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Pediatric Radiology

, Volume 49, Issue 5, pp 652–662 | Cite as

Human immunodeficiency virus-related cerebral white matter disease in children

  • Christelle AckermannEmail author
  • Ronald van Toorn
  • Savvas Andronikou
Pictorial Essay
  • 230 Downloads

Abstract

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.

Keywords

Central nervous system Children Computed tomography Human immunodeficiency virus Magnetic resonance imaging White matter 

Introduction

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 [1].

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 [5] 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

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 [8]. 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 [9].

The hallmark of HIV infection in children is early cerebral involvement, especially in perinatal infection [10]. Hematogenous neuroinvasion via perivascular pathways has been described, which accounts for the fact that the largest concentration of the virus can be found in the central periventricular white matter and basal ganglia [11, 12]. Viral latency can delay onset of central nervous system symptoms in adults. In contrast, the developing brain is more vulnerable to early central nervous system involvement [4, 13] (Fig. 1).
Fig. 1

HIV encephalopathy in a 3-year-old girl with HIV and on antiretroviral therapy, not virally suppressed. Axial T2-weighted MR image (repetition time/echo time [TR/TE] 5,510/99 ms) demonstrates marked central atrophy with enlargement of the lateral ventricles and bilateral, symmetrical hyperintense T2 signal change of the periventricular white matter (arrow). Typically there is no mass effect or contrast enhancement. Alternative diagnoses to consider in this clinical context would be progressive multifocal leukoencephalopathy and lymphoma; however these have distinct clinical presentations and are usually only seen in advanced HIV disease with CD4 counts below 100 cells/mm3. HIV human immunodeficiency virus

Caution is advised when interpreting white matter changes in children younger than 18 months because myelination of the centrum semiovale and peritrigonal white matter (which might be delayed even beyond 2 years) is incomplete (Fig. 2). In addition, perivascular spaces should not be confused with abnormal white matter lesions [14, 15] (Fig. 3).
Fig. 2

Terminal myelination in a 2-year-old girl with HIV and on antiretroviral therapy. She presented with brisk reflexes and increased tone in the lower limbs, with normal birth history and milestones. Axial fluid-attenuated inversion recovery (FLAIR) MR image (TR/TE/TI 8,000/97/2,370 ms) demonstrates bilateral peritrigonal white matter hyperintensity, symmetrical and smooth (arrow), in keeping with terminal myelination, which might easily be confused with pathological white matter changes. HIV human immunodeficiency virus, TE echo time, TR repetition time

Fig. 3

Normal perivascular spaces in a 2-year-old girl with HIV and on antiretroviral therapy. She presented with neurodevelopmental delay. Axial fluid-attenuated inversion recovery (FLAIR) image (TR/TE 8,000/109 ms, IR 2,340) demonstrates bilateral, symmetrical peritrigonal linear hyperintensities (arrow), in keeping with white matter high signal associated with normal perivascular spaces. HIV human immunodeficiency virus, TE echo time, TI inversion time, TR repetition time

White matter hyperintensities in children with HIV

White matter hyperintensities are reported in healthy HIV-uninfected children and adolescents. The pathogenesis is poorly understood and most likely multifactorial [16, 17]. Some consider white matter hyperintensities in children older than 1.5 years as abnormal [18], while others report a prevalence as high as 31% of healthy children and adolescents. In a study by Cohen et al. [19] comparing cerebral injury in perinatally HIV-infected children with controls, white matter hyperintensities were also demonstrated in 18% of controls. This should be considered when reporting white matter lesions in children with HIV (Fig. 4).
Fig. 4

White matter hyperintensities in a 1-year-9-month-old boy with HIV and on antiretroviral therapy. He presented with brisk reflexes and increased tone in the lower limbs but normal milestones. a, b Axial fluid-attenuated inversion recovery (FLAIR) MR images (TR/TE 8,000/109 ms, IR 2,340) at the levels of the lateral ventricle bodies (a) and the superior convexities (b) demonstrate typical bilateral, asymmetrical focal (open arrow) and confluent (solid arrow) hyperintensities of the periventricular and subcortical white matter, termed HIV-related white matter hyperintensities. A predilection for the fronto-parietal lobes has been described, but more recent studies report no specific lobar predominance. HIV human immunodeficiency virus, TE echo time, TI inversion time, TR repetition time

Acute disseminated encephalomyelitis

Acute disseminated encephalomyelitis is a monophasic demyelinating disorder of the central nervous system associated with various viral infections such as HIV, influenza virus, Epstein–Barr virus, herpes simplex virus and cytomegalovirus [14, 20]. It is extremely rare in perinatal HIV infection. In older children and adults, it typically occurs during seroconversion when the immune system is still competent. HIV-related immune dysfunction can, however, result in more aggressive and atypical presentations of acute disseminated encephalomyelitis such as tumefactive lesions, corpus callosum demyelination and recurrent and relapsing disease. Information regarding the child’s immune status is therefore important [21] (Fig. 5).
Fig. 5

Acute disseminated encephalomyelitis in a 6-year-old boy with HIV, not on antiretroviral therapy, who presented with weakness of the right arm and leg preceded by fever and cough. a Axial fluid-attenuated inversion recovery (FLAIR) MR image (TR/TE 8,000/97 ms, IR 2,370) demonstrates a large hyperintense lesion (open arrow) in the left globus pallidus, putamen and thalamus, with bridging of the posterior limb of the internal capsule, as well as smaller subcortical lesions (solid arrows) involving the left parieto-temporal region. Typically lesions are multifocal, asymmetrical, ill-defined T2 and FLAIR hyperintensities. b Axial gadolinium-enhanced T1-weighted MR image (TR/TE 840/10 ms) demonstrates incomplete ring (open arrow) and nodular enhancement of the peripheral lesions (solid arrow), which is a characteristic pattern of enhancement for acute disseminated encephalomyelitis. Subcortical white matter is nearly always involved, with lesions also seen in central white matter, brainstem and spinal cord. HIV human immunodeficiency virus, TE echo time, TI inversion time, TR repetition time

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 [1].

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 [22].

As opposed to HIV encephalopathy, progressive multifocal leukoencephalopathy affects the subcortical white matter in an asymmetrical distribution with predominate involvement of the occipital, parietal and frontal white matter [23]. Lesions are single or multifocal, might become confluent as disease progresses, are hyperintense on T2 and fluid-attenuated inversion recovery (FLAIR) sequences, and usually do not cause mass effect or show enhancement, a distinguishing feature from lesions seen in acute disseminating encephalomyelitis. The corpus callosum, basal ganglia, cerebellar peduncles and cerebellum might be involved. In immune reconstitution syndrome, the lesions might have a more aggressive appearance, with irregular peripheral enhancement and mass effect [22, 23] (Fig. 6).
Fig. 6

Schematic summary and comparison of the predominant demyelinating white matter lesions seen in pediatric HIV. Progressive multifocal leukoencephalopathy is asymmetrical, predominantly posterior parietal and occipital (shaded area, right) with subcortical involvement sharply demarcated from overlying cortex (shaded area, left). HIV encephalopathy white matter changes are periventricular and associated with central atrophy (periventricular shaded area). Acute disseminating encephalomyelitis typically demonstrates nodular or incomplete ring enhancement (shaded left posterior parietal lesion); subcortical white matter is almost always involved (shaded area, right frontal). HIV white matter hyperintensities are often randomly distributed (small shaded lesions on the right) and care must be taken when assessing the peritrigonal regions in children (left peritrigonal shaded area) younger than 2 years to not confuse lesions with terminal myelination. HIV human immunodeficiency virus

HIV-associated cerebral vasculopathy and infarction

HIV-associated cerebral vasculopathy predominantly affects the medium-size cerebral vessels, causing aneurysmal dilatation (fusiform aneurysms — more common in HIV-infected children than adults) [24], arterial stenosis complicated by ischemic infarction, and secondary moyamoya syndrome [25]. The incidence of cerebrovascular disease increases with disease severity and predominately occurs in children with perinatally acquired HIV [6, 24]. Most children are asymptomatic in the early stages of disease, which justifies the importance of vascular imaging with MRI [6] (Fig. 7).
Fig. 7

Moyamoya disease in a 9-year-old boy with HIV and on antiretroviral therapy who presented with severe headache and neck stiffness with features of HIV-related vasculopathy. a Coronal T2-weighted MR image (TR/TE 4,000/104 ms) demonstrates signal change in the right frontal white matter (open arrow) and large chronic infarcts involving the right basal ganglia with associated atrophy (solid arrow). Imaging features vary according to chronicity, with acute to subacute infarcts involving cortex and subcortical white matter, also commonly seen in the internal capsule or basal ganglia. b Coronal T1-weighted MR image (TR/TE 531/14 ms) demonstrates an acute intraventricular hemorrhage (arrowhead); this is uncommon but might be a complication of HIV-cerebrovascular disease in children. No cerebral aneurysm was identified. c Axial T2-weighted MR image (TR/TE 4,000/104 ms) demonstrates complete occlusion of the right internal carotid artery and proximal middle cerebral artery with multiple small collaterals (arrow), consistent with moyamoya disease, which manifests as progressive stenosis of the distal carotid arteries and circle of Willis. Multiple small collateral vessels proliferate, and these are typically seen as small flow voids along the course of the thalamo-striatal and lenticulo-striatal arteries, with sequelae of previous strokes in the rest of the brain. There is also Wallerian degeneration of the right cerebral peduncle, reflecting the right hemispheric parenchymal losses (black arrow). HIV human immunodeficiency virus, TE echo time, TR repetition time

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 [14]. 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 [14].

Cytomegalovirus

Birth prevalence of congenital cytomegalovirus infection is reported to be very high despite maternal prenatal antiretroviral prophylaxis, and it is therefore commonly encountered [26] (Fig. 8). Cytomegalovirus in older children with very low CD4 counts is caused by reactivation of a latent infection. Imaging findings are often nonspecific and might even be normal. Periventricular enhancement (indicating acute ventriculitis) is seen with meningoencephalitis [3, 14, 23].
Fig. 8

Congenital cytomegalovirus in an 11-month-old girl with HIV and on antiretroviral therapy with undetectable viral load. She presented with left arm and leg weakness. She had a very high cytomegalovirus viral load at birth. a, b Axial (a) and coronal (b) T2-weighted MR images (TR/TE 5,720/80 ms) demonstrate bilateral, asymmetrical white matter hyperintensity, slightly more prominent posterior parietal lobe (open arrow). Associated subependymal heterotopic gray matter (white arrow) bilateral lateral ventricles as well as polymicrogyria in the right temporal-parietal and perisylvian juncture (black arrow), very typical findings in congenital cytomegalovirus infection. Other typical imaging findings include coarse periventricular and basal ganglia calcifications, periventricular cysts and atrophy. White matter abnormalities are asymmetrical; sometimes focal, patchy or confluent; and can have a predominant frontal, parietal or posterior involvement. HIV human immunodeficiency virus, TE echo time, TR repetition time

Tuberculosis and tuberculous meningitis

The incidence of tuberculosis has reached epidemic proportions in sub-Saharan Africa because of the heavy HIV burden. Brain injury in tuberculosis meningitis is a consequence of an immune-mediated vasculopathy causing infarctions. HIV-related immune dysfunction might lessen the production of thick basal meningeal exudates that result in cerebral parenchymal infarction and non-communicating hydrocephalus [27] (Fig. 9). White matter hyperintensities represent parenchymal edema caused by focal meningoencephalitis, granulomas or infarction, particularly border-zone infarctions [27, 28] (Figs. 10 and 11).
Fig. 9

Tuberculous meningitis in HIV. Schematic representation shows fewer basal ganglia infarctions (absence indicated by the cross), decreased and more focal asymmetrical patterns of leptomeningeal enhancement (shaded gray area of sylvian fissure) and accentuated atrophy rather than hydrocephalus

Fig. 10

Tuberculous meningitis in a 22-month-old girl with HIV and tuberculosis who presented with acute-onset left hemiplegia. CT (not shown) demonstrated acute hemorrhage in the right putamen. a Axial diffusion-weighted MR image (TR/TE 3,200/94 ms) demonstrates restricted diffusion in the head of the left caudate nucleus and globus pallidus (arrow). b Axial fluid-attenuated inversion recovery (FLAIR) MR image (TR/TE 8,000/109 ms, IR 2,340) demonstrates periventricular white matter hyperintense signal change (arrow) and central atrophy, in keeping with HIV encephalopathy. In addition, the hyperintense foci in the right globus pallidus and right thalamus (arrowheads) are in keeping with infarcts secondary to inflammatory vasculitis caused by tuberculous meningitis. c Axial post-gadolinium T1-weighted MR image (TR/TE 739/14 ms) demonstrates multiple enhancing lesions representing tuberculous granulomas (arrows) on a background of marked cerebral atrophy. There is no pronounced leptomeningeal enhancement. HIV human immunodeficiency virus, TE echo time, TI inversion time, TR repetition time

Fig. 11

Tuberculous granulomas in a 6-year-old boy with HIV and tuberculous meningitis. The boy was on antiretroviral therapy. a Axial T2-weighted MR image (TR/TE 4,280/104 ms) demonstrates multiple lesions in the right medial temporal lobe with T2-hypointense signal (open arrow) and peripheral edema (solid arrow). b T1-weighted post-gadolinium MR image (TR/TE 739/14 ms) demonstrates intense rim enhancement of these lesions (arrows), representing tuberculous granulomas. HIV human immunodeficiency virus, TE echo time, TR repetition time

Toxoplasmosis

There has been a dramatic decline in the incidence of toxoplasmosis in the post highly active antiretroviral therapy era [29]. 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 [23].

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 [23]. 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.

Tumors

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.

MRI shows diffuse or focal ring-enhancing mass lesions, predominantly periventricular (as opposed to the more peripheral location of toxoplasmosis) but also involves the basal ganglia and corpus callosum. Lymphoma can be very difficult to differentiate from toxoplasmosis; however lymphoma is much more common in the pediatric population, especially if lesions involve the corpus callosum [3, 30] (Fig. 12).
Fig. 12

Toxoplasmosis vs. lymphoma. Schematic representation shows the differences in imaging features. Toxoplasmosis typically affects the basal ganglia and peripheral subcortical white matter (shaded area representing ring enhancement with surrounding edema). Lymphoma is commonly subependymal and in the periventricular white matter (shaded area). Spectroscopy might confirm a raised choline level in cases of lymphoma

Additional imaging findings specific to HIV

Atrophy

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) [4].

A simple caliper measurement of the prefrontal corpus callosum thickness (genu) is advised because of the early development and stability of the genu over age. A median prefrontal corpus callosum segment thickness measurement of 9 mm (interquartile range 7.4–10.3 mm) for children ages 1–3 years is considered normal when evaluating African patients and the thickness is similar at 9.1 mm for European children [32]. Measurements less than 7 mm are indicative of white matter volume loss (Fig. 13).
Fig. 13

White matter volume loss in a 3-year-old girl with HIV and on antiretroviral therapy, not virally suppressed. She presented with HIV encephalopathy. Sagittal T1-weighted MR image (TR/TE 700/8.3 ms) demonstrates atrophy of the corpus callosum. The genu of the corpus callosum (arrow) in this girl measured 6.3 mm. The degree of thinning of the corpus callosum corresponds with the degree of cerebral volume loss and can act as a surrogate marker of cerebral atrophy. HIV human immunodeficiency virus, TE echo time, TR repetition time

Calcification

Basal ganglia calcification, traditionally deemed an indicator of congenital HIV, is now thought to represent a calcific vasculopathy based on neuropathology findings and the occurrence of progression on serial imaging. These calcifications are not commonly seen before 10 months of age [11, 12, 31]. Basal ganglia calcifications and generalized atrophy are less frequently encountered in the post highly active antiretroviral therapy era (Fig. 14).
Fig. 14

Calcifications in a 2-year-old girl with HIV and on antiretroviral therapy. She presented with meningitis. Axial non-contrast CT scan of the brain demonstrates bilateral punctate calcifications (arrow) in the basal ganglia. Calcifications are usually bilateral and symmetrical. HIV human immunodeficiency virus

Imaging in practice

CT of the brain is more accessible than MRI but not sensitive enough to pick up early changes in HIV-related disease and further contributes to the radiation burden in children. MRI is, therefore, the principal modality used in imaging the brain in HIV. Standard structural scans might be normal in the presence of early white matter pathology but remain valuable in evaluating brain volume and excluding alternative pathologies (Fig. 15). The roles of the radiologist in diagnosing and managing pediatric patients with HIV-related brain disease are:
  • 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.

Fig. 15

Flow diagram provides guidance to diagnose commonly encountered white matter disease on MRI in children with HIV. ADEM acute disseminating encephalomyelitis, CMV cytomegalovirus, HIV human immunodeficiency virus, PML progressive multifocal leukoencephalopathy, TB tuberculosis

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.

Conclusion

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.

Notes

Compliance with ethical standards

Conflicts of interest None

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Christelle Ackermann
    • 1
    Email author
  • Ronald van Toorn
    • 2
  • Savvas Andronikou
    • 3
  1. 1.Department of Radiology, Faculty of Medicine and Health SciencesUniversity of StellenboschTygerbergSouth Africa
  2. 2.Department of Pediatrics and Child Health, Faculty of Medicine and Health SciencesUniversity of StellenboschTygerbergSouth Africa
  3. 3.Department of Pediatric Radiology, Children’s Hospital PhiladelphiaUniversity of PennsylvaniaPhiladelphiaUSA

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