Indolent course of progressive multifocal leukoencephalopathy during natalizumab treatment in MS

Vennegoor, Anke; Wattjes, Mike P.; Munster, E. T. L. van; Kriekaart, R. L.; Oosten, Bob W. van; Barkhof, Frederik; Killestein, Joep; Polman, Chris H.

doi:10.1212/wnl.0b013e31820b7644

Cited by 27 publications

(17 citation statements)

References 3 publications

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“…One prior reported case suggests that asymptomatic MRI changes can be captured several months prior to initial manifestation of PML symptoms 14. The story of the present case suggests that the screening for preclinical signs of PML might be achieved through periodic T2/FLAIR brain MRI scans in patients with known PML risk factors such as prior immunosuppressant exposure, natalizumab treatment duration over 2 years and JC virus seropositivity.…”

Section: Discussionmentioning

confidence: 72%

MRI preclinical detection and asymptomatic course of a progressive multifocal leucoencephalopathy (PML) under natalizumab therapy: Figure 1

Phan-Ba¹,

Lommers

Tshibanda

et al. 2011

J Neurol Neurosurg Psychiatry

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Early detection of progressive multifocal leucoencephalopathy (PML) in the setting of natalizumab therapy currently is performed by rapid evaluation of new symptoms occurring in treated patients. The role of MR scanning has not been investigated but holds promise since MR detection is highly sensitive for PML lesions. The authors report a case of presymptomatic PML of the posterior fossa detected by MR scans. Immediate suspension of natalizumab and plasma exchanges resulted in a rapid decline of natalizumab serum concentration. Intravenous steroids started together with plasma exchanges followed by an oral tapering course were used to minimise the immune reconstitution inflammatory syndrome. No symptoms (beyond mild headache) developed, and the repeat PCR for JC Virus (JCV) DNA detection performed 10 weeks later was negative. This case suggests that: (1) periodic brain MR scans may detect signs of presymptomatic PML in MS patients treated with natalizumab, (2) corticosteroid management of inflammatory reaction may contribute to optimal control of the immune reconstitution inflammatory syndrome routinely seen with natalizumab-associated PML and (3) early radiological detection of PML can have an excellent outcome even in a clinically critical region and despite prior immunosuppressant exposure. The potential benefit of regular MR scanning just using the T2/FLAIR modalities could be further investigated in order to detect early natalizumab-associated PML, leading to benign outcomes.

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Section: Discussionmentioning

confidence: 72%

MRI preclinical detection and asymptomatic course of a progressive multifocal leucoencephalopathy (PML) under natalizumab therapy: Figure 1

Phan-Ba¹,

Lommers

Tshibanda

et al. 2011

J Neurol Neurosurg Psychiatry

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“…Since PML is a progressive disease 6 and MRI signs of N-PML tend to develop over several months 7 before symptoms (as illustrated here and in other reported cases 6,7 ), brain MRI scans every 3-4 months could be considered for interval MRI vigilance.…”

Section: The Earlier the Smaller The Better For Natalizumab-associamentioning

confidence: 68%

The earlier, the smaller, the better for natalizumab-associated PML: In MRI vigilance veritas?

et al. 2012

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THE EARLIER, THE SMALLER, THE BETTER FOR NATALIZUMAB-ASSOCIATED PML: IN MRI VIGILANCE VERITAS?Natalizumab-associated progressive multifocal leukoencephalopathy (N-PML) in multiple sclerosis (MS) is due to CNS infection by the opportunistic JC virus (JCV). As of December 2011, 193 confirmed cases of N-PML have been observed, giving rise to an overall risk of approximately 0.202%. 1 N-PML pathogenesis remains partially elusive although risk factors have now been clearly delineated.2 In patients with prior JCV infection detected by serum anti-JCV antibodies, 3 duration of therapy and prior use of immunosuppressants (IS) increase the risk of N-PML. The clinical outcome of patients with MS who developed N-PML was highly variable, ranging from asymptomatic case 4 to varying degrees of neurologic disability or even death.5 It was also observed in real-life setting that the earlier N-PML was diagnosed and treated, the better was the clinical outcome.5 Clinical vigilance is now considered as the established cornerstone of PML risk-management algorithm. 2Here we present early MRI features of 4 out of 8 N-PML cases, which were observed in WalloniaBrussels and Northern France in more than 4 years of postmarketing utilization of natalizumab for both regions. We are not aware of the specific context and outcome of the 4 other N-PML cases, which were diagnosed and treated in other centers. The reported cases emphasize that 1) N-PML can have a long presymptomatic course while still being clearly detectable with MRI, 2) N-PML can have a benign outcome provided it is diagnosed and treated early, 3) a clinically symptomatic N-PML may be a further advanced infection with a poorer prognosis, and 4) periodic brain MRI scans, particularly in high-risk situations, are likely to provide earlier detection of N-PML 4 and better outcomes. Written informed consent was obtained from all 4 patients.Case discussion. We describe in the figure the clinico-radiologic features of 4 N-PML cases in which early preclinical MRI signs were captured. Case 1 was a left cerebellar peduncle lesion 4 (Liège, Belgium). Cases 2, 3 (Lille, France), and 4 (Brussels, Belgium) were left occipital, left posterior parietal, and right anterior frontal lesions, respectively. Case 4 emphasizes how slow and long can be the preclinical phase of N-PML and to what extent the size of the lesion at diagnosis is indicative of the duration of preclinical infection. The early MRI signs of supratentorial cases 2, 3, and 4 were all located in the cortical/juxtacortical white matter. Consistent with previous data, the Expanded Disability Status Scale status, the size of the MRI lesion, and the age of the patient at the time of diagnosis may correlate with the clinical outcome. 4 In cases 2, 3, and 4, the emergence of N-PML symptoms was concurrent with the development of T1 hypointensity (dark) within the lesion due to immune reconstitution inflammatory syndrome (IRIS) occurrence in cases 2 and 3 (not shown) and at the time of a late-stage clinical diagnosis in case 4 ( figure).Th...

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“…Future strategies in this respect might include MRI screening, 28–30 assessment of JCV-specific T-cell responses, 31–33 JCV DNA in serum or peripheral blood cells, 25,26,34,35 or cellular surface phenotyping. 36 However, none of these tools has yet been prospectively validated.…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal fluid JC virus antibody index for diagnosis of natalizumab‐associated progressive multifocal leukoencephalopathy

Warnke

Geldern

Markwerth

et al. 2014

Annals of Neurology

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Objective Progressive multifocal leukoencephalopathy (PML), caused by JC virus (JCV), can occur in patients receiving natalizumab for multiple sclerosis (MS). JCV detection by quantitative polymerase chain reaction (qPCR) in cerebrospinal fluid (CSF), or brain biopsy, is required for probable or definite diagnosis of PML. However, in some patients only low levels of JCV DNA (<100 copies/ml) are present in CSF, making the diagnosis challenging. Our objective was to assess the complementary value of a CSF JCV antibody index (AIJCV) in the diagnosis of natalizumab-associated PML. Methods AIJCV was assessed in 37 cases of natalizumab-associated PML and 89 MS-patients treated with natalizumab without PML. Sera and CSF were tested in a capture enzyme-linked immunosorbent assay, using JCV-VP1 fused to glutathione S-transferase as antigen. Albumin levels and total immunoglobulin G concentration were determined by immunonephelometry, and the AIJCV was calculated as published. Results Twenty-six of 37 (70%) patients with natalizumab-associated PML exhibited an AIJCV > 1.5, whereas this was seen in none of the controls (p < 0.0001). At time of the first positive qPCR for JCV DNA, 11 of 20 (55%) patients with natalizumab-associated PML had an AIJCV > 1.5. JCV DNA levels of <100 copies/ml were seen in 14 (70%) of these 20 patients, of whom 8 (57%) demonstrated an AIJCV > 1.5. Interpretation Determination of the AIJCV could be an added tool in the diagnostic workup for PML and should be included in the case definition of natalizumab-associated PML.

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Indolent course of progressive multifocal leukoencephalopathy during natalizumab treatment in MS

Cited by 27 publications

References 3 publications

MRI preclinical detection and asymptomatic course of a progressive multifocal leucoencephalopathy (PML) under natalizumab therapy: Figure 1

MRI preclinical detection and asymptomatic course of a progressive multifocal leucoencephalopathy (PML) under natalizumab therapy: Figure 1

The earlier, the smaller, the better for natalizumab-associated PML: In MRI vigilance veritas?

Cerebrospinal fluid JC virus antibody index for diagnosis of natalizumab‐associated progressive multifocal leukoencephalopathy

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