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. 2018 Feb;98(2):497-504.
doi: 10.4269/ajtmh.17-0309. Epub 2018 Jan 4.

1.5 Tesla Magnetic Resonance Imaging to Investigate Potential Etiologies of Brain Swelling in Pediatric Cerebral Malaria

Michael J Potchen  1   2 , Samuel D Kampondeni  3   2 , Karl B Seydel  4   5 , E Mark Haacke  6 , Sylvester S Sinyangwe  7 , Musaku Mwenechanya  7 , Simon J Glover  8 , Danny A Milner  9 , Eric Zeli  10 , Colleen A Hammond  11 , David Utriainen  12 , Kennedy Lishimpi  10   1 , Terrie E Taylor  4   5 , Gretchen L Birbeck  13   14
Affiliations

1.5 Tesla Magnetic Resonance Imaging to Investigate Potential Etiologies of Brain Swelling in Pediatric Cerebral Malaria

Michael J Potchen et al. Am J Trop Med Hyg. 2018 Feb.

Abstract

The hallmark of pediatric cerebral malaria (CM) is sequestration of parasitized red blood cells in the cerebral microvasculature. Malawi-based research using 0.35 Tesla (T) magnetic resonance imaging (MRI) established that severe brain swelling is associated with fatal CM, but swelling etiology remains unclear. Autopsy and clinical studies suggest several potential etiologies, but limitations of 0.35 T MRI precluded optimal investigations into swelling pathophysiology. A 1.5 T MRI in Zambia allowed for further investigations including susceptibility-weighted imaging (SWI). SWI is an ideal sequence for identifying regions of sequestration and microhemorrhages given the ferromagnetic properties of hemozoin and blood. Using 1.5 T MRI, Zambian children with retinopathy-confirmed CM underwent imaging with SWI, T2, T1 pre- and post-gadolinium, diffusion-weighted imaging (DWI) with apparent diffusion coefficients and T2/fluid attenuated inversion recovery sequences. Sixteen children including two with moderate/severe edema were imaged; all survived. Gadolinium extravasation was not seen. DWI abnormalities spared the gray matter suggesting vasogenic edema with viable tissue rather than cytotoxic edema. SWI findings consistent with microhemorrhages and parasite sequestration co-occurred in white matter regions where DWI changes consistent with vascular congestion were seen. Imaging findings consistent with posterior reversible encephalopathy syndrome were seen in children who subsequently had a rapid clinical recovery. High field MRI indicates that vascular congestion associated with parasite sequestration, local inflammation from microhemorrhages and autoregulatory dysfunction likely contribute to brain swelling in CM. No gross radiological blood brain barrier breakdown or focal cortical DWI abnormalities were evident in these children with nonfatal CM.

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Figures

Figure 1.
Figure 1.
The finding of vasogenic edema demonstrated by isolated white matter T2/fluid attenuated inversion recovery (FLAIR) signal changes encompasses multiple potential etiologies for brain swelling. Two distinct types of white matter changes seen in pediatric cerebral malaria are seen on the 1.5 Tesla (T) MRI based in Zambia. They appear as areas of increased (bright) signal on (A) T2 2D SE TR 3400 TE 85 slice thickness 4/0 matrix 256 × 192 and (B) FLAIR IR with TR 9000 TE 130 TI 220 slice thickness 4/0 matrix 256 × 192 (curved arrows), illustrated in a 4-year-old female. The image shows a subcortical distribution with involvement of the u-fibers and sparing of the deep white structures. The other type, as illustrated on (C)-T2 2D SE TR 3400 TE 85 slice thickness 4/0 matrix 256 × 192 and (D)-FLAIR R with TR 9000 TE 130 TI 220 slice thickness 4/0 matrix 256 × 192 (open curved arrows), is seen in a 3-year-old female with images demonstrating a periventricular distribution, predominately in the peritrigoneal regions. This figure appears in color at www.ajtmh.org.
Figure 2.
Figure 2.
The capillary walls of the cerebral blood vessels are of continuous type with tight junctions and a continuous basement membrane which forms the blood brain barrier (BBB). It provides a physical resistance to the passage of lipophilic substances from the cerebral capillaries into the extravascular spaces. Gadolinium, a lipophilic magnetic resonance imaging contrast agent, does not cross an intact barrier. Following contrast administration, normal expected intracranial contrast enhancement can be seen within the vascular structures such as the arteries (A, yellow arrow) and veins (A, red arrow), cavernous sinuses (B, curved arrows), and in the limited circumventricular organs which have fenestrated basement membranes, and therefore, lack a BBB, such as the pituitary (B, vertical arrow) and choroid plexus (C, two headed arrow) as seen on these postcontrast T1-weighed images (TR–TE) in this 5-year-old female with cerebral malaria (CM). The lack of gross extravasation into other areas of the brain in this population of pediatric CM patients is indicative of an intact BBB. This figure appears in color at www.ajtmh.org.
Figure 3.
Figure 3.
Deep venous obstruction tends to have focal areas of involvement. This includes the basal ganglia. Classical basal ganglia lesions were seen (arrows) and frequently had regional predominance in pediatric cerebral malaria such as seen in this 3-year-old female (A) T2 2D SE TR 3400 TE 85 slice thickness 4/0 matrix 256 × 192 and (B) fluid attenuated inversion recovery (FLAIR) 2D FLAIR IR with TR 9000 TE 130 TI 220 slice thickness 4/0 matrix 256 × 192 having disproportionate signal changes in the Globi Pallidi. Similar findings are also seen to a somewhat lesser extent in this 4-year-old male (C) T2 2D SE TR 3400 TE 85 slice thickness 4/0 matrix 256 × 192 and (D) FLAIR 2D FLAIR IR with TR 9000 TE 130 TI 220 slice thickness 4/0 matrix 256 × 192. Note that the involvement is primarily along the posterior medial margin. This figure appears in color at www.ajtmh.org.
Figure 4.
Figure 4.
Abnormal susceptibility-weighted imaging (SWI) signal is shown as dark signal within the structure indicating an increase in paramagnetic susceptibility. SWI (3D SWI TR 9500 TE 110 TI 2000 slice thickness 4/0 matric 512 × 256) phase comparing subjects with normal appearing brain tissue (A–C) and those with abnormal findings (D–F) in SWI. The splenium and genu of the corpus callosum (A, D), the junction of cortical gray matter and subcortical white matter (B, E), and cerebellum (C, F) are shown and labeled.
Figure 5.
Figure 5.
Autoregulatory dysfunction is demonstrated by cortical swelling with underlying white matter changes shown by increased T2 and diffusion-weighted imaging (DWI) signals. These findings are shown in this 6-year-old female with cerebral malaria. Although the cortical swelling is mild in this case, the underlying subcortical white matter changes (arrows), including increased (bright) T2/fluid attenuated inversion recovery (FLAIR) signal on (A) T2 2D SE TR 3400 TE 85 slice thickness 4/0 matrix 256 × 192 and (B) FLAIR 2D FLAIR IR with TR 9000 TE 130 TI 220 slice thickness 4/0 matrix 256 × 192 as well as the associated restricted water movement (diffusion), as demonstrated by increased (bright) DWI signal (C) DWI TR 9000 TE 70 slice thickness 5/0 matrix 132 × 128 and decreased (dark) apparent diffusion coefficients (ADC) signal (D) DWI TR 9000 TE 70 slice thickness 5/0 matrix 132 × 128 and is the ADC are evident. These findings in this child who rapidly and fully recovered clinically are consistent with posterior reversible encephalopathy syndrome, although repeat imaging was not obtained to confirm reversibility of the structural abnormalities. This figure appears in color at www.ajtmh.org.
Figure 6.
Figure 6.
Gross pathologic image of a typical brain at autopsy (A) from a fatal pediatric patient (not from a participant in this study) demonstrates the presence of petechial hemorrhages in the white matter (black arrows, left half of image). If the cortical ribbon is demarcated from the white matter (blue line, right half of image), it is clear that the hemorrhages are restricted to the subcortical and deep white matter. Also note the swollen gyri. This correlates well with the in vivo magnetic resonance imaging (MRI) images seen specifically as low signal (arrows) on (B) susceptibility-weighted imaging (SWI) (3D SWI TR 9500 TE 110 TI 2000 slice thickness 4/0 matric 512 × 256) and high signal (arrows) on (C) fluid attenuated inversion recovery (FLAIR) (2D FLAIR IR with TR 9000 TE 130 TI 220 slice thickness 4/0 matrix 256 × 192) of an 8-year-old female with cerebral malaria (CM). The dark signal on the SWI sequence is the result of increased ferromagnetic substances associated with parasite sequestration and microhemorrhages which causes magnetic field inhomogeneity and MRI signal loss.
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