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At least 19 recordsLinked to original sources
PubMed1986

Characterisation of the host response to Plasmodium falciparum infection. I. Cerebral malaria.

Cerebral malaria is a major form of complicated malaria consequent upon cerebral damage associated with endothelial cell necrosis. We have used assays of Plasmodium falciparum growth inhibition in vitro to study serum inhibitory factors in patients with cerebral malaria. Serum from children with cerebral malaria inhibited parasite growth in a non-synchronised 72-hour assay to a greater extent than did sera from immune adults or asymptomatic children (p less than 0.001). The high level of non-specific inhibition of parasite growth was particularly evident when sera were tested against three P. falciparum isolates, and contrasted with the inhibitory effect of sera from non-malaria febrile controls. In this study, serum from patients with cerebral malaria was more inhibitory than serum from the other groups (p less than 0.001) and its between-isolate variation, when tested against a panel of P. falciparum isolates in growth assays, was significantly less than that of the other groups tested (p less than 0.005). These results are consistent with the hypothesis of toxin-induced endothelial cell damage, with the sequence of pathogenic events involving host-derived serum factors capable of damaging P. falciparum.

Adolescent↗
PubMed2005

Pathogenesis, clinical features, and neurological outcome of cerebral malaria.

Cerebral malaria is the most severe neurological complication of Plasmodium falciparum malaria. Even though this type of malaria is most common in children living in sub-Saharan Africa, it should be considered in anybody with impaired consciousness that has recently travelled in a malaria-endemic area. Cerebral malaria has few specific features, but there are differences in clinical presentation between African children and non-immune adults. Subsequent neurological impairments are also most common and severe in children. Sequestration of infected erythrocytes within cerebral blood vessels seems to be an essential component of the pathogenesis. However, other factors such as convulsions, acidosis, or hypoglycaemia can impair consciousness. In this review, we describe the clinical features and epidemiology of cerebral malaria. We highlight recent insights provided by ex-vivo work on sequestration and examination of pathological specimens. We also summarise recent studies of persisting neurocognitive impairments in children who survive cerebral malaria and suggest areas for further research.

Age Factors↗
PubMed1995

In vivo sequestration of Plasmodium falciparum-infected human erythrocytes: a severe combined immunodeficiency mouse model for cerebral malaria.

Cerebral malaria is a fatal complication of infection by Plasmodium falciparum in man. The neurological symptoms that characterize this form of malarial disease are accompanied by the adhesion of infected erythrocytes to the vasculature of the brain. To study this phenomenon in vivo, an acute phase severe combined immunodeficiency (SCID) mouse model was developed in which sequestration of P. falciparum-infected human erythrocytes took place. During acute cerebral malaria in humans, the expression of intercellular adhesion molecule-1 (ICAM-1) is induced in vascular endothelium by inflammatory reactions. Acute phase ICAM-1 expression can also be obtained in SCID mice. The endothelium of the midbrain region was the most responsive to such inflammatory stimulus. It is noteworthy that the reticular formation in the midbrain controls the level of consciousness, and loss of consciousness is a symptom of cerebral malaria. We found that infected human erythrocytes were retained 24 times more than normal erythrocytes in ICAM-1-positive mouse brain. Sequestration to the brain was reduced by anti-ICAM-1 antibodies. These in vivo results were confirmed by the binding of P. falciparum-infected erythrocytes to the ICAM-1-positive endothelium in tissue sections of mouse brain. We conclude that the SCID mouse serves as a versatile in vivo model that allows the study of P. falciparum-infected erythrocyte adhesion as it occurs in human cerebral malaria. Upregulation of ICAM-1 expression in the region of the midbrain correlates with increased retention of malaria-infected erythrocytes and with the symptoms of cerebral malaria.

Animals↗
PubMed2006

Adjuvant therapy in cerebral malaria.

Cerebral malaria is the most common cause of non-traumatic encephalopathy in the world. The mainstay of therapy is either quinine or artemisinin, both of which are effective antimalarials. The clinical picture of cerebral malaria may persist or even become worse in spite of the clearance of parasites from blood. The death rate is unacceptably high even with effective antimalarials in tertiary care hospitals. The mortality increases in presence of multi organ failure (renal failure, jaundice, respiratory distress, severe anaemia, lactic acidosis, etc.). The pathogenesis of cerebral malaria is multifactorial and includes clogging, sequestration, rosette formation, release of cytokines, cerebral oedema, increased intracranial hypertension, etc. Attempts are made to use adjuvant therapy which will act through alternate mechanisms and address one or more of the pathogenetic processes. In this review, we have discussed the role of corticosteroids, pentoxifylline, desferrioxamine, mannitol and newer agents in the treatment of cerebral malaria. Though the literature on adjuvant therapy in cerebral malaria is large enough, there are a number of shortcomings in the clinical trials, many being open and non randomized or of very small sample size. Further research is of utmost importance through large multicentric, double-blind controlled trials to show the efficacy of any of these drugs.

Adrenal Cortex Hormones↗
PubMed1992

Overview: pathophysiology and management of cerebral malaria.

Cerebral malaria is still a major cause of death in patients suffering from malaria. Much of the research work in the past two decades has been done to clarify the pathophysiology of cerebral malaria which hopes to improve the management of the disease and concomitantly reduce mortality. However, the pathogenesis of cerebral malaria is still not clear. The pathophysiology of coma is believed to be brain anoxia from ischemia due to sequestration of erythrocytes containing mature parasites in cerebral capillaries and venules. Three possible mechanisms of sequestration (cytoadherence, rosette formation and decreased deformability of the infected erythrocytes) are postulated. The management of cerebral malaria includes early diagnosis and early treatment with potent antimalarial drugs, early detection and treatment of complications, correction of fluid and electrolyte imbalance and proper nursing care. In spite of these efforts, a high mortality rate (ranging 10-40%) is still encountered.

Antimalarials↗
PubMed2006

Perforin mediated apoptosis of cerebral microvascular endothelial cells during experimental cerebral malaria.

Cerebral malaria is a serious complication of Plasmodium falciparum infection. We have investigated the role of perforin in the pathogenesis of cerebral malaria in a murine model (Plasmodium berghei ANKA (PbA) infection). C57BL/6 mice demonstrated the typical neuropathological symptoms of experimental cerebral malaria infection from day 5p.i. and became moribund on day 6p.i. This pathology was not seen in PbA-infected, perforin-deficient (pfp-/-) mice. From days 5-6p.i. onwards there was a significant increase in mRNA for granzyme B and CD8, but not CD4, in brain tissue from PbA-infected C57BL/6 and pfp-/- mouse brains. Perforin mRNA was strongly increased in the brains of PbA-infected C57BL/6 mice on day 6p.i. Immunohistochemistry revealed increased perforin staining and elevated numbers of CD8(+) cells within the cerebral microvessels in PbA-infected C57BL/6 at days 5 and 6p.i. compared with uninfected animals. At day 6p.i., there were TUNEL-positive cells and activated caspase-3 positive cells of endothelial morphology in the CNS of PbA-infected C57BL/6 mice. The TUNEL-positive cells were greatly reduced in pfp-/- mice. These results suggest that CD8(+)T lymphocytes induce apoptosis of endothelial cells via a perforin-dependent process, contributing to the fatal pathogenic process in murine cerebral malaria.

Animals↗
PubMed2000

Cerebral malaria.

Cerebral malaria is a rapidly progressive potentially fatal complication of Plasmodium falciparum infection. It is characterized by unarousable and persistent coma along with symmetrical motor signs. Children, pregnant women and non-immune adults are more susceptible to have cerebral malaria. Several clinical, histopathological and laboratory studies have suggested that cytoadherence of parasitized erythrocytes (mechanical hypothesis), and neuronal injury by malarial toxin and excessive cytokine (e.g. tissue necrosis factor-alpha) production (cytotoxic hypothesis) are possible pathogenic mechanisms. Several associated systemic complications like hypoglycemia, hypovolemia, hyperpyrexia, renal failure, bleeding disorders, anemia, lactic acidosis and pulmonary oedema may contribute in the pathogenesis of coma, and are responsible for high mortality. The meticulous supportive care along with intravenous administration of antimalarial drugs are corner-stone of the treatment. Quinine is currently, drug of choice. Artimisinin derivatives are equally effective and can be used by intramuscular route. In severe cases exchange blood transfusion may be an effective alternative. Corticosteroids has no place in the management of cerebral malaria. The occurrence of convulsions are common in children, these can be prevented with the use of single intramuscular administration of phenobarbitone. Despite advances in the management mortality and morbidity have not changed much. A large number of surviving patients are left with permanent neurological sequelae. There is a need to search for effective malaria prevention and interventional strategies to avert high mortality and morbidity associated with cerebral malaria.

Adult↗
PubMedDate not supplied

Macrophages/microglial cells in patients with cerebral malaria.

Cerebral malaria is a life threatening sequel of Plasmodium falciparum infection and contributes significantly to malaria mortality, especially among children. Accumulation of macrophages and proliferation of microglial cells play key roles in cerebral malaria and are thought to contribute to the pathophysiological alterations observed in these patients, which include enhanced adherence of infected erythrocytes to the cerebral vasculature by expression and secretion of proinflammatory molecules, disruption of the blood-brain barrier, recruitment of other inflammatory cells to the lesion site. In this review, recent advances in the understanding of the involvement of macrophages/microglial cells in the development of cerebral malaria are summarized.

Blood-Brain Barrier↗
PubMed2002

Breaking down the blood-brain barrier: signaling a path to cerebral malaria?

Cerebral malaria is a major killer in the developing world, but we still know very little about the causes of this disease. How does Plasmodium falciparum cause such a devastating neurological disease while it is in the brain vasculature? Why do some patients die, whereas others survive? What processes contribute to disease in the brain, and can we reverse them? Here, the latest evidence from post-mortem, in vitro and animal studies is reviewed to highlight the role of blood-brain barrier breakdown in cerebral malaria. Blood-brain barrier integrity is disturbed during severe malaria, causing leakage of cerebral vessels. Understanding how this happens and how it contributes to the pathogenesis of coma may provide new opportunities for the treatment of cerebral malaria.

Animals↗
PubMed2005

[Imported cerebral malaria].

Cerebral malaria is one of the most serious complications of Plasmodium falciparum infection. Its diagnosis may sometimes be difficult. We report the case of a 63-year-old woman who presented with abdominal pain and nausea, rapidly followed by delirium and stupor, a few days after a travel in Africa. No prophylactic measures were prescribed. The main clinical features concerning cerebral malaria, diagnostic tools and therapeutic measures are discussed.

Adult↗
PubMed2004

Cyclooxygenase-2 in the pathogenesis of murine cerebral malaria.

Cerebral malaria (CM) is a severe complication of malaria, in which cytokine production can produce immunopathological consequences. Cytokines can up-regulate prostaglandin synthesis via an increase in cyclooxygenase (COX) enzyme activity. We investigated the expression of COX enzymes, COX-1 and COX-2, in the brain by use of murine models of CM and of malaria without cerebral involvement. Although COX-1 mRNA was induced in the brain in both models of malaria, COX-2 mRNA was induced specifically in CM. Inhibition of COX-2 with celecoxib resulted in an earlier onset of CM. Treatment with celecoxib did not alter the outcome of malaria infection without cerebral involvement. These data suggest that induction of COX-2 expression and prostaglandin synthesis may have a protective effect in CM.

Animals↗
PubMed2002

On the pathogenic role of brain-sequestered alphabeta CD8+ T cells in experimental cerebral malaria.

Cerebral malaria (CM) develops in a small proportion of persons infected with Plasmodium falciparum and accounts for a substantial proportion of the mortality due to this parasite. The actual pathogenic mechanisms are still poorly understood, and in humans investigations of experimental CM are unethical. Using an established Plasmodium berghei-mouse CM model, we have investigated the role of host immune cells at the pathological site, the brain. We report in this study the detailed quantification and characterization of cells, which migrated and sequestered to the brain of mice with CM. We demonstrated that CD8(+) alphabeta T cells, which sequester in the brain at the time when neurological symptoms appear, were responsible for CM mortality. These observations suggest a mechanism which unifies disparate observations in humans.

Animals↗
PubMed2005

Diffusion-weighted imaging of cerebral malaria.

Cerebral malaria occurs in 2% of patients infected by Plasmodium falciparum. Magnetic resonance imaging findings of small white matter infarcts due to cerebral malaria have been previously reported, however nonspecific. Since diffusion-weighted imaging can differentiate acute embolic infarcts from other chronic or nonspecific white matter lesions, it may aid diagnosis of this illness in patients who travel to endemic areas.

Aged↗
PubMed2002

The efficacy of artemether versus quinine in the treatment of cerebral malaria.

Cerebral malaria remains a major cause of childhood morbidity. Quinine is the drug of choice for which resistance is now emerging. A total of 77 children admitted to Khartoum Children Emergency Hospital who conform to WHO criteria of cerebral malaria were randomly allocated to receive either artemether (1.6 mg/kg body wt., repeated after 12 hrs and then daily for four days) or quinine (10 mg/kg body wt in 10 ml/kg body wt of 5% dextrose in 0.9% saline intravenously. Repeated every 8 hrs and changed to oral administration when the child was able to drink to finish seven days). Response to therapy was evaluated using fever clearance time (FCT), time of regaining consciousness (TRC) and parasite clearance time (PCT). The FCT (mean+SD), TRC and PCT for the artemether-treated group were 32 (+13) hrs, 21 (+11) hrs and 36 (+18) hrs, respectively, while for the quinine-treated group the respective figures were 36 (+18), 26 (+15) hrs and 41 (+12) hrs. The response to artemether was slightly better than that of quinine, but the differences between the two groups were not statistically significant. The outcome in terms of cure rate, neurological sequalae and case fatality was also comparable.

Adolescent↗
PubMed2000

Cerebral malaria.

Cerebral malaria may be the most common non-traumatic encephalopathy in the world. The pathogenesis is heterogeneous and the neurological complications are often part of a multisystem dysfunction. The clinical presentation and pathophysiology differs between adults and children. Recent studies have elucidated the molecular mechanisms of pathogenesis and raised possible interventions. Antimalarial drugs, however, remain the only intervention that unequivocally affects outcome, although increasing resistance to the established antimalarial drugs is of grave concern. Artemisinin derivatives have made an impact on treatment, but other drugs may be required. With appropriate antimalarial drugs, the prognosis of cerebral malaria often depends on the management of other complications-for example, renal failure and acidosis. Neurological sequelae are increasingly recognised, but further research on the pathogenesis of coma and neurological damage is required to develop other ancillary treatments.

Adult↗
PubMed1992

Cerebral malaria.

Cerebral malaria is the most important manifestation of severe Plasmodium falciparum infection. The clinical picture in South East Asian adults differs from that in African children. The children are more likely to have abnormal brain stem reflexes, signs suggestive of cerebral herniation, and raised CSF opening pressure, and to suffer persistent neurological sequelae. The mortality remains high at about 20%. The diagnosis must be considered in all patients with fever and impaired consciousness who may have been exposed to the infection. The pathophysiology of cerebral malaria may involve mechanical obstruction of the cerebral circulation by parasitized erythrocytes which have adhered to the vascular endothelium. Cytokines such as tumor necrosis factor may also contribute. The most important element of treatment is early, optimal chemotherapy with quinine, but artemisinine derivatives may prove even more effective.

Adult↗
PubMed2005

Reduced cerebral blood flow and N-acetyl aspartate in a murine model of cerebral malaria.

Cerebral malaria is an important cause of morbidity and mortality in many parts of the world. It has been suggested that cerebral malaria is associated with reduced perfusion due to the blockage of blood vessels by parasitized erythrocytes; although, no quantitative validation of this has been done. We infected C57BL/6 mice with the ANKA strain of Plasmodium berghei and on day 6 of infection we investigated alterations in brain function using arterial spin labeling MRI and proton MRS. MR images did not demonstrate signs of damage. However, there was a significant reduction in cerebral blood flow (P<0.012) and the ratio of N-acetyl-aspartate (NAA) to creatine (Cr) (P<0.01) relative to non-infected mice. The NAA/Cr ratios were significantly correlated with cerebral perfusion (r=0.87) suggesting a relationship between impaired oxygen delivery and neuronal dysfunction. Pathological examination revealed accumulations of damaged axons providing a correlate for the decreased NAA/Cr ratio in infected mice. This murine model will permit non-invasive studies of neurologic function during malarial infection.

Animals↗
PubMed2006

A role for Fas-Fas ligand interactions during the late-stage neuropathological processes of experimental cerebral malaria.

Cerebral malaria (CM) kills more than 1 million children each year. Using a murine model of CM, we investigated the role of Fas-Fas ligand interactions in the neuropathogenesis of this disease. Lpr and Gld mice, deficient in Fas and Fas ligand, respectively, were protected from fatal CM, although they demonstrated some pathological features associated with CM in the wild type mouse. Fas-Fas ligand mRNA and protein expression were increased in the brain in mice with CM, and activated caspase-3-positive apoptotic astrocytes were observed. We suggest that Fas-mediated apoptosis of astrocytes is likely to be a critical factor in late-stage murine CM pathogenesis.

Animals↗