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A prospective cohort study of retinopathy-confirmed cerebral malaria (CM) survivors identified 42 of 132 with neurologic sequelae. The 38 survivors with sequelae who were alive when magnetic resonance imaging (MRI) technology became available underwent brain MRIs. Common MRI abnormalities included periventricular T2 signal changes (53%), atrophy (47%), subcortical T2 signal changes (18%), and focal cortical defects (16%). The χ2 tests assessed the relationship between chronic MRI findings, acute clinical and demographic data, and outcomes. Children who were older at the time of CM infection (P = 0.01) and those with isolated behavioral problems (P = 0.02) were more likely to have a normal MRI. Acute focal seizures were associated with atrophy (P = 0.05). Acute papilledema was associated with subcortical T2 signal changes (P = 0.02). Peripheral retinal whitening (P = 0.007) and a higher admission white blood cell count (P = 0.02) were associated with periventricular T2 signal changes. Chronic MRI findings suggest seizures, increased intracranial pressure, and microvascular ischemia contribute to clinically relevant structural brain injury in CM.
The case fatality rate of pediatric cerebral malaria (CM) is 12–25%1,2 and ~30% of survivors experience neurological sequelae, including behavioral disorders, epilepsy, and developmental delay often with devastating neurologic deficits.3 Clinical risk factors for neurologic sequelae are higher maximum temperature, seizures, male gender, and a more profound coma at presentation.3 Aside from gross motor or functional deficits, many neurological sequelae are not apparent at discharge, but become manifest during more prolonged follow-up with directed history and assessment. To date, insights into central nervous system (CNS) structural abnormalities in pediatric CM have been largely limited to autopsy studies4 and a recent publication describing the acute brain magnetic resonance imaging (MRI) findings5 of CM. We set out to describe the follow-up brain MRI findings of pediatric CM survivors with neurologic sequelae from a previously published prospective cohort study.3 The MRI technology was not available at the time these children had their acute CM infection.
Thirty-eight (38) brain-injured pediatric CM survivors, a subset† of a previously published prospective cohort study,3 underwent brain MRI at 6–24 months post sequelae identification. These CM survivors were prospectively enrolled and clinically characterized during their acute infection, including direct and indirect ophthalmoscopy through dilated pupils and serial electroencephalographs (EEG). Seizures were characterized according to clinical semiology and acute EEG findings. Prospective quarterly follow-ups were conducted to identify and characterize post-CM neurological sequelae.
Once MRI became available, MRIs were obtained on CM survivors in this cohort with neurologic sequelae using a 0.35T GE Signa Ovation magnet, with Sag T1, Ax Flair, Ax T2, and Ax diffusion weighted imaging sequences. Ethical approvals from the appropriate United States and Malawian institutional entities were obtained for the study and informed parental consent was required for this follow-up imaging.
Two radiologists interpreted the MRI images using a custom-designed computer program, NeuroInterp. NeuroInterp is a web-based program that requires interpreting radiologists to evaluate and quantify specific MRI findings (normal versus a scaled rating of any abnormality).6 Data were generated independently by two radiologists and NeuroInterp identified interpretations requiring adjudication based on predetermined criteria. Consensus reads were determined when adjudications were required. They were provided only with study subject's age and were therefore blinded to details of the sequelae.
An exploratory χ2 analysis was carried out using the dichotomous outcome “any MRI abnormality” against “no abnormality” to assess possible associations between clinical characteristics and MRI abnormalities. We anticipated limited power for any analyses involving MRI findings with a frequency of < 15%, therefore any specific MRI abnormality seen in at least 15% of study subjects was also dichotomized and a similar analysis done. Given the exploratory nature of this analysis, no Bonferroni adjustment was made.
Among brain-injured CM survivors, 25 of 38 (66%) were male. The age range was 10–102 months (median 47 months). Neurological deficits indicative of CM-induced brain injury identified during follow-up included behavioral disorders in 12 (31.6%), developmental delay ± gross neurologic deficits in 23 (60.5%), and epilepsy in 9 (23.7%). Survivors frequently experienced multiple sequelae.
Brain MRI abnormalities were evident in 28 of 38 (74%) patients (see Table 1 and Figure 1). Abnormalities were generally seen in the cerebral hemispheres rather than the posterior fossa. Common MRI abnormalities included periventricular T2 signal changes (53%) (Figure 1), generalized cerebral atrophy (47%) (Figure 2), subcortical T2 signal changes, which tended to extend throughout the deep white matter with relative sparing of the U fibers (18%) (Figure 3), and focal cortical defects (16%) (Figure 4). Abnormalities were less common in children with behavioral disorders compared with children with epilepsy and/or developmental delay (42% versus 68%; P = 0.02).
Table 2 details the MRI abnormalities seen and the findings of the exploratory analysis aimed at evaluating the association between acute clinical characteristics and demographic characteristics and chronic MRI abnormalities. Children who were older at the time of the acute CM infection were more likely to have a normal brain MRI. Seizures during CM (100% versus 44.4%; P = 0.05) and a higher admission white blood cell count (14,964 versus 8.075; P = 0.02) were associated with periventricular white matter changes. Two features of acute malarial retinopathy were associated with chronic brain MRI abnormalities. The presence of papilledema was associated with subcortical white matter changes (42% versus 8%; P = 0.02) and patients in whom peripheral retinal whitening was observed were more likely to have chronic periventricular white matter changes (63% versus 0%; P = 0.007).
In a post-hoc analysis, we compared children who experienced one type of sequelae to those with more than one type of sequelae to see if there were any differences in structural abnormality frequency. Nine of the 38 children experienced more than one type of sequelae. No significant differences in the frequency of structural abnormalities (any overall abnormality or any specific abnormality) were identified (all P-values > 0.05).
This study offers insights into structural brain lesions evident on follow-up MRIs of pediatric CM survivors with very detailed acute clinical data as well as systematic long-term follow-up during which neurologic sequelae were evident. The primary limitations include the exploratory nature of the analysis, the absence of acute MRI data, the 0.35T MRI technology used, and the select nature of this group, which included only children with neurologic sequelae and only those who survived to imaging.
Structural brain abnormalities were evident in nearly three-quarters of the CM survivors with neurological deficits. Focal seizures during CM, which were often multifocal, prolonged, and refractory to treatment3 were associated with subsequent generalized cerebral atrophy. This atrophy may represent significant neuronal injury and subsequent neuronal death associated with prolonged seizures in the context of CM-associated metabolic challenges. Similar seizure frequency and severity has been reported in a Kenyan CM population with routine EEG monitoring.7 Prolonged and recurrent seizures in the source population3 for this study and in Kenya7 are associated with a higher risk of neurologic sequelae. Intracranial pressure (ICP) monitoring in CM has shown ICP surges during seizures8 suggesting that larger studies could facilitate more complex, multivariate modeling to more fully elucidate the relationship between seizures, ICP, neurologic sequelae, and structural injury.
The exploratory analysis presented here also suggests a link between acute increased ICP, as evidenced by papilledema, and subsequent subcortical white matter gliosis. This appeared as a subtle graying of the subcortical white matter. It was generally diffuse throughout the peripheral deep white matter but had relative sparing of the U fibers. Previous autopsy-based studies have identified axonal injury as a key feature of CM9; the subcortical changes identified in the CM survivors with sequelae may represent axonal injury caused by increased ICP. Alternatively, axonal injury caused by impaired perfusion and/or other CM-mediated events, may lead to increased ICP. Serial acute imaging studies in CM are underway that may further elucidate the temporal order of events. The finding that increased ICP is associated with long-term structural abnormalities is also congruent with recent report that increased brain volume evident on MRI in acute CM predicts acute mortality.10
Peripheral retinal whitening, thought to be a manifestation of retinal ischemia caused by vascular obstruction from parasitized, sequestered red blood cells,11 was associated with periventricular gliosis. This tended to be patchy but did have a predilection for the periventricular regions and provides further evidence that peripheral retinal whitening correlates to analogous brain ischemia likely from microvascular sludging and ischemia. As with other neurological conditions, funduscopy may be offering a “window” into the brain in CM. Prospective studies with acute serial brain MRIs, EEGs, and funduscopic examinations in children with CM are underway.
We thank Monica Sapuwa, Clara Antonio, and Juliet Simwinga whose contributions through patient follow-up made this work possible. We are grateful to the children and their parents and guardians who took part in the study. The Department of Paediatrics of the University of Malawi College of Medicine and the Queen Elizabeth Central Hospital provided ward accommodation and essential support for these studies.
Financial support: NIH K23NS046086, NIH 5R01AI034969, and Intramural Michigan State University funding CDFP App #: 09-CDFP-1771.
Disclosure: S. Kampondeni received research funding from the U.S. National Institute of Health. G. L. Birbeck received research funding from the U.S. National Institute of Health and the Dana Foundation. N. A. V. Beare received research funding from The Wellcome Trust, and has received travel expenses to attend scientific conferences from Novartis. K. B. Seydel and M. J. Potchen received research funding from the U.S. NIH and the Dana Foundation. S. Glover received research funding from the Wellcome Trust. T. E. Taylor received research funding from the U.S. NIH.
Authors' addresses: Sam D. Kampondeni, Blantyre Malaria Project, Blantyre, Malawi, E-mail: s.kampo154/at/gmail.com. Michael J. Potchen, Department of Radiology Michigan State University, East Lansing MI, E-mail: mjp/at/rad.msu.edu. Nicholas A. V. Beare, FRCOphth, St. Paul's Eye Unit, Royal Liverpool University Hospital, Liverpool, UK, E-mail: nbeare/at/btinternet.com. Karl B. Seydel, Department of Osteopathic Medical Specialties, College of Osteopathic Medicine, Michigan State University, East Lansing, MI, E-mail: seydel/at/msu.edu. Simon J. Glover, Ophthalmology Department, Raigmore Hospital, Inverness, UK, E-mail: Simontheeyeman/at/hotmail.com. Terrie E. Taylor, Department of Osteopathic Specialties Michigan State University, East Lansing, MI, E-mail: ttmalawi/at/msu.edu. Gretchen L. Birbeck, Department of Neurology & Ophthalmology and Department of Epidemiology & Biostatistics International Neurologic and Psychiatric Epidemiology Program, Michigan State University, East Lansing, MI, E-mail: birbeck/at/msu.edu.