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

Abstract

Objective: As of 3 September 2013, 399 cases of natalizumab-associated progressive multifocal leukoencephalopathy (PML) were confirmed in multiple sclerosis (MS) patients. We evaluated outcomes of natalizumab-treated MS patients who were asymptomatic at PML diagnosis.

Methods: Analyses included data available as of 5 June 2013. Asymptomatic patients diagnosed with PML by magnetic resonance imaging (MRI) findings and JC virus DNA detection in the central nervous system were compared with patients presenting with symptoms at diagnosis. Demographics, MRI, and survival over 12 months were analyzed. Expanded Disability Status Scale (EDSS) and Karnofsky Performance Scale (KPS) scores were recorded pre-PML, at diagnosis, and at 6 and 12 months post-diagnosis.

Results: A total of 372 PML cases were analyzed; 30 patients were asymptomatic and 342 were symptomatic at PML diagnosis. Classifications of PML lesions on MRI in asymptomatic versus symptomatic patients were unilobar in 68% versus 37%, multilobar in 21% versus 24%, and widespread in 11% versus 40%. In both groups with unilobar lesions, frontal lobe lesions predominated. Prior to PML, mean EDSS and KPS scores were similar for asymptomatic and symptomatic patients. At diagnosis, mean EDSS score was significantly lower for asymptomatic patients (4.1; n = 11) than for symptomatic patients (5.4; n = 193; P = 0.038). Six months after PML diagnosis, asymptomatic patients had less functional disability than symptomatic patients. As of 5 June 2013, 96.7% of asymptomatic patients and 75.4% of symptomatic patients were alive.

Interpretation: PML patients asymptomatic at diagnosis had better survival and less functional disability than those who were symptomatic at diagnosis.

Figure 1

Distribution of PML lesions in asymptomatic and symptomatic PML patients. MRI data for 46 patients, including two asymptomatic patients, were not available. Total percentages may be greater than 100% due to rounding. PML, progressive multifocal leukoencephalopathy; MRI, magnetic resonance imaging.

Figure 2

Representative MRI scans of progression from asymptomatic to symptomatic PML. Asymptomatic PML was diagnosed in a 43-year-old woman with no prior IS use who had previously received interferon beta-1a. Twenty-two months after natalizumab initiation, she had no clinical signs of PML, but MRI showed a hyperintense cortical ribbon on both sides of the superior frontal sulcus (panel 1). Four months later the patient was still asymptomatic, but follow-up imaging showed multilobar lesions and natalizumab was discontinued (panel 2). Six months after first visualization of PML on MRI, PML symptoms, primarily visual, had developed and widespread lesions were present on brain MRI scan (panel 3). Anti-JCV antibody was detected in CSF at this time. MRI, magnetic resonance imaging; PML, progressive multifocal leukoencephalopathy; IS, immunosuppressive; JCV, JC virus; CSF, cerebrospinal fluid.

Figure 3

(A) EDSS and (B) KPS scores for asymptomatic and symptomatic PML patients measured over time. Weighted polynomial regression using the LOWESS algorithm. The EDSS and KPS scores for asymptomatic and symptomatic PML patients are shown for time points prior to PML diagnosis, at PML diagnosis, and post-PML diagnosis. Each symbol represents a single patient measurement at a single time point. EDSS and KPS scores were not available for all patients at all time points. Data prior to diagnosis were gathered from medical records. The dark gray lines represent polynomial regression trend-lines (LOWESS curves) for asymptomatic patients; the light gray lines represent polynomial regression trend-lines (LOWESS curves) for symptomatic patients. EDSS, Expanded Disability Status Scale; KPS, Karnofsky Performance Scale; PML, progressive multifocal leukoencephalopathy; LOWESS, locally weighted scatterplot smoothing.