Pathogenesis and experimental models of cerebral malaria. Review pathogenesis, clinical features, and neurological. Malaria is a mosquitoborne infectious disease that affects humans and other animals. Cerebral malaria cm forms part of the spectrum of severe malaria, with a case fatality rate ranging from 15% in adults in southeast asia to 8. Clinical features of cerebral malaria in african children children who are admitted with cerebral malaria present with a day history of fever, anorexia, vomiting, and sometimes coughing. Cerebral malaria may be the most common nontraumatic encephalopathy in the world. Episodes of plasmodium falciparum pf caused cm may be lethal, while survivors are likely to suffer from persistent debilitating neurological deficits, especially. Frontiers pathogenesis of cerebral malariainflammation.
Recent studies have elucidated the molecular mechanisms of pathogenesis and raised possible interventions. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. Cerebral malaria cm is a severe neurological complication of malaria in humans and other hosts. The most dangerous of the plasmodia infecting humans is plasmodium falciparum.
However, in man, the role of vitamin a in malaria pathogenesis is multifaceted, and p. Good, genevieve milon malaria is a disease caused by repeated cycles of growth of the parasite plasmodium in the erythrocyte. Cerebral malaria is usually caused by plasmodium falciparum infection and is often fatal. Pathogenesis, the manner of development of a disease, for a human malaria clinical illness is a complex story that has many players, settings, and potential outcomes. There is a strong association between thrombocytopenia and outcome in malaria, suggesting a role for platelets in the pathogenesis of malaria. One of the most common central nervous system diseases in tropical countries is cerebral malaria cm. Cerebral malaria malaria site history, pathogenesis. In addition, more than 10 % of children surviving cm have neurological and longterm cognitive deficits. Cerebral malaria has few specific features, but there are differences in clinical.
Pdf despite decades of research on cerebral malaria cm there is still a paucity of knowledge about what actual causes cm and why certain. Aswillbe discussedlater, bothifnyandtnfa may play roles in dyserythropoietic anemia, and tnfa may contribute to cerebral malaria as a result of upregulation of intercellular adhesionmolecule1 icam1 in cerebral blood vessel endothelium. Interventions targeting the underlying pathophysiology of cerebral malaria may improve outcomes compared to treatment with antimalarials alone. Pathophysiology, clinical presentation and treatment of cerebral.
Interferons and interferon regulatory factors in malaria. The prertnf era to our knowledge, paul cannon was the first to argue, in 1941, that the diseases caused by malaria and bacterial infections would prove to be governed by the same pathologic principles. Immunological processes in malaria pathogenesis nature. Pathogenesis of malaria and clinically similar conditions. Antimalarial drugs like chloroquine, quinine, mefloquine and halofantrine also can cause altered behaviour, convulsions, hallucinations and even psychosis. Pathogenesis of cerebral malariainflammation and cytoadherence. Understanding the pathogenesis of cm enables design of supportive treatment, reducing neurological morbidity and. As will be discussed later, both ifn and tnfcl may play roles in dyserythropoietic anemia, and tnfa may contribute to cerebral malaria as a result of upregulation of intercellular adhesion molecule1 icam1 in cerebral blood vessel endothelium. Infection with plasmodium falciparum can cause severe disease in the non immune individual.
The changing views on childhood cerebral malaria are. Cytokines and chemokines in cerebral malaria pathogenesis. Cerebral malaria is the most severe neurological complication of infection with plasmodium falciparumand is a major cause of acute nontraumatic encephalopathy in tropical countries panel1. Autopsy studies show that infected erythrocytes adhere to and occlude cerebral vessels and that fibrin deposition occurs. Malarial pathogenesis pfemp1 plasmodium falciparum erythrocyte membrane protein 1 adhesion protective protein produced by p. This thrombocytopenia is likely due to platelet activation possibly through an interaction. In severe cases it can cause yellow skin, seizures, coma, or death. Jul 20, 2017 cerebral malaria is among the major causes of malaria associated mortality and effective adjunctive therapeutic strategies are currently lacking.
Insights into the processes leading to cerebral malaria might identify targets for a vaccine that allows infection and the acquisition of immunity, but prevents cerebral malaria. The pathogenesis of plasmodium falciparum malaria in humans. Pathogenesis, clinical features, and neurological outcome. The pathogenesis of severe malaria therefore involves a cascading interaction between parasite and red cell membrane products, cytokines and endothelial receptors, leading to inflammation, activation of platelets, hemostasis, a procoagulant state, microcirculatory dysfunction and tissue hypoxia, resulting in various organ dysfunctions. Cytokines in the pathogenesis of and protection against.
Most of the clinical signs of this disease are caused by the parasite at stages in which it multiplies asexually in red blood cells. Even though this type of malaria is most common in children living in subsaharan africa, it should be considered in anybody with impaired consciousness that has recently travelled in a malariaendemic area. Pathophysiology, clinical presentation, and treatment of com. Summary there is now wide acceptance of the concept that the similarity between many acute infectious diseases, be they viral, bacterial, or parasitic in origin, is caused by the overproduction of inflammatory cytokines initiated when the organism interacts with the innate immune system. Even though this type of malaria is most common in children living in subsaharan africa, it should be considered in anybody with impaired consciousness that has recently travelled in a malaria endemic area. Apr 26, 2019 cerebral malaria is the most common cause of death in patients with malaria. If not properly treated, people may have recurrences of the.
This article examines the pathogenesis of cerebral malaria, an often fatal consequence of malaria resulting from the presence of p. Malaria is a disease caused by repeated cycles of growth of the parasite plasmodium in the erythrocyte. The pathogenesis of malaria is complex and most likely entails immunologic and nonimmunologic mechanisms. Infection with malaria parasites may result in a wide variety of symptoms, ranging from absent or very mild symptoms to severe disease and even death. Nov 01, 2011 malarial pathogenesis pfemp1 plasmodium falciparum erythrocyte membrane protein 1 adhesion protective protein produced by p. Cerebral malaria is a severe neuropathological complication of plasmodium falciparum infection. Angiopoietin2 levels are associated with retinopathy and predict mortality in malawian children with cerebral malaria. The pathogenesis of plasmodium falciparum malaria in. Cerebral malaria journal of neurology, neurosurgery. The pathogenesis of cerebral malaria is poorly defined and progress in understanding the condition is severely hampered by the inability to study in detail, antemortem, the parasitological and.
Interventions with rapid drug treatment for anyone with a fever will drastically reduce the burden of mortality. Malaria pathogenesis has a broad and narrow context depending on the frame of reference. This may seem simple but, in fact, is a complex answer. For fatal disease, the sequestration of pf in tissues along with upregulation of cytokines, toxic substances, and a lack of adequate, timely therapy, are key features of the process.
The pathogenic mechanisms leading to cerebral malaria. Cerebral malaria is in most cases just one of the organs affected by the disease. Pathophysiology, clinical presentation and treatment of. Cerebral malaria is the most severe pathology caused by the malaria parasite, plasmodium falciparum. Jul 29, 2014 plasma and cerebrospinal proteomes from children with cerebral malaria differ from those of children with other encephalopathies. Grau abstract malaria is possibly the most serious infectious disease of humans, infecting 510% of the worlds population, with 300600 million clinical cases and more than 2 million deaths annually. The clinical presentation and pathophysiology differs between adults and children.
Cerebral malaria cm is the most severe complication and the major cause of death. Clinical features and pathogenesis of severe malaria for many years, severe malaria was pictured as essentially two major syndromes, with relatively simple underlying pathogenic processes. Under certain circumstances plasmodium infection causes severe anemia or cerebral malaria. Immunohistochemical staining for inos and nitrotyrosine is being carried out on a range of formalin. As with any truly successful parasite, the observed outcome of evolution in malaria is the undisturbed transition from mosquito to human to mosquito with little impact on the. Symptoms usually begin ten to fifteen days after being bitten by an infected mosquito. Clinical features and pathogenesis of severe malaria. Intravenous artesunate is superior to quinine in the. Beeson2 and kevin marsh1 1centre for geographic medicine research coast, kenya medical research institute wellcome trust collaborative programme, kili. Recent experimental data and possible applications for humans jinning lou,1 ralf lucas,2 and georges e. The direct cause of coma in cerebral malaria remains obscure. Infection with plasmodium falciparum can cause severe disease in the nonimmune individual.
The basic underlying defect seems to be clogging of the cerebral micocirculation by the parasitized red cells. Pathogenesis, clinical features, and neurological outcome of. Common pathophysiological pathways include impaired microcirculation, due to sequestration of parasitized erythrocytes, systemic inflammatory responses, and endothelial activation. Malaria malaria fever is a protozoal disease caused by any one or combination of 5 species of plasmodium. Cerebral malaria is in most cases just one of the organs affected by.
These dysfunctions often lead to metabolic acidosis and localized ischemia. The main neurological features are coma, seizures, and brainstem signs. The concept of vascular occlusion leading to cm is based on the ability of mature p. Recent findings cerebral malaria and aki are serious and well recognized complications of severe malaria. Plasmodium falciparum causes malignant malaria, whereas rest of species produce benign form of. Clinical signs of acidosis carry a higher risk of death but nevertheless cm accounts for a significant proportion of malaria mortality. Dysregulation of angiopoietin1 plays a mechanistic role. Grau3 department of surgery1 and medical intensive care,2 university of geneva, ch1211 geneva 14, switzerland, and inserm emi 0019, ufr pharmacie, universite. Immunological processes in malaria pathogenesis louis schofield and georges e. Further definition of the phenotype of cerebral malaria would help provide insights into the pathogenesis, in particular the associations with genetic polymorphisms. Pdf pathogenesis, clinical features, and neurological. Cerebral malaria is the most important complication of falciparum malaria. Platelets have a prominent role in both immune responses and vascular obstruction. The vascular bed of every organ brain, lung, bone marrow, placenta, etc.
In adults, cerebral sequestration is correlated with coma and earlier death, and it has been suggested that microvascular obstruction is key to the pathogenesis of coma ponsford et al. Various cellular and molecular strategies allow the parasite to evade the human immune response for many cycles of parasite multiplication. In some reports, cm accounts for up to 10% of all cases of plasmodium. Malaria is a major cause of morbidity and mortality in the developing world and cerebral malaria is responsible for the majority of malariaassociated deaths. The malariaspecific protection conferred by heterozygous carriage hbas, is well established for clinical attacks and even stronger for cerebral malaria and severe malarial anemia. Pdf cerebral malaria is the most severe pathology caused by the malaria parasite, plasmodium falciparum. Clinical features and pathogenesis of severe malaria claire l. Pathophysiology, clinical presentation, and treatment of.
In general, it is now accepted that severe malaria is the consequence of alterations in many tissues and organs. However, its pathophysiology is not completely understood. The role of platelets in the pathogenesis of cerebral malaria. All patients with plasmodium falciparum malaria with neurologic manifestations of any degree should be urgently treated as cases of cerebral. The pathogenesis of cm involves vascular inflammation, immune stimulation, and obstruction of cerebral capillaries. Pathogenesis of severe malaria the infection of the red cells by malaria parasites, particularly p. Later that decade, brian maegraith, quoting cannon, reasoned that a range of infectious agents, including plasmodium, probably all caused disease by generating acute general inflammation.
Pathogenesis of cerebral malaria nejm journal watch. Even though this type of malaria is most common in children living in subsaharan africa, it should be considered in anybody with impaired consciousness. Cerebral malaria is the most severe neurological complication of infection with. Performance of malaria rapid diagnostic tests as part of routine malaria case management in kenya. Cerebral malaria is the most severe neurological complication of plasmodium falciparum malaria.
Frontiers pathogenesis of cerebral malariainflammation and. Hypoglycemia, either due to severe malaria or due to drugs like quinine. Plasmodium falciparum causes malignant malaria, whereas rest of species produce benign. Absence of highgrade fever and of falciparum parasitemia may suggest such a possibility. Due to delay in treatment, cerebral malaria cm remains a significant complication of plasmodium falciparum infection and is a common cause of death from malaria. It is caused by the apicomplexan parasite plasmodium, of which p. Malaria disease can be categorized as uncomplicated or severe complicated.
The pathogenesis is heterogenous and the neurological complications are often part of a multisystem dysfunction. Cytokines in the pathogenesis of and protection against malaria. Pathogenesis of cerebral malaria inflammation and cytoadherence. Despite decades of research on cerebral malaria cm there is still a paucity of knowledge about what actual causes cm and why certain people develop it.
Malaria is a common protozoan infection that is responsible for enormous worldwide mortality and economic burden on the society. Its asexual replication in the red blood cells rbc. A multidisciplinary and crossgeographical approach. Malaria is a devastating infectious disease with an estimated 207 million cases and 627,000 deaths, mainly in children under 5 years of age in subsaharan africa, in 2012 world health organization, 20. This is also true of certain noninfectious states, such as the tissue injury syndromes.
Sequestration of infected erythrocytes within cerebral blood vessels seems to be an essential component of the pathogenesis. In general, malaria is a curable disease if diagnosed and treated promptly and correctly. Recent experimental data and possible applications for humans. Withrespect to tnfaproduction, tcellswhether they express 1ys 3 or. Jan, 2014 to clarify the pathogenesis of cerebral malaria, investigators analyzed recent studies and noted the following. A ll the manifestations of malarial illness are caused by the infection of the red blood cells by the asexual forms of the malaria parasite and the involvement of the red cells makes malaria a potentially multisystem disease, as every organ of the body is reached by the blood. The main cause of coma is not known, and besides obstruction, a range of other mechanisms have been postulated. Cerebral malaria is a leading cause of global morbidity and mortality. Pdf pathogenesis of cerebral malariainflammation and. Brain swelling and death in children with cerebral malaria. The symptoms of cerebral malaria are similar to those of toxic encephalopathy. Microvascular leak plays an important role in the pathogenesis of cerebral malaria.
The malaria specific protection conferred by heterozygous carriage hbas, is well established for clinical attacks and even stronger for cerebral malaria and severe malarial anemia. Central pathophysiological processes involved in the development of cerebral malaria include an imbalance of pro and antiinflammatory responses to plasmodium infection, endothelial cell activation, and loss of bloodbrain barrier integrity. Two central concepts to explain cm pathogenesis have evolved and they are likely mutually dependent the vascular occlusion hypothesis and the inflammation hypothesis storm and craig, 2014. Cerebral malaria clinical manifestations and pathogenesis. A compromised microcirculation, with sequestration of parasitized erythrocytes, is central in the pathogenesis.