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

Abstract

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...

Natalizumab-Related Progressive Multifocal Leukoencephalopathy in Multiple Sclerosis: Findings from an Italian Independent Registry

“…The three deaths occurred indeed in patients with symptomatic PML and higher numbers of CSF-DNA viral copies at PML diagnosis. This is in line with previously published data on predictors of survival and functional outcomes [16–18] and indicates that the later the PML diagnosis was made, the more the disease was widespread. Therefore, our study strongly supports the deferral of further NTZ dosing until exclusion of PML diagnosis in case of unexpected clinical worsening or new MRI lesions occurring beyond the first year of therapy [39].…”

“…Some clinical and paraclinical features at NTZ-related PML diagnosis have been reported to be predictive of bad outcome, including older age, high pre-PML disability, MRI findings consistent with multifocal damage, elevated number of JCV copies detected in cerebrospinal fluid (CSF) and symptomatic PML [16–18]. However, literature data regarding clinical outcomes after PML suffer from several biases, including incomplete data collection, largely heterogeneous management of patients and not univocal definition of PML-IRIS [15, 19].…”

Outcome and survival of asymptomatic PML in natalizumab‐treated MS patients

“…Meanwhile, European centers may have been performing MRI scans more frequently, as suggested in a PML case report published in 2012 in which the authors described performing brain MRI scans every 6 months for all relapsing MS patients treated with natalizumab 38. The PML case reported by Phan-Ba and colleagues was also included in a case series, in which a group of European authors suggested that “brain MRI scans every 3–4 months could be considered for interval MRI vigilance.”24 Similarly, in a set of recommendations published in 2011 by the International Multiple Sclerosis Expert Forum, it was stated that “more frequent MRI has been suggested (every 3–6 months)” in patients at increased risk for PML 12. Although our data were limited, no clear pattern of frequency of MRI testing was discerned between those patients who were asymptomatic and those who were symptomatic.…”

“…In the context of opportunistic infections, the current data and a number of recent case reports17,18,21,23,24 suggest that PML may be diagnosed based on brain MRI findings and the presence of JCV DNA in the CSF or on brain biopsy in the absence of clinical symptoms. This observation departs from the traditional 3-part diagnostic algorithm requiring clinical symptoms in combination with MRI findings and JCV DNA detection in the CNS for a diagnosis of definite PML 10,35,36.…”

“…The utility of routine MRI for monitoring natalizumab-treated patients has been highlighted in several recent case reports and case series 15,17–25. In some reports, patients were diagnosed with PML in the absence of clinical symptoms when radiologic signs of PML were detected on routine MRI and confirmed by JCV DNA detection in the CSF by polymerase chain reaction 17,18,21,23,24. In others, MRI findings consistent with PML were retrospectively identified on MRI scans obtained several months before clinical symptoms of PML were apparent 19,20,25…”