Among the 76 patients (28 [36.8%] women, 48 [63.2%] men, mean age 55.4±14.9 years [range, 19–80 years]), 51 (67.1%) patients were immune compromised and 25 (32.9%) were immune competent. At baseline, 22 (28.9%) patients presented with encephalitis. In baseline MRI, median BG-, CS-, and total ePVS scores were 2 [1–3], 2 [0–3], and 4 [1–6], respectively. Periventricular lesion extension was found in 41 (53.9%), cryptococcoma in 12 (15.8%), and hydrocephalus in 10 (13.2%) patients. Inter-rater reliability was 0.97 (95% CI: 0.95–1.00) for a baseline ePVS score of ≥5, 0.95 (95% CI: 0.92–0.98) for a periventricular lesion extension, 0.96 (95% CI: 0.93–0.99) for a cryptococcoma, and 0.99 (95% CI: 0.95–1.00) for a hydrocephalus. The median time to treatment initiation was 3 [2–7] days from the onset of symptoms. For induction treatment, amphotericin was used in 76 (100.0%), flucytosine in 43 (56.6%), and fluconazole in 23 (30.3%) patients. For consolidation and maintenance, fluconazole was used in 74 (97.4%) patients. Amphotericin was maintained for 30 [20.3–42], flucytosine for 19 [10.5–31.5], and fluconazole for 110 [60–223] days.
The cumulative number of patients who achieved CSF antigen clearance at 10 weeks was 50 (65.8%). At 6 months, median mRS score was 2 [0–4] and mortality rate was 15 (19.7%). Detailed clinical, CSF, baseline MRI, treatment, and outcome profiles are described in Table 1. Numbers of patients with magnetic resonance image (MRI) evaluations included at each time points were 76, 40, 49, and 59 at baseline, 2-week, 10-week, and 6-months, respectively..
In the univariate analysis, poor 6-month outcome was associated with baseline encephalitis feature (P<.001), elevated CSF opening pressure (P<.001), the presence of periventricular extension (P=.001), cryptococcoma (P=.022), hydrocephalus (P<.001), and higher scores of GB-, CS-, and total ePVS (all P<.001) in the baseline MRI. Demographics, underlying immune status, treatment profiles were comparable between the groups with poor or good outcomes (Table 1). Subsequently, logistic regression analysis indicated that total ePVS score (Odds ratio [OR]: 5.068, 95% CI: 1.627−15.785 for 1 score increment, P=.005) was independently associated with a poor 6-month outcome. The association of the periventricular lesion extension was marginal (P=.056). When total ePVS score was dichotomized, an ePVS score of ≥5 (OR: 94.173, 95% CI: 7.507−1181.295, P<.001), baseline encephalitis feature (OR: 44.487, 95% CI: 1.689−1172.082, P=.023), and periventricular lesion extension (OR: 51.965, 95% CI: 2.592−1041.673, P=.010) were all independently associated with a poor 6-month outcome (Table 2).
In the univariate analysis for the factors associated with 6-month mortality, the mortality of 6-month was associated with baseline encephalitis feature (P=.013), elevated CSF opening pressure (P=.032), periventricular lesion extension (P<.001), cryptococcoma (P=.013), and higher scores of GB-, CS-, and total ePVS (all P<.001) in the baseline MRI (Table 3). Due to low frequency (n=15), multivariate analysis for mortality was not performed.
We compared the clinical profiles and the outcomes between the groups with or without baseline encephalitis feature. The group with baseline encephalitis feature was associated with a higher frequency of HIV infection (P=.015), GCS score <15 (P<.001), elevated CSF opening pressure (P<.001), the presence of periventricular extension (P<.001), cryptococcoma (P=.015), and hydrocephalus (P=.021) in the baseline MRI, and lower baseline mRS scores and higher scores of GB-, CS-, and total ePVS, compared to the group without encephalitis feature (all P<.001). The 6-month mRS score was also lower in the subgroup with baseline encephalitis feature (P<.001, Supplemental Table 2).
In the regression analysis to evaluate the factors associated with poor 6-month outcomes in the subpopulation without baseline encephalitis feature, total ePVS score (OR: 4.331, 95% CI: 1.457−12.875 for 1 score increment, P=.008) was associated with a poor 6-month outcome. In the model with dichotomized ePVS value, ePVS score ≥5 (OR: 60.073, 95% CI: 5.152−700.485, P=.001) and periventricular lesion extension (OR: 23.106, 95% CI: 2.796−297.176, P=.016) were significantly associated with a poor 6-month outcome (Supplemental Table 3).
Risk score for a poor 6-month outcome was calculated by summing up the number of the factors associated with poor outcomes (encephalitis feature, ePVS score ≥5, and periventricular lesion extension), with a score range of 0−3. In ROC curve analysis for the total study population, the risk score predicted a poor 6-month outcome with area under the curve (AUC) of 0.978 (95% CI: 0.950−1.000, P<.001) and 6-month mortality with AUC of 0.836 (95% CI: 0.745−0.927, P<.001, Fig 2A and 2B). The risk score of 2 predicted a poor 6-month outcome with a sensitivity of 94.1% and a specificity of 95.2%, and 6-month mortality with a sensitivity of 93.3% and a specificity of 67.2%. For the subgroup without baseline encephalitis feature, the risk score predicted a poor 6-month outcome with AUC of 0.952 (95% CI: 0.896−1.000, P<.001) and 6-month mortality with AUC of 0.870 (95% CI: 0.764−0.978, P=.003, Fig 2C and 2D). In this subgroup, the risk score of 2 predicted a poor 6-month outcome with a sensitivity of 85.7% and a specificity of 95.0%, and 6-month mortality with a sensitivity of 83.3% and a specificity of 81.2%.
Two-week follow-up MRI evaluation data were available for 40 (59.7%), 10-week follow-up MRI for 49 (64.5%), and 6-month follow-up MRI for 59 (77.6%) patients. The median number of MRI evaluations analyzed per patient was 3 [3–3]. When the serial changes in the MRI parameters were analyzed in association with the changes in mRS scores, the subgroup with baseline ePVS score ≥5 showed gradual deterioration in the mRS score along with progressive increment of the frequency of cryptococcoma and hydrocephalus (Fig 3A), whereas the subgroup with baseline ePVS score <5 showed gradual improvement in the mRS score and maintained a low frequency of periventricular lesion extension, cryptococcoma, and hydrocephalus in the follow-up MRIs (Fig 3B). A similar trend was observed in the subgroup without baseline encephalitis feature (Fig 3C and 3D, see Fig 4 for representative cases). The profiles of the MRI parameters between the groups evaluated using 1.5-T or 3.0-T MRI machines were comparable (Supplemental Table 4).