Hyperperfusion in progressive multifocal leukoencephalopathy is associated with disease progression and absence of immune reconstitution inflammatory syndrome

Abstract

We sought to characterize perfusion patterns of progressive multifocal leukoencephalopathy lesions by arterial spin labelling perfusion magnetic resonance imaging and to analyse their association with immune reconstitution inflammatory syndrome, and survival. A total of 22 patients with progressive multifocal leukoencephalopathy underwent a clinical evaluation and magnetic resonance imaging of the brain within 190 days of symptom onset. The presence of immune reconstitution inflammatory syndrome was determined based on clinical and laboratory criteria. Perfusion within progressive multifocal leukoencephalopathy lesions was determined by arterial spin labelling magnetic resonance imaging. We observed intense hyperperfusion within and at the edge of progressive multifocal leukoencephalopathy lesions in a subset of subjects. This hyperperfusion was quantified by measuring the fraction of lesion volume showing perfusion in excess of twice normal appearing grey matter. Hyperperfused lesion fraction was significantly greater in progressive multifocal leukoencephalopathy progressors than in survivors (12.8% versus 3.4% P = 0.02) corresponding to a relative risk of progression for individuals with a hyperperfused lesion fraction ≥ 4.0% of 9.1 (95% confidence interval of 1.4-59.5). The presence of hyperperfusion was inversely related to the occurrence of immune reconstitution inflammatory syndrome at the time of scan (P = 0.03). Indeed, within 3 months after symptom onset, hyperperfusion had a positive predictive value of 88% for absence of immune reconstitution inflammatory syndrome. Arterial spin labelling magnetic resonance imaging recognized regions of elevated perfusion within lesions of progressive multifocal leukoencephalopathy. These regions might represent virologically active areas operating in the absence of an effective adaptive immune response and correspond with a worse prognosis.

Keywords: magnetic resonance imaging; neuroimmunology; neuroinflammation; perfusion imaging; progressive multifocal leukoencephalopathy.

Figure 1

PML lesions contain areas of elevated perfusion. Four representative cases of PML lesions on FLAIR with corresponding ASL perfusion sequences are shown. Areas of increased perfusion are marked by an arrow. (A) Right frontal lesion in a PML progressor. HLF of the PML lesion was 10.9%. (B) Left fronto-parietal lesion in a PML progressor with an HLF of 26.0%. (C) Left fronto-parietal lesion in a PML survivor with an HLF of 34.6% (D) Left fronto-parietal and splenium of corpus callosum lesion in a PML progressor with an HLF of 11.3%. Perfusion was more commonly elevated along the edge rather than the core of the PML lesions (B, C and D).

Figure 2

Perfusion is increased in brain lesions of PML progressors. Each circle (PML survivors) or triangle (PML progressors) represents the HLF in PML lesions of a given patient at the first MRI. A filled symbol represents patients with active IRIS. The dotted line indicates the 4.0 cut-off separating survivors and progressors. The bars represent the standard deviations and the means. *the only PML survivor with an HLF >4.0. This 37-year-old HIV-infected male had a CD4+ T cell count of 47/µl at the time of the first MRI and had been on combined anti-retroviral therapy for ∼3 months. The CD4+ T cell count increased to 161/µl when he had his second MRI months later. **the only PML progressor with IRIS. ***the only PML progressor with contrast enhancement.

Figure 3

Discrepancies between perfusion in PML lesions, contrast enhancement and IRIS. FLAIR, ASL sequences and post-gadolinium T₁-weighted images of representative cases are shown. (A) Left parietal lesion of a PML progressor (PML-P) without IRIS shows increased perfusion (B, arrow) and no enhancement (C). The HLF was 26.7%; (D) right cerebellar lesion from a PML progressor without IRIS has increased perfusion (E, arrow) and no enhancement (F). The HLF of the PML lesion was 22.0%; (G) left cerebellar lesion from a PML progressor with IRIS has normal perfusion (H) and does enhance after contrast administration (I, arrowhead). The HLF of the PML lesion was 0%; (J) bilateral frontal lesions of a PML survivor (PML-S) with IRIS have normal perfusion (K) and no enhancement (L). The HLF of the PML lesion was 0.02%. Elevated perfusion along the edge of the PML lesions can be seen in B and E.