Central Nervous System Safety During Brief Analytic Treatment Interruption of Antiretroviral Therapy Within 4 Human Immunodeficiency Virus Remission Trials: An Observational Study in Acutely Treated People Living With Human Immunodeficiency Virus.

BACKGROUND: The central nervous system (CNS) is a likely reservoir of human immunodeficiency virus (HIV), vulnerable to viral rebound, inflammation, and clinical changes upon stopping antiretroviral therapy (ART). It is critical to evaluate the CNS safety of studies using analytic treatment interruption (ATI) to assess HIV remission. METHODS: Thirty participants who started ART during acute HIV infection underwent CNS assessments across 4 ATI remission trials. ART resumption occurred with plasma viral load >1000 copies/mL. CNS measures included paired pre- vs post-ATI measures of mood, cognitive performance, and neurologic examination, with elective cerebrospinal fluid (CSF) sampling, brain diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS). RESULTS: Median participant age was 30 years old and 29/30 were male. Participants' median time on ART before ATI was 3 years, and ATI lasted a median of 35 days. Post-ATI, there were no differences in median mood scores or neurologic findings and cognitive performance improved modestly. During ATI, a low level of CSF HIV-1 RNA was detectable in 6 of 20 participants with plasma viremia, with no group changes in CSF immune activation markers or brain DTI measures. Mild worsening was identified in post-ATI basal ganglia total choline MRS, suggesting an alteration in neuronal membranes. CONCLUSION: No adverse CNS effects were observed with brief, closely monitored ATI in participants with acutely treated HIV, except an MRS alteration in basal ganglia choline. Further studies are needed to assess CNS ATI safety in HIV remission trials, particularly for studies using higher thresholds to restart ART and longer ATI durations.

Resting-state neural signatures of depressive symptoms in acute HIV.

Depressive symptoms are often elevated in acute and chronic HIV. Previous neuroimaging research identifies abnormalities in emotion-related brain regions in depression without HIV, including the anterior cingulate cortex (ACC) and amygdala. However, no studies have examined the neural signatures of depressive symptoms in acute HIV infection (AHI). Seed-based voxelwise resting-state functional connectivity (rsFC) for affective seed regions of interest (pregenual ACC, subgenual ACC [sgACC], bilateral amygdala) was computed for 74 Thai males with AHI and 30 Thai HIV-uninfected controls. Group analyses compared rsFC of ACC and amygdala seed regions between AHI and uninfected control groups. Within the AHI group, voxelwise regression analyses investigated the relationship between depressive symptoms and rsFC for these affective seed regions. Group analyses revealed alterations in rsFC of the amygdala in AHI versus uninfected controls. Depressive symptoms associated with decreased rsFC between ACC regions and posterior cingulate/precuneus, medial temporal, and lateral parietal regions in AHI. Symptoms of depression also correlated to increased rsFC between ACC regions and lateral prefrontal cortex, sgACC, and cerebellum in AHI. Similar to the ACC, depressive symptoms associated with decreased rsFC between amygdala and precuneus. Of blood biomarkers, only HIV RNA inversely correlated with rsFC between posterior sgACC and left uncus. We found that depressive symptoms in AHI associate with altered rsFC of ACC and amygdala regions previously implicated in depression. Longitudinal research in this cohort will be necessary to determine whether these early alterations in rsFC of affective network regions are related to persistent depressive symptoms after combination antiretroviral therapy.

Pediatric optic nerve and optic nerve sheath diameter on magnetic resonance imaging.

BACKGROUND: The normal values of optic nerve diameter and optic nerve sheath diameter might be beneficial in defining an abnormality such as optic nerve hypoplasia, or enlarged subarachnoid space, reflecting the state of increased intracranial pressure. OBJECTIVE: To study the normal optic nerve diameter and optic nerve sheath diameter on magnetic resonance imaging (MRI) in the early years of postnatal visual development from MRI of the brain. MATERIALS AND METHODS: MRI of the brain in patients ages 4 years and younger were gathered. Forty-two studies with normal intracranial findings and a lack of history of increased intracranial pressure were retrospectively reviewed by two reviewers using axial T2-weighted images. Measurements were performed in transverse diameter perpendicular to the optic nerve at 3 mm behind the globe. RESULTS: The mean optic nerve diameter of the 77 optic nerves were 2.5 mm (95% confidence interval [CI] 2.4-2.6). The mean optic nerve sheath diameter values of the 79 optic nerve sheath complexes were 5.0 mm (95% CI 4.9-5.1). The mean±standard deviation optic nerve diameter and optic nerve sheath diameter stratified by each age groups were, respectively, 0 to <1 year: 2.3±0.40 and 4.81±0.37; 1 to <2 years: 2.6±0.2 and 5.0±0.4; 2 to <3 years: 2.4±0.3 and 4.9±0.6, and 3 to <4 years: 2.9±0.4 and 5.2±0.60 mm. CONCLUSION: Seventy-four of the 77 measurements (96%) were of the measurements were above the threshold of 2 mm for optic nerve diameter. Seventy-seven of the 79 measurements (97%) were of the measurements were below the threshold of 6 mm for optic nerve sheath diameter.

The effectiveness of cinacalcet: a randomized, open label study in chronic hemodialysis patients with severe secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism (SHPT) is associated with high incidences of cardiovascular disease, bone fracture, and mortality. This study was conducted to demonstrate the effectiveness of cinacalcet treatment on chronic kidney disease-mineral bone disorder (CKD-MBD) markers in chronic hemodialysis patients with severe SHPT. METHODS: In phase 1, 30 adult HD patients were randomized to cinacalcet or control groups for 12 weeks to explore the achievement of >30% reduction of iPTH. In phase 2, 45 patients were participated to further explore the effect of cinacalcet on CKD-MBD parameters for 24-week follow up and 12 additional weeks after cinacalcet discontinuation. RESULTS: In phase 1, the baseline serum iPTH levels were not different [1374 (955, 1639) pg/mL in the control group vs. 1191 (1005, 1884) pg/mL in the cinacalcet group], the percentage of patients achieving iPTH target were significantly higher in the treatment group [80% vs. 13%, p = .001]. In phase 2, the significant reductions of iPTH, FGF-23, tartrate-resistant acid phosphatase 5b, and slightly decreased size of parathyroid gland and stabilized vascular calcification were observed at 24-week follow up and markedly rebounded after discontinuation of cinacalcet. CONCLUSIONS: The effectiveness of cinacalcet were still obviously demonstrated even in chronic HD patients with severe SHPT. In addition, the improvements of bone markers and FGF-23, and stabilization of vascular calcification were observed. Therefore, cinacalcet can provide salutary effects on CKD-MBD in severe SHPT and might be an initially effective PTH-lowering therapy prior to surgical parathyroidectomy as well as an alternative treatment in the patients unsuitable for surgery. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT02056730. Date of registration: February 4, 2014.

Pituitary height at magnetic resonance imaging in pediatric isolated growth hormone deficiency.

BACKGROUND: Magnetic resonance imaging (MRI) is used for neuroradiologic evaluation of patients with idiopathic growth hormone deficiency (IGHD). OBJECTIVES: To compare pituitary height and morphology at MRI between patients with IGHD and controls. MATERIALS AND METHODS: This retrospective study was conducted in pediatric patients, 3 years-15 years old, who had had brain MRI with non-contrast-enhanced midsagittal T1-weighted images. These images were measured for pituitary height and morphology of the pituitary gland including shape, stalk and posterior pituitary bright spot was evaluated. RESULTS: One hundred and nineteen patients were included, with 49 and 70 patients assigned to the study and control groups, respectively. Mean pituitary height was significantly less in the IGHD group than in the control group (3.81 mm±1.38 vs. 4.92 mm±1.13, retrospectively; P<0.001). Subgroup analysis revealed a significant difference in the pituitary height between groups in the prepubertal (8-10 years) and pubertal (11-13 years) periods (P=0.039 and P=0.006, respectively) and a trend toward significance in the postpubertal period (P=0.053). There was a significant difference in pituitary shape between IGHD and controls when combining grades III, IV and V (P=0.007). Other abnormal MRI findings of the pituitary stalk and posterior bright spot were significantly more often observed in the IGHD group (P<0.05). CONCLUSION: Pituitary height was significantly smaller in patients with IGHD than in controls during prepuberty and puberty. Abnormal concave superior contour, hypoplastic stalk and absent/ectopic posterior bright spot were observed significantly more often among patients with IGHD.

Mid-cervical flame-shaped pseudo-occlusion: diagnostic performance of mid-cervical flame-shaped extracranial internal carotid artery sign on computed tomographic angiography in hyperacute ischemic stroke.

PURPOSE: Flame-shaped pseudo-occlusion of the extracranial internal carotid artery (ICA) is a flow-related phenomenon that creates computed tomographic angiography (CTA) and digital subtraction angiography (DSA) findings that mimic tandem intracranial-extracranial ICA occlusion or dissection. We aim to determine the diagnostic performance of mid-cervical flame-shaped extracranial ICA sign on CTA in hyperacute ischemic stroke patients. METHODS: We retrospectively included consecutive anterior circulation ischemic stroke patients presenting within 6 h of symptom onset who underwent 4D brain CTA and arterial-phase neck CTA using a 320-detector CT scanner during August 2012 to July 2015. Two blinded readers independently reviewed arterial-phase neck CTA and characterized the extracranial ICA configurations into mid-cervical flame-shaped, proximal blunt/beak-shaped, and tubular-shaped groups. 4D whole brain CTA was used as a reference standard for intracranial ICA occlusion detection. Diagnostic performance of the mid-cervical flame-shaped extracranial ICA sign and interobserver reliability were calculated. RESULTS: Of the 81 cases, 11 had isolated intracranial ICA occlusion, and 6 had true extracranial ICA occlusion. Mid-cervical flame-shaped extracranial ICA sign was found in 45.5% (5/11) of isolated intracranial ICA occlusions but none in the true extracranial ICA occlusion group. The sensitivity, specificity, PPV, NPV, and accuracy of the mid-cervical flame-shaped extracranial ICA sign for the detection of isolated intracranial ICA occlusion were 45.5, 100, 100, 92.1, and 92.6%, respectively. Interobserver reliability was 0.90. CONCLUSION: The mid-cervical flame-shaped extracranial ICA sign may suggest the presence of isolated intracranial ICA occlusion and allow reliable exclusion of tandem extracranial-intracranial ICA occlusion in hyperacute ischemic stroke setting.

Incidence of Associated Brain and Ophthalmic Anomalies in Frontoethmoidal Encephalomeningocele Evaluated by Multidetector Computed Tomography Facial Bone Imaging.

INTRODUCTION: Frontoethmoidal encephalomeningocele (FEEM) is a congenital disorder characterized by herniation of brain and meninges through an anterior skull defect. The main pathological changes are found internally at the foramen cecum and externally at the frontonaso-orbital region. The aim of this study was to determine the incidence of developmental anomalies found in FEEM using multidetector computed tomography images of the facial bone. METHODS: A total of 78 patients who underwent multidetector computed tomography scan of the facial bone during the January 1, 2003 to June 31, 2012 study period were retrospectively reviewed. Demographic data, size of internal defect, and intracranial anomalies were recorded. RESULTS: Associated brain and ophthalmic anomalies were identified in 53 patients (67.9%), and all of those had brain anomalies. The most common brain anomalies were absent/undetermined septum pellucidum (75.5%), ventricular dilatation (71.7%), abnormal frontal horn (67.9%), and dysgenesis of the corpus callosum (58.5%). Eight patients (10.3%) had ophthalmic anomalies. Patients with brain and ophthalmic anomalies tended to have a higher incidence of large-size internal defects. CONCLUSION: The authors found a high prevalence of developmental anomalies in FEEM patients. Absent/undetermined septum pellucidum was the most commonly found anomaly in this study. Brain and ophthalmic anomalies tended to have a higher incidence of large-size internal bone defects. Consistent with the authors' acknowledged limitation, further studies using dedicated brain MRI and magnetic resonance angiography to evaluate parenchymal abnormalities and vascular anomalies may be beneficial for surgical planning, prognosis, and the identification of clinical correlations.

Minimal detection of cerebrospinal fluid escape after initiation of antiretroviral therapy in acute HIV-1 infection.

OBJECTIVE: Despite suppression of HIV-1 replication in the periphery by antiretroviral therapy (ART), up to 10% of treated individuals have quantifiable HIV-1 in the CSF, termed CSF escape. CSF escape may be asymptomatic but has also been linked to progressive neurological disease, and may indicate persistence of HIV in the central nervous system (CNS). CSF escape has not yet been assessed after initiation of ART during acute HIV-1 infection (AHI). DESIGN: Prospective cohort study. SETTING: Major voluntary counseling and testing site in Bangkok, Thailand. PARTICIPANTS: Participants identified and initiated on ART during AHI who received an optional study lumbar puncture at pre-ART baseline or after 24 or 96 weeks of ART. MAIN OUTCOME MEASURES: Paired levels of CSF and plasma HIV-1 RNA, with CSF greater than plasma HIV-1 RNA defined as CSF escape. RESULTS: Two hundred and four participants had paired blood and CSF sampling in at least one visit at baseline, week 24, or week 96. Twenty-nine participants had CSF sampling at all three visits. CSF escape was detected in 1/90 at week 24 (CSF HIV-1 RNA 2.50 log10 copies/ml, plasma HIV-1 RNA <50 copies/ml), and 0/55 at week 96. CONCLUSION: Although levels of CSF HIV-1 RNA in untreated AHI are high, initiating treatment during AHI results in a very low rate of CSF escape in the first 2 years of treatment. Early treatment may improve control of HIV-1 within the CNS compared with treatment during chronic infection, which may have implications for long-term neurological outcomes and CNS HIV-1 persistence.

Regional brain volumetric changes despite 2 years of treatment initiated during acute HIV infection.

OBJECTIVE: To assess changes in regional brain volumes after 24 months among individuals who initiated combination antiretroviral therapy (cART) within weeks of HIV exposure. DESIGN: Prospective cohort study of Thai participants in the earliest stages of HIV-1infection. METHODS: Thirty-four acutely HIV-infected individuals (AHI; Fiebig I-V) underwent brain magnetic resonance (MR) imaging and MR spectroscopy at 1.5 T and immediately initiated cART. Imaging was repeated at 24 months. Regional brain volumes were quantified using FreeSurfer's longitudinal pipeline. Voxel-wise analyses using tensor-based morphometry (TBM) were conducted to verify regional assessments. Baseline brain metabolite levels, blood and cerebrospinal fluid biomarkers assessed by ELISA, and peripheral blood monocyte phenotypes measured by flow cytometry were examined as predictors of significant volumetric change. RESULTS: Participants were 31 ±â€Š8 years old. The estimated mean duration of infection at cART initiation was 15 days. Longitudinal analyses revealed reductions in volumes of putamen (P < 0.001) and caudate (P = 0.006). TBM confirmed significant atrophy in the putamen and caudate, and also in thalamic and hippocampal regions. In exploratory post-hoc analyses, higher baseline frequency of P-selectin glycoprotein ligand-1 (PSGL-1)-expressing total monocytes correlated with greater caudate volumetric decrease (ρ = 0.67, P = 0.017), whereas the baseline density of PSGL-1-expressing inflammatory (CD14CD16) monocytes correlated with putamen atrophy (ρ = 0.65, P = 0.022). CONCLUSION: Suppressive cART initiated during AHI may not prevent brain atrophy. Volumetric decrease appears greater than expected age-related decline, although examination of longitudinal change in demographically similar HIV-uninfected Thai individuals is needed. Mechanisms underlying progressive HIV-related atrophy may include early activation and enhanced adhesive and migratory capacity of circulating monocyte populations.

Mapping abnormal subcortical neurodevelopment in a cohort of Thai children with HIV.

Alterations in subcortical brain structures have been reported in adults with HIV and, to a lesser extent, pediatric cohorts. The extent of longitudinal structural abnormalities in children with perinatal HIV infection (PaHIV) remains unclear. We modeled subcortical morphometry from whole brain structural magnetic resonance imaging (1.5 T) scans of 43 Thai children with PaHIV (baseline age = 11.09±2.36 years) and 50 HIV- children (11.26±2.80 years) using volumetric and surface-based shape analyses. The PaHIV sample were randomized to initiate combination antiretroviral treatment (cART) when CD4 counts were 15-24% (immediate: n = 22) or when CD4 < 15% (deferred: n = 21). Follow-up scans were acquired approximately 52 weeks after baseline. Volumetric and shape descriptors capturing local thickness and surface area dilation were defined for the bilateral accumbens, amygdala, putamen, pallidum, thalamus, caudate, and hippocampus. Regression models adjusting for clinical and demographic variables examined between and within group differences in morphometry associated with HIV. We assessed whether baseline CD4 count and cART status or timing associated with brain maturation within the PaHIV group. All models were adjusted for multiple comparisons using the false discovery rate. A pallidal subregion was significantly thinner in children with PaHIV. Regional thickness, surface area, and volume of the pallidum was associated with CD4 count in children with PaHIV. Longitudinal morphometry was not associated with HIV or cART status or timing, however, the trajectory of the left pallidum volume was positively associated with baseline CD4 count. Our findings corroborate reports in adult cohorts demonstrating a high predilection for HIV-mediated abnormalities in the basal ganglia, but suggest the effect of stable PaHIV infection on morphological aspects of brain development may be subtle.

Structural and functional brain imaging in acute HIV.

Background: HIV RNA is identified in cerebrospinal fluid (CSF) within eight days of estimated viral exposure. Neurological findings and impaired neuropsychological testing performance are documented in a subset of individuals with acute HIV infection (AHI). The purpose of this study was to determine whether microstructural white matter and resting-state functional connectivity (rsFC) are disrupted in AHI. Methods: We examined 49 AHI (100% male; mean age = 30 ±â€¯SD 9.9) and 23 HIV-uninfected Thai participants (78% male; age = 30 ±â€¯5.5) with diffusion tensor imaging (DTI) and rsFC acquired at 3 Tesla, and four neuropsychological tests (summarized as NPZ-4). MRI for the AHI group was performed prior to combination antiretroviral treatment (ART) in 26 participants and on average two days (range:1-5) after ART in 23 participants. Fractional anisotropy (FA), mean (MD), axial (AD), and radial diffusivity (RD) were quantified for DTI. Seed-based voxelwise rsFC analyses were completed for the default mode (DMN), fronto-parietal, and salience and 6 subcortical networks. rsFC and DTI analyses were corrected for family-wise error, with voxelwise comparisons completed using t-tests. Group-specific voxelwise regressions were conducted to examine relationships between imaging indices, HIV disease variables, and treatment status. Results: The AHI group had a mean (SD) CD4 count of 421(234) cells/mm3 plasma HIV RNA of 6.07(1.1) log10 copies/mL and estimated duration of infection of 20(5.5) days. Differences between AHI and CO groups did not meet statistical significance for DTI metrics. Within the AHI group, voxelwise analyses revealed associations between brief exposure to ART and higher FA and lower RD and MD bilaterally in the corpus callosum, corona radiata, and superior longitudinal fasciculus (p < 0.05). Diffusion indices were unrelated to clinical variables or NPZ-4. The AHI group had reduced rsFC between left parahippocampal cortex (PHC) of the DMN and left middle frontal gyrus compared to CO (p < 0.002). Within AHI, ART status was unrelated to rsFC. However, higher CD4 cell count associated with increased rsFC for the right lateral parietal and PHC seeds in the DMN. Direct associations were noted between NPZ-4 correspond to higher rsFC of the bilateral caudate seed (p < 0.002). Conclusions: Study findings reveal minimal disruption to structural and functional brain integrity in the earliest stages of HIV. Longitudinal studies are needed to determine if treatment with ART initiated in AHI is sufficient to prevent the evolution of brain dysfunction identified in chronically infected individuals.