Metabolic profile of PML lesions in patients with and without IRIS: an observational study

Abstract

Objective: To characterize progressive multifocal leukoencephalopathy (PML) lesions by contrast-enhanced MRI and evaluate their metabolism using proton magnetic resonance spectroscopy ((1)H- MRS) in the setting of immune reconstitution inflammatory syndrome (IRIS).

Methods: A total of 42 patients with PML underwent a clinical evaluation as well as brain MRI and (1)H-MRS at baseline and 3, 6, and 12 months later. The presence of IRIS was determined based on clinical and laboratory criteria. Ratios of N-acetylaspartate (NAA), choline (Cho), myo-inositol (mI), and lipid/lactate (Lip1 and Lip2) to creatine (Cr) were measured and correlated with the presence of contrast enhancement (CE) in PML lesions.

Results: IRIS occurred in 16 of 28 (57.1%) PML survivors (PML-S) and 1 of 14 (7.1%) PML progressors (PML-P). Lesions of patients with PML-IRIS showed significantly higher Cho/Cr (p = 0.0001), mI/Cr (p = 0.02), Lip1/Cr (p < 0.0001), and Lip2/Cr (p = 0.002) ratios and lower NAA/Cr (p = 0.02) ratios than patients with PML who did not have IRIS. An elevated Cho/Cr ratio was associated with CE within the (1)H-MRS voxel, whereas lipid/Cr ratios were elevated in PML-IRIS lesions independently of CE. Follow-up until 33 months from PML onset showed persistent elevation of the mI/Cr ratio in lesions of patients with PML-IRIS. A Lip1/Cr ratio greater than 1.5 combined with the presence of CE yielded a 79% probability of IRIS compared with 13% in the absence of these criteria.

Conclusion: (1)H-MRS is a valuable tool to recognize and track IRIS in PML and may prove useful in the clinical management of these patients.

Figure 1. MRI and proton magnetic resonance spectroscopy (¹H-MRS) characteristics of progressive multifocal leukoencephalopathy (PML) and PML-immune reconstitution inflammatory syndrome (IRIS) lesions

(A–F) Cerebral PML lesion of an HIV− patient with PML-IRIS (A–C) and PML without IRIS (D–F) seen on fluid-attenuated inversion recovery (FLAIR) (A, D), and T1-weighted images with gadolinium (B, E). The area of enhancement is marked by an arrow (B), and the ¹H-MRS spectrum (C, F) shows elevated choline (Cho) and lipid peaks in the patients with PML-IRIS. (G–L) Cerebellar PML lesion of an HIV− patient with PML-IRIS (G–I) and an HIV+ patient with PML without IRIS (J–L) seen on FLAIR (G, J) and T1-weighted image with gadolinium (H, K). The area of enhancement is marked by an arrow (H), and the ¹H-MRS spectrum (I, L) shows elevated Cho and lipid peaks in the patient with IRIS. Cr = creatine; Lip1 = lipid/lactate; Lip2 = lipid/macromolecules; mI = myo-inositol; NAA = N-acetylaspartate.

Figure 2. Comparison of metabolite ratios within progressive multifocal leukoencephalopathy (PML) lesions of patients with and without immune reconstitution inflammatory syndrome (IRIS)

All MRIs were obtained within 1 year of onset of PML symptoms. Each dot represents the ratio obtained within one lesion. The bars represent the median ratio: (A) N-acetylaspartate (NAA)/creatine (Cr) ratio; (B) choline (Cho)/Cr ratio; (C) myo-inositol (mI)/Cr ratio; (D) lipid/lactate (Lip1)/Cr ratio and (E) lipid/macromolecules (Lip2)/Cr ratio.

Figure 3. Longitudinal evolution of metabolite ratios in patients with immune reconstitution inflammatory syndrome (IRIS) vs those without IRIS

Metabolite/creatine (Cr) ratios obtained in progressive multifocal leukoencephalopathy (PML) lesions of patients with IRIS (solid dots) and patients without IRIS (white dots) up to 30 months after symptom onset are shown. (A) N-Acetylaspartate (NAA)/Cr ratios in patients with IRIS increase over time, but remain overall lower than those in the group without IRIS (not significantly different). (B) The choline (Cho)/Cr ratio decreases quickly over time in the group with IRIS, and after 30 months there is no difference between the groups with and without IRIS. (C) Myo-inositol (mI)/Cr ratios of patients with IRIS remain statistically significantly higher over time compared with those of patients without IRIS. (D) Lipid/lactate (Lip1)/Cr and (E) lipid/macromolecules (Lip2)/Cr ratios decrease quickly over time in the group with IRIS, and after 30 months there is no difference between the groups with and without IRIS.