activity and help to distinguish recurrent multiple sclerosis activity from PML progression.

Natalizumab-associated progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS): \u201ca case report from Ireland with review of literature, clinical pitfalls and future direction\u201d

BackgroundProgressive multifocal leukoencephalopathy (PML) is one of the most serious treatment-related complications that is encountered in patients with multiple sclerosis (MS). PML is a serious complication of MS treatment which is most commonly related to natalizumab.Case presentationWe report clinical course of progressive multifocal leukoencephalopathy (PML) in a 40-year-old man who was on treatment for highly active relapsing-remitting multiple sclerosis with natalizumab (Nz). He was treated with steroids, cidofovir, and mirtazapine and went on to develop long-term disability. The case describes the evolution of PML from diagnosis up till 5 months with changes on sequential brain scans and clinical symptoms in our patient.ConclusionPatients who are on natalizumab should be aware and consented for the risk of PML. They should be periodically re-assessed for their relative PML risk. There is a growing body of evidence that suggests switching patients from natalizumab who have a higher risk of PML to other safer treatment options.

Progressive multifocal leukoencephalopathy: MRI findings in HIV-infected patients are closer to rituximab- than natalizumab-associated PML.

ObjectivesTo compare brain MRI findings in progressive multifocal leukoencephalopathy (PML) associated to rituximab and natalizumab treatments and HIV infection.Materials and methodsIn 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.ResultsThe 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.ConclusionImaging 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.

Reader response: Prospective validation of the PML risk biomarker l-selectin and influence of natalizumab extended intervals.

With great interest I read the article by Schwab et al.1 on the risk of natalizumab-associated progressive multifocal leukoencephalopathy (PML) as a function of CD62L-expression. However, for the statistical analyses, unlike in earlier studies,2,3 the authors also took blood samples drawn at diagnosis into account. Given that CD62L often increases during the acute stage of PML,2 this may have adversely affected the marker's estimated sensitivity. Another bias was presumably introduced through the inclusion of patients who were JC virus (JCV)-seronegative, disregarding that the latter have a substantially lower risk,4 which is relevant because expression of CD62L in fact negatively correlates with JCV antibody titers.3 Therefore, it would have been more clinically meaningful to restrict the assessments to users of natalizumab who were JCV-seropositive, and, for those developing PML, to samples obtained at least 6 months before the outbreak—cf. Biogen's risk stratification by JCV-index.4,5 In addition, it might be informative to have a chart showing the temporal evolution of CD62L for all patients with PML in the cohort (how long before diagnosis each available value was measured—cf. again work by the drugmaker5). The 2 outliers—with minimum expression in the range of 50%–60% and thus well above the median1—seem to impair the predictive power of the test. Finally, Schwab et al. remarked that the methodology “currently” limited widespread usage of their assay,1 suggesting that this may change in the future. It would be helpful to have further detail on this.

Lipid-specific IgMs induce antiviral responses in the CNS: implications for progressive multifocal leukoencephalopathy in multiple sclerosis

Progressive multi-focal leukoencephalopathy (PML) is a potentially fatal encephalitis caused by JC polyomavirus (JCV). PML principally affects people with a compromised immune system, such as patients with multiple sclerosis (MS) receiving treatment with natalizumab. However, intrathecal synthesis of lipid-reactive IgM in MS patients is associated with a markedly lower incidence of natalizumab-associated PML compared to those without this antibody repertoire. Here we demonstrate that a subset of lipid-reactive human and murine IgMs induce a functional anti-viral response that inhibits replication of encephalitic Alpha and Orthobunyaviruses in multi-cellular central nervous system cultures. These lipid-specific IgMs trigger microglia to produce IFN-β in a cGAS-STING-dependent manner, which induces an IFN-α/β-receptor 1-dependent antiviral response in glia and neurons. These data identify lipid-reactive IgM as a mediator of anti-viral activity in the nervous system and provide a rational explanation why intrathecal synthesis of lipid-reactive IgM correlates with a reduced incidence of iatrogenic PML in MS.

Application of "Mentzer's PML case definition" to natalizumab-treated patients in the setting of strict MRI-based pharmacovigilance.

To compare the available diagnostic criteria for progressive multifocal leukoencephalopathy (PML) diagnosis in a real-world cohort of patients with natalizumab-associated PML and to explore opportunities for improvement of such criteria in the context of pharmacovigilance of immunosuppressive therapies. We applied the "Mentzers PML case definition" to a dataset of 28 patients with natalizumab-associated PML (many of whom were identified through MRI screening in the context of pharmacovigilance), who were previously rated according to the American Academy of Neurology (AAN) PML diagnostic criteria, and compared the response to both sets of criteria. The "Mentzers case definition" resulted in a level of certainty 1-3 in patients with a positive JC virus PCR, termed 'definite' and 'probable' PML according to the AAN diagnostic criteria. Patients that tested negative for JC virus in CSF (29%) were classified level 4 by the "Mentzers case definition", neglecting the longitudinal clinical and radiological signs of PML available, while the AAN diagnostic criteria separated these patients in 'possible' and 'not PML'. Both the AAN PML diagnostic criteria and the "Mentzers case definition" require the positive detection of JC virus DNA in CSF to define patients at a higher degree of suspicion of PML. However, as sensitivity of JC virus PCR in CSF is limited and often returns negative in particular in early cases of PML with a mere MRI-based PML suspicion, both criteria have obvious limitations when frequent MRI is used for pharmacovigilance purposes. Thus, revision of PML diagnostic criteria is needed, including the incorporation of lesion evolution, and longitudinal CSF studies that also assess for the presences of intrathecally produced anti-JC virus antibodies.

Updated Incidence of Natalizumab-associated Progressive Multifocal Leukoencephalopathy (PML) and Its Relationship with Natalizumab Exposure Over Time (2815)

Updated Incidence of Natalizumab-associated Progressive Multifocal Leukoencephalopathy (PML) and Its Relationship with Natalizumab Exposure Over Time (2815)

Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: risk reduction, management and possibilities for subsequent immunoregulation

The risk of progressive multifocal leukoencephalopathy (PML) is one of the factors limiting the widespread use of natalizumab (NTZ). As a strategy for potentially reducing the frequency of the NTZ-associated PML, while maintaining the high therapy efficacy, in addition to the widely-used risk stratification strategy based on anti-JC virus antibody index and therapy duration, we propose the administration of NTZ with an extended dosing interval. Opinions vary on the effectiveness of plasmapharesis in confirmed cases of PML. The most challenging problem is how to manage patients, who develop PML, and what MS disease-modifying therapy should be considered for the subsequent use.

PARP-1 deregulation in multiple sclerosis.

BackgroundPoly (ADP-ribose) polymerase 1 (PARP-1) plays pivotal roles in immune and inflammatory responses. Accumulating evidence suggests PARP-1 as a promising target for immunomodulation in multiple sclerosis and natalizumab-associated progressive multifocal leukoencephalopathy.ObjectiveThis study explores expression of PARP-1 and downstream effectors in multiple sclerosis and during natalizumab treatment.MethodsTranscriptional expressions were studied by real-time reverse transcriptase polymerase chain reaction on CD4+T/CD8+T/CD14+/B cells and peripheral blood mononuclear cells from healthy volunteers, untreated and natalizumab-treated non-progressive multifocal leukoencephalopathy and progressive multifocal leukoencephalopathy multiple sclerosis patients.ResultsPARP-1 expression was higher in CD4+T, CD8+T and B cells from untreated patients compared to healthy volunteers. Natalizumab treatment restored deregulated PARP-1 expression in T cells but not in B cells. Sustained upregulation of PARP-1 was associated with decreased expression of downstream PARP-1 factors such as TGFBR1/TGFBR2/BCL6 in B cells. Notably, a higher expression of PARP-1 was detected in progressive multifocal leukoencephalopathy patients.ConclusionsGiven the importance of PARP-1 in inflammatory processes, its upregulation in multiple sclerosis lymphocyte populations suggests a potential role in the immune pathogenesis of multiple sclerosis. Strikingly higher PARP-1 expression in progressive multifocal leukoencephalopathy cases suggests its involvement in progressive multifocal leukoencephalopathy disease pathomechanisms. These results further support the value of PARP-1 inhibitors as a potential novel therapeutic strategy for multiple sclerosis and natalizumab-associated progressive multifocal leukoencephalopathy.

Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing

ObjectiveTo use the large dataset from the Tysabri Outreach: Unified Commitment to Health (TOUCH) program to compare progressive multifocal leukoencephalopathy (PML) risk with natalizumab extended interval dosing (EID) vs standard interval dosing (SID) in patients with multiple sclerosis (MS).MethodsThis retrospective cohort study included anti-JC virus antibody-positive patients (n = 35,521) in the TOUCH database as of June 1, 2017. The effect of EID on PML risk was evaluated with 3 planned analyses using Kaplan-Meier methods stratified by prior immunosuppressant use. Risk of PML was analyzed by Cox regression adjusted for age, sex, prior immunosuppressants, time since natalizumab initiation, and cumulative number of infusions.ResultsThis study included 35,521 patients (primary analysis: 1,988 EID, 13,132 SID; secondary analysis: 3,331 EID, 15,424 SID; tertiary analysis: 815 EID, 23,168 SID). Mean average dosing intervals were 35.0 to 43.0 and 29.8 to 30.5 days for the EID and SID cohorts, respectively. Hazard ratios (95% confidence intervals) of PML risk for EID vs SID were 0.06 (0.01–0.22, p < 0.001) and 0.12 (0.05–0.29, p < 0.001) for the primary and secondary analyses, respectively. Relative risk reductions were 94% and 88% in favor of EID for the primary and secondary analyses, respectively. The tertiary analysis included no cases of PML with EID.ConclusionNatalizumab EID is associated with clinically and statistically significantly lower PML risk than SID.Classification of evidenceThis study provides Class III evidence that for patients with MS, natalizumab EID is associated with a lower PML risk than SID.

Progressive Multifocal Leukoencephalopathy Incidence and Risk Stratification Among Natalizumab Users in France

Risk of developing progressive multifocal leukoencephalopathy (PML) is the major barrier to using natalizumab for patients with multiple sclerosis (MS). To date, the association of risk stratification with PML incidence has not been evaluated. To describe the temporal evolution of PML incidence in France before and after introduction of risk minimization recommendations in 2013. This observational study used data in the MS registry OFSEP (Observatoire Français de la Sclérose en Plaques) collected between April 15, 2007, and December 31, 2016, by participating MS expert centers and MS-dedicated networks of neurologists in France. Patients with an MS diagnosis according to current criteria, regardless of age, were eligible, and those exposed to at least 1 natalizumab infusion (n = 6318) were included in the at-risk population. A questionnaire was sent to all centers, asking for a description of their practice regarding PML risk stratification. Data were analyzed in July 2018. Time from the first natalizumab infusion to the occurrence of PML, natalizumab discontinuation plus 6 months, or the last clinical evaluation. Incidence was the number of PML cases reported relative to the person-years exposed to natalizumab. A Poisson regression model for the 2007 to 2016 period estimated the annual variation in incidence and incidence rate ratio (IRR), adjusted for sex and age at treatment initiation and stratified by period (2007-2013 and 2013-2016). In total, 6318 patients were exposed to natalizumab during the study period, of whom 4682 (74.1%) were female, with a mean (SD [range]) age at MS onset of 28.5 (9.1 [1.1-72.4]) years; 45 confirmed incident cases of PML were diagnosed in 22 414 person-years of exposure. The crude incidence rate for the whole 2007 to 2016 period was 2.00 (95% CI, 1.46-2.69) per 1000 patient-years. Incidence significantly increased by 45.3% (IRR, 1.45; 95% CI, 1.15-1.83; P = .001) each year before 2013 and decreased by 23.0% (IRR, 0.77; 95% CI, 0.61-0.97; P = .03) each year from 2013 to 2016. The results of this study suggest, for the first time, a decrease in natalizumab-associated PML incidence since 2013 in France that may be associated with a generalized use of John Cunningham virus serologic test results; this finding appears to support the continuation and reinforcement of educational activities and risk-minimization strategies in the management of disease-modifying therapies for multiple sclerosis.

Susceptibility-Weighted MR Imaging Hypointense Rim in Progressive Multifocal Leukoencephalopathy: The End Point of Neuroinflammation and a Potential Outcome Predictor.

Progressive multifocal leukoencephalopathy (PML) represents a life-threatening demyelinating disorder of the brain caused by reactivation of a rare opportunistic infection with JC Polyomavirus. The aims of this study were to describe the incidence of a susceptibility-weighted imaging hypointense rim in patients with multifocal leukoencephalopathy and to explore the histologic correlates and prognostic value of the rim with regard to the clinical outcome. This retrospective study included 18 patients with a definite diagnosis of progressive multifocal leukoencephalopathy. Ten patients were HIV-positive, 3 patients had natalizumab-associated progressive multifocal leukoencephalopathy, 1 patient had multiple myeloma, 3 patients had a history of lymphoma, and 1 was diagnosed with acute myeloid leukemia. Patients were divided into short- (up to 12 months) and long-term (>12 months) survivors. A total of 93 initial and follow-up MR imaging examinations were reviewed. On SWI, the presence and development of a hypointense rim at the periphery of the progressive multifocal leukoencephalopathy lesions were noted. A postmortem histologic examination was performed in 2 patients: A rim formed in one, and in one, there was no rim. A total of 73 progressive multifocal leukoencephalopathy lesions were observed. In 13 (72.2%) patients, a well-defined thin, linear, hypointense rim at the periphery of the lesion toward the cortical side was present, while in 5 (27.8%) patients, it was completely absent. All 11 long-term survivors and 2 short-term survivors presented with a prominent SWI-hypointense rim, while 5/7 short-term survivors did not have this rim. The thin, uniformly linear, gyriform SWI-hypointense rim in the paralesional U-fibers in patients with definite progressive multifocal leukoencephalopathy might represent an end-point stage of the neuroinflammatory process in long-term survivors.