loading . . . Long-Term Neurocognitive Outcomes After Severe Malaria Infection: No Peace of MIND In 1948, Salil Ghosh wrote of the near-miraculous recovery of several children with severe “malignant malaria” who had been treated with quinine.1 One illustrative patient, a “girl aged 9 years,” was admitted with 2 days of “unconsciousness with delirium” and found to have “rings plenty,” the classic finding of blood-stage Plasmodium falciparum infection seen on peripheral blood smear. Following administration of intramuscular, and then oral, quinine, the patient “went home in perfect health.”
Today, malaria remains a leading cause of global morbidity and mortality, with an estimated 282 million cases and more than 600 000 deaths in 2024.2 The burden is concentrated in the World Health Organization’s Africa Region, which accounted for 94% of all malaria cases and 95% of malaria deaths in 2024. Malaria disproportionally affects children younger than 5 years, who account for more than three-fourths of all global deaths.
During the past few decades, the widespread availability of artemisinin-based antimalarial drugs has significantly improved outcomes in acute malaria infection. For severe malaria, intravenous artesunate reduces the risk of mortality by about 24% compared with quinine, the previous standard of care.3 These medicines, along with malaria vaccines and insecticide-treated nets, are estimated to have averted more than 14 million deaths between 2000 and 2024.2
For decades, the dramatic recoveries following quinine (and later artemisinin-based therapies) observed by Ghosh and others reinforced a “common dogma”: that those surviving severe malaria infections made a full and uneventful recovery.4,5 However, it is now recognized that the consequences of malaria extend well beyond hospital discharge. Children with severe malaria are at higher risk of repeat hospitalization and mortality in the months after initial hospitalization.6,7 Acute kidney injury during infection can progress to chronic kidney disease.8 Two forms of severe malaria—cerebral malaria and severe malarial anemia—have also been associated with neurocognitive impairment in young children 1 to 2 years after infection.9
In this issue of JAMA, Bangirana and colleagues10 report results from the Malarial Impact on Neurobehavioral Development (MIND) study, which assessed long-term neurocognitive and academic outcomes among children with prior episodes of severe malaria. This study, conducted at 2 clinical sites in Uganda, included participants enrolled in 2 prior prospective studies of severe malaria conducted between 2008 and 2018. The first of these 2 cohorts enrolled children aged 18 months to 12 years at initial enrollment with cerebral malaria or severe malaria anemia, and the second cohort included children aged 6 months to 4 years at initial enrollment with 1 of 5 common forms of severe malaria (cerebral malaria, severe malaria anemia, respiratory distress, complicated seizures, or prostration). For both cohorts, community children without malaria were included as controls. For the MIND study, the primary outcomes were long-term effects on overall cognition, attention, reading, and math skills, all measured using validated assessment tools.
In total, 939 participants were successfully identified and enrolled in the MIND study, representing 75% of participants from the 2 parent studies. This, in itself, is an incredible feat, given that some participants had originally been enrolled 15 years prior. For the entire MIND study population, participants were tested an average of 8.4 years (range, 4-15 years) after the initial enrollment episode of severe malaria.
In the current study, the authors found that children with cerebral malaria or severe malaria anemia had lower overall cognitive ability scores and math achievement scores compared with community controls at long-term follow-up. No differences were observed in attention or reading scores between children with cerebral malaria and severe malaria anemia. These findings align with those from prior studies that showed cognitive impairment 1 to 2 years after infection. However, this new evidence suggests that this impairment may unfortunately persist for many years after an episode of severe malaria.
Severe malaria infection is defined by the presence of 1 or more clinical features or laboratory findings, including impaired consciousness (in cerebral malaria), severe anemia (in severe malaria anemia), hyperparasitemia, acute kidney injury, respiratory distress, multiple convulsions, prostration, acidosis, shock, or bleeding. The presence of any of these findings indicates more severe disease and a higher risk of mortality. Using the second MIND cohort, the authors examined if other common forms of severe malaria—respiratory distress, complicated seizures, or prostration—were associated with long-term neurocognitive impairment. They observed no long-term differences between cognitive or academic outcomes for children with these severe malaria phenotypes when compared with community controls.
Together, these findings suggest that the long-term cognitive impairment associated with cerebral malaria or severe malaria anemia is not simply related to severe illness or prolonged hospitalization. Rather, there appears to be something distinct about the pathophysiology of cerebral malaria and severe malaria anemia that contributes to longer-term cognitive decline. In P falciparum malaria, the parasite modifies the plasma membrane of its host cell with sticky, parasite-produced proteins that mediate adherence to vascular endothelium. Adherence of infected erythrocytes to the cerebral microvasculature is a key feature of cerebral malaria, causing an inflammatory cascade that results in blood-brain barrier dysfunction, cerebral edema, and ultimately, herniation (in fatal cases).11,12 Severe malaria anemia is complex and multifactorial. Erythrocyte turnover increases—in both infected and uninfected cells—even as production drops; however, vascular adherence and sequestration remain common features in severe malaria anemia, as they are in cerebral malaria.13
Substantial heterogeneity exists in the presentation and outcomes of individuals with cerebral malaria and severe malaria anemia. The authors also examined whether specific risk factors or biomarkers might predict long-term cognitive impairment. The presence of acute kidney injury, hyperuricemia, or elevated levels of angiopoietin-2 at the time of initial infection were associated with lower overall cognitive ability at the time of follow-up. Because angiopoietin-2 is a marker and potential driver of both endovascular injury and decreased blood-brain barrier integrity, this finding hints at a possible mechanism for how cerebral malaria and severe malaria anemia might compromise long-term cognition.14
For cerebral malaria, elevated levels of plasma tau, a marker of acute brain injury, at the time of initial infection was associated with long-term cognitive impairment, as was the presence of continued neurologic deficits, such as abnormal gait, aphasia, paresis, or impaired hearing or vision, 6 to 12 months after discharge. Cognitive scores at 12 months were associated with long-term cognitive impairment, both for patients with cerebral malaria and for those with severe malaria anemia, suggesting that early assessments could help predict future outcomes.
The study by Bangirana and colleagues10 does have limitations. The study was conducted in a single country, and additional studies in other locations are necessary to determine how factors such as malaria transmission intensity or seasonality might affect generalizability. While many children (75%) from the initial studies were identified and reenrolled, loss to follow-up may have influenced the observed results. Last, given the prospective, descriptive study design, it is not possible to infer a causal relationship between severe malaria infection and future cognitive performance.
Despite limitations, the demonstrated association of long-term cognitive impairment with cerebral malaria and severe malaria anemia highlights the urgent need to identify therapies to prevent or ameliorate these effects. Postdischarge malaria chemoprevention has been shown to decrease rates of readmission and death.15 It will be important to examine if these measures also improve cognitive outcomes. Importantly, studies have also shown that cognitive rehabilitation training can improve short-term cognitive outcomes in patients with severe malaria.16 Additional studies are necessary to determine if the benefits of cognitive rehabilitation persist over time and if specific modalities yield better long-term outcomes.
Examining the underlying pathophysiology of long-term cognitive impairment in cerebral malaria and severe malaria anemia may help identify additional adjunctive therapies. Additional studies will help clarify whether hyperuricemia or elevations in angiopoietin-2 levels are drivers of cognitive impairment or simply markers of more severe malaria disease. Manipulation of endothelial angiopoietin signaling has become an attractive therapeutic target for cancer and other conditions, with multiple monoclonal antibodies and small molecule inhibitors in development.17 If elevations of angiopoietin-2 levels reflect a pathogenic role in severe malaria, adjunctive therapies at the time of acute infection might prove to be of benefit. Cognitive impairment has also been observed in pediatric and neonatal sepsis, and future studies should examine whether these effects occur through a common mechanism.18,19 Studies such as these will be critical in providing more comprehensive care for patients with severe malaria, with a focus on both decreasing mortality as well as improving long-term quality of life.
Over the last 2 decades, substantial progress has been made in preventing infections and death due to malaria. Today, these gains are threatened by cuts to global aid and global health research. The findings of the MIND study are a poignant reminder that the burden of malaria extends far beyond the acute infection and reinforce the importance of continued investment in malaria elimination.
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Article Information
Corresponding Author: Audrey R. Odom John, MD, PhD, Department of Pediatrics, Division of Infectious Diseases, Children’s Hospital of Philadelphia, 3501 Civic Center Blvd, 10006 CTRB, Philadelphia, PA 19104 ([email protected]).Published Online: April 18, 2026. doi:10.1001/jama.2026.4290Conflict of Interest Disclosures: Dr Sundararaman reported receiving grants from the National Institutes of Health, Thrasher Research Foundation, Pediatric Infectious Diseases Society, and St Jude Children’s Research Hospital outside the submitted work. Dr Odom John reported holding a patent (issued, no license) for malaria biomarkers.
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