cerebral malaria

Ventilatory Support May Help Children With Cerebral Malaria

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Most deaths in children with cerebral malaria may be due to increased brain volume leading to raised intracranial pressure, according to research from Malawi.

Therefore, a therapeutic approach “that capitalizes on the fact that, in survivors, the brain swelling resolves over one to two days, would be to treat the effect of brain swelling, which is respiratory arrest,” Dr. Terrie E. Taylor, of Michigan State University in Lansing told Reuters Health by email.

In fact, she concluded, “It may be that providing ventilatory support would be enough to, in effect, tide the children over the vulnerable period.”

In a March 19 online paper in The New England Journal of Medicine, Dr. Taylor and colleagues note that case fatality rates among African children with cerebral malaria remain in the range of 15% to 25%.

Magnetic resonance imaging (MRI) became available in Malawi in 2009, and the team used it to investigate the role of brain swelling in 168 children with the disease.

In all, 25 (15%) of these children died, including 21 (84%) with evidence of severe brain swelling on MRI at admission. However, severe brain swelling was seen in only 39 (27%) of the 143 survivors. In addition, serial MRI scans showed evidence of decreasing brain volume in the survivors who had brain swelling initially.

“Among survivors, the volume increase was transient, and the long-term outcomes were similar to those observed in survivors with normal brain volumes, suggesting that interventions that decrease brain swelling or sustain respiration temporarily, while the brain is swollen, may reduce mortality without increasing morbidity,” the authors conclude.

Blood pressure build-up from white blood cells may cause cerebral malaria death.

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Intracranial hypertension—increased blood pressure inside the head—can predict a child’s risk of death from malaria. A study published on December 4th in PLOS Pathogens reports that accumulation of white blood cells impairs the blood flow out of the brain and causes blood pressure increases in mice with experimentally induced cerebral malaria.

Ute Frevert, from New York University School of Medicine, USA, and colleagues compared the blood vessel architecture in the brain between two different mouse models. Mice infected with one particular species of the malaria parasite called Plasmodium berghei ANKA (PbA) develop experimental (ECM, similar to the most deadly form of malaria in humans) whereas those infected with another species called Plasmodium yoelii XL (PyXL) die from severe anemia without neurological symptoms.

The researchers used high-resolution microscopy to examine the blood vessels in the brain of uninfected mice, of PbA mice with ECM, and of PyXL mice without overt neurological symptoms. Venous (outflowing) vessels from mice with ECM show serious abnormalities. Instead of the smooth inner wall along which were moving easily that was seen in uninfected mice, vessels from mice with ECM have large numbers of attached to or crawling along their inner vessel wall. Mice infected with PyXL also accumulated some white in their venous vessels, though many fewer than the mice with ECM. In the latter, the accumulation of white blood cells results in a substantial reduction of blood flow through these vessels, though they were not completely blocked.

Analyzing the white blood cells in more detail, the researchers found that macrophages, neutrophils, and CD8+ T cells are the primary white blood cells that were increased in the vessels of mice with ECM. When mice were infected with PbA and also treated with FTY720, a drug that is known to prevent ECM, they had not only fewer, but also a different kind of white blood cells in their venous vessels. The blood flow was much less impaired and the mice showed no neurological signs.

Most cases of human malaria are caused by Plasmodium falciparum. This parasite, the deadliest of all Plasmodium species, causes infected red blood cells to become “sticky” by coating their surface with parasite proteins. These altered red blood cells then stick to venous blood vessels similar to the white blood cells in the ECM mice in this study and are also thought to impair the venous blood flow. The researchers conclude that “despite fundamental differences in parasite biology, the rodent parasite PbA could be used as a model to better understand how changes in blood flow might lead to death from human P. falciparum cerebral malaria.”

In addition, a related , Plasmodium vivax, is also responsible for a large fraction of human disease. Neither P. vivax nor PbA (the species used in this study to induce experimental cerebral malaria) cause the infected red blood cells to become sticky. However, restrictions in the venous caused by white blood cell accumulation could also explain the cerebral complications that are increasingly reported for P. vivax infections. Therefore, the authors suggest that the PbA-infected are also a good model to study severe P. vivax disease.