Predictors of neurocognitive outcomes on antiretroviral therapy after cryptococcal meningitis: a prospective cohort study

Abstract

Cryptococcal meningitis is the most common cause of adult meningitis in Africa, yet neurocognitive outcomes are unknown. We investigated the incidence and predictors of neurologic impairment among cryptococcal survivors. HIV-infected, antiretroviral-naive Ugandans with cryptococcal meningitis underwent standardized neuropsychological testing at 1, 3, 6, and 12 months. A quantitative neurocognitive performance z-score (QNPZ) was calculated based on population z-scores from HIV-negative Ugandans (n = 100). Comparison was made with an HIV-infected, non-meningitis cohort (n = 110). Among 78 cryptococcal meningitis survivors with median CD4 count of 13 cells/μL (interquartile range: 6-44), decreased global cognitive function occurred through 12 months compared with the HIV-infected, non-cryptococcosis cohort (QNPZ-6 at 12 months, P = 0.036). Tests of performance in eight cognitive domains was impaired 1 month after cryptococcal diagnosis; however, cryptococcal meningitis survivors improved their global neurocognitive function over 12 months with residual impairment (mean z-scores < -1), only in domains of motor speed, gross motor and executive function at 12 months. There was no evidence that neurocognitive outcome was associated with initial demographics, HIV parameters, or meningitis severity. Paradoxically, persons with sterile CSF cultures after 14 days of induction amphotericin therapy had worse neurocognitive outcomes than those still culture-positive at 14 days (P = 0.002). Cryptococcal meningitis survivors have significant short-term neurocognitive impairment with marked improvement over the first 12 months. Few characteristics related to severity of cryptococcosis, including Cryptococcus burden, were associated with neurocognitive outcome.

Figure 1. Neurocognitive function of cryptococcal meningitis survivors over 12 months compared with HIV-infected and HIV-negative population controls

Figure 1 displays the neurocognitive function of cryptococcal meningitis survivors compared with an HIV-infected Ugandan cohort (n=110). The z-scores were normalized to an HIV-negative adult Ugandan population (n=100), adjusted for age and education (population average z-score = 0). The summary quantitative neurocognitive performance z-score (QNPZ-6) was collected after cryptococcal diagnosis at 1 month (n=78), 3 months (n=69), 6 months (n=68), and 12 months (n=64). The QNPZ-6 was composed of the average z-score of: grooved pegboard (mean of both hands), symbol digit, WHO-UCLA auditory verbal learning test (both immediate and delayed recall), and color trails 1 and 2. Each individual score is depicted by a dot and the black line depicts the median score for each group. Nine individuals (12%) died during follow-up between 1 and 12 months.

Figure 2. Association of global neurocognitive outcome with CSF culture status at day 14 of amphotericin induction therapy

The figure displays the mean QNPZ-8 score over 12 months of follow-up stratified by CSF culture status after 14 days of amphotericin 0.7-1.0mg/kg/day with fluconazole 800mg/day induction therapy. Error bars represent 95% confidence intervals. Individuals with a sterile CSF culture at day 14 (n=25) had worse QNPZ-8 scores at any given visit over 12 months than individuals with a non-sterile CSF (n=21) at day 14 (P=0.002). Those with sterile cultures had worse outcomes (adjusted QNPZ-8 mean difference = -0.9, 95% CI: -1.4 to -0.3; P=0.002) when adjusted for baseline CSF fungal burden, CSF WBC count, pre-ART CD4 and pre-ART HIV viral load in a linear regression model incorporating a random intercept for intra-person repeated measures. These results did not change when adjusted for ART timing (difference = -0.90; 95% CI: -1.4 to -0.3; P=0.002). The baseline fungal burden for those with a non-sterile day 14 CSF culture was a mean (±SD) of 4.8 (±1.2) log₁₀ CFU/mL of CSF and for those with a sterile day 14 CSF culture was 3.8 (±1.9) log₁₀ CFU/mL. Twenty-three individuals did not have a CSF culture results available after 14 days of amphotericin, and these individuals had QNPZ-8 scores similar to those with a negative culture. Among those with missing culture status at day 14, the QNPZ-8 mean (±SD) were at 1 month = -2.6 (± 1.5), 3 months = -1.6 (±1.2), 6 months = -1.3 (±1.1), and 12 months = -1.6 (±1.2).