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Objective: To identify the main causes of confirmed malaria deaths and assess the validity and the relevance of use of the MDIF in determining areas for improvement of care., Design: A cross sectional study., Setting: United Bulawayo Hospitals, a tertiary hospital in Zimbabwe., Subjects: Patients whose cause of death was malaria using MIDF., Results: Of 470 confirmed cases admitted in UBH during the study period, 53 (11.2%) died and were included in the study. Most deaths occurred in the over 15 years age group (88.6%) with only 3 deaths each in the other groups. All patients were referred or admitted to UBH with complicated and severe malaria; 39(74 %) had more than one complication such as CM and acute renal failure (ARP). Most patients came from or had visited a rural area and did not implement basic prophylactic and therapeutic measures put in place by the NMCP such as early self-medication. Three pregnant women aborted. Guidelines regarding investigations and treatment were not strictly adhered to. Delay in seeking treatment and in referring was generally observed at all levels of the health system. Cases of malaria deaths were found in the city in people who had not travelled to rural area. The MDIF was used in one case only., Conclusion: Malaria mortality accounted for 11 % of confirmed cases. Main causes of death were CM and ARP Parameters contained in the MDIF were those utilised by most authors who have investigated malaria mortality in Africa and there was a similarity in the observations. In view of the information it could provide if properly used, the MDIF is a valid tool for collecting data that the NMCP needs in order to rationalise its strategies at UBH and in other health facilities. Its use should be generalised and compulsory.

In three cases of cerebral malaria, MR imaging disclosed either cortical infarcts (one case) or hyperintense areas of white matter (two cases) on T2-weighted and fluid-attenuated inversion-recovery sequences. These white matter abnormalities were, in one case, sharply limited, symmetrical, hyperintense, and unenhanced; in the other case, they were diffuse, hyperintense, and had a more limited focus. The diffuse hyperintensity was probably due to edema, whereas focal lesions were probably associated with gliosis.

The current clinical and therapeutic aspects of cerebral malaria in non-immune adult subjects living in endemic areas of Africa were evaluated in 10 men (mean age: 40 +/- 11.4 years). On admission, 8 patients had fever, 3 were truly comatose with a Glasgow score of 7 or more. All had negative central venous pressure and only one was in a state of hyperkinetic shock. Respiratory symptoms were present in 8 cases, and jaundice was observed in 8 cases. Three patients has a haemoglobin level lower than 8 g/100 ml, and 8 had thrombocytopenia. Blood creatinine levels above 240 mumol/l and blood bilirubin levels above 50 mumol/l were found in 6 and 8 patients respectively. Plasma creatine phosphokinase was above 500 IU/l in 7 cases, and PaO2 was below 70 mmHg in 7 cases. All patients received quinine, combined with doxycycline in 6 cases. Infectious complications occurred in 5 patients, with 2 septic shocks. Two patients developed acute pulmonary oedema. Five patients died. This study shows that cerebral malaria in non-immune subjects living in endemic areas produces multivisceral deficiency similar to that observed in imported malaria. Its prognosis can be improved by loading doses of quinine and by a better prevention of nosocomial infections.

Opening lumbar cerebrospinal fluid (CSF) pressure was measured with a paediatric spinal fluid manometer in 26 of 61 Kenyan children (mean age 39 months) with cerebral malaria. In all cases pressure was above normal (mean [SD]22.6 [7.4] cm CSF, range 10.5-36). Clinical features of our patients suggest that intracranial hypertension is important in the pathogenesis of cerebral malaria in children, especially as a cause of death. We suggest that raised intracranial pressure is secondary to increased cerebral blood volume. Lowering intracranial pressure may significantly reduce the mortality and morbidity of cerebral malaria. The potential risks and benefits of lumbar puncture should be considered carefully in patients with suspected cerebral malaria.

Thirty-nine falciparum malaria autopsy cases from the Hospital for Tropical Diseases, Mahidol University, Bangkok, Thailand were divided into two groups that had had either cerebral malaria (CM) or non-cerebral malaria (NCM). We then studied significant pathological differences between these groups in order to investigate the correlation between parasitized erythrocyte (PRBC) sequestration in small blood vessels in the brain, heart, lungs and small intestines. We found that the percentage of PRBC sequestration in the organs which we studied was higher in the CM patients than in the NCM patients. The difference of PRBC sequestration among the organs of two groups was significant (P less than 0.05). In the CM group, the average percentage of PRBC sequestration in the brain was significantly higher than in the heart, lungs and small intestines (P less than 0.05). No statistically significant difference was found between PRBC sequestration in the brains, hearts, lungs and small intestines in the NCM group (P greater than 0.05). Our study indicates that severity of malaria in the CM patients depends on PRBC sequestration, especially in the brain. A combination of functional disturbances of the other organs, in addition to the cerebral pathology, may augment the severity of the disease.

From January 1987 up to April 1990, sixty two patients diagnosed as cerebral malaria were admitted to the Department of Child Health, Medical School Sam Ratulangi University, Gunung Wenang General Hospital were included in this study. They were treated with quinine dihydrochloride intravenously continued orally for a total of 7 days combined with fansidar by nasogastric tube for 2 days. All patients were also receiving intravenous fluid drips and other symptomatic treatment. They were divided into three groups. Group I received heparin 300 u/kg body weight intramuscularly once daily for 3 consecutive days; group II received dexamethasone 0.5 mg/kg body weight intravenously, three times daily for three consecutive days; group III didn't receive dexamethasone nor heparin. The mortality rate of the three group combined was 1 out of 21 patients (1.61%). In group I, all 21 patients were alive. One out of 21 patients of group II died (4.76%). In group III, all 20 patients were alive. The average period of regaining consciousness was 1.45 days in group I, 2.85 days in group II and 2.76 days in group III. There was a significant difference between group I and II, and also between group I and III. The average duration of fever was 2.60 days in group I, 2.40 days in group II and 3.69 days in group III. There was a significant difference between group I and III and also between group II and III. The average hospitalization days was 8.0 days in group I, 11.1 days in group II and 10.5 days in group III.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral malaria is a rapidly progressive encephalopathy with up to 50% mortality. A cardinal feature is the massing of red cells containing mature Plasmodium falciparum within the cerebral capillaries. Adhesion of these parasitised red cells to endothelium, an event which may initiate cerebral malaria, is being studied at the molecular level. However, the relevance of these studies to the pathophysiology and treatment of human cerebral malaria is uncertain. Although chloroquine is still widely used to treat falciparum malaria, resistance has spread to most of the endemic zone. Quinine is emerging as the only effective treatment for cerebral malaria, though resistance to this drug threatens to become a problem. Alternative drugs are urgently needed.

This study reflects the clinical pattern, diagnosis and management of cerebral malaria in 55 consecutive patients from Chittagong Hill Tracts. The predominant clinical features were: impaired consciousness with convulsion in a febrile patient with temporary residence in the endemic zone. Younger people were more prone to develop this condition. Thirty two patients (58.18%) were between 18-25 years. A high incidence of cerebral malaria was noted in blood group 'O' (37.5%) and group 'B' (33.33%). The malarial parasite count MPC was not proportional to the severity of the disease. Twenty four patients (43.63%) had malarial parasite count below 100% cumm. Anaemia (63.63%) and Jaundice (34.54%) were common, Splenomegaly (7.27%) was uncommon. Clinical features of cerebral oedema/raised intracranial pressure were not evident. CSF study was unremarkable except for raised pressure in 7 patients (12.65%). Response to intravenous quinine was satisfactory and yet the mortality was 11%.

In cerebral malaria, pathological changes can be found in the brain of infected people and in the brain of Plasmodium berghei-infected mice. The pathogenesis of cerebral malaria in mice is believed to be due to an immunopathological reaction giving rise to an excessive production of cytokines such as interferon gamma (IFN-gamma) and tumor necrosis factor (TNF). We find that low doses of interleukin 1 (IL-1) protect mice against cerebral malaria; IL-1 also inhibits parasitemia. The IL-1 effect on parasitemia was not observed in nude mice and was at least partly reversed in mice treated with IL-1 in combination with antibody to IFN-gamma, indicating the involvement of T cells. Mice protected against development of cerebral malaria by IL-1 treatment developed the syndrome when TNF was given as observed in control infected mice or infected mice treated with inactivated IL-1.

The production of Interleukin 6 (IL-6) was studied during experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA (PbA) infection. IL-6 is present in the serum of mice with ECM, the highest concentrations being observed in mice with full-blown neurological syndrome. High IL-6 levels were also observed, however, in the absence of pathology in nonlethal malaria infection. These data suggest that IL-6 is produced in large amounts during malaria infection, but does not play a major role in the pathogenesis of ECM. A modulation of IL-6 production in ECM was achieved by in vivo treatment with other anticytokine antibodies: antibodies to interferon (IFN-gamma) or to tumor necrosis factor (TNF) abolished the rise of IL-6, while anti-IL-3 and anti-granulocyte/macrophage colony-stimulating factor antibodies only partially prevented this rise, suggesting that the two cytokines IFN-gamma and TNF are important intermediates in IL-6 production. Passive immunization against IL-6 did not prevent ECM, but significantly reduced serum IgG levels in malaria-infected mice. Thus, by its effects on B cells, IL-6 may be involved in hypergammaglobulinemia and immune-complex diseases, e.g., glomerulonephritis observed during malaria infection.

A case of cerebral malaria in a young British traveller, successfully treated by exchange transfusion of whole blood, is reported and the literature regarding the use of this technique in P. falciparum malaria is briefly reviewed.

Histopathologic and immunopathologic features of cerebral malaria have been defined in a study of six autopsy cases with severe Plasmodium falciparum infection. In five cases, immunofluorescent studies demonstrated intense deposition of P falciparum antigen, IgG, and fibrin in cerebral vessels associated with the histopathologic finding of hemorrhage in the white matter of cerebrum and cerebellum regardless of the presence of parasitized erythrocytes in the cerebral vessels. Immunofluorescent study also demonstrated the extravascular deposits of P falciparum granular antigen associated with acute inflammatory lesion in cerebral tissue in one case. These findings suggested that the immunopathogenic mechanism may in some way play a role in the pathogenesis of cerebral malaria.

In endemic areas, most of the people who die from falciparum malaria are young children. Death is commonly preceded by coma (cerebral malaria). The possible role of cytoadherence in this clinical picture is considered.

The cerebral pathology observed in Plasmodium berghei ANKA-infected CBA mice has been attributed to overproduction of TNF, the mice in which this syndrome is seen being those with the highest serum TNF levels. To investigate this further, we injected recombinant human TNF into malaria-primed mice to see if we could reproduce the cerebral changes observed in P. berghei ANKA infections. A range of doses, administered as a single or repeated injections, or via osmotic pumps, failed to reproduce these changes, but did induce hypoglycaemia, midzonal liver necrosis and neutrophil adhesion in pulmonary vessels. This pathology is seen in terminal Plasmodium vinckei infections, but absent in terminal P. berghei ANKA. In addition, the permeability of the blood-brain barrier to Evan's blue, which is present in P. berghei ANKA but not in normal or P. vinckei-infected mice, was not induced by exogenous TNF. Serum levels of TNF were measured in an ELISA assay, and found to be consistently higher in P. vinckei rather than P. berghei ANKA terminal infections. This is consistent with the pathological changes we could reproduce by injecting TNF. For these reasons we suggest that the cerebral pathology seen in mice infected with P. berghei ANKA may be governed by TNF produced locally by monocytes sequestered within the cerebral blood vessels, not simply by systemic levels of this cytokine.

Based on the cerebral malaria coma scale, 39 falciparum malaria autopsy cases from the Hospital for Tropical Diseases, Mahidol University, Bangkok, Thailand were divided into two groups of patients that had either cerebral malaria or non-cerebral malaria. We then studied significant pathological differences, such as parasitized erythrocyte (PRBC) sequestration, ring hemorrhages and cerebral edema, between these two groups in order to investigate the correlation between the clinical coma scale and pathological findings. Patients with a coma grade of 2 and higher were designated as having cerebral malaria, and had erythrocyte PRBC sequestration in cerebral microvessels. Ninety four percent (94%) of cerebral microvessels showed PRBC sequestration when quantitatively analyzed. On the other hand, only 13% of cerebral microvessels showed sequestration in non-cerebral malaria patients with a coma grade of 1 and lower, although some degree of PRBC sequestration was found in 50% of these patients. Our study, therefore, clearly demonstrated that the degree of the PRBC sequestration in cerebral microvessels appeared to correlate closely with the clinical coma scale.

An in vitro model of Plasmodium falciparum-infected red blood cell sequestration which uses C32 amelanotic melanoma cells as targets has been used to examine the binding capacity of infected red blood cells from subjects with naturally acquired P. falciparum infections of varying severity. The binding of infected red blood cells (IRBCs) to melanoma cells was specific to cells containing mature parasites. Variations in target cell density and in conditions of growth had significant effects on binding. Binding was pH dependent, being maximum at a pH of 6.9. Using standardized conditions the binding capacity of individual isolates of P. falciparum could be measured with a high degree of reproducibility. Binding capacity of IRBCs from 51 subjects between the ages of 6 months and 15 years varied between 12 and 1254 IRBCs per 100 melanoma cells when RBC suspensions at a 1% parasitemia and 4% hematocrit were used. Variation in binding was not related to the level of peripheral parasitemia of the isolate or to differences in adaptation to culture conditions. The binding capacity of parasitized cells from subjects with cerebral malaria did not differ from that of IRBCs from subjects with less serious clinical manifestations.

We compared placebo and dexamethasone (initial dose, 3 mg/kg; total, 11.4 mg/kg per 48 h) in a double-blind trial involving 10 stuporous and 28 comatose patients with cerebral malaria. Patients were 18 mo to 42 y of age (geometric mean, 10.2 y), and the 19 patients in each group were comparable on admission. All patients received intravenous quinine therapy. Four patients (21%) in each group died. There were no significant differences between the placebo- and dexamethasone-treated groups in time until patients became afebrile (median, 51 vs. 19 h), the level of consciousness became normal (mean, 80 vs. 83 h), or parasitemia was cleared (mean, 2.1 vs. 3.4 d) or in the incidence of complications. Coma or hyperparasitemia (greater than or equal to 5% of erythrocytes parasitized) at the time of admission and hypoglycemia at any time during hospitalization were significantly correlated with a fatal outcome, which was not improved by using dexamethasone. We conclude that high-dose dexamethasone is not indicated for treating cerebral malaria.

Retinal hemorrhages were seen in 21 patients among a group of 144 with strictly-defined cerebral malaria. Hemorrhages were multiple in 17 cases and bilateral in 14. There was subhyaloid extension in two. Soft exudates were seen in two, the retinae were considered edematous in four and in one there was bilateral papilledema. Retinal hemorrhages were significantly associated with several indices of severity of Plasmodium falciparum infection: high parasitemia with schizontemia, anemia, elevated serum creatinine and reduced plasma antithrombin III. Only two patients with hemorrhages were both severely anemic and thrombocytopenic. It is suggested that retinal hemorrhages, a frequent finding in cerebral malaria, may be visible evidence of vascular lesions involved in the pathogenesis of this condition.

Cerebral malaria is an acute diffuse encephalopathy associated only with Plasmodium falciparum. It is probably a consequence of the rapid proliferation of the parasites in the body of man in relation to red cell invasion, and results in stagnation of blood flow in cerebralcapillaries with thromobotic occlusion of large numbers of cerebral capillaries. The subsequent cerebral pathology is cerebral infarction with haemorrhage and cerebral oedema. The wide prevalence of P. falciparum in highly endemic areas results in daily challenges to patients from several infected mosquitoes. It is thus important to understand the characteristics of P. falciparum, since this is one of the most important protozoan parasites of man and severe infection from it constitutes one of the few real clinical emergencies in tropical medicine. One of the more important aspects of the practice of medicine in the tropics is to establish a good understanding of the pattern of medical practice in that area. This applies to malaria as well as to other diseases. The neophyte might be somewhat surprised to learn, for example that an experienced colleague who lives in a holoendemic malarious area such as West Africa, sees no cerebral malaria. But the explanation is simple when the doctor concerned has a practice which involves treating adults only. Cerebral malaria is rare in adults, because in highly endemic areas, by the age of 1 year most of the infants in a group under study have already experienced their first falciparum infection. By the time they reach adult life, they have a solid immunity against severe falciparum infections. In fact, "clinical malaria" could occur in such a group under only two circumstances: 1) in pregnancy, a patent infection with P. falciparum might develop, probably due to an IgG drain across the placenta to the foetus;2) in an individual who has constantly taken antimalarials and who may have an immunity at such a low level that when antimalarial therapy is interrupted, clinical malaria might ensue. The above examples emphasise the paramount importance of the clinician dealing with malaria having some insight into the complex immunity processes operative in the human host; these have been reviewed by McGregor.

Limulus amoebocyte lysate test (LALT) was used to detect endotoxin-like substances in the plasma of 15 patients with cerebral malaria, 28 patients with uncomplicated falciparum malaria and 30 healthy controls. On admission, 67% of cerebral malaria patients were positive, whereas only 21.4% of uncomplicated malaria patients and none of controls were positive. Among uncomplicated malaria cases, four of eight patients with parasitaemia over 90,000/mm3 were LALT positive whereas only two of 20 patients with parasitaemia of less than 90,000/mm3 were positive. A follow-up study in cerebral malaria patients showed some variation in LALT positivity rate from day to day (85.7% on day 1, 53.3% on day 3 and all negative on discharge from hospital). LALT positivity bore no relationship to gram negative bacteraemia. Leucocytosis and elevated serum enzymes were more frequently found in LALT-positive patients. Our results suggest that endotoxin (LALT positivity) of the plasma of malaria patients is derived from either the parasites themselves or from the gut. It relates to parasitaemia, leucocytosis and elevated serum enzymes, but not to the clinical syndrome of cerebral malaria.

The following report using light and electron microscopic and immunological techniques is based on a series of 19 Burmese patients who died of cerebral malaria. The principal change was blockage of cerebral capillaries by Plasmodium falciparum-infected erythrocytes. Ring hemorrhages and segmental necrosis of cerebral capillaries were common. Cerebral edema was variable in these cases. Electron-dense knobs, 40 X 80 nm in size, which protruded from the membrane of infected erythrocytes, formed focal junctions between endothelial cells and erythrocytes. These junctions resulted in the entrapment of erythrocytes and caused blockage in the capillary lumen. Immunoperoxidase study revealed that P. falciparum antigens and IgG deposits in the capillary basement membrane. This implies that damage to the cerebral capillary could be related to immune mechanisms.

Recent experimental studies have added greatly to our knowledge of malarial plasmodia and their interaction with the host. However, the current hypotheses on the pathogenesis of malaria and its cerebral complications are still largely based on speculations. Little, if any, consideration is given to biologic properties of the parasite and to postmortem examination findings, even though the processes underlying malaria infection and its complications can be brought to light by collating pathologic, clinical, and parasitologic data.

Humoral immune responses to malaria were studied in 100 patients with cerebral malaria of whom 53 had added complications, 108 patients with acute malaria, and 100 blood donors. The methods employed were indirect hemagglutination (IHA), indirect fluorescent antibody (IFA), enzyme-linked immunosorbent assay (ELISA), and parasite growth inhibition (PGI) tests. Patients with cerebral malaria, especially those with complications, had histories of fewer attacks of malaria in the previous 5 years than did those with acute malaria, suggesting that the cerebral malaria patients were less immune. The combined cerebral malaria group (complicated and uncomplicated) did not show defective humoral immune responses, since the initial seronegative rate and the mean initial IHA and IFA antibody titers were not significantly different from those of acute malaria patients and the mean initial ELISA titer was even higher than that of the acute malaria group. Reduced humoral responses were found only in complicated cerebral malaria patients, as their mean initial IHA titer was lower and their IHA seronegative rate was higher than those in acute malaria patients and in the uncomplicated cerebral malaria group. The combined cerebral malaria group had greater PGI activity than that of acute malaria patients, but this increased activity was entirely due to the higher results obtained in the complicated cerebral malaria group. The increased PGI activity returned to normal after recovery. An IgG preparation from seven of eight of these sera failed to exert the growth inhibition effect. Factors other than IgG were therefore responsible for the inhibition of parasite growth.

Fifty-six adult patients diagnosed as having 'cerebral malaria' were admitted and treated over a 4 month period. The presenting symptoms were similar to those of control patients with malaria without cerebral manifestations except that vomiting and convulsions were significantly more frequent and joint pains were less frequent in the cases than in the controls. Physical examination revealed significantly more frequent occurrence of nuchal rigidity, positive Kernig's sign, confusion, muteness, pallor and jaundice in the cases than controls, while splenomegaly was significantly more common in controls than cases. Laboratory data showed that cerebral malaria cases had significantly lower haemoglobin and significantly higher reticulocyte count and erythrocyte sedimentation rate than controls. There was no significant difference in the parasite density between the cases and controls. All patients were treated with 200 mg base of intravenous chloroquine in 250 ml of isotonic saline infused over 2 h and repeated 12 hourly till oral therapy was possible. This proved to be efficacious and the recovery rate was over 90%. Five patients died and the diagnosis was confirmed in three in whom autopsy was permitted. A simple staging system is proposed which retrospectively seems to have prognostic value. It is recommended that the validity of this system be tested prospectively.

The neurological complications of malaria--an almost universal problem although it occurs mainly in the tropics--constitute the commonest cause of death and morbidity. These complications usually occur in P. falciparum infections and in those who are non-immune, such as children, pregnant women and visitors to areas endemic for malaria. They are rare in children suffering from protein-calorie malnutrition. Febrile convulsions, the commonest childhood emergency in the African and cerebral malaria are the commonest neurological complications. Spinal cord disorders and polyneuropathy have been described but are rare. It has been suggested that various forms of mental illness and psychoses may be related to malarial infections, but much research is needed to establish cause and effect relationship. The neuropathology and pathogenesis, clinical presentations, treatment and mortality of the neurological complications are reviewed.

Of the seventy cases of cerebral malaria seen at the Duchess of Kent Hospital, Sandakan between January 1984 and June 1986, 57 (81.4%) were due to plasmodia falciparum and 13 (18.6%) were due to mixed p. vivax--p. falciparum infections. Mixed infection cerebral malaria was associated with a more severe anaemia and may carry a poorer prognosis. Indigenous children under five years of age are particularly at risk of death from mixed infections.

The pathophysiology of malaria infection is presented from animal studies and the various manifestations occurring in human cases. Maegraith (1974) proposed the concept of a chain reaction of physiological processes that leads to the disease following malarial infection. It may be seen that the malaria parasites first damage the infected red blood cells directly and then initiate a chain reaction of nonspecific inflammatory processes and later on immunological responses aggravating further the inflammatory reactions. Because of ther interdependence in nature of these changes as suggested by Maegraith in 1977 it is usually difficult to clearly identify these three mechanisms.

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.

Data concerning 11 cases of cerebral malaria treated with high doses of chloroquine base (18mg/kg/day) are reported. The risk of chloroquine resistance (already described in Tanzania) and the fact that only chloroquine is available on the island of Pemba, were the reasons for increasing the usual dose. High doses clinically seem to offer better results, only one of 11 dying (9.1%) compared with four of 30 (13.3%) in the control group given normal doses. However, the lack of significant differences between the two groups and the greater risk with high doses of chloroquine may not always justify their use to overcome a RI chloroquine resistance in adults and adolescents.

Serum samples from 95 patients with acute uncomplicated falciparum malaria (AM) and 95 patients with cerebral malaria (CM) were tested by the indirect immunofluorescent assay (IFA) for IgG and IgM antibodies against Plasmodium falciparum and P. vivax sporozoites. Forty-six (48%) CM patients were positive for antibodies against P. falciparum sporozoites whereas only 23 (24%) were positive for antibodies against P. vivax sporozoites (P less than 0.002). A similar result was obtained in AM patients. However, CM patients had significantly lower mean IgG anti-sporozoite titer for P. falciparum than did AM patients (P less than 0.05), especially when only anti-sporozoite antibody-positive CM and AM patients were compared (P less than 0.0005), suggesting that CM patients had relatively less exposure and were probably less immune to malaria than were AM patients. The persistence of anti-sporozoite antibodies also was investigated in paired sera taken 63 days apart from 108 patients with acute falciparum malaria. There were significant decreases in the mean antibody titers in the follow-up sera during the period of stay in the malaria-free area. It was proposed that determination of anti-sporozoite antibody be made as a substitute for, or in addition to, anti-blood stage antibody for seroepidemiological study of malaria, especially in the monitoring of the success of the malaria control program.

For investigation of the pathogenesis of cerebral malaria, immediate postmortem samples from brain and other tissues of patients dying with Plasmodium falciparum malaria, with (CM) or without (NCM) cerebral malaria, were processed for electron microscopy. Counts of parasitized erythrocytes (PRBCs) in cerebral and other vessels showed that the proportion of PRBCs was higher in CM than in NCM, and also that the proportion of PRBCs was higher in the brain than in other organs examined in both CM and NCM. Cerebral vessels from CM patients were more tightly packed with RBCs than those from NCM patients, but there was no significant difference in the amount or degree of endothelial damage or numbers of vessels with endothelial pseudopodia. Fibrillar (fibrin) deposits were present in a small proportion of vessels, but no thrombosis was present. There was neither acute nor chronic inflammation, and leukocytes were absent within or outside cerebral vessels. There was no immune complex deposition in cerebral vessels. Parasites in cerebral vessels were mainly trophozoites or schizonts. Occasional RBC remnants following parasite release were seen. Some parasites were degenerate, resembling crisis forms. PRBCs adhered to endothelium via surface knobs. It is concluded that there is no evidence for an inflammatory or immune pathogenesis for human cerebral malaria and that the clinical effects probably relate to anoxia and the metabolic activities of the parasites.

Cases of malaria caused by Plasmodium falciparum resistant to chloroquine treatment have been probably occurring in Vanuatu for many years. In this survey, seven patients with P. falciparum malaria were investigated for evidence of resistance to chloroquine. In-vitro resistance to chloroquine was demonstrated in four. Two further patients who had clinical resistance to chloroquine treatment developed cerebral malaria. It is of interest that one of these patients was subsequently successfully treated with mepacrine. Two additional cases are cited as examples of resistance to chloroquine treatment encountered in the past.

Bone marrow aspirates from patients with cerebral malaria were studied with the light and electron microscopes. Various abnormalities were found including: (1) an increase in plasma cells and macrophages, sometimes to a marked degree; (2) phagocytosis of parasitized red cells by macrophages and of merozoites by neutrophil metamyelocytes, neutrophil granulocytes and macrophages; (3) an increase in the proportion of eosinophil granulocytes and their precursors; (4) the presence of giant metamyelocytes; and (5) morphological abnormalities of erythroblasts, particularly irregularly-shaped nuclei and karyorrhexis. A high percentage of the red cells within marrow sinusoids were parasitized and the parasitized cells were attached to the endothelium. Some marrow sinusoids were packed with and completely obstructed by parasitized cells. Strands of electron-dense material were sometimes found connecting the knobs of parasitized red cells to endothelial cells or to the knobs of adjacent parasitized red cells. A striking finding was a complex interdigitation between cytoplasmic processes developed by some of the parasitized red cells and those developed by the endothelial cells to which they were attached. Occasionally, cytoplasmic processes arising from marginated parasitized red cells completely penetrated the endothelial cell and emerged extravascularly. Several parasitized red cells were also found extravascularly between haemopoietic cells. Sequestration of parasitized red cells within small blood vessels may play a part in the pathogenesis not only of the encephalopathy of cerebral malaria but also of the bone marrow dysfunction in severe malaria.

We studied the relationship between presenting features and outcome in 131 Malawian children admitted with cerebral malaria (P. falciparum malaria and unrousable coma). A method was devised for the measurement of depth of coma in children too young to speak. Twenty patients (15 per cent) died and 12 (9 per cent) recovered with residual neurological sequelae. Presenting clinical signs significantly associated with adverse outcome (death or sequelae) were profound coma, signs of decerebration, absence of corneal reflexes, convulsions at the time of admission and age under three years. Laboratory findings of prognostic significance were hypoglycaemia, leucocytosis, hyperparasitaemia, elevated plasma concentrations of alanine and 5'-nucleotidase, and elevated plasma or cerebrospinal fluid lactate. A prognostic index based on eight of these risk factors that can readily be ascertained at the bedside or in a ward sideroom, was more accurately predictive of outcome than any single feature. Such an index may be valuable as a measure of severity of illness for establishing the comparability of study groups, and for evaluating the role of other factors in the pathogenesis of cerebral malaria.