Perinatally HIV-infected Children Research Articles

Development of retinal structure in perinatally HIV-infected children and adolescents: A longitudinal and cross-sectional assessment.

In perinatally HIV-infected (PHIV) children, cross-sectional studies reported on subtle structural retinal differences and found associations between the retina and structural brain changes. Our objective is to investigate whether neuroretinal development in PHIV children is similar to the development in healthy matched controls and to explore associations with the brain structure. We measured RT using optical coherence tomography (OCT) on two occasions in 21 PHIV children or adolescents and 23 matched controls-all with good visual acuity-with a mean interval of 4.6 years (SD 0.3). We also included 22 participants (11 PHIV children and 11 controls) together with the follow-up group for a cross-sectional assessment using a different OCT device. Magnetic resonance imaging (MRI) was used to assess the white matter microstructure. We used linear (mixed) models to assess changes in RT and its determinants (over time), adjusting for age and sex. The development of the retina was similar between the PHIV adolescents and controls. In our cohort, we found that changes in the peripapillary RNFL was significantly associated with changes in WM microstructural makers: fractional anisotropy (coefficient = 0.030, p = 0.022) and radial diffusivity (coefficient = -0.568, p = 0.025). We found comparable RT between groups. A thinner pRNFL was associated with lower WM volume (coefficient = 0.117, p = 0.030). PHIV children or adolescents appear to have a similar development of the retinal structure. In our cohort, the associations between RT and MRI biomarkers underscore the relation between retina and brain.

Longitudinal Assessment of Lipoprotein(a) Levels in Perinatally HIV-Infected Children and Adolescents.

HIV is an independent risk factor of cardiovascular disease (CVD); therefore, perinatally HIV-infected (PHIV) children potentially have a greater CVD risk at older age. Lipoprotein(a) (Lp(a)) is an established risk factor for CVD in the general population. To evaluate a potential increased CVD risk for PHIV children, we determined their lipid profiles including Lp(a). In the first substudy, we assessed the lipid profiles of 36 PHIV children visiting the outpatient clinic in Amsterdam between 2012 and 2020. In the second substudy, we enrolled 21 PHIV adolescents and 23 controls matched for age, sex and ethnic background on two occasions with a mean follow-up time of 4.6 years. We assessed trends of lipid profiles and their determinants, including patient and disease characteristics, using mixed models. In the first substudy, the majority of PHIV children were Black (92%) with a median age of 8.0y (5.7–10.8) at first assessment. Persistent elevated Lp(a) levels were present in 21/36 (58%) children (median: 374 mg/L (209–747); cut off = 300). In the second substudy, the median age of PHIV adolescents was 17.5y (15.5–20.7) and of matched controls 16.4y (15.8–19.5) at the second assessment. We found comparable lipid profiles between groups. In both studies, increases in LDL-cholesterol and total cholesterol were associated with higher Lp(a) levels. A majority of PHIV children and adolescents exhibited elevated Lp(a) levels, probably associated with ethnic background. Nonetheless, these elevated Lp(a) levels may additionally contribute to an increased CVD risk.

Lower IQ and poorer cognitive profiles in treated perinatally HIV-infected children is irrespective of having a background of international adoption.

HIV-associated cognitive deficiency in perinatally HIV-infected (PHIV) children has been studied in Western countries in a population of which an increasing proportion has been internationally adopted. Studies often lack an appropriate internationally adopted HIV-uninfected control group, potentially confounding the relationship between HIV and cognitive functioning. This study aims to further elucidate the association between treated HIV infection and cognitive development by addressing the background of international adoption. We cross-sectionally studied the impact of HIV on cognition by comparing PHIV children and HIV- uninfected controls, matched for age-, sex-, ethnicity-, socioeconomic status (SES)- and adoption status. We used a standardized neuropsychological test battery to measure intelligence (IQ), and the cognitive domains of processing speed, working memory, executive function, learning ability and visual-motor function and compared outcomes using lineair regression models, adjusted for IQ. We determined cognitive profiles and cognitive impairment by using multivariate normative comparison (MNC) and explored associations with HIV disease- and treatment-related factors. We enrolled fourteen PHIV children (mean age 10.45 years [1.73 SD], 93% adopted from sub-Saharan Africa at a median age of 3.3 years [IQR 2.1-4.2]) and fifteen HIV- uninfected controls. Groups did not clinically nor statistically differ in age, sex, ethnicity, SES, region of birth, adoption status and age at adoption. PHIV scored consistently lower on all cognitive domains and MNC outcomes. Compared to controls, PHIV children had a significant lower IQ (mean 81 [SD 11] versus mean 97 [SD 15], p = 0.005), and a poorer cognitive profile by MNC (Hotelling's T2 mean -4.36 [SD 5.6] versus mean 0.16 [SD 4.5], p = 0.021), not associated with HIV disease- and treatment-related factors. Two PHIV (14%) and one control (7%) were classified as cognitively impaired (p = 0.598). Findings indicate treated HIV-infection to be independently associated with lower IQ and poorer cognitive profiles in PHIV children, irrespective of a background of international adoption.

885. HIV-1 Treatment Failure and Extensive Drug Resistance in Perinatally Infected Children Failing First-Line Antiretroviral Therapy in Western Kenya

BackgroundUnderstanding drug resistance in perinatally HIV-infected children (PHIC) when viral load (VL) monitoring is limited is critical for life-long antiretroviral use. Resistance data in PHIC in sub-Saharan Africa are limited. Though guidelines recommend PI-based first-line regimens in PHIC, many worldwide remain on NNRTI-based regimens. We examined treatment failure, resistance, and outcomes in Kenyan PHIC on first-line NNRTI-based therapy.MethodsPHIC were enrolled in 2010–2013 at the Academic Model Providing Access to Healthcare in Eldoret, Kenya, a large program caring for >160,000 HIV patients; >15,000 PHIC. VL testing, not routinely available then, was done for all, and resistance testing was done in viremic PHIC. Clinical data were derived from medical records. Subtype and resistance interpretation were with Stanford Database tools. Associations between failure (>1,000 copies/mL) or resistance, and demographic, clinical or lab variables were evaluated with Fisher exact and Wilcoxon rank-sum tests.ResultsOf 482 PHIC enrolled, 52% were female, median age 8.4 years (range 1–15), median CD4% 28 (range 0–53), 79% on zidovudine (AZT)/abacavir (ABC)+lamivudine(3TC)+efavirenz (EFV)/nevirapine (NVP) for median 2.3 years. Treatment failure was seen in 31%, associated with low CD4% and count. Genotypes were available in 124, 47% female, median age 8.3 years (range 2–15), median CD4% 22 (range 0–45), 81% on AZT/ABC+3TC+EFV/NVP for median 2.5 years, median VL 7,515 copies/mL. Subtypes were A 76%, C 3%, D 15%, recombinants 6%. Reverse transcriptase mutations were in 93%; 93%-NNRTIs, median 2/patient, most common Y181C (44%); 89%-NRTIs, median 3/patient, most common M184V (85%); 89%-dual class, median 5/patient. Intermediate-high resistance to potential second-line drugs included 62% etravirine, 66% rilpivirine, and 19% tenofovir. Of 92/124 (74%) PHIC with follow-up data, 27% remained on NNRTI-based first-line (median CD4 count 461), of whom 24% had suppressed VL and 48% died; and 73% switched to PI-based second-line (median CD4 count 591), of whom 72% had suppressed VL and 6% died (P < 0.05 for both).ConclusionPHIC in western Kenya on NNRTI-based first-line regimens had high treatment failure rates and extensive drug resistance with poor clinical outcomes, demanding urgent interventions.Disclosures All Authors: No reported Disclosures.

Serum Vitamin D is Differentially Associated with Socioemotional Adjustment in Early School-Aged Ugandan Children According to Perinatal HIV Status and In Utero/Peripartum Antiretroviral Exposure History.

An impact of vitamin D in neurocognitive function has been theorized but it remains unknown whether vitamin-D insufficiency (VDI) is associated with worse socio-emotional adjustment (SEA) in vulnerable early school-aged children. This study examines the thesis that deficits in SEA are related to VDI using longitudinal data from 254 children that are perinatally HIV-infected (PHIV), exposed-uninfected (HEU), or unexposed-uninfected (HUU). In utero/peripartum antiretroviral (IPA) exposure was established per medical record documentation of biological mother’s ART regimen in pregnancy. Four caregiver-reported age- and sex-standardized measures of SEA were obtained at months 0, 6, and 12 for dependent children aged 6–10 years: externalizing problems (EPC), internalizing problems (IPC), behavioral symptoms index (BSI), and adaptive skills index (ASI). VDI was highly prevalent (74%, n = 188), and its association with change in SEA measures over 12 months varied by HIV-status (VDI*HIV, all p-values < 0.03). There was further variation in relationship of vitamin-D to SEA by IPA among PHIV (for ASI, BSI, and EPC, vitamin-D*IPA, p-value ≤ 0.01) and HEU (for BSI and EPC, vitamin-D*IPA, p-value ≤ 0.04). Among HUU, BSI (β = −0.32, 95% CI: −0.50, −0.13), IPC (β = −0.28, 95% CI: −0.47, −0.09), and EPC (β = −0.20, 95% CI: −0.37, −0.02) all declined moderately per quartile increment in VD. Among PHIV, on the one hand higher vitamin D predicted ASI gains (moderate vs. low VD, β = 0.52, p = 0.002), but this protective association was absent for BSI, EPC, and IPC (β = 0.36–0.77, p < 0.05). In absence of IPA-exposure, increasing vitamin-D predicted declines in BSI and EPC (moderate vs. low Vitamin D, β = −0.56 to −0.71, p ≤ 0.02) among HEU. However, given IPA exposure among HEU, higher VDI predicted moderate elevation in BSI (β = 0.39, 95% CI: 0.00, 0.78) and IPC (β = 0.48, 95% CI: 0.05, 0.92). Interaction between VD and IPA exposure for SEA outcomes among HEU and PHIV children warrants further investigation. The vitamin-D associated SEA improvement among HUU and HEU without IPA exposure suggests vitamin-D supplementation may remediate behavioral and adaptive deficits in this groups.

Low risk of neurodevelopmental impairment among perinatally acquired HIV-infected preschool children who received early antiretroviral treatment in Thailand.

IntroductionAntiretroviral therapy (ART) is recommended in perinatally HIV‐infected (PHIV) infants immediately upon diagnosis. We aimed to compare neurodevelopmental outcomes between PHIV children who initiated ART within 12 months of life and perinatally HIV‐exposed uninfected (PHEU) children and to assess neurodevelopmental outcomes by timing of ART.MethodsThis prospective cohort study included Thai children aged 12 to 56 months who were assessed with the Mullen Scales of Early Learning (MSEL) at enrolment and at 48 weeks. Global Developmental Impairment (GDI) was defined as Early Learning Composite (ELC) ≤ 70 on the MSEL; typical developmental pattern was defined as ELC > 70 at both visits. Logistic regression was used to compare prevalence of any GDI. Predictors of changing ELC scores were analysed with generalized estimating equations linear regression model.ResultsFrom 2016 to 2017, 50 PHIV (twenty‐seven early ART within three months and twenty‐three standard ART within three to twelve months) and 100 PHEU children were enrolled. Median (IQR) age at first assessment was 28 (19 to 41) months. PHIV children had lower age‐relevant Z scores for weight, height and head circumference compared to the PHEU group (p < 0.05).The prevalence of overall GDI was 18% (95% CI 11 to 27) and 32% (95% CI 20 to 47) in PHEU and PHIV children respectively (p = 0.06). In subgroup analysis, 22% (95% CI 9 to 42) of early ART PHIV children and 44% (95% CI 23 to 66) of standard ART PHIV children had overall GDI. There was a higher rate of GDI in standard ART PHIV children (p = 0.01), but not in the early ART group (p = 0.62) when compared with PHEU children. The standard ART PHIV group demonstrated lower typical developmental pattern than both the early ART PHIV group and the PHEU group (57% vs. 77% vs. 82% respectively). Non‐attendance at nursery school was associated with changes in ELC score during study participation (adjusted coefficient −3.8; 95% CI −6.1 to −1.6, p = 0.001).ConclusionsPreschool children with HIV who initiated ART in the first three months of life had a similar rate of GDI as PHEU children. Lack of nursery school attendance predicted poor developmental trajectory outcomes among PHIV children.

Treatment outcomes in perinatally infected HIV-positive adolescents and young adults after ≥10 years on antiretroviral therapy.

The burden of paediatric HIV in South Africa has shifted to older children and adolescents. Nevertheless, information on long-term treatment outcomes of perinatally HIV-infected (PHIV) children is limited. To examine long-term immunological and virological outcomes of children who were in care for at least 10 years after starting antiretroviral therapy (ART). We performed a retrospective cohort study of 127 PHIV children who initiated ART at a Cape Town clinic between 2002 and 2005 and were followed up for ≥10 years from the ART initiation date. CD4+ counts and viral loads (VLs) were analysed for each successive year on ART. Treatment history, resistance test results, growth data, hospital admissions and opportunistic infection history were described. The median age at ART initiation was 2.6 years (interquartile range (IQR) 1.3 - 4.9) and the median CD4+ percentage 13.0% (IQR8.9 - 18.0). The first ART regimen was non-nucleoside reverse transcriptase inhibitor based (63.8%) or protease inhibitor based (36.2%). Median follow-up was 12.2 years (IQR 11.1 - 13.0). At the last assessment, 49.6% of patients were on first-line and 43.3% on second-line ART. At the last assessment, the median CD4+ count was 686 cells/µL (IQR 545 - 859) and 78.7% of children had CD4+ counts &gt;500cells/µL (92.1% of those on first-line v. 70.9% on second-line ART; p=0.003). At the last assessment, 79.5% of patients were virally suppressed (VL &lt;400 copies/mL), 86.2% of those on first-line v. 76.8% on second-line ART (p=0.183). The 10-year probability of experiencing viral failure (VF) was 56.7% (95% confidence interval (CI) 48.3 - 65.5) and the 10-year probability of switching to second-line ART 45.7% (95% CI 37.5 - 54.8). The probability of experiencing VF between the ages of 10 and 18 years was 37.4% (95% CI 25.4 - 52.8). Virological and immunological outcomes were good overall in PHIV children who remained in care for ≥10 years at this clinic, but &gt;40% of children were on second-line ART with poorer immunological outcomes.

Immunity After Childhood Vaccinations in Perinatally HIV-exposed Children With and Without HIV Infection in Latin America.

Perinatally HIV-infected (PHIV) children are at risk for under-vaccination and poor vaccine response at 4 years of age. Childhood vaccine coverage and immune response were compared between PHIV and HIV-exposed uninfected (HEU) children in Latin America and the Caribbean. PHIV and HEU children were enrolled prospectively at 15 sites from 2002 to 2009. Full vaccination by age 4 years was defined as: 3 hepatitis B virus vaccine doses; 4 tetanus toxoid-containing vaccine doses; 3 doses of Haemophilus influenzae type b vaccine by age 12 months or ≥1 dose given after age 12 months; one measles-containing vaccine dose; one rubella-containing vaccine dose. Immunity was defined by serum antibody titer. Fisher exact test (for categorical measures) and t test (for continuous measures) were used for comparisons. Among 519 children seen at age 4 years, 191 had serum specimens available (137 PHIV, 54 HEU). Among those with specimens available, 29.3% initiated combination antiretroviral therapy (cART) <12 months of age, 30.9% initiated at ≥12 months of age, and 39.8% had not received cART by the time they were seen at 4 years of age. At 4 years of age, 59.9% were on PI-containing cART (cART/PI), and 20.4% were on no ART. PHIV children were less likely than HEU children to be fully vaccinated for tetanus (55.5% vs. 77.8%, P = 0.005) and measles and rubella (both 70.1% vs. 94.4%, P < 0.001). Among those fully vaccinated, immunity was significantly lower among PHIV than HEU for all vaccines examined: 20.9% versus 37.8% for hepatitis B virus (P = 0.04), 72.0% versus 90.5% for tetanus (P = 0.02), 51.4% versus 68.8% for H. influenzae type b (P = 0.05), 80.2% versus 100% for measles (P < 0.001) and 72.9% versus 98.0% for rubella (P < 0.001) vaccine, respectively. Compared with HEU, PHIV children were significantly less likely to be immune to vaccine-preventable diseases when fully vaccinated. Strategies to increase immunity against vaccine-preventable diseases among PHIV require further study.

Quality of life among perinatally HIV-affected and HIV-unaffected school-aged and adolescent Ugandan children: a multi-dimensional assessment of wellbeing in the post-HAART era.

To examine quality of life (QOL) in perinatally HIV-infected (PHIV) or HIV-exposed uninfected (PHEU) vs. healthy HIV-unexposed uninfected (HUU) children during school-age/adolescence. PHIV infection was diagnosed via DNA PCR. Current HIV status was confirmed by HIV rapid diagnostic test. Three HIV groups were defined: PHIV, PHEU, and HUU. QOL was assessed with proxy and self-report versions of the PedsQL™ 4.0 instrument at 6-18years of age. QOL scores ranged from zero (least QOL) to 100 (highest QOL) in the following dimensions: combined QOL inventory (CQOLI), multi-dimensional vigor (MDV), general wellbeing (GWB), present functioning, and general cognitive functioning (CF). Multivariable linear regression models estimated HIV-related percent differences (β) in QOL scores and 95% confidence intervals (CI). Compared to HUU CQOLI deficits ranged from 6.5 to 9.2% (95% CI -15.4, -1.6), GWB deficit ranged from 6.5 to 10.5% (95% CI -16.0, -1.3), MDV deficit ranged from 6.8 to 11.6% (95% CI -14.5, 0.9), and CF deficit ranged from 9.7 to 13.1% for PHIV children. QOL deficits of similar magnitude and direction in most domains were observed for PHIV compared to PHEU. However, self-reported indicators of GWB (β=-3.5; 95% CI -9.0, 2.0) and present functioning (β=4.0; 95% CI -4.6, 12.5) were similar for PHIV compared to PHEU. QOL scores were generally similar for PHEU compared to HUU. PHEU and HUU had similar QOL profile but PHIV predicted sustained deficits in multiple QOL domains. PHIV and PHEU children were similar with respect to general wellbeing and present functioning. Psychosocial and scholastic interventions in combination with HIV care are likely to improve QOL in PHIV.

Phenotypic Coreceptor Tropism in Perinatally HIV-infected Youth Failing Antiretroviral Therapy.

Perinatally HIV-infected (PHIV) children and youth are often heavily treatment-experienced, with resultant antiretroviral resistance and limited treatment options. For those with virologic failure (VF), new agents such as CCR5 (R5) antagonists may be useful; however, reports of R5 antagonist susceptibility in children have mostly relied on genotypic testing, which may not accurately reflect the phenotypic tropism of the viral populations. We characterized phenotypic coreceptor usage among PHIV children and youth with VF on antiretroviral treatment to identify predictors of CXCR4 (X4) tropism which preclude R5 antagonist use. Plasma samples with >1000 HIV RNA copies/mL were obtained from 73 PHIV antiretroviral treatment-treated children and youth (age 9-21 years) enrolled in the multicenter Pediatric HIV/AIDS Cohort Study. Samples were analyzed using the Trofile phenotypic assay. Multiple logistic regression was performed to identify factors associated with detectable X4 tropism. Tropism results were obtained for 59 (81%) of the 73 children and youth; 32 (54%) had X4-tropism. Persistent viremia (≥80% of HIV RNA measurements >400 copies/mL) was associated with detectable X4 tropism (adjusted odds ratio: 6.6, 95% confidence interval: 1.4, 31.4), while longer cumulative nucleoside reverse transcriptase inhibitor use was associated with lower risk of X4 tropism (adjusted odds ratio: 0.6, 95% confidence interval: 0.5, 0.9). Using a phenotypic assay, >50% of PHIV children and youth with VF had X4 tropism, similar to that in experienced adults, and higher than the 30% reported for children using genotypic assays. Persistent viremia and shorter nucleoside reverse transcriptase inhibitor exposure are associated with X4-tropism in children and youth and may help target phenotypic testing to those most likely to benefit from R5 antagonist.

CD4+ and viral load outcomes of antiretroviral therapy switch strategies after virologic failure of combination antiretroviral therapy in perinatally HIV-infected youth in the United States.

Objective:This study compared 12-month CD4+ and viral load outcomes in HIV-infected children and adolescents with virological failure, managed with four treatment switch strategies.Design:This observational study included perinatally HIV-infected (PHIV) children in the Pediatric HIV/AIDS Cohort Study (PHACS) and Pediatric AIDS Clinical Trials (PACTG) Protocol 219C.Methods:Treatment strategies among children with virologic failure were compared: continue failing combination antiretroviral therapy (cART); switch to new cART; switch to drug-sparing regimen; and discontinue all ART. Mean changes in CD4+% and viral load from baseline (time of virologic failure) to 12 months follow-up in each group were evaluated using weighted linear regression models.Results:Virologic failure occurred in 939 out of 2373 (40%) children. At 12 months, children switching to new cART (16%) had a nonsignificant increase in CD4+% from baseline, 0.59 percentage points [95% confidence interval (95% CI) −1.01 to 2.19], not different than those who continued failing cART (71%) (−0.64 percentage points, P = 0.15) or switched to a drug-sparing regimen (5%) (1.40 percentage points, P = 0.64). Children discontinuing all ART (7%) experienced significant CD4+% decline −3.18 percentage points (95% CI −5.25 to −1.11) compared with those initiating new cART (P = 0.04). All treatment strategies except discontinuing ART yielded significant mean decreases in log10VL by 12 months, the new cART group having the largest drop (−1.15 log10VL).Conclusion:In PHIV children with virologic failure, switching to new cART was associated with the best virological response, while stopping all ART resulted in the worst immunologic and virologic outcomes and should be avoided. Drug-sparing regimens and continuing failing regimens may be considered with careful monitoring.

Undervaccination of perinatally HIV-infected and HIV-exposed uninfected children in Latin America and the Caribbean.

Perinatally HIV-infected (PHIV) children may be at risk of undervaccination. Vaccination coverage rates among PHIV and HIV-exposed uninfected (HEU) children in Latin America and the Caribbean were compared. All PHIV and HEU children born from 2002 to 2007 who were enrolled in a multisite observational study conducted in Latin America and the Caribbean were included in this analysis. Children were classified as up to date if they had received the recommended number of doses of each vaccine at the appropriate intervals by 12 and 24 months of age. Fisher's exact test was used to analyze the data. Covariates potentially associated with a child's HIV status were considered in multivariable logistic regression modeling. Of 1156 eligible children, 768 (66.4%) were HEU and 388 (33.6%) were PHIV. HEU children were significantly (P < 0.01) more likely to be up to date by 12 and 24 months of age for all vaccines examined. Statistically significant differences persisted when the analyses were limited to children enrolled before 12 months of age. Controlling for birth weight, sex, primary caregiver education and any use of tobacco, alcohol or illegal drugs during pregnancy did not contribute significantly to the logistic regression models. PHIV children were significantly less likely than HEU children to be up to date for their childhood vaccinations at 12 and 24 months of age, even when limited to children enrolled before 12 months of age. Strategies to increase vaccination rates in PHIV are needed.

Perinatally HIV-infected youth presenting with acute stroke: Progression/evolution of ischemic disease on neuroimaging

Although HIV infection is decreasing in infants and children, there is a steady cohort of perinatally HIV-infected (PHIV) children that are growing older. Increased risk of acute stroke has been reported in PHIV children. Our goal was to evaluate evolution/progression of neuroimaging findings in PHIV youth initially presenting with acute stroke. The medical records of PHIV pediatric patients (n = 179) from 1996 to 2010 were reviewed and patients with clinical documentation of acute stroke referred to the neuroradiology service were eligible for the study. Neuroimaging (brain CT, MRI, and MRA) and charts were evaluated; clinical and neuroimaging findings at the initial acute stroke and at the last presentation to the neuroradiology service were documented and analyzed. Eight PHIV patients with clinical findings of acute stroke referred to the neuroimaging were identified. CT and MRI findings of infarction were found in all (8/8) patients in their first and/or last neuroimaging study; including basal ganglia-thalami (BGT) infarction (7/8), focal cortical infarction (4/8), and internal capsule infarction (4/8). Imaging depicted cortical atrophy (5/8), BGT calcification (3/8), and posterior reversible encephalopathy syndrome, wallerian degeneration, and periventricular white matter hyperintense T2 signal each in one patient. No tumors or infectious masses, cysts or abscesses were identified. Subsequent available neuroimaging revealed progression of the cerebrovascular disease in seven patients, 5/7 in the absence of new clinical signs or symptoms. Segmental occlusion, narrowing or narrowing/dilatation in the circle of Willis was found in 6/6 patients who underwent MR angiography and fusiform aneurysms were detected in three of them, a saccular aneurysm in one patient. Asymptomatic progression of cerebrovascular disease was found in PHIV adolescents with prior stroke. These findings may have implications for long-term risk and outcomes for this patient population. There should be a low threshold to evaluate for CNS pathology even with minor symptoms in this population. More studies are necessary to determine if there is a benefit from screening of asymptomatic patients.