Cerebral malaria

Plasmodium falciparum parasite infection among red blood cells

Cerebral malaria or CM is a neurological complication that arises due to infection of Plasmodium falciparum, the most common and dangerous parasite that causes malaria. CM is the deadliest of all complications associated with malaria and most of the incidences of cerebral malaria found are within children under the age of five. In severe cases where the infection is not diagnosed in time or treatment is not provided, unarousable coma is common and in many hospitals in Sub-Saharan Africa, there are wards full of children in a coma from one or a combination of both the advanced progression of the infection and the lack of medical treatment facilities. Children who survive a bout with CM often develop long-term cognitive issues such as memory impairment, language and verbal deficiencies, and motor deficits. The majority of the cases occur in developing nations, especially in the Sub-Saharan African region, with approximately one million deaths to children alone since the medical infrastructure and education about health are often not as well developed compared with other areas of the world. It is also primarily isolated to tropical areas where mosquito control is made particularly difficult including Central and South America as well as Southeastern Asia. There is not a vaccine currently available possibly due to the decrease in incidence of the disease in the developed world to almost being completely eradicated with the exception of cases due to migrants and tourism to tropical areas so current treatment for cerebral malaria is anti-parasitic treatments which prove to halt the rapid advancement of the infection but survivors often still experience neurological side effects.

Signs and symptoms

Symptoms of malarial infection by Plasmodium falciparum and cerebral malaria are often the same and are noticed 9 to 14 days after the initial infection. Certain initial flu-like symptoms such as sweats, fever, headache, and shivers occur in advance to the categorization of cerebral malaria, but once the infection becomes advanced enough, impairment of the brain or spinal cord occurs with certain symptoms as seizures or loss of consciousness. Liver and kidney damage often also occur when malaria gets severe enough. Cerebral malaria can only occur with infection by P. falciparum, which causes the most severe forms of malaria. Children under the age of 5 years are most at risk for infection with African children 0–5 accounting for 75% of the total malarial deaths per year. This is believed to be due to the more at risk immune system of children just like the immune system of pregnant women who are also significantly more at risk for infection. Spleen enlargement is one of the side effects of malarial infection and spleens of children who are constantly exposed to malarial infection can be noticed to be ten times the size of children from more developed areas. Adults who are exposed to malarial infection for long periods of time have an improved immune response to the parasite, reducing its spread in the body. It is also thought that those that are carriers for sickle-cell anemia are given greater immunity to malarial infection due to blocking of the entry of the parasite. Those that are homozygous for the sickle-cell trait though have irregularly shaped red blood cells often causing blockage of vessels and often causing premature cardiovascular disease and death. One of the largest and most deadly symptoms of cerebral malaria is hypoglycemia due to the inability of the brain to take in glucose since the blood brain barrier loses its specificity.

Cause

Plasmodium falciparum parasite developmental cycle after infection

Mosquitoes carrying the P. falciparum parasite infect a human host. The parasite then travels through blood vessels into liver cells where it is proliferated and then infects red blood cells. The virus continues replicating until the red blood cells burst causing the virus to infect other areas. If the invading red blood cells burst in the brain, the endothelial cells that form the inner layer of the vasculature of the brain are infected by the P. falciparum parasite. These endothelial cells are responsible for blood barrier specificity that is essential to keeping the brain energy and oxygen requirements at normal levels. The areas that are responsible for the particular specificity of the nutrient exchange across the capillaries to the brain are called gap junctions. These gap junctions, when infected by the virus, begin to break causing blood-brain barrier specificity to be halted and thus nutrients, toxins, and anything else that is present in the blood is free to enter and leave with very little regulation. Cerebral malaria occurs so commonly since about 25% of the blood circulation goes to the brain due to the brain's large energy requirements being only 2% of the body weight but consuming 20% of the carbohydrates per day (see Selfish Brain Theory). Recent studies have been done looking into co-infection with certain diseases and malaria including HIV co-infection and others which involve severe impairment of the immune system. In addition to the damage done to the blood brain barrier in the brain, there is some damage to the myelin which surrounds the nerves and this is caused by some of the immune responses to the parasite.

Diagnosis

Right now the most effective way to diagnose cerebral malaria is the same as the way to diagnose regular malaria, with a commonly used blood smear checking for the presence of the parasite. Cerebral malaria requires a greater amount of care and treatment than regular malaria since it is an extreme form of malaria where the parasite infects the brain causing adverse effects within the brain. But another way to classify if cerebral malaria is present is to do PCR testing to see if the virus is actually P. falciparum not any other parasite since only P. falciparum causes cerebral malaria. Other testing that can be done to check the progression of the disease includes complete blood count to check for anemia from reduced red blood cell function, liver function test, and blood glucose test to check if the patient is hypoglycemic. Acute renal failure, acute lung injury, severe metabolic acidosis, shock anaemia, status epilepticus and raised intracranial pressure are other severe complications associated with malaria and often those suffering with cerebral malaria are also affected by one or more of the aforementioned conditions. Much of the time, especially in the areas where cerebral malaria is most common, diagnosis is not determined until postmortem but from certain autopsy results of the brain, the effects can be seen very easily. The entire brain is shown to be affected since every areas with gap junctions are broken down. In addition, the brain dissections of cerebral malaria patients show a greenish pigment present which is called hemozoin and is very common and evident. The increased cranial pressure is caused by cerebral edema and is one of the major causes of the neurological problems that are common in cerebral malaria cases since constant pressure of the brain upwards into the skull causes neurological damage if not decreased. This increased pressure is caused by the leaking of fluid through the junctions and an increased size of the ventricles is also noticeable in many cases.

Prevention

Ecotourism and the nature of the world today where it is so easy to travel to remote locations is responsible for the reemergence of cerebral malaria in the developed world. It is still a large problem in the developing world especially in tropical areas since it is difficult to control mosquitoes that have P. falciparum infection in areas like Sub-Saharan Africa, Southeast Asia, and Central and South America. If one is traveling to a nation in the areas previously mentioned, it is advised to check if there are any recommended preventative measures to be taken in order to avoid malarial infection. It is often recommended by the Center for Disease Control (CDC) to take certain antibiotics and antimalarials listed on their website, which are often quite effective in preventing the infection from occurring. The assigned medication is often recommended to be taken around a week before traveling to the area that has potential for P. falciparum infection. Some of the common antimalarials that are recommended by the CDC include chloroquine, mefloquine, and doxycycline. Each of these are different in the amount of time it needs to be ingested before traveling to the tropical area and have a number of other side effects that come along with use, some of which are psychological. An additional problem with the currently used antimalarials is that they are not actually 100% effective in preventing malaria as there have been a number of cases reported of the virus gaining resistance to drugs. This problem is partially due to the increased prevalence of malaria in third world nations in combination with the lack of regulation of distribution of antibiotics and antimalarials. This misuse of antibiotics along with lack of continuation of use of antibiotics and antimalarials after the symptoms leave causes drug-resistant strains to occur more commonly. Research has been going in animal models for some time now looking into certain steroids and other molecules that affect the elasticity of blood vessels but nothing yet is provided for human use.

Treatment

There is currently no vaccine present for the cure of malaria. Right now the treatment of malaria is to use oral antimalarials in all cases, but in most cases, death from cerebral malaria already occurs within 24 hours, often before antimalarial effects have made any effect. Due to the lack of accessibility to proper healthcare in a timely manner, most of the children with cerebral malaria have a delayed admission to the hospital and already exhibit symptoms such as impaired consciousness, repeated seizures, severe anemia, respiratory distress, shock, or hypoglycemia. Many of the hospitals in Sub-Saharan Africa and other areas where cerebral malaria is a part of everyday life for physicians do not have the capabilities to even properly treat the symptoms associated such as hemodialysis machines to replenish the patient's red blood cell count, which are commonplace in more developed hospitals. But in specific with severe malaria which is commonly what occurs in the case of cerebral malaria sometimes hemodialysis is necessary to replenish the red blood cells and platelets. Also respiratory machines or other aid to help with the many other complications that occur with malaria are often necessary in order to keep the cerebral malaria patients out of a coma, but again many of the facilities in these underdeveloped areas do not have this technology at hand. This is why it is not uncommon for hospitals in poorer African areas such as Ivory Coast to have many of their beds filled with children in a coma from cerebral malaria with very little chance of coming out of the coma since the patient is often too sick to transport to a different hospital and the hospital that the patient is at does not have the equipment to treat the symptoms present.

Epidemiology

Map showing countries where Malaria is known to occur

Malaria is one of the more historically significant diseases in human history. Malaria has been present in areas such as Sweden, Washington D.C., and Italy even up to the Civil War time. In fact malaria comes from an Italian word meaning "bad air". Now it is essentially eradicated from the developed world except in cases where someone has visited a tropical area and a little more than a week later begins to experience flu-like symptoms that are commonly associated with malaria. Now the annual estimated number of malaria cases is over 500 million with about 90% of these episodes taking place in sub-Saharan Africa. Generally cerebral malaria infection is isolated to very poor areas including sub-Saharan Africa, Southeastern Asia, and Central and South America and primarily areas where there is little to no access to healthcare. This is because in areas with proper medical conditions, generally a physician will have diagnosed the patient with malaria before the advancement of cerebral malaria occurs. This is why there are still some cases of malaria present in the United States and other developed nations, but there are only very rare cases of cerebral malaria in these areas and they are mostly related to tourism to areas where parasite is commonly found.