SUMMARY

Celebral Malaria is the most important course of P.falciparum infection with mortality rates of up to 50%. The clinical criteria consist of unarousable coma, exclusion of other encephalopathies and the confirmation of P.falciparum infection. Beside unarousable coma in up to 80% epileptic seizures are observed in cerebral malaria. Frequently other organs are involved parallel dysfunction. The golden standard of therapy for severe P.falciparum malaria, incl. cerebral malaria, is intravenous quinine dihydrochloride. Although anticonvulsive therapy is recommended, there is no real scientific proof that such therapy in cerebral malaria given prophylactically will improve the outcome. The same applies to low molecular weight dextrane, full scale heparinisation or dexamethasone, pentoxifylline, given as adjuctive therapy, possibly provides a therapeutic value in cerebral malaria.

Besides the mortality rate, neurological sequelae until recently often denied, can occur on average in up to 7% of patients with cerebral malaria, protracted convulsions prolonged coma and severe anemia being frequently associated with the development of neurological sequelae.

Keywords : Cerebral Malaria, diagnosis clinical features

RESUME

La paludisme cerebral est la plus importante complication de l’infection a P. Fqfciparum. Sa mortalite depasse 50%. Les criteres cliniques reposent sur un coma profond, l’elimination d’autres encephalopathies et la confirmation de l’infection

Par P. falciparum. Au cours du coma, on observe don 80% des cas des crises d’epilepsie. D’autres organes sont consrnes en fonction de l’atteinte cerebrale. La regle d’or du traitement du paludisme a P. falciparum et du paludisme cerebral est le dihydrochloride de quinine intaveineux. Bien que le traitement anticonvulsif soit recommended il n’y a pas de preuve scientifique que dans ce cas un tel traitement soit benefique. Il en va de meme pour la dextrane de faible poids moleculaire, l’heparinisation a dose elevee ou la dexamethasone. La pentoxifylline en traitement d’appoint du paludisme cerebral presenterait un certain interet. En plus de la mortalite des sequelles neurologiques souvent contestees encore recemment peuvent apparaitre. 7% des patients atteints de paludisme cerebral avec coma profond, convulsions prolongees et une anemic importante sont frequemment atteints de sequelles neurologiques.

INTRODUCTION

Malaria represents the leading parasitic disease in today’s world (1). Half of the population of the globe is at risk to malaria and the infected population may exceed 300 million (2). Per year more than one million die from malaria, most of them from cerebral manifestation (3). Cerebral malaria (C.M.) is the most important course of Plasmodium falciparum infection with mortality rates of up to 50% (4-6).

However it is not merely a disease of tropical countries, it is seen in all its clinical aspects in all parts of the world, frequently taking a more serious course in northern countries due to delay of diagnosis and specific therapy (7,8).

DEFINITION

Celebral malaria is an acute febrile and mainly diffuse encephalopathy, occurring in a patient infected with Plasmodium falciparum (9).

The World Health Organisation Malaria Action Programme proposed three criteria for the diagnosis of cerebral malaria:

• unarousable come (motor response to noxious stiumuli in non localizing or absent)
• exclusion of other encephalopathies
• confirmation of Plasmodium infection. Asexual forms of P. falciparum must be demonstrated in peripheral blood smear or bone marrow smear during life or in a brain smear after death (10).

There is frequently severely impaired function of other organs. Parameters with indirect influence onto the brain function are:

Metabolic, circulatory functions may be severly disturbed, additionally there might be acute pulmonary edema and hematological dysfuntion as well as severe impairment of coagulation (11-14).

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS OF CEREBRAL MALARIA

Cerebral malaria is the most severe and common complication affecting up to 7% of all P. falciparum malaria cases (3,5,6, 15). Twenty to fifty percent of deaths from P. falciparum malaria are reported to be due to the involvement of the central nervous system (3,5, 15). In non-immune individuals C.M. occurs at all ages, but in holoendemic areas it mainly strikes children less than five years old, the peak frequency being between the second and third year of age (3-6). A seasonal distribution of C.M. can be observed, in particular in rural tropical areas with a clear peak in incidence at the end of the rainy season (3-6).

Incubation Period.

Incubation period, or the interval between the infecting mosquito bite and the elevation of temperature above 37.8, is 11-14 days in P. falciparum infection. It correlates directly with the primary hepatic phase of the infection following sporozoite invasion of the hepatic cells. However, the incubation period is quite variable, depending on the infecting parasite strain, the type, dose and frequency of any chemoprophylactic agents taken by the patient and the type of exposure to malaria (mosquito, transfusion, congenital). Initial attacks of P. falciparum may be suppressed for weeks to months (16). During 1980 and 1981 the interval between entry into the United States and onset of P. falciparum disease exceeded 1 month in one quarter of the patients (17). Incubation periods have also varied widely in reported cases of transfusion malaria ranging from 4.to 17 days (18). In congenial malaria the onset of symptoms usually occurs 3 to 8 weeks after birth (16).

Presenting Features:

Prodome:

Initially patients often complain of unspecific symptoms, even days before the onset of the paroxysm: malaise, headache, myalgia and fatigue are easily mistaken for beginning viral illness (16). Children usually experience an abrupt onset, frequently with hyperpyrexia, headache, restlessness and vomiting. Within hours but sometimes much slower features of CNS involvement set in (3-6, 16).

Paroxysms:

Characteristic malaria paroxysms have 3 stages

• rigor and chill
• highly elevated body temparature (<40 C)
• defervescence – profuse sweating.

Duration of paroxysms usually is 3 to 6 hours. In malignant falciparum malaria however an asynchronous cycle of parasite multiplication leads to continuous, remittent or irregular fever, typical paroxysms occurring only in a minority of patients.

Table 1: List of disease process in cerebral malaria

CNS- Involvement:

Cerebral malaria is defined as febrile and mainly diffuse encephalopathy, impairment of conciousness being a prominent feature. Unarousable coma may be preceded by severe headache, confusion, drowsiness and in many instances convulsions. It is not possible to differentiate the immediate postictal state from beginning cerebral malaria, but if coma persists for more than six hours after a convulsion in a child with P. falciparum malaria then cerebral malaria should be diagnosed (10).

Neurological signs of C .M. are those of symmetrical upper motor neuron and brain stem disturbances including dysconjugate gaze, decerebrate and decorticate postures ( 3-6, 15 ) resembling and frequently paralleling the development of midbrain syndrome (6). In a series of 66 Tanzanian children, 73% presented – at the time of admission – with unarousable coma and 15% had an organic psychosyndrome with confusion, disorientation and restlessness. Almost a quarter showed localizing signs. Two thirds of the children had generalized or – rarely – focal seizures frequently heralding the development of coma, i.e.C.M. (6). In 52 of 65 Malawian children (80%)convulsions have been observed before admission (19). In Thai patients seizures were estimated to occur in one third of the mainly adult C.M. patients (15). Meningeal irritation is rare, as are extrapyramidal or cerebellar signs (36, 15). Infrequently retinal hemorrhages and exudates are observed (20), Hyperpyrexia and splenomegaly are frequently extracranial physical findings. Less often hepatomegaly is present, frequently associated with severe anemia and high output congestive heart failure (16). In advanced disease severe anemia, icterus, renal failure, acute pulmonary oedema, heart failure, bleeding tendencies and spontaneous hemorrhages (e.g. from the upper gastrointestinal tract) and hypoglycemia complicate the course of P. falciparum (10, 21). A mainstay in diagnostic C.M. is to take careful history, in particular as to exposure of the parasite-descendance from or travelling to endemic areas as – in rare instances – transfusion of infected blood.

ROLE OF TESTING IN DIFFERENTIAL DIAGNOSIS:

The diagnosis of C.M. – principally a clinical one based on the definition excluding all other causes is deemed to be « definite » if asexual forms of P. falciparum are found in the peripheral blood smear. Thick blood films are stained with Field’s A and B stain and thin films with Leishman’s stain, Giemsa staining being equally appropriate and superior for speciation (10,22). Although a higher density of parasites appears in circulation during fever paroxysms as schizonts burst and release merozoites it is important that blood films are obtained several times daily and for several days to establish the diagnosis in patients with low density infections, which do not preclude cerebral involvement (10,16,22). Mixed infections can occur if more than 2% of the erythrocytes are infected. P. falciparum should be suspected (22). Gametocytes of P. falciparum are distinct and crescent – shaped.

Quantification of parasitemia should be done: parasites are counted against 200 leucocytes in thick film, or as percentage of 500-red blood cells in thin film (22). While high parasite-densities can be equated with severity the reverse is not always true, particulady in non-immune individuals. Any parasitemia above 250.000/m1 or more than 5% of red cells has to be considered as medical emergency. Serum antiplasmodial antibodies (immunoglobulins A,M and G class) synthesized in P. falciparum malaria have no place in the diagnosis of cerebral malaria (23). Lumbar puncture has to be done to exclude meningitis and encephalitis, although meningeal irritation is uncommon in C.M.. Cell count and protein content in CFS is usually within normal limits as well as opening pressure, although recent reports (24) indicate that patients with poor outcome tend to have elevated opening pressure in spinal tap. The search for even more sensitivity and specificity in diagnosing life-threatening malaria has lead to the development of diagnostic DNA probes for P. falciparum (25,26). The golden standard however is still the direct parasitological diagnosis by means of blood smear examination.

NATURAL HISTORY OF SEVERE P. FALCIPARUM MALARIA

A primary attack of P. lalciparum in a non immune patient is short, severe and often fatal if not treated (approximately 25%). Up to 7% develop C.M., its mortality rate ranging from 2 to 38%, the average in 15 published series being 18.6% (282/1513) (19). If the patient survives, in an untreated infection the illness usually subsides within several weeks.

Recrudescence of latent blood stages occur for up to one year, rarely longer. Contrary to other plasmodium species, there is no latent hepatic phase in P. falciparum malaria. Neurological long term sequelae do exist, convulsions and localizing signs being the most prominent features (7%=106/1513)(9).

DISEASE SPECIFIC SEVERITY SCALES

In C .M. initial neurological findings and the degree of parasitemia determine the severity and, hence, the course of disease.

Molyneux et al adapted the Glasgow Coma scale for cerebral malaria children with a minimum of O and a maximum of 5 points (4 or less is abnormal). It uses motor and crying responses to pain and includes the ability to watch (5).

The same authors developed a bedside prognostic index based on age. coma scoring, absence of corneal reflexes. signs of decerebration, witnessed convulsions, blood-glucose, white blood cell count and parasitemia, positive predictive value for an unfavorable outcome was 83%, sensitivity was 66% (5).

The level of parasitemia parallels the severity of CNS affection as well as involvement of other organs and metabolic derangements leading to secondary affection of the central nervous system. Parasitemia in more than 5% of erythrocytes is considered a medical emergency. The parasitemia is expressed in thin films in terms of percentage of erythrocytes being parasitized. In using thick film methos that parasites are counted against 500 leucocytes (22).

ACUTE TREATMENT DECISIONS

There are a number of classes of antimalarials, each of which may have an effect on a different stage of the parasite and different species.

Table 2: Classes of antimalarials

* those which can be of use for cerebral malaria are marked with an asterix modified according to Holtmann, 1986 (27)

Adjunctive therapy:
-Exchange blood transtusion
-Anticonvulsive therapy
-Antipyretics
-Fluid and electrolyte therapy
-Treatment of complications

Anaemia

lactic acidosis

renaal failure

pulmonary oedma

Hoptension – cardiac failure

Disseminated, intravascular coagulation

gram negative septicaemia

Aspiration pneumonia

TNF synthesis inhibitors

??herapin

??low molecular weight dextran

??epinephrine

??: denotes unproven therapeutic recommendations

Table 2 denotes the classes of antimalarials with specific reference to it’s cerebral manifestations (27). Rapid reduction and clearing of parasitemia require blood schizontocidal drugs, i.e. antimalarials which are effective against the erythrocytic, asexual stage of the parasite..Antiimalarial treatment has to be initiated at the earliest possible point of disease. Intravenous quinine dihydrochloride has been and still is the golden standard of therapy for severe P. falciparum malaria inclusive C.M. (28). A loading dose of 20 mg salt/kg body weight is given over 4 hours by intravenous infusion, maintenance dosage is 10mg salt/kg body weight by i.v. infusion (2-4 hours duration at 8 hours intervals (29). At least seven days « treatment » should be completed. Where available, intensive care monitoring and appropriate nursing care are mandatory. The blood glucose concentration is checked frequently to avoid hypoglycemia. Acute renal failure prompts early dialysis; exchange blood transfusion, if considered in case of severe parasitemia, is recommended as early as possible. Convulsions, being an important cause of morbidity and mortality and being associated with poor prognosis (10,30) are to be contained as strictly as possible, however there is no real scientific proof that anticonvulsive therapy in cerebral malaria given prophylactically will improve the outcome (31 ). Neither low molecular weight dextrane, heparinization or dexamethasone have been proven efficacious in C.M. (32,33), pentoxifylline therapy, however suggests a possible therapeutic value in C.M. (34).

Outcome:

Neurological sequelae, until recently often denied (15) occur in an avarage of 7% of patients with cerebral malaria (3-6,19,30). Death rates range trom 5 to 38% with an avarage of 18,6%. Epileptic seizures, both focal and generalized, and focal neurological signs, like hemiplegia or aphasia, are most frequently observed, in few cases blindness, cerebellar ataxia and diffuse psychoorganic syndrome and even decerebrate state (35) might ensue. The development of neuroplical sequelae is associated with protracted convulsions, proplonged coma and sever anaemia (19). Some of these deficits resolved at least partially even months after the acute disease.

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.

SUMMARY

To determine the effect of the timing of scorpion sting, and that of whole blood exchange on the mortality, we studied 82 cases presenting at a rural health center in Egypt. Fourty six patients received only classic traetment, and 36 patients received the classic treatment and whole blood exchange. The mortality rate was significantly higher for early night stings and for the group treated classically. Undue visits scorpion infested areas is to be avoided in the early night period. Whole blood exchange seems beneficial as addition therapy to the classical methods. Further studies need to be done to clarify this benefit.

RESUME

82 cas de morsures de scorpion survenues dans une zone rurale du centre de l’Egypte ont ete etudies afin de determiner l’influence sur la mortalite: du moment de la morsure dans la journee et aussi de l’efficacite du traitement par transfusion de sang.

46 patients ont eu un traitement classique et 36 une transfusion. La mortalite a ete significativement plus elevee lorsque la morsure avait lieu au debut de la nuit ainsi que sur le groupe traite classiquement.

La frequentation des lieux ou il y a beaucoup de scorpions est deconseillee au debut de la nuit.

La transfusion de sang associee a la therapeutique classique parait efficace. Il faudrait entreprendre d’autres etudes pour preciser cette efficacite.

Keywords : scorpion sting, Egypt