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African Journal of Neurological Sciences
Pan African Association of Neurological Sciences
ISSN: 1015-8618
Vol. 17, Num. 1, 1998
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The African Journal of Neurological Sciences Vol 14
No
The African Journal of Neurological Sciences Vol 17 No.1,
1998
The physiopathology of cerebral malaria
TOUZE J.E., VAN de WALLE J.P., FOURCADE I., MAFART B.,
LAROCHE R.
Tropical Medical Institute for French Army, Marseille,
France
Code Number: NS98002
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.
KEY WORDS: 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.
References
1. WARRELL.DA, LOORASEESUWAN. S, WARRELL. M.J et al.
Dexamethasone proves deleterous in cerebral malaria. A double blind
trial in 100 comatose patients. New. Engl,Med.J 1982; 306:313-9
2. HOMMEL.B.M.Amplification of cytoadherence in cerebral
malaria. Towards a more rational explanation of disease
pathophysiology Ann. Trop. Med.Parasito11993; 87:627-35
3. CLARK.I.A., CHAUDHRI. G. COWDEN. W.D. Role of Tumor necrosis
factor in the illness and pathology of malaria. Trans. Roy.
Soc.Med. Trop.Hyg 1989; 83:436-440
4. KWAITOWSKI. D. HILL. A.V.S. SAMBU.I et al. TFN concentration
in fatal cerebral, non fatal cerebral and uncomplicated Plasmodium
falciparum malaria; Lancet 1990; 336:1201-4
5. GRAU G.E. PIGUET.P.F.VASSALLI.P.LAMBERT.P.H Tumor necrosis
factor and other cytokines in cerebral malaria: experimental and
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6. WHO. Severe and complicated malaria.Trans. Roy. Soc.Med.Trop.
Hyg 1990; 84 (suppl 2):1-65
7. SCHOFIELD.L, VIVAS.L, HACKETT et al. Neutralizing monoclonal
antibodies to glycosyl phosphatidyl inositol, the dominant TNF
inducing toxin of Plasmodium falciparum: prospects for the
immunotherapy of severe malaria Annals. Trop. Med.Parasitology
1993; 87:617-26
8. KWIATOWSKI.D, MOLYNEUX.M.E, STEPHEN .S. et al. Anti TNF
therapy inhibits fever in cerebral malaria. Quartely..l.Med. 1993;
86:91-8
Copyright 1995 Pan African Association of Neurological
Sciences
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