Neurologic outcomes in retinopathy-negative cerebral malaria survivors

Abstract

Objectives: Patients surviving retinopathy-positive cerebral malaria (CM) are at high risk for the development of epilepsy, developmental disabilities, and behavioral abnormalities. We aimed to establish whether retinopathy-negative CM is also a risk factor for these outcomes. Between 2005 and 2007, survivors of CM and concurrently hospitalized controls in Blantyre, Malawi, were followed to assess the development of neurologic abnormalities. At discharge and every 3 months thereafter, incident cases of epilepsy and developmental disabilities were ascertained using screening questionnaires and confirmatory neurologic examinations. Incident cases of epilepsy and developmental disabilities were compared in retinopathy-negative CM survivors to controls and retinopathy-positive CM survivors. Methods:Results: Thirty-five retinopathy-negative CM survivors were enrolled. Their neurologic outcomes were compared to 132 retinopathy-positive CM survivors and 272 controls. Compared to survivors of retinopathy-positive CM, children without malaria retinopathy have an equal odds of adverse neurologic outcome (odds ratio [OR] ϭ 1.0, 95% confidence interval [CI] 0.4-2.2). Eleven of 35 survivors of retinopathy-negative CM had at least 1 adverse neurologic outcome compared to 2 of 272 controls (OR 61.9, 95% CI 13.0-295.5). In retinopathy-negative CM survivors, a Blantyre Coma Scale score Յ1 on admission was associated with an adverse outcome. Conclusions:Compared with controls, children surviving either retinopathy-negative or -positive CM are at similar high risk for adverse neurologic outcomes. Studies to evaluate preventive and therapeutic strategies in children with both retinopathy-negative and -positive CM are needed to improve mortality, morbidity, or both. Neurology Cerebral malaria (CM) is defined as an otherwise unexplained coma in a patient with circulating Plasmodium falciparum parasitemia.1 Children with CM are not a homogeneous group. A clinical-autopsy study revealed that approximately 23% of children meeting case criteria for CM lacked evidence of sequestration of parasitized red blood cells in cerebral vasculature.2 This pathologic finding is thought to indicate that P falciparum was most likely responsible for the patient's illness and coma. Premorbid differentiation of children with case-defined CM but without cerebral sequestration was impossible until the description of malaria retinopathy and correlation of retinopathy status with autopsy findings. The presence of malaria retinopathy is 95% sensitive and 90% specific for the histologic presence of sequestered parasitized erythrocytes and suggests that the clinical syndrome in an individual patient is likely caused by P falciparum. Retinopathy-negative CM may represent an asymptomatic incidental parasitemia with a second exposure (possibly viral) producing fever and coma.4 A clinical-autopsy study supported

Pediatric Cerebral Malaria: A Scourge of Africa

“…A subgroup analysis of those with CM revealed nonstatistically significantly different mortality rates of 21% in those treated with quinine versus 18% in the artesunate arm. Rates of neurologic morbidity in survivors were not affected by antimalarial choice, although the proportion of survivors with neurologic sequelae in this study was much lower than found in more recently published cohort studies of cerebral malaria survivors [10,11]. Artemisinin derivatives are now the treatment of choice for all forms of malaria and are not inferior to cinchona alkaloids for the treatment of CM.…”

“…Despite optimal treatment, mortality is 15-22% [7][8][9]. Survivors do not escape unscathed; cohort studies show that approximately one-third of CM survivors have persistent neurologic sequelae [10,11].…”

“…Major neurologic deficits, including epilepsy, neurodevelopmental disorders and cognitive-behavioral problems are seen in 30% of those who survive their acute illness [10,11]. Other studies estimate rates of cognitive deficits alone as 24 and 29%.…”

“…Although onequarter of children given this clinical diagnosis probably have a nonmalarial cause of coma (and are retinopathy negative, see 'Diagnosis' section), the odds of adverse neurologic outcome in CM survivors is the same whether malarial retinopathy is present [10] or not [11]. Children may be diagnosed with CM in the setting of uncomplicated malaria and a prolonged postictal state.…”

Brain MRI of Children with Retinopathy-Negative Cerebral Malaria

“…Longterm follow-up of these children after hospital discharge was not done. Because CM sequelae may develop weeks to months after hospital discharge, 28 this may have also led to misclassification of outcomes in survivors. This misclassification may have been more common in younger children, whose discharge neurologic and developmental examinations may have been more challenging.…”