Human immunodeficiency virus-related cerebral white matter disease in children
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The human immunodeficiency virus (HIV) epidemic seems largely controlled by anti-retroviral treatment with resultant large numbers of children growing up with the disease on long-term treatment, placing them at higher risk to develop HIV-related brain injury, ongoing cognitive impairment and treatment-related neurological complications. Cerebral white matter involvement is a common radiologic finding in HIV infection and the causes of this have overlapping appearances, ranging from diffuse widespread involvement to focal lesions. The varied pathophysiology is broadly grouped into primary effects of HIV, opportunistic infection, vascular disease and neoplasms. White matter changes in children can be different from those in adults. This review provides guidance to radiologists with the diagnostic dilemma of nonspecific cerebral white matter lesions in children with HIV. The authors discuss common causes of HIV-related cerebral white matter disease as well as the role of neuroimaging in the management of these children.
KeywordsCentral nervous system Children Computed tomography Human immunodeficiency virus Magnetic resonance imaging White matter
Cerebral white matter involvement is a common radiologic finding in HIV infection and its causes have overlapping appearances, ranging from diffuse widespread involvement to focal lesions. The varied pathophysiology is broadly grouped into primary effects of HIV, opportunistic infection, vascular disease and neoplasms. White matter changes in children can also exhibit specific differences in comparison to findings in adults with HIV.
HIV-related white matter damage includes demyelination and axonal injury with dysfunction. Myelin injury is postulated to induce disruption of the brain–blood barrier, which is essential for HIV-1 entrance to the brain. HIV infection also adversely influences cerebral re-myelination, a process that requires proliferation, migration and survival of oligodendrocyte progenitor cells .
Previously, conventional neuroimaging played a vital role in the diagnosis of HIV-related cerebral atrophy, vasculopathy, opportunistic infections and tumors as well as monitoring the evolution of brain lesions and response to therapy [2, 3, 4]. Structural cerebral imaging alone in HIV-infected patients does not reveal the extent of HIV-related white matter abnormalities. In addition, it has limited value in asymptomatic patients  because of poor diagnostic yield; despite this, some clinicians continue to advocate that all people newly diagnosed with HIV infection undergo baseline imaging and that there should be a low threshold to image people with minimal neurological symptoms because they could have significant central nervous system disease [6, 7].
This review gives a concise summary of common causes of HIV-related cerebral white matter disease in children and provides guidance to radiologists with the diagnostic dilemma of nonspecific cerebral white matter lesions in children with HIV.
Spectrum of HIV-related white matter changes
HIV encephalopathy comprises deterioration of cognitive functions that are associated with white matter disease and cerebral atrophy. The World Health Organization defines HIV encephalopathy as at least one of the following, progressing over at least 2 months in the absence of another illness: (1) failure to attain, or loss of developmental milestones or loss of intellectual ability; (2) progressive impaired brain growth demonstrated by stagnation of head circumference; (3) acquired symmetrical motor deficit accompanied by two or more of paresis, pathological reflexes, ataxia and gait disturbances . HIV encephalitis (meningoencephalitis), as opposed to encephalopathy, represents active infection of the brain and meninges characterized by acute symptoms such as headache, neck stiffness, confusion and seizures .
White matter hyperintensities in children with HIV
Acute disseminated encephalomyelitis
Progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy is a progressive nervous system disorder of demyelination that is almost exclusively seen in immunocompromised patients and is caused by the John Cunningham virus. In contrast to HIV, which primarily infects astrocytes and microglia, John Cunningham virus predominantly infects oligodendrocytes, which causes oligodendrocyte damage and further demyelination .
Wide-ranging clinical presentation is seen from cognitive dysfunction to limb weakness and cranial nerve palsies, mostly described in adults. It is rare in the pediatric population because the seroprevalence of the virus rises according to age from 16% in children to 34% in adults by ages 21–50 years. A review published in 2014 found only 19 reports in the literature on progressive multifocal leukoencephalopathy in children with HIV .
HIV-associated cerebral vasculopathy and infarction
Infective lesions and edema
White matter changes related to viral infections can be caused either by direct viral infection of the central nervous system with resultant encephalitis or by an autoimmune response to the virus such as with acute disseminated encephalomyelitis and vasculitis . Focal infective lesions such as tuberculosis and toxoplasmosis also manifest as T2 and FLAIR white matter hyperintensity because of surrounding vasogenic edema.
Herpes simplex virus
MRI reveals asymmetrical T2 and FLAIR hyperintensity of the cortex and white matter with frontoparietal lobe extension distinct from the medial temporal lobe involvement characteristically seen in adults. Leptomeningeal and gyral enhancement, petechial and confluent hemorrhage might be observed .
Tuberculosis and tuberculous meningitis
There has been a dramatic decline in the incidence of toxoplasmosis in the post highly active antiretroviral therapy era . Infection in infants and young children is thought to be congenital in most cases, and in older children it is the result of reactivation of latent infection, usually with CD4 counts below 50 cells/mm3 .
Disease is most commonly located in the basal ganglia, thalamus and the cortex/peripheral white matter junction. On MR, focal lesions show hyper- to mixed signal intensity on T2-W images, surrounded by vasogenic edema; lesions show nodular or ring-enhancement and occasionally demonstrate peripheral hemorrhage. The target sign, consisting of a small eccentric nodule adjacent to an enhancing ring, has been described as highly suggestive of toxoplasmosis but is insensitive and seen in less than 30% of cases . Differential diagnoses include lymphoma and tuberculosis. Repeat imaging after 2 weeks of toxoplasmosis treatment can be a useful method of confirming the diagnosis [3, 23]. A positive response to therapy is judged by the regression in size of all lesions.
Primary central nervous system tumors occur less commonly in children compared to adults and when observed are usually associated with low CD4 counts and advanced disease. High-grade B cell lymphoma is the most common central nervous system malignancy related to HIV and is often associated with Epstein-Barr virus infection [3, 30]. In adults, toxoplasmosis is one of the main differential diagnoses to consider.
Additional imaging findings specific to HIV
Central atrophy is predominant and is the result of initial concentration of the HIV antigen within the basal ganglia, manifesting as enlarged lateral ventricles. The degree of atrophy is directly related to severity of disease and usually correlates with poorer neurocognitive performance. Cortical atrophy is seen later in the disease [2, 31]. Atrophy has become an infrequent finding in virally suppressed children, which complicates early detection of white matter volume loss on conventional MRI [2, 4].
Corpus callosum thinning
Atrophy of the corpus callosum correlates with decreased CD4 levels. In a study of 33 children with HIV-related brain disease, the length of the corpus callosum correlated with microcephaly and the motor segment thickness with neurodevelopmental score (general quotient on the Griffiths Mental Development Scales) .
Imaging in practice
To diagnose HIV encephalopathy and distinguish it from other causes of white matter hyperintensity.
To diagnose opportunistic infections and tumors associated with HIV because these are treatable.
To establish baseline brain volume and white matter macro-structural integrity for making early diagnosis of HIV-related brain disease, initiating early treatment and monitoring response to treatment.
To monitor disease progression and the effects of antiretroviral therapy because HIV is now a chronic illness.
At the outset the detailed clinical history, including neurodevelopment and immunological parameters such as CD4 count and viral load should be considered in context when reporting because imaging findings usually vary according to the stage and severity of disease. A CD4 count of less than 350 cells/mm3 is immunological grounds for diagnosing advanced HIV disease, with severe disease seen at CD4 count of less than 200 cells/mm3 in children 5 years and older.
Cerebral white matter abnormality is a common radiologic finding in HIV infection, the cause of which can range from diffuse widespread involvement to focal lesions. The etiology is varied, with specific differences in pathology when compared to HIV-infected adults. Radiologists are an integral part of the team in the diagnosis of HIV-related brain disease and it is therefore essential to have a working knowledge of relevant disease entities that might be encountered and the imaging features that can distinguish the multiple causes of white matter abnormalities on MRI.
Compliance with ethical standards
Conflicts of interest None
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