Neuro-imaging in paediatric HIV, a MRI/DTI study

Ackermann, Christelle (2020-03)

Thesis (PhD)--Stellenbosch University, 2020.

Thesis

ENGLISH ABSTRACT: The HIV epidemic has been largely controlled by antiretroviral treatment (ART) which improves neurodevelopmental outcomes. Nevertheless, many HIV-infected (HIV+) children on long-term treatment may have HIV-related brain injury, ongoing cognitive impairment and treatment-related neurological complications. Magnetic resonance imaging (MRI) and in particular diffusion tensor imaging (DTI) are sensitive tools in assessing the integrity of white matter (WM) microstructure in HIV. The pictorial review describes common causes of HIV-related cerebral WM disease as well as the role of neuro-imaging in managing these patients. In the following chapters the characteristics of WM signal abnormalities on MRI and DTI (using DTI derived measures - fractional anisotropy (FA), mean (MD), axial (AD) and radial diffusion (RD)) in children with HIV, recruited as part of the Children with HIV early antiretroviral (CHER) trial and who started ART within the first year of life, are described. In the CHER trial, infants were randomized to early limited or deferred continuous ART. Methods: Structural MRI scans of children at mean age 39.1 months were reviewed and correlated with clinical and neurodevelopmental data, virological markers and time on ART. DTI was acquired in a similar cohort (which included several children in the first study and control subjects) at mean age of 64.7 months. Voxel-based group comparisons were performed to determine regions where FA and MD differed between HIV+ and uninfected children. Associations of DTI parameters with timing of ART initiation and correlations of DTI parameters in abnormal WM with directed neurodevelopmental tests were examined. Results: MRI scans of 44 children were reviewed at mean age of 39.1 months: 10 on deferred and 34 on early CHER treatment arms, commencing ART at mean age of 18.5 and 8 weeks respectively. Multiple high signal intensity lesions on T2 /FLAIR were documented in 22 patients (50%), predominantly in frontal (91%) and parietal (82%) WM. There were no differences in neurodevelopmental scores in children with and without WM signal abnormalities. Neither lesion load nor distribution showed significant correlation with neurodevelopmental scores or neurological examination. There was a trend for association of WM signal abnormalities and longer time on ART (p=0.13) and nadir CD4% (p=0.08). 39 HIV+ children (15 male) and 13 controls (5 male) were imaged (using DTI) at mean age of 64.7 months. 2 Clusters with decreased FA and 7 clusters with increased MD were identified in the HIV+ group with symmetrical distribution predominantly due to increased RD, suggestive of decreased myelination. Children on early interrupted ART had lower FA compared to those receiving continuous treatment. The only neurodevelopmental domain with a trend of difference between the HIV+ children and controls (p=0.08), was personal social quotient which correlated to improved myelination of the forceps minor in the control group. As a combined group there was a negative correlation between visual perception and RD in the right superior longitudinal fasciculus and left inferior longitudinal fasciculus which may be related to these tracts, part of the visual perception pathway, are at a crucial state of development at age 5. Conclusion: Half of children at mean age of 39.1 months, referred with HIV-related brain disease had WM signal abnormalities on T2/FLAIR structural MRI. HIV+ children at 5 years have WM abnormalities measured by FA, despite early ART, confirming that early ART does not fully protect the WM either from peripartum or in utero infection. In contrast to adults, the corticospinal tracts are predominantly involved rather than the corpus callosum. Continuous early ART, however limits the extent of WM damage. Even directed neurodevelopmental tests will underestimate the degree of microstructural WM damage detected by DTI. The visual perception deficit detected in the HIV study population should be further examined as it persists in longitudinal follow up of these patients at age 7.

AFRIKAANSE OPSOMMING:Die MIV-epidemie is tans grootliks onder beheer deur effektiewe anti-retrovirale terapie (ART) en selfs wanneer dit onderbreek word, verbeter die neuro-ontwikkelingsuitkomste. Dit het daartoe gelei dat baie kinders met die siekte op langtermynbehandeling grootword, met gevolglike hoër risiko om MIV-verwante breinbesering, voortgesette kognitiewe inkorting en behandelingsverwante neurologiese komplikasies te ontwikkel. Magnetiese resonansie beelding (MRI) en veral diffusie tensor beeldvorming (DTI) is effektiewe metodes om die integritiet van witstof-mikrostruktuur in MIV te assesseer. Die eerste hoofstuk beskryf algemene oorsake van MIV-verwante serebrale witstof-siekte asook die rol van neuro-beelding in die behandeling van hierdie pasiënte. In die volgende hoofstukke word die eienskappe van witstof sein abnormaliteite op MRI en DTI (met behulp van DTI afgeleide maatstawwe - fraksionele anisotropie (FA), gemiddelde (MD), aksiale (AD) en radiale diffusie (RD)) in kinders met MIV, en wat met ART in die eerste jaar van die lewe begin het, beskryf. Metodes: Strukturele MRI skanderings van kinders op gemiddelde ouderdom van 39,1 maande is hersien en gekorreleer met kliniese en neuro-ontwikkelingsdata, virologiese merkers en durasie van ART. DTI is in 'n soortgelyke kohort (wat verskeie kinders in die eerste studie en kontroles insluit) op die gemiddelde ouderdom van 64,7 maande, verwerf. Voxel-gebaseerde groep vergelykings is uitgevoer om streke te bepaal waar FA en MD verskil tussen MIV + en onbesmette kinders. Assosiasies van DTI parameters met begin tydperk van ART en korrelasies van DTI parameters in abnormale witstof met direkte neuro-ontwikkelingsuitkomste was ondersoek. Resultate: MRI-skanderings van 44 kinders, gemiddelde ouderdom van 39,1 maande is geevalueer: 10 was op uitgestelde en 34 op vroeë CHER-behandelingsarms. ART is begin op gemiddelde ouderdomme van 18,5 en 8 weke onderskeidelik. Veelvuldige hoë sein intensiteit letsels op T2 / FLAIR is gedokumenteer in 22 pasiënte (50%), hoofsaaklik in frontale (91%) en parietale (82%) witstof. Geen verskille in neuro-ontwikkeling van kinders met en sonder witstof-seinafwykings is gevind nie. Geen letsellading of verspreiding het beduidende korrelasie met neuro-ontwikkelingstellings of neurologiese ondersoeke getoon nie. Daar was 'n tendens vir die assosiasie van witstof sein abnormaliteite en langer tyd op ART (p=0.13) en CD4% (p=0.08). 39 MIV+ kinders (15 manlik) en 13 kontroles (5 manlik) is op die gemiddelde ouderdom van 64,7 gebeeld met DTI. 2 gegroepeerde areas met verlaagde FA en 7 met verhoogde MD is in die MIV + -groep geïdentifiseer (oorwegende simmetriese verspreiding) as gevolg van verhoogde RD, wat dui op verminderde mielinisasie. Kinders met vroeë onderbreekte ART het laer FA vergeleke met diegene wat deurlopende behandeling ontvang het. Die enigste neuro-ontwikkelingsdomein met 'n tendens van verskil tussen die MIV + -kinders en kontroles (p = 0.08) was persoonlike sosiale kwotiënt wat verband hou met verbeterde mielinisasie van die forceps-minor in die kontrolegroep. As 'n gekombineerde groep was daar 'n negatiewe korrelasie tussen visuele persepsie en RD in die regter superior longitudinale fasciculus en linker inferior longitudinale fasciculus wat verband hou met die feit dat hierdie gebiede, wat deel vorm van die visuele waarnemingsbane, in 'n kritieke toestand van ontwikkeling is op die ouderdom van 5 jaar. Gevolgtrekking: Die helfte van kinders wat verwys is met MIV-verwante brein siekte, op 'n gemiddelde ouderdom van 39,1 maande, het witstof sein abnormaliteite op T2 / FLAIR strukturele MRI. MIV+ kinders op 5 jarige ouderdom het witstof-abnormaliteite, gemeet aan FA, ten spyte van vroeë ART, wat bevestig dat vroeë ART nie die witstof ten volle beskerm teen peripartum of in utero-infeksie met MIV nie. In teenstelling met volwassenes, is die kortikospinale bane hoofsaaklik aangetas, eerder as die corpus callosum. Deurlopende vroeë ART beperk egter die omvang van witstof-skade. Selfs gerigte neuro-ontwikkelingstoetse sal die mate van mikrostrukturele witstof-skade wat deur DTI bespeur kan word, onderskat. Die visuele persepsie tekort wat in die MIV-studiepopulasie waargeneem is, moet verder ondersoek word aangesien dit voortduur in longitudinale opvolg van hierdie pasiënte op die ouderdom van 7 jaar.

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