Cerebral Malaria, a Wily Foe

Halima, a three-year-old girl, was brought to the hospital in Kenya after running a fever for almost two days.  At first, the fever seemed nothing to be particularly concerned about, so Halima’s mother gave her paracetamol (acetaminophen) to bring down her temperature and left her in the care of an older sister while she went out to work on the farm. But when she returned a few hours later, she was unable to wake her child. She shook her gently and Halima’s eyes opened, but the girl stared blankly ahead, unable to make eye contact.  Her sister told their mother that Halima had had a convulsion earlier, her arms and legs jerking uncontrollably for several minutes before her body went limp. It was then that the mother began the arduous four-hour trek to the hospital for treatment.

The hospital physician noted that Halima’s fever was over 103° Fahrenheit and her gaze was blank and roving.  Shortly after the initial examination, Halima began convulsing again, and the physician administered an anticonvulsant drug. The physician listened to her mother’s story—one that physicians hear day after day in Kenya, Malawi, and other parts of sub-Saharan Africa—and made a tentative diagnosis of cerebral malaria, a form of severe malarial infection.  He began presumptive treatment with quinine and intravenous fluids and waited to see if Halima would be one of the lucky ones who manage to survive.

Hundreds of millions of people contract malaria each year, primarily in the poor countries of sub-Saharan Africa.  Most are sick for only a few days. But in a small percentage of those infected, including Halima, the malarial parasites will attach to blood vessels and capillaries in the brain, causing coma, neurological damage, organ failure, and, often, death.

How does malaria produce such profound symptoms?  Could the body itself be causing damage in its attempts to keep the parasite at bay?  What lies behind why some people are stricken with one of the most brutal variations of the disease, while others are not?  Scientists are currently working to answer those questions by studying the malaria parasite itself, the human immune response to this intruder, and the variations in how people experience the disease.  Promising research on cerebral malaria is taking place around the globe, in university laboratories from the United States to Australia and in the field in Africa.

A Terrible Prognosis

Malaria is an infectious disease caused by the release of protozoan parasites into the bloodstream by the bite of a parasite-carrying Anopheles mosquito.  After an incubation period of one to four weeks, initial malaria symptoms begin that usually include fever, headaches, vomiting, chills, and general malaise, similar to the flu.  These symptoms are caused by the release of the parasites’ products into the bloodstream.  Most people, if treated, recover relatively easily, but the unlucky others, like Halima, will develop the disease’s more severe form, cerebral malaria, in which the parasite-infected red blood cells attach in large numbers to the circulatory vessels of the brain.

What is the prognosis for a child whose malarial infection has localized in the blood vessels of the brain?  If not immediately treated, cerebral malaria is likely to be fatal.  But even with treatment, the physician can only wait to see the outcome.  For most children, the coma will reverse and they will recover.  But within three to seven years, approximately a quarter of those who do recover will show impairment in memory, attention, and other cognitive skills.

Halima became more responsive after 15 hours of the simple treatment with quinine and fluids.  By the end of two days, her alertness had continued to improve, but she was still unable to fix her gaze or follow a moving object.  She also experienced weakness on her right side.  A month after discharge from the hospital, her vision had improved, but she still walked with a limp.  And one year later, she was developing on course with her peers but had developed epilepsy, a disorder that will require medication for the rest of her life to control what would otherwise be unprovoked, aggressive seizures.

Sadly, Halima’s recovery is considered a relatively good outcome, because a significant portion of those who contract cerebral malaria each year—an estimated 15–20 percent—die of the disease.

Developing Immunity

The form of malaria that invades the brain is usually caused by Plasmodium falciparum, one of the four malarial parasites that can infect humans. According to Charles Newton, M.D., a physician and researcher with the KEMRI-Wellcome Trust Research Programme in Kilifi, Kenya, more than 2 billion people are exposed to falciparum malaria in the world annually. The 500 million plus episodes of the disease each year—some of them repeated illnesses in the same person—result in at least one million deaths, making falciparum malaria the most fatal parasitic disease in the world.  Young children in sub-Saharan Africa bear the brunt of this burden.

Over time, most people native to endemic malarial areas, who become infected with the uncomplicated form of the disease over and over again, build up a resistance to it because their bodies develop an effective antibody defense.  Although this immunity has been well established epidemiologically, scientists do not yet fully understand the mechanisms behind it.

“Malaria doesn’t induce a ‘sterilizing immunity,’ like measles or smallpox, where you get it once and never get it again,” says David Sullivan, M.D., an associate professor at the Johns Hopkins Bloomberg School of Public Health.  He explains that as the body develops antibodies that fight malarial infection, the parasites lose the ability to attach to the lining of the blood vessels in numbers as great as in severe falciparum disease.

But those antibodies do not totally prevent a person from contracting malaria again.  Instead, they keep the number of infected blood cells below the threshold that would cause the more severe forms of the disease.  Children under the age of six years and people who are not native to areas where malaria is pervasive have not yet fostered this immunity by building up enough antibodies, and so they are left susceptible to the more severe manifestations of the disease, such as cerebral malaria.

Questions for Research

To date, efforts to prevent or at least control malaria primarily involve spraying with insecticides, particularly spraying bed nets, and administering multiple doses of antimalarial drugs such as Malarone and Lariam to people traveling to areas where malaria parasites are rampant.  “These methods are ways of preventing malaria,” says Terrie E. Taylor, D.O., a Michigan State University Distinguished Professor who for more than 20 years has spent the African rainy season, January to June, treating patients at the Queen Elizabeth Central Hospital in Blantyre, Malawi.  “But the caveat is that they have to be sustainable for an indefinite period.”

Malaria’s incidence has soared over the past two decades as a result of mosquito resistance to pesticides and parasite resistance to common antimalarial drugs.  Tied to this increased rate of regular malarial infection is the growing number of people contracting, and dying from, cerebral malaria. This has made the development of new methods and treatments to help stanch the disease’s substantial mortality and morbidity rates a focal project not only in areas where malaria is endemic but for several deep-pocketed pharmaceutical firms and charitable organizations across the world.

What do we know of the malarial parasite that brings about the cerebral form of the disease?  Surprisingly little.  “Malaria is a very complicated disease with a complicated life cycle,” says Diane Griffin, M.D., Ph.D., the Alfred and Jill Sommer Chair of Microbiology at the Johns Hopkins Bloomberg School of Public Health and director of the Malaria Research Institute.  “We need to understand all components of that life cycle better in order to control it.”

As more attention and funds have been allocated to fight the spread of malaria in general, and its crueler manifestations such as cerebral malaria, increased understanding of the mechanisms underlying how the malaria parasite can attack brain function is raising new hopes for preventing malaria’s most fatal forms.  But surprisingly, greater knowledge about what scientists do not know about malaria is also helping to drive research in the right direction, both in clinical research and in investigations into the human immune response to malarial parasites.

Why Halima, as opposed to one of her friends, parents, or siblings, would come down with cerebral malaria is only one of the many questions about how cerebral malaria operates. At a more basic level, researchers are looking to solve how a parasite that remains in the blood vessels in the brain but does not invade the brain tissue itself can bring about such profound symptoms and neurological problems that may include, besides those Halima experienced, aphasia, ataxia, and cortical blindness, coma, and, finally, death.  When answers are found, scientists can develop better methods to prevent the more deadly types of malarial disease.

Surprises, and a Better Diagnosis

Terrie Taylor focuses on clinical research with children who have cerebral malaria in Blantyre, an industrial center in Malawi.  To better understand how malaria can cause coma and death, she and her team have embarked on an autopsy study of children, with the hope of identifying how cerebral malaria damages the brain.   She and her colleagues have not yet answered many of the questions they had when they started the study, but they have made interesting discoveries that will change how cerebral malaria is diagnosed and examined.

One area that Taylor’s team has focused on is the endothelial cells, the unique, flat cells that form the lining of blood vessels.  These cells are an integral part of the blood-brain barrier, which protects vulnerable brain tissue from invaders. “We know that the small blood vessels of the brain have parasitized red cells that adhere to the endothelial cells in those vessels,” says Taylor.  “But in terms of what is causing what, lots of different facets need to be considered.”

Taylor thinks that several problems could be responsible for the more complicated forms of malaria and their neurological symptoms, for example a lack of blood flow to the brain or slower blood flow resulting in brain damage, swelling, and inflammation of clogged blood vessels, or perhaps damage stemming from seizures.  She hopes to learn more as the autopsy study continues.

One of the most significant discoveries from Taylor’s study is that approximately one quarter of children autopsied, who met the standard case definition for cerebral malaria before they died, actually died of completely unrelated infections or diseases.  “This really calls into question a lot of work that’s been done on severe malaria to date,” says Taylor.  “The studies might have included patients who were not suffering from malaria at all because the researchers were using case definitions that lacked precision.”

This valuable insight led other physicians, partnered with Taylor, to determine that the only clinical difference between those children who died of cerebral malaria and those with malarial infection who died from other causes was a complication of cerebral malaria that damages the retina, called malarial retinopathy.  Using just an ophthalmoscope, clinicians can check the eyes of sick children to see if telltale whitening of the eye’s infected blood vessels and swelling of the optic nerve are apparent.  If so, the child is most likely suffering from cerebral malaria, not from another disease with just an incidental malarial infection.

“It’s important to note that not all malarial infection is equal to malarial disease,” says Taylor.  “There are plenty of people walking around with malaria parasites that are incidental and have no relationship to the disease they might have.” Improving the case definition by checking for malarial retinopathy will help clinicians correctly diagnose cerebral malaria and administer treatment more quickly and effectively, and it will also enable scientists who are studying malaria to be sure they are including in their studies only those who truly have the disease, thereby removing potential ambiguity from their research.

Taylor’s research has yielded other interesting results as well. She found that those children in the autopsy study who did die of true cerebral malaria all had parasites attached to the brain’s blood vessels.  But she identified two distinct forms of this pathology, the first showing just the parasites sequestered in the blood vessels and the second showing the parasite-filled vessels along with hemorrhages, clots, and other tissue damage. “We have a long way to go until we can work out the cause-and-effect relationship,” says Taylor.  “We are not certain if these are two separate disease processes or perhaps different stages of the same process.”

Understanding the Deadly Parasite

While Taylor’s group has focused on clinical research, David Sullivan and Monique Stins and their research team at Johns Hopkins are examining the biological mechanisms of the Plasmodium falciparum parasite and how it can cause coma and other neurological problems even though it is not able to cross the blood-brain barrier. According to Sullivan, “The question is, what are the signals that the malaria parasite is able to send through the endothelium so that it does not invade the brain tissue itself but is still able to choke off the brain’s function.”

Their laboratory has found that malaria parasites, after sticking to the receptors on endothelial cells and plugging thin blood vessels called “capillaries,” also release proteins and molecules that make the blood vessel wall leaky.  “In some ways, malaria is a disease at the capillary level,” says Sullivan.  “That’s how the parasite homes in on the brain, blocking the blood vessels, and causes the more severe cerebral malaria.”

More than 100 different types of highly variable Plasmodium falciparum proteins have been identified that cause sticking to vessels.  In the future, Sullivan hopes to understand how malarial parasites are able to send messages from the endothelial cells to the microglial cells and neurons in the brain, causing coma and other neurological consequences of severe malarial infection. “We’re still looking for the messenger molecules that turn off the brain in such a reversible fashion, without a lot of inflammation,” he says.  “Even when the patient is in a coma, the brain tissue itself appears to be normal.”

The Link to Neurological Impairment

But the influence of cerebral malaria does not end if and when the child recovers.  The disease can cause brain damage that will stay with those afflicted for the rest of their lives.  Charles Newton, who both sees patients and does research full-time in Kenya, studies the link between cerebral malaria infection and later neurological impairment.  His group has found that nearly one quarter of children who survive cerebral malaria will go on to show problems with memory, attention, and other cognitive function years later. Scores of children like Halima will live out their lives with the aftereffects of the disease, aftereffects that hinder their ability to finish school, find and keep employment, and take care of their own families.

Newton’s group has also shown an association between severe malaria and the development of epileptic conditions like that with which Halima was diagnosed a year after her initial recovery from cerebral malaria.  At first glance, lack of blood flow (ischemia) due to blocked blood vessels may seem like the obvious cause for this kind of neurological damage, but Newton argues that other features of the disease are at play. “Although reduction of blood flow due to blockage of blood vessels may contribute, it cannot be the only cause,” says Newton.  He explains that most children with cerebral malaria do not show any physical evidence of ischemia in the brain.

Newton’s group has looked at other potential causes of neurological damage and has proposed several possibilities, including raised intracranial pressure from the blocked vessels and an immunological antibody response against neurons.  Several other researchers are also seeing great promise in better understanding the human immune response to malarial parasites.

The Role of the Immune System

One of those researchers, Georges E. R. Grau, M.D., chair of Vascular Immunology at the University of Sydney, Australia, focuses on analyzing and deciphering the biological mechanisms of the immune response.  He suggests that the reason that some people contract cerebral malaria while others develop only an uncomplicated form of infection pertains more to individual differences in how the immune system responds to the parasite than to the parasite itself.

“Every patient with falciparum malaria will have some parasites binding to blood vessels in his or her brain,” says Grau.  “But only one percent of those patients will develop cerebral malaria.  Certainly there might be some parasite factors that we do not know about yet, but people with cerebral malaria have an abnormal immune response.”

Grau and his colleagues have worked for many years on cultures of mice endothelial cells that have been exposed to malarial parasites.  But it is not clear that the mouse variety of cerebral malaria is completely analogous to the human kind.  Still, in human studies, Grau’s laboratory has shown that a particular cytokine, or protein produced by immune system cells, called tumor necrosis factor (TNF) is produced in excessive amounts in humans with cerebral malaria.  But Grau cautions that more than one inappropriate immune response to the invasion of malarial parasites appears likely.

“This is only one of the host responses that is abnormal,” says Grau.  His group has also found that those with cerebral malaria also show an elevated number of microparticles, or plasma membrane fragments released by blood cells when stimulated by TNF, in the blood.  These microparticles may cause inflammation in the brain, leading to the coma, neurological damage, and death.

Newton is examining other immunologic aspects of the disease as well.  In collaboration with Beth Lange, at the University of Oxford, he has found that children with cerebral malaria have an elevated number of antibodies that are associated with blocking a neuron’s calcium voltage gated channels, a key part of the cell membrane that assists in the neuron’s release of neurotransmitters.  But how these immunological responses work to eventually lead to coma and other neurological impairment is still under investigation.

Cautious Optimism

Researchers who focus on cerebral malaria caution that we are still only at the beginning stages of the search for scientific methods to prevent the disease.  Taylor states that understanding severe malarial infection is more complicated than she thought it would be. “It’s a wily foe,” she says.  “I thought the autopsy study would have answered it all by now, and instead it’s just thrown up more questions.  I think the actual development of interventions will be handed off to the next generation.”

But others believe some forms of more immediate relief are nearer at hand.  Newton is looking into developing clinical interventions that might help prevent seizures and also ways to improve the passage of red blood cells through clogged vessels in the brain.  And Grau believes that current research is providing a strong foundation for future interventions.  He thinks that the scientific community is well on its way to being able to identify those who might be at risk for the more complicated forms of the disease as well as to developing a vaccine. “An anti-disease vaccine would not kill the malaria parasite completely but would, rather, prevent the abnormal set of events that follow the infection,” he commented.  “It’s aiming at a reduction of the inappropriate host immune responses.”

Wider Implications

Scientists in the field also argue that understanding the mechanisms underlying cerebral infection can play a part in understanding other diseases and neurological problems.  Malaria’s ability to so quickly reverse its effects is of particular interest. “Working out how a parasite can produce such a profound coma so quickly and then reverse just as quickly will be very instructive,” says Taylor.

Even now, malaria is helping researchers to discover new things about the brain.  By examining the brains of those who have died from the disease, a group in England led by Dr. Isabelle Medana and Dr. Gareth Turner has found that the brain has a backup reservoir of capillaries. “Normally, you can’t see these capillaries because they are shut tight,” says Sullivan.  “But with the clogging from malaria, these reserve blood vessels open up and we now see that there are lots more capillaries in the brain itself.” He argues that this finding has implications for all neurological processing and for how the brain responds to injury.

Sullivan also suggests that understanding whatever is causing the coma and overall dysfunction after malarial infection can further illuminate the ways that oxygen deprivation from blocked arteries (ischemia) causes brain damage. Newton agrees.  “Cerebral malaria may serve as a useful model to study the processes set up by hypoxia, low blood flow through the vasculature.”

Though malaria is not giving up its secrets easily, clinicians and researchers alike are pleased that malaria has received increased attention in the past few years.  “Malaria is a preventable and treatable condition,” says Newton.  “It aggravates poverty and impairs the development of many regions of the world.  It deserves to be high on the agenda for funding.”

With the additional funding being provided for malaria research, the medical community is hopeful that it can provide answers to some of the more daunting questions about the cunning mechanisms of the disease and its human host’s response. “It’s a tricky disease,” says Taylor.  “It’s going to take another five to ten years to figure out what’s going on, how it does what it does.” But confidence is growing that stories like Halima’s will become less commonplace and that eventually there will be no need to tell such a tale again.