Cerebral Malaria
Disease Details
Family Health Simplified
- Description
- Cerebral malaria is a severe form of malaria that affects the brain, caused by the Plasmodium falciparum parasite, leading to neurological symptoms and potentially fatal complications.
- Type
- Cerebral malaria is not a genetically transmitted condition; it is an infectious disease caused by the Plasmodium falciparum parasite. This type of malaria occurs when the parasites infect the brain, leading to severe neurological symptoms and complications.
- Signs And Symptoms
- Adults with malaria tend to experience chills and fever – classically in periodic intense bouts lasting around six hours, followed by a period of sweating and fever relief – as well as headache, fatigue, abdominal discomfort, and muscle pain. Children tend to have more general symptoms: fever, cough, vomiting, and diarrhea.Initial manifestations of the disease—common to all malaria species—are similar to flu-like symptoms, and can resemble other conditions such as sepsis, gastroenteritis, and viral diseases. The presentation may include headache, fever, shivering, joint pain, vomiting, hemolytic anemia, jaundice, hemoglobin in the urine, retinal damage, and convulsions.The classic symptom of malaria is paroxysm—a cyclical occurrence of sudden coldness followed by shivering and then fever and sweating, occurring every two days (tertian fever) in P. vivax and P. ovale infections, and every three days (quartan fever) for P. malariae. P. falciparum infection can cause recurrent fever every 36–48 hours, or a less pronounced and almost continuous fever.Symptoms typically begin 10–15 days after the initial mosquito bite, but can occur as late as several months after infection with some P. vivax strains. Travellers taking preventative malaria medications may develop symptoms once they stop taking the drugs.Severe malaria is usually caused by P. falciparum (often referred to as falciparum malaria). Symptoms of falciparum malaria arise 9–30 days after infection. Individuals with cerebral malaria frequently exhibit neurological symptoms, including abnormal posturing, nystagmus, conjugate gaze palsy (failure of the eyes to turn together in the same direction), opisthotonus, seizures, or coma.
- Prognosis
- When properly treated, people with malaria can usually expect a complete recovery. However, severe malaria can progress extremely rapidly and cause death within hours or days. In the most severe cases of the disease, fatality rates can reach 20%, even with intensive care and treatment. Over the longer term, developmental impairments have been documented in children who have had episodes of severe malaria. Chronic infection without severe disease can occur in an immune-deficiency syndrome associated with a decreased responsiveness to Salmonella bacteria and the Epstein–Barr virus.During childhood, malaria causes anaemia during a period of rapid brain development, and also direct brain damage resulting from cerebral malaria. Some survivors of cerebral malaria have an increased risk of neurological and cognitive deficits, behavioural disorders, and epilepsy. Malaria prophylaxis was shown to improve cognitive function and school performance in clinical trials when compared to placebo groups.
- Onset
- Cerebral malaria typically presents with a rapid onset of symptoms. This form of malaria is a severe and potentially fatal complication caused by Plasmodium falciparum. Symptoms may escalate quickly, often within days of the initial malaria symptoms, and can include fever, headache, seizures, confusion, and loss of consciousness. Immediate medical attention is crucial to manage and treat the condition effectively.
- Prevalence
- The exact global prevalence of cerebral malaria is not well-documented in terms of specific percentages. However, it is a severe neurological complication of Plasmodium falciparum malaria, predominantly affecting children under five years of age and pregnant women in sub-Saharan Africa. Cerebral malaria is less common in regions where Plasmodium vivax is the primary malaria parasite.
- Epidemiology
- The WHO estimates that in 2021 there were 247 million new cases of malaria resulting in 619,000 deaths. Children under five years old are the most affected, accounting for 67% of malaria deaths worldwide in 2019. About 125 million pregnant women are at risk of infection each year; in Sub-Saharan Africa, maternal malaria is associated with up to 200,000 estimated infant deaths yearly. Since 2015, the WHO European Region has been free of malaria. The last country to report an indigenous malaria case was Tajikistan in 2014. There are about 1300–1500 malaria cases per year in the United States. The United States eradicated malaria as a major public health concern in 1951, though small outbreaks persist. Locally acquired mosquito-borne malaria occurred in the United States in 2003, when eight cases of locally acquired P. vivax malaria were identified in Florida, and again in May 2023, in four cases, as well as one case in Texas, and in August in one case in Maryland. About 900 people died from the disease in Europe between 1993 and 2003. Both the global incidence of disease and resulting mortality have declined in recent years. According to the WHO and UNICEF, deaths attributable to malaria in 2015 were reduced by 60% from a 2000 estimate of 985,000, largely due to the widespread use of insecticide-treated nets and artemisinin-based combination therapies. Between 2000 and 2019, malaria mortality rates among all ages halved from about 30 to 13 per 100,000 population at risk. During this period, malaria deaths among children under five also declined by nearly half (47%) from 781,000 in 2000 to 416,000 in 2019.Malaria is presently endemic in a broad band around the equator, in areas of the Americas, many parts of Asia, and much of Africa; in Sub-Saharan Africa, 85–90% of malaria fatalities occur. An estimate for 2009 reported that countries with the highest death rate per 100,000 of population were Ivory Coast (86.15), Angola (56.93) and Burkina Faso (50.66). A 2010 estimate indicated the deadliest countries per population were Burkina Faso, Mozambique and Mali. The Malaria Atlas Project aims to map global levels of malaria, providing a way to determine the global spatial limits of the disease and to assess disease burden. This effort led to the publication of a map of P. falciparum endemicity in 2010 and an update in 2019. As of 2021, 84 countries have endemic malaria.The geographic distribution of malaria within large regions is complex, and malaria-afflicted and malaria-free areas are often found close to each other. Malaria is prevalent in tropical and subtropical regions because of rainfall, consistent high temperatures and high humidity, along with stagnant waters where mosquito larvae readily mature, providing them with the environment they need for continuous breeding. In drier areas, outbreaks of malaria have been predicted with reasonable accuracy by mapping rainfall. Malaria is more common in rural areas than in cities. For example, several cities in the Greater Mekong Subregion of Southeast Asia are essentially malaria-free, but the disease is prevalent in many rural regions, including along international borders and forest fringes. In contrast, malaria in Africa is present in both rural and urban areas, though the risk is lower in the larger cities.
- Intractability
- Cerebral malaria is a severe and potentially life-threatening form of malaria caused by Plasmodium falciparum. It is a medical emergency requiring prompt treatment. While it can be very severe, it is not considered intractable if treated quickly and effectively with appropriate antimalarial medications. However, delays in treatment or lack of access to adequate medical care can lead to complications and increased mortality.
- Disease Severity
- Cerebral malaria is considered a severe and life-threatening form of malaria. It can lead to serious complications, including brain damage, coma, and death if not promptly treated.
- Healthcare Professionals
- Disease Ontology ID - DOID:14069
- Pathophysiology
- Malaria infection develops via two phases: one that involves the liver (exoerythrocytic phase), and one that involves red blood cells, or erythrocytes (erythrocytic phase). When an infected mosquito pierces a person's skin to take a blood meal, sporozoites in the mosquito's saliva enter the bloodstream and migrate to the liver where they infect hepatocytes, multiplying asexually and asymptomatically for a period of 8–30 days.After a potential dormant period in the liver, these organisms differentiate to yield thousands of merozoites, which, following rupture of their host cells, escape into the blood and infect red blood cells to begin the erythrocytic stage of the life cycle. The parasite escapes from the liver undetected by wrapping itself in the cell membrane of the infected host liver cell.Within the red blood cells, the parasites multiply further, again asexually, periodically breaking out of their host cells to invade fresh red blood cells. Several such amplification cycles occur. Thus, classical descriptions of waves of fever arise from simultaneous waves of merozoites escaping and infecting red blood cells.Some P. vivax sporozoites do not immediately develop into exoerythrocytic-phase merozoites, but instead, produce hypnozoites that remain dormant for periods ranging from several months (7–10 months is typical) to several years. After a period of dormancy, they reactivate and produce merozoites. Hypnozoites are responsible for long incubation and late relapses in P. vivax infections, although their existence in P. ovale is uncertain.The parasite is relatively protected from attack by the body's immune system because for most of its human life cycle it resides within the liver and blood cells and is relatively invisible to immune surveillance. However, circulating infected blood cells are destroyed in the spleen. To avoid this fate, the P. falciparum parasite displays adhesive proteins on the surface of the infected blood cells, causing the blood cells to stick to the walls of small blood vessels, thereby sequestering the parasite from passage through the general circulation and the spleen. The blockage of the microvasculature causes symptoms such as those in placental malaria. Sequestered red blood cells can breach the blood–brain barrier and cause cerebral malaria.
- Carrier Status
- Cerebral malaria does not have a carrier status. It is a severe neurological complication of infection with the Plasmodium falciparum parasite, transmitted through the bite of an infected Anopheles mosquito. There are no asymptomatic carriers similar to some bacterial or viral diseases.
- Mechanism
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Cerebral malaria is a severe neurological complication of infection with *Plasmodium falciparum*. The exact mechanisms underlying cerebral malaria are complex and not completely understood, but several key factors are involved.
1. **Sequestration**: Infected red blood cells (iRBCs) adhere to endothelial cells in brain capillaries and post-capillary venules through the interaction of parasite proteins, such as PfEMP1 (Plasmodium falciparum erythrocyte membrane protein 1), with endothelial receptors. This sequestration obstructs blood flow and contributes to localized hypoxia, metabolic disturbances, and can lead to blood-brain barrier (BBB) disruption.
2. **Host Immune Response**: The immune response against the parasite involves the release of pro-inflammatory cytokines (e.g., TNF-α, IFN-γ) that can exacerbate inflammation, cause endothelial activation and dysfunction, and increase BBB permeability. This contributes to cerebral edema and further disrupts neuronal function.
3. **Microvascular Obstruction**: The sequestration of iRBCs and adherence of platelets and leukocytes can lead to microvascular obstruction, which impairs oxygen and nutrient delivery to brain tissues, leading to tissue damage and neuronal injury.
4. **Endothelial Activation and Damage**: The interaction between iRBCs and the endothelium triggers endothelial cells to express adhesion molecules (e.g., ICAM-1, VCAM-1). This can cause endothelial activation, oxidative stress, and ultimately damage, contributing to BBB integrity loss.
5. **Molecular Mechanisms**: On a molecular level, multiple pathways are involved:
- **PfEMP1 Variants**: Variants of PfEMP1 expressed on the surface of iRBCs mediate binding to endothelial receptors such as ICAM-1, EPCR, and CSA. This interaction is critical for sequestration in brain vessels.
- **cytoadherence and rosetting**: PfEMP1 interaction with host receptors promotes cytoadherence (iRBCs binding to endothelial cells) and rosetting (iRBCs forming clusters with uninfected RBCs), both processes contributing to microvascular obstruction.
- **Cytokine Signaling**: TNF-α and other pro-inflammatory cytokines activate endothelial cells, leading to increased expression of adhesion molecules and disruption of function, as well as recruitment of additional immune cells that can cause further damage.
Understanding these mechanisms is essential for developing effective therapeutic strategies and interventions for cerebral malaria. - Treatment
- Malaria is treated with antimalarial medications; the ones used depends on the type and severity of the disease. While medications against fever are commonly used, their effects on outcomes are not clear. Providing free antimalarial drugs to households may reduce childhood deaths when used appropriately. Programmes which presumptively treat all causes of fever with antimalarial drugs may lead to overuse of antimalarials and undertreat other causes of fever. Nevertheless, the use of malaria rapid-diagnostic kits can help to reduce over-usage of antimalarials.
- Compassionate Use Treatment
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Compassionate use or experimental treatments for cerebral malaria may include investigational drugs and therapies used when standard treatments have failed. Some of the off-label or experimental treatments include:
1. **Artemisinin-Based Compounds**: Artesunate, an artemisinin derivative, is often used off-label in severe cases, including cerebral malaria, due to its rapid action against the malaria parasite.
2. **Intravenous (IV) Artesunate**: This is the preferred treatment for severe malaria, including cerebral malaria, and is often used under compassionate use protocols where it is not yet approved.
3. **Adjunctive Therapies**: Medications like statins, erythropoietin, or citicoline have been investigated for their potential neuroprotective effects, though not yet standard practice.
4. **Immunomodulatory Agents**: Drugs like dexamethasone or other corticosteroids have been explored for mitigating brain inflammation, although their effectiveness remains controversial.
5. **Anti-Malarial Drugs Combination**: Combining existing antimalarials such as quinine with other therapies under study.
These treatments are subject to ongoing research, and their use is determined on a case-by-case basis, often in clinical settings or under special regulatory frameworks. - Lifestyle Recommendations
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Cerebral malaria is a severe, potentially fatal complication of malaria that affects the brain. It is essential to seek immediate medical attention if suspected. While lifestyle changes alone cannot treat cerebral malaria, preventive measures can reduce the risk of contracting malaria.
1. **Prevent Mosquito Bites**:
- Use insect repellent containing DEET or picaridin.
- Wear long-sleeved shirts and long pants, especially during dusk and dawn when mosquitoes are most active.
- Sleep under insecticide-treated bed nets.
2. **Travel Precautions**:
- When traveling to malaria-endemic areas, take prophylactic antimalarial medications as prescribed by a healthcare provider.
- Be aware of malaria symptoms and seek prompt medical care if symptoms develop.
3. **Environmental Control**:
- Eliminate standing water around living areas to reduce mosquito breeding sites.
- Use screens on windows and doors to keep mosquitoes out of living spaces.
Following these recommendations can significantly minimize the risk of malaria and its severe complications, including cerebral malaria. - Medication
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Malaria parasites contain apicoplasts, organelles related to the plastids found in plants, complete with their own genomes. These apicoplasts are thought to have originated through the endosymbiosis of algae and play a crucial role in various aspects of parasite metabolism, such as fatty acid biosynthesis. Over 400 proteins have been found to be produced by apicoplasts and these are now being investigated as possible targets for novel antimalarial drugs.With the onset of drug-resistant Plasmodium parasites, new strategies are being developed to combat the widespread disease. One such approach lies in the introduction of synthetic pyridoxal-amino acid adducts, which are taken up by the parasite and ultimately interfere with its ability to create several essential B vitamins. Antimalarial drugs using synthetic metal-based complexes are attracting research interest.
(+)-SJ733: Part of a wider class of experimental drugs called spiroindolone. It inhibits the ATP4 protein of infected red blood cells that cause the cells to shrink and become rigid like the aging cells. This triggers the immune system to eliminate the infected cells from the system as demonstrated in a mouse model. As of 2014, a Phase 1 clinical trial to assess the safety profile in human is planned by the Howard Hughes Medical Institute.
NITD246 and NITD609: Also belonged to the class of spiroindolone and target the ATP4 protein.On the basis of molecular docking outcomes, compounds 3j, 4b, 4h, 4m were exhibited selectivity towards PfLDH. The post docking analysis displayed stable dynamic behavior of all the selected compounds compared to Chloroquine. The end state thermodynamics analysis stated 3j compound as a selective and potent PfLDH inhibitor. - Repurposable Drugs
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Repurposable drugs for cerebral malaria include:
1. **Artemisinin and its Derivatives**: These include artesunate and artemether, which are frontline treatments but can also be used in severe cases like cerebral malaria.
2. **Quinine**: An older antimalarial drug that can be used intravenously for severe and cerebral malaria when artemisinin is not available.
3. **Doxycycline and Clindamycin**: These antibiotics are often used in combination with quinine to enhance treatment efficacy.
Combining these drugs with the standard treatment regimens can improve outcomes, but always under strict medical supervision due to potential side effects and drug interactions. - Metabolites
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Cerebral malaria is a severe neurological complication of infection with Plasmodium falciparum. The primary metabolites involved in the pathophysiology include:
1. **Lactate**: Elevated levels due to anaerobic glycolysis as a result of impaired oxygen delivery.
2. **Nitric Oxide (NO)**: Overproduction can lead to vasodilation and contribute to cerebral edema.
3. **Pro-inflammatory Cytokines**: Such as TNF-α, IL-1, and IFN-γ, which can disrupt the blood-brain barrier and promote inflammation.
4. **Hemozoin**: A byproduct of hemoglobin digestion by parasites, which can cause oxidative stress and damage.
These metabolites play significant roles in the development and progression of cerebral malaria, impacting the severity and outcomes of the disease. - Nutraceuticals
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Nutraceutical interventions for cerebral malaria are not well-documented and are not considered a primary treatment. Cerebral malaria is a severe neurological complication of infection with the Plasmodium falciparum parasite and requires prompt medical treatment, typically with antimalarial drugs such as artesunate or quinine. Nutraceuticals (foods or food products that provide medical or health benefits, including the prevention and treatment of disease) might be used as supportive care to improve overall health and recovery but are not replacements for medical treatment.
Regarding nanotechnology, research is ongoing into the use of nanoparticles for the targeted delivery of antimalarial drugs to improve efficacy and reduce side effects. Some studies suggest that nanoparticles can enhance the delivery and effectiveness of drugs like artemisinin and chloroquine. However, this is still an emerging field and not yet a widely available or standard treatment option for cerebral malaria. - Peptides
- Cerebral malaria is a severe neurological complication of infection with Plasmodium falciparum. Peptides and nanoparticles (nan) have been explored in research for diagnostic and therapeutic purposes in this context. Certain peptides are being investigated for their ability to inhibit parasite adhesion to endothelial cells, potentially reducing disease severity. Nanoparticles have been studied for delivering antimalarial drugs more efficiently to the brain, offering a targeted approach to treat cerebral malaria while minimizing systemic side effects.