SUMMARY

A review of old and new pathogenetic hypothesis is presented with criticism in the case of the sludge theory and the permeability hypothesis. The hypothesis of cytoadherence is supported and complimented by the concept of cytokine secretion and host-disease interaction. Although some of the view expressed (use of dexameyhazone and quinine) are not universally accepted, the article offers a modern view on this complex matter.

RESUME

Les anciennes et nouvelles hypotheses concernant la pathogenese du paludisme sont presentees et la theorie de l’agglutination et de la permeabilite discutee. L’hypothese de la cytoadherence repose sur le concept de la secretion de cytokine et de l’interaction hote-maladie. Bien que certains des points de vue exprimes, l’utilisation de la dexamethazone et de la quinine en particulier, ne soient pas acceptes par tous, l’article apporte un regard nouveau sur ce sujet comlexe.

Keywords : Cerebral Malaria-physiopathology

Cerebral malaria is the major expression of Plasmodium falciparum infection. It occurs only in non immune patients such as travellers, pregnant women and children. Its pathophysiology was explained during several decades by two theories, a sludging theory and a permeability hypothesis.

The sludging theory was based on pathological observations with a high concentration of parasitized erythrocytes in cerebral capillaries. Gaskell & Millar suggested on these data that the flow was significantly reduced by parasitized cells ahich induced a sequestration. This hypothesis was further ctiticized with three arguments. First, sequestration was ovserved elsewhere in arterial and capillary venule, second anoxic changes were inconstantly observed on histological samples, third sequestration was never observed with P. vivax which induced large trophozoites and schizontes.

The permeability hypothesis was based on experiment of Maigraith & Fletcher. The essential observation was an increase in blood brain barrier permeability to l-labelled albumin in rhesus monkey infected with P. knowlesi. This increase in permeability was further reversed rapidly by hydrocortisone. In this theory, there was a sequence orevents: increase permeability, leakage of plasma, and cerebral oedema. Following these data corticosteroids were widely used in cerebral malaria.

As with the sludging theory, this last hypothesis can be criticized in several ways:

-First, Warrell and his team have clearly demonstrated that dexamethasone was deleterous in several falciparum malaria. In a double blind controlled trial with dexamethasone or pacebo, coma was significantly prolonged in the corticosteroid group (1).

-Second, many studies carried out in. Africa have shown that cerebrospinal fluid pressure was not significantly increased in cerebral malaria.

-Third, cerebral tomodensitometry studies have never observed features of brain oedema in cerebral malaria.

After the forsaking of these two theories, a new conception in the pathophysiology was bornthese last years. With Hommel, we can consider that cerebral malaria implicates a cascade of events including a parasite cytoadherence, enhance cytokines secretion and a background where parasitic and host factors play an important role (2).

Cytoadherence was the result of rosetting, « knob » formation and attachment of infected erythroctes to specific endothelial receptors. Rosetting is a phenomenon where parasitized red cells agglutinate around normal red cells. This complex of red cells induce sequestration in deep capillaries. The second partner in cytoadherence is the presence of red cells of protusuion, so called ‘knobs’. These knobs contain specific falciparum antigents such as histidin rich protein and RESA protein. These knobs are essential for cytoadherence and facilitate the attachment of the red cell to the vascular endothelial cell. The last partner implicated in cytoadherence is represented by specific endothelial receptors: ICAM-1, CD-36 protein, VCAM-1, E-selection and thrombospondin. Infected red cell were attached by ligands to these specific endothelial receptors.

The second event involved in cerebral malaria is a cytokine secretion. All has begun with Clark’s experiment where TNF infected to mice induced the same disorders than in cerebral malaria (3). After this study it seems that TFN could be involved in the pathogenesis of fever, hypoglycemia and pulmonary oedema. Furthermore, Kwiatowski has showed that the severity of falciparum malaria was strongly correlated with TNF level (4). In fact, TNF was not the only one cytokine involved in the pathophysiology of cerebral malaria. Gamma interferon, IL-1, GMCSF, IL-2 and IL-10 are also implicated in macrophage activation and TNF secretion.

Besides these mechanisms, the main question in cerebral malaria is why some patients did a cerebral malaria and others did not. Grau has proposed to answer this question a theory with two types of response after a falciparum infection. In the first case, T4 lymphocyte production was increased with a high TNF secretion, haemodynamic disorders and associated infections conduct to pathology and cerebral malaria. In the second case, there is a low response of T4 lymphocytes, TNF secretion was decreased and blocked by specific inhibitors. 1n this case the host was protected by genetic factors and immunity against cerebral malaria (5).

With this new approach, we should not forget that cerebral malaria is first of all a systemic disease with many clinical and biological disorders (WHO, 1990) which play an essential role in the prognosis.

Nevertheless, this conception in pathophysiology should consider new perspectives in therapy. It would be possible to block cytoadherence and sequestration by immunoadhesins and specfic monoclonal antibody towards endothelial receptors. We could also inhibate TNF secretion by monoclonal antibody against plasmodium antigens (7). In experimental data encouraging results have been obtained, unfortunately in a clinical trial, Kwiatowski obtained a significant result only on fever, but no improvement on coma recovery and death rate ( 8 ).

In conclusion, cerebral malaria is the result of a cascade of events including a red cell disease with a cytoadherence which conduct to sequestration, and an enhance cytokines secretion which is involved in visceral lesions. With the failure of immune therapy, treatment of cerebral malaria was still based on a good management: severe falciparum malaria should be early identified, effective antimalarials drugs should be early delivered with a high maintenance quinine regimen, complications should be early identified and treated, then harmful drugs corticosteroids, heparin….) should be avoided.