Use of Diffusion-Weighted Imaging to Evaluate the Initial Response of Progressive Multifocal Leukoencephalopathy to Highly Active Antiretroviral Therapy: Early Experience

摘要

BACKGROUND AND PURPOSE: IRIS occurs in a small percentage of patients with AIDS following the initiation of HAART. Because PML lesions have a characteristic DWI/ADC appearance, our purpose was to determine if DWI/ADC measurements of PML lesions can be used to follow HAART treatment response and/or identify patients at risk for IRIS. MATERIALS AND METHODS: Six patients with AIDS and PML who had recently started HAART were retrospectively identified. On the basis of clinical history, patients were classified as having slow (non-IRIS) or rapid (IRIS) progression. Images were obtained at pre-HAART (time point 1) and post-HAART (time point 2). ADC parameters were measured and compared by using the 2-tailed t test. RESULTS: Seven lesions (4 rapidly progressing, 3 slowly progressing) were identified. Lesions from patients with rapid clinical progression had higher maximal ADC ratios at time point 1. There were also significant correlations between ADC parameters, time to clinical deterioration, and JCV titers. CONCLUSIONS: The ADC parameters of PML lesions were different for patients with rapid-versus-slow clinical progression. In our preliminary experience, ADC was helpful in diagnosing rapid clinical progression and IRIS. ADC values may correlate with the pathologic changes in PML lesions following HAART therapy. Abbreviations: ADC, apparent diffusion coefficient • AIDS, acquired immunodeficiency syndrome • CI, confidence interval • CLWM, contralateral white matter • DWI, diffusion-weighted imaging • HAART, highly active antiretroviral therapy • HIV, human immunodeficiency virus • IRIS, immune reconstitution inflammatory syndrome • JCV, JC virus • Max, maximum • PML, progressive multifocal leukoencephalopathy • T2WI, T2-weighted imaging PML is a demyelinating disease caused by the JCV in immunocompromised hosts. Approximately 5%–14% of patients with AIDS develop PML during the course of their disease,1 and PML is the cause of death in 0.7% of them.2 Untreated, the disease has a rapid and fatal course, with an average life expectancy of 4 months.3 The use of HAART in the treatment of PML has increased the 1-year survival rate by 10%–50%.4 However, even when HAART successfully restores immune function, 50% of patients with PML die.5 Approximately 6% of these patients show rapid clinical deterioration following HAART.6 This paradoxical deterioration in clinical status, termed IRIS, is thought to be secondary to the restoration of the immune system.7 The effect of IRIS on long-term survival is uncertain, with many but not all case reports suggesting that it results in short-term morbidity but heralds favorable long-term outcome.7 While clinical deterioration after HAART therapy is the sine qua non of IRIS, there are no unanimous diagnostic criteria.8 A number of clinical and imaging features have been associated with both IRIS and treatment response to HAART.9,10 Clinically, a low CD4 count and early initiation of treatment are thought to increase the risk for IRIS, though the specificity of these findings is limited.2 On imaging, lesion contrast enhancement has been associated with both IRIS and response to therapy,11 but because this enhancement is typically transient, its sensitivity as a marker for therapy response is limited. Therefore, there is a need to identify more accurate imaging characteristics of HAART treatment in PML, especially in regard to the diagnosis and development of IRIS. DWI and ADC detect changes in diffusion of water in brain parenchyma. Several studies have reported ADC/DWI imaging changes in PML lesions. In particular, PML lesions demonstrate patchy restricted diffusion at their periphery correlating with areas of lesion expansion.12–15 High central ADC may reflect the evolution of PML lesions, indicating both how long they have existed and how likely they are to expand,16 and ADC/DWI changes are thought to correlate directly with the pathophysiology of the disease.13 Furthermore, initial studies of PML lesions following HAART therapy suggest that ADC/DWI may correlate with treatment outcomes.14 The purpose of our study was to determine whether ADC/DWI measurements of PML lesions before and after initiation of HAART can be used to follow treatment response, in particular, the development of IRIS. Materials and Methods All patients with AIDS seen at the New York Presbyterian Hospital between 2003 and 2005 were retrospectively reviewed, and 6 cases were found that fit the following criteria: 1) HIV positive, 2) diagnosis of PML established through JCV in CSF, 3) off HAART at the time of diagnosis or recently initiated HAART before the diagnosis of PML, and 4) T2WI and DWI with or without contrast performed before (time point 1) and initially after (time point 2) the commencement of HAART. The clinical history of all patients was reviewed for the first 60 days following the introduction of HAART. Patients who showed signs of significant clinical deterioration (new symptoms, worsening of initial symptoms related to PML requiring re-hospitalization, or death) within the first 60 days following initiation of HAART were classified as "rapidly progressive." Patients who demonstrated no significant progression of symptoms in the first 60 days or who were admitted for reasons thought to be unrelated to their PML were deemed "slowly progressive." All data were obtained in accordance with the Health Insurance Portability and Accountability Act, and the study was approved by the institutional review board. MR imaging was performed on 1.5T systems by using T1 (TR/TE, 500/15 ms; matrix, 288 x 192; FOV, 22 x 22 cm) and T2WI (TR/TE, 4000/85 ms; matrix, 288 x 192; FOV, 22 x 22 cm) sequences in at least 2 planes. Axial DWI and ADC maps were acquired by using echo-planar sequences (TR/TE, 8000/85 ms; matrix, 128 x 128; FOV, 22 x 22 cm) at b-values of 0, 500, and 1000 s/mm2. Imaging was performed at 2 time points, separated by an average of 40 days (range, 11–91 days; the "scan interval"). To facilitate comparison between images acquired at different time points, we used a spatial normalization algorithm to align the coordinates of the ADC and T2WI sequences at time points 1 and 2. After spatial normalization, the same coordinate corresponded to the same anatomic location for every image in the series, regardless of the time point or the image sequence (ADC, T2WI). Image analysis was performed by using the MRICro system (http://www.sph.sc.edu/comd/rorden/mricro.html). Consistent with prior descriptions,11 PML lesions were defined as continuous asymmetric scalloped lesions in the white matter on axial T2WI with areas of restricted diffusion on DWI/ADC in patients with clinical, pathologic, and/or laboratory evidence for PML. Using MRICro, we drew individual regions of interest freehand on ADC images at the border of normal-appearing white matter determined by visual inspection by using a window centered at 130 x 10–5 s/mm2 with a width of 120 x 10–5 mm2/s in each axial image in which the lesion was present. The overall lesion region of interest was the composite of these individual axial regions of interest. The standard error in the freehand estimate of a region of interest was estimated at 10% on the basis of the differences between repeated measurements. Quantitative data were obtained for both components of lesion progression, lesion expansion and lesion evolution. Lesion expansion was defined as the number of pixels within the PML lesion with region-of-interest methods as described above. Lesions with fewer than 80 pixels could not be reliably identified and were excluded from analysis. By definition, expansion was diagnosed when the lesion area at time point 2 was greater than the lesion area at time point 1, with the opposite being true for lesion regression. Lesion expansion was also correlated with the total area and average ADC values within regions of restricted diffusion at the periphery of the lesions. Regions of restricted diffusion were identified on DWIs and quantified by using regions of interest placed on corresponding ADC maps. Data analysis for lesion expansion took into account the interval in days between time points 1 and 2 (the scan interval) by measuring the rate of expansion as follows: Lesion evolution was evaluated by comparing ADC parameters and their changes between time points 1 and 2. Three parameters were measured by using statistics obtained from regions of interest drawn around the entire lesion (average and maximal ADC) and, when present, a central area of ADC values > 160 x 10–5 mm2/s. Data analysis for lesion evolution took into account variations in ADC of normal brain, known to vary 15% between patients.17 To control for variations in ADC of presumed normal brain tissue, we measured the ADC of CLWM by using an initial 3D region of interest in MRICro (difference from origin, 16; difference at edge, 16; radius of region of interest, 32) and then manually modified it to emulate the contour and position of the lesion. The average and maximal ADC ratios were then calculated as follows: The third parameter—high central ADC area—was calculated as the percentage of pixels within the lesion with ADC 160 x 10–5 mm2/s. While patients with HIV can have a global decrease in white matter ADC due to diffuse leukoencephalopathy, which could cause the overestimation of measured ADC ratios, average contralateral ADC for the patients in this study was 80 x 10–5 mm2/s, similar to the average established by Sener18 for normal controls of 84 x 10–5 mm2/s. ADC parameters for lesions associated with rapid and slow clinical progression were compared and were correlated with clinical and imaging variables, including rate of lesion growth, days to rehospitalization, presence of clinical deterioration, JCV titers when available, and immunologic status (CD4 count and viral load). In both cases, significance was determined by using a 2-sample 2-tailed t test with an assumption of unequal variances and a significance threshold of .05. Results Most patients meeting the selection criteria were new to the hospital, presenting with PML, with limited documentation of their HIV history. All patients were off HAART at the time of presentation. One patient had toxoplasmosis a year before admission, but there were no concurrent AIDS-defining illnesses at the time of presentation. The duration of illness was unknown in half of the patients and ranged from 1 month to 6 years in the others. Pertinent available clinical data are presented in Table 1. View this table: [in this window] [in a new window] Table 1: Clinical and demographic characteristics of the 6 patients A total of 7 lesions were identified in 6 patients, 4 in the posterior fossa and 3 in the subcortical white matter of the frontal and parietal lobes. Lesion Expansion Measurements For patients with slow clinical progression (n = 3), a total of 3 separate lesions were identified. For patients with rapid clinical progression (n = 3), 4 lesions were identified. Rapid-progressing lesions expanded at an average rate of 168 ± 78 pixels/day, 9 times faster than slow-progressing lesions (20 ± 78 pixels/day). All lesions showed areas of restricted diffusion at their periphery, and none were associated with significant mass effect. Lesion Evolution Measurements ADC parameters for each lesion are presented in Table 2. Representative data is shown in Figures 1–3. There was a statistically significant difference between maximal ADC ratios for the rapid and slow clinical progression groups (P 160 x 10–5 mm2/s, indicated by pink and white). B, One month after therapy, ADC values in the lesion center have increased but only slightly and to a lesser magnitude than lesions in patients with rapid progression. There was no significant correlation between ADC parameters and immunologic status as measured by both CD4 and viral load. However, there was a significant correlation between JCV titers and high central ADC area at time point 1 (r = +0.96, P sup> .01). Time to clinical deterioration was also correlated with both maximal ADC ratio (r = –0.89, P < .01) and high central ADC (r = –0.94, P 160 x 10–5 mm2/s, indicated by pink and white). B, One month after therapy, areas of both the total lesion and central high ADC core have substantially increased.