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Clinicopathological Case - CNS Aoife a third year medical student from Trinity College decides to spend some time in Kenya for her medical overseas voluntary elective. Q What vaccinations or medications is she going to need prior to travel? Vaccinations: Hepatitis A Recommended for all travellers Typhoid Recommended for all travellers Yellow fever Recommended for all travellers greater than nine months of age Polio One-time booster recommended for any adult traveller who completed the childhood series but never had polio vaccine as an adult Hepatitis B For travellers who may have intimate contact with local residents, especially if visiting for more than 6 months Rabies For travellers who may have direct contact with animals and may not have access to medical care Measles, mumps, rubella (MMR) Two doses recommended for all travellers born after 1956, if not previously given Tetanus-diphtheria Revaccination recommended every 10 years Malaria: Prophylaxis with Lariam, Malarone, or doxycycline is recommended for all areas except Nairobi and the highlands (above 2500 m) of Central, Eastern, Nyanza, Rift Valley, and Western Provinces. She receives the appropriate vaccinations and begins taking Mefloquine (Lariam) once weekly in a dosage of 250 mg, one-to-two weeks before she travels which she continues through the trip. While in Africa she feels generally unwell with symptoms of nausea, vomiting and insomnia. Comment on these symptoms. She returns home after her elective and stops taking Mefloquine one week later. While travelling home she had mild flu like symptoms, so she took paracetamol and they seemed to clear up after a couple of days. 10 days after her return she developed a fever which lasted two days during which time she took some more paracetamol to bring her temperature down. Her flatmate arrived home to find her un-rousable. She shook her gently and Aoife’s eyes opened, but the girl stared blankly ahead, unable to make eye contact. Her friend called her mother and by the time she arrived Aoife had suffered a convulsion - her arms and legs jerking uncontrollably for several minutes before her body went limp. They called an ambulance and she was immediately transferred to A&E. The hospital physician noted that Aoife’s fever was over 103° Fahrenheit and her gaze was blank and roving. Shortly after the initial examination, Aoife began convulsing again, and the physician administered an anticonvulsant drug. Q What tests should be ordered? LABORATORY AND MICROSCOPIC EXAMINATION: Table 1. Laboratory values at admission Full Blood Count Cell Type Value WBC * 2.6 RBC * 3.06 Hgb * 9.0 Hematocrit (HCT) * 25.8 MCV 84.2 MCH 29.5 MCHC 35 RDW * 16.7 Differential Neutrophils * 21 Absolute Neutrophils * 0.55 Lymphocytes * 61 Absolute Lymphocytes 1.58 Monocytes * 15 Absolute Monocytes 0.39 Eosinophils 1 Absolute Eosinophils 0.03 Basophils 0 Absolute Basophils 0.00 Bands 2 Absolute Bands 0.05 Platelets * 98 * = out of reference range Reference 4.5-13 (x109/L) 4.5-5.3 (x109/L) 13.5-17.5 (g/L) 37.0-49.0 % 78-98 fL 24-30 pg 32-36 g/dL 11.8-15.2 % 31-61 % 1.80-8.00 (x109/L) 28-48 % 1.40-5.90 (x109/L) 3-9 % 0.00-0.80 (x109/L) 0-3 % 0.00-0.60 (x109/L) 0-2 % 2-8 % 156-369 (x109/L) Q What is the tentative diagnosis? A Cerebral malaria. Q What causes morbidity associated with Malaria? Much of the morbidity and mortality associated with malaria is caused by the rupture of iRBCs (infected red blood cells) during the asexual reproductive stages of the parasite. Intense fever, occurring in 24-72 hour intervals, is accompanied by nausea, headaches, and muscular pain among other symptoms. The characteristic fever spike has been correlated with incremental rises in serum levels of TNF- associated with the release of parasite proteins during erythrocytic rupture. Furthermore, a variety of potentially fatal symptoms, including liver failure, renal failure, and cerebral disease are associated with untreated P. falciparum. These symptoms are consequences of the unique ability of the parasite to bind to endothelial surfaces; this adherence inhibits circulation and causes localized oxygendeprivation and sometimes hemorrhaging. It has been proposed that ICAM-1, E-selectin, VCAM-1, and chondroitin sulfate A (CSA), and CD36 are some of the surface molecules responsible for parasite-endothelial adherence. Why is the patient anaemic? The growing parasite consumes and degrades the intracellular proteins, mainly haemoglobin. The transport properties of the red cell membrane are altered, cryptic surface antigens are exposed and new parasite derived proteins are inserted. The red cell becomes more spherical and less deformable. In P. falciparum infection, membrane protuberances appear on the red cell surface in the second 24-hour of the asexual cycle. Accretions of electrondense, histidine-rich parasite proteins are found under these 'knobs'. These knobs extrude a strain specific, adhesive variant protein of high molecular weight that mediates red cell attachment to receptors on venular and capillary endothelium, causing cytoadherence. P. falciparum infected red cells also adhere to uninfected red cells to form rosettes. Cytoadherence and rosetting are central to the pathogenesis of P. falciparum malaria, resulting in the formation of red cell aggregates and intra vascular sequestration of red cells in the vital organs like the brain and the heart. This further interferes with the microcirculation and metabolism and allows parasite development away from the principal host defense, splenic processing and filtration. As a result, in P. falciparum malaria, only younger forms of the parasite are found in the peripheral circulation and the peripheral parasitemia is usually an underestimate of the true parasite load. Mature forms of P. falciparum are rarely seen in the peripheral blood and when found, indicate severe infection. Sequestration does not occur in cases of P. vivax and P. malariae infections and therefore, all stages of the parasite can be seen in the peripheral blood and complications are very rare. Anaemia is a fairly common problem encountered in malaria and it poses special problems in pregnancy and in children. It can be due to multiple causes. Repeated hemolysis of infected red cells is the most important cause for a reduction in haemoglobin levels. Anaemia depends on the degree of parasitemia, duration of the acute illness and the number of febrile paroxysms. It may occur even after 3-5 febrile paroxysms. P. vivax predominantly invades young red cells and the number of parasites infected rarely exceeds 2%. P. malariae develops mostly in mature red cells and the parasitemia is rarely greater than 1%. P. falciparum affects red cells of all ages and the parasitemia can be as high as 20-30% or more. Massive destruction of red cells accounts for rapid development of anemia in P. falciparum malaria. Immune and non-immune haemolysis of non-infected red cells, increased splenic clearance of parasitized as well as non-parasitized red cells, reduction of red cell survival even after disappearance of parasitaemia, dyserythropoeisis in the bone marrow, drug induced haemolysis etc. can also contribute to the anaemia. Some of these mechanisms may perpetuate anaemia even after completion of the treatment. Anaemia of malaria is usually normocytic hypochromic with increase in the number of reticulocytes and polychromatophils. Rarely, atypical manifestations like macrocytic anaemia or pseudoaplastic picture with pancytopenia may be seen. Anaemia may be associated with hyperbilirubinemia of the indirect type, due to the haemolytic process. Splenomegaly may also be seen. Leukocyte count is usually low to normal in most cases of malaria. Increased leukocyte count indicates either a severe infection or secondary bacterial infection. Reduction in the leukocyte count is attributed to hypersplenism or sequestration in the spleen. Relative lymphocytosis, monocytosis, eosinopenia, presence of stab neutrophils are observed with prolonged duration of the illness. Thrombocytopenia is also fairly common in malaria. It has been observed that the platelet count shows a moderate decline during the paroxysms of fever. Thrombocytopenia may be related to the sequestration of the platelets in the spleen. Severe thrombocytopenia however indicates severe infection and may herald bleeding syndromes. Erythrocyte Sedimentation Rate is usually elevated in malaria up to 30-50 mm in one hour. Prolonged malaria, severe anaemia and severe malaria are usually associated with a higher ESR. Q What is Malaria? A Malaria is an infectious disease caused by the release of protozoan parasites into the bloodstream by the bite of a parasite-carrying Anopheles mosquito. After an incubation period of one to four weeks, initial malaria symptoms begin that usually include fever, headaches, vomiting, chills, and general malaise, similar to the flu. These symptoms are caused by the release of the parasites’ products into the bloodstream. Most people, if treated, recover relatively easily, but the unlucky others, like Halima, will develop the disease’s more severe form, cerebral malaria, in which the parasite-infected red blood cells attach in large numbers to the circulatory vessels of the brain. GENERAL REVIEW OF PLASMODIUM SP. LIFE CYCLE The Plasmodium parasite undergoes two cycles of replication; sporogony (the sexual cycle) and schizogony (the asexual cycle). Sporogony occurs in the intestinal tract of the anopheline mosquito. Sporozoites, the product of sporogony, migrate to the salivary glands and are injected into the bloodstream when a mosquito bites a person. The sporozoites circulate briefly in the peripheral blood then enter hepatocytes. Inside hepatocytes (the exoerythrocytic stage) multiplication occurs. After approximately ten days, the merozoites enter the peripheral blood and infect erythrocytes (the intraerythrocytic stage). Inside the erythrocyte, the merozoite develops into the trophozoite or "ring form". The trophozoite develops into a schizont made up of multiple merozoites, a process called schizogony (the asexual replication cycle). The schizont matures causing rupture of the erythrocyte and releasing merozoites into the circulation which in turn infect other erythrocytes. The paroxysms or cyclical fevers classically associated with malaria occur shortly before or at the time of erythrocyte rupture. Infection with P. malaria causes paroxysms every 72 hours (quartan malaria). Infection with P. ovale or P. vivax cause tertian malaria with paroxysms every 48 hours. P. falciparum tends to produce irregular fever spikes superimposed upon a continuous fever or the tertian malaria paroxysms every 48 hours. Merozoites will develop into gametocytes (female macrogametocytes and male microgametocytes) following several intraerythrocytic cycles. The gametocytes are infectious to the mosquito when ingested. In the intestine of the mosquito, the microgametocyte enters the macrogametocyte (sporogony) and zygotes are produced. The zygotes enter intestinal cells and develop into sporozoites. These sporozoites then migrate to the salivary glands continuing the Plasmodium life cycle. CLINICAL MANIFESTATIONS Fever develops 7-10 days following infection, during the exoerythrocytic cycle of merozoite development in hepatocytes. It is during the intraerythrocytic cycle that the spiking fevers associated with erythrocyte lysis occur. Other symptoms include malaise, fatigue, anemia, headache and myalgias. Complications associated with P. falciparum infection include acute renal failure, pulmonary edema, and cerebral malaria (with seizures and coma). Hepatomegaly and splenomegaly have been documented with splenic rupture most commonly associated with P. vivax infection. P. malariae has been associated with an immune complex glomerulonephritis. Abnormal laboratory findings include decreased hemoglobin, hematocrit, platelet count and haptoglobin. Lactic dehydrogenase and reticulocyte count are generally increased. Increased bilirubin and increased serum enzymes may be noted and are not specifically associated with the exoerythrocytic stage. DIAGNOSIS Diagnosis is best made utilizing thick smears of peripheral blood but thin smears can also be used. In P. falciparum infection the parasite is identified as a tiny ring form within normal sized erythrocytes. These ring forms often show double nuclei and "applique" morphology against the cytoplasmic membrane. Multiple ring forms are commonly seen in P. falciparum. Merozoites when seen are usually >24 per cell. The gametocytes show a classic boomerang or banana shape. In P. vivax infection the parasite is identified as large ring forms (approximately 1/3 of cell width) in an enlarged erythrocyte. Shuffner's dots (pink granules) are commonly seen. Merozoites usually number between 12-24 per erythrocyte. Gametocytes are large and circular or ameoboid. P. malariae may demonstrate band like trophozoites. In P. malariae, the ring forms are rarely multiple and when multiple the possibility of a double infection with another Plasmodium species should be considered. Usually less than 12 merozoites per cell are seen. Indirect immunofluorescence may be used for serodiagnosis of malaria and a titer greater than 1:64 is considered diagnostic. TREATMENT Decisions regarding treatment of malaria must take into account where the patient will be living while on therapy, the parasite load, the need for natural acquired immunity, patient symptoms, complications, and the problem of drug resistance. Pharmacologic treatment of malaria has become complicated by the emergence of drug resistant forms of parasites. Resistant forms of P. falciparum have been well documented for almost all antimalarial drugs, including chloroquine, other 4-aminoquinolines, and Fansidar. Cross resistance has quickly developed due to molecular similarities of drugs and limited modes of action on the parasite. • • • • • • Cerebral malaria is a life-threatening complication of P. falciparum infestation that occurs in approximately 2% of the cases. In endemic areas it affects mainly children. Occurrence in adults is far less frequent, yet it is seen among persons who have lived away from endemic areas for a sufficient time to have lost their immunity. Progressive clinical changes occur along with high fever and chills. The neurologic manifestations are nonspecific because of diffuse involvement of the brain. Transient extrapyramidal and neuropsychiatric manifestations as well as isolated cerebellar ataxia may occur, but localizing signs are rare. Coma may ensue, and approximately one third of patients die. • • • These red blood cells, shown in a coloured electron micrograph, are infected with malarial parasites. The parasites swell the cells and eventually break out and spread, infecting additional cells. The more blood cells infected, the more severe the disease. Q What is the treatment? A Quinine and intravenous fluids. Q How does malaria produce such profound symptoms? Several reasons could be responsible for the more complicated forms of malaria and their neurological symptoms, for example a lack of blood flow to the brain or slower blood flow resulting in brain damage, swelling, and inflammation of clogged blood vessels, or perhaps damage stemming from seizures. It is likely that the reason that some people contract cerebral malaria while others develop only an uncomplicated form of infection pertains more to individual differences in how the immune system responds to the parasite than to the parasite itself. Q Could the body itself be causing damage in its attempts to keep the parasite at bay? CM is the result of an over-vigorous immune response originally evolved for the protection of the host. Evidence in support of this second hypothesis comes from studies in murine malaria models in which T cells, monocytes, adhesion molecules and cytokines, have been implicated in the development of the cerebral complications. Recent studies of human CM also indicate a role for the immune system in the neurological complications. However, it is likely that multiple mechanisms are involved in the induction of cerebral complications and both the presence of parasitized erythrocytes in the central nervous system (CNS) and immunopathological processes contribute to the pathogenesis of CM. Most studies examining immunopathological responses in CM have focused on reactions occurring primarily in the systemic circulation. However, these also do not fully account for the development of cerebral complications in CM. Many host and parasite factors have been proposed to play a role in the induction of cerebral complications during P. falciparum infection (reviewed in Newton and Warrell). The more prominent theories include: mechanical or sequestration, toxin, cytokine, nitric oxide (NO), reactive oxygen species (ROS), permeability, immunological hypotheses. One of the dominant hypotheses, the 'sequestration' hypothesis (reviewed in Berendt et al.), suggests that sequestration causes multifocal abnormalities in cerebral blood flow (including both vascular obstruction and dilatation) leading to microheterogeneous hypoxaemia, acidosis, hypoglycaemia and other metabolic derangements affecting brain function, resulting in coma. However, this mechanism seems insufficient to explain all the known features of human CM. For example, blockage of blood flow would be expected to result in stroke-like pathology involving anoxic neuronal injury and severe residual impairment. This contrasts with the findings in the majority of human CM cases, in which prolonged coma proceeds to apparent functional recovery. Q What are the Histologic findings in Cerebral malaria? • • The histologic findings in cerebral malaria include: – sequestration of infected erythrocytes in brain vessels, mainly cortical and perforating arteries, with peri-vascular ring haemorrhages and white matter necrosis. Presence of oedema is more difficult to document pathologically because, in postmortem studies, brain oedema may not be appreciated Pathological features in patients who died of clinically defined cerebral malaria. (a) Example of sequestration. Fresh coronal section of brain is swollen and slightly grey in colour, and has no visible haemorrhages. Bottom left, highpower (x100) view of cortex showing many parasitized vessels. Bottom right, single cortical vessel (under oil immersion (x1,000) containing unpigmented parasites. (b) Pattern of sequestration and microvascular pathology. Fixed coronal section of brain is swollen and has multiple petechial haemorrhages in the cortical white matter. Bottom left, high-power (x400) view of cortex showing haemorrhage surrounding a parasitized vessel. Bottom right, higher-power (x400) view of cortex showing ring haemorrhage around vessel containing parasites and a thrombus. • White matter changes. The first examination, 2 days after the onset of cerebral malaria, shows hyperintensity in the semiovale centrum along with abnormal signal in the splenium of the corpus callosum (arrow) on fast spin-echo T2-weighted MR images (4700/102 (A and B) and on fast FLAIR images (10,000/ 145; TI 5 2200) (C and D). On contrast-enhanced T1-weighted images (620/10) (E and F), only the unenhanced hypointense lesion of the corpus callosum is visible. • • • At follow-up examination, 1 week after the onset of illness, T2weighted (G and H) and FLAIR (I and J) images show resolution of hyperintensities, except for the lesion of the splenium of the corpus callosum. In comparison with the first examination, there is a widening of the sulci and volume enhancement of the ventricles. These changes may have been caused by initial brain swelling or by subsequent atrophy, the former being the most likely, because of the short time between examinations. The immune response to malaria T cells appear to be central to both malaria immunity and to the manifestations of CM. Using murine models it has been shown that the primary immune response to asexual blood stage parasites is mediated by CD4+ T cells, which are required for cell mediated immunity, but not for help in antibody production. There is evidence of marked T-cell activation in human CM.Riley and colleagues examined, in a malaria-endemic population with differing levels of clinical immunity to malaria, the relationship between: (i) soluble IL-2 receptors and lymphoproliferative responses to malaria antigens; and (ii) plasma IL-2 receptor levels, age, malaria parasitaemia and clinical symptoms. They found high levels of soluble IL-2 receptor in the plasma of malariainfected individuals and this was independently associated both with age and parasitaemia. As the plasma concentration of soluble IL-2 receptor is an indication of T-cell activation in vivo, this group concluded that a vigorous cellular immune response to malaria antigen occurs in vivo. Monocyte and macrophage involvement in immunity to murine and human malaria Hepatomegaly and splenomegaly are characteristic features of murine and human malaria infection and have been attributed not only to erythrophagocytosis, but also to increased numbers of macrophages recruited from the circulation The role of spleen macrophages and liver Kupffer cells in the host response to malaria is well established experimentally. Macrophages in the spleen and liver have been shown to eliminate parasites from mice infected with plasmodia. It is believed that circulating pRBC become coated with antibody against parasite-derived proteins, facilitating phagocytosis. Some events proposed to be of importance in the pathogenesis of murine cerebral malaria. Astrocytes regulate CNS Function An important role of astrocytes in the normal CNS is to induce and maintain BBB properties in the vascular endothelium. The endothelial cells themselves have complete belts of tight junctions between each cell that are uninterrupted by gap junctions. These features of the endothelium restrain the rate of exchange of solutes between the blood and nervous tissue by reducing the effects of fluctuations in the blood plasma metabolites and other constituents, helping to maintain the unique CNS milieu conducive to neuronal functioning. Astrocytes also make close contact with neuronal synapses and are thought to be intimately involved in maintaining acid-base, electrolyte and neurotransmitter balance. In addition, astrocytes regulate the concentration of neurotransmitters, such as glutamate, in the extracellular fluid. Any alteration in these astrocyte functions has profound effects on normal neuronal function. Microglia are the central nervous system counterpart of the mononuclear phagocyte system Microglial cells comprise 5–20% of the total glial population in the brain and are pluripotent members of the monocyte/ macrophage lineage. Just like other tissue macrophages, microglia, when stimulated by substances such as LPS and IFN- , can secrete IL-1, IL-6 and TNF- .IL-1 released by microglia has been shown to be an astrocyte mitogen. TNF- has been shown in some studies to have a cytotoxic effect on oligodendrocytes and to destroy myelin structure, and is induced on microglia in demyelinating lesions. In addition, both IL-1 and TNF- have been found on activated microglia surrounding senile plaques in Alzheimer's disease. REFERENCES: Review Article Immunology and Cell Biology (2001) 79, 101–120; doi:10.1046/j.14401711.2001.00995.x Central nervous system in cerebral malaria: 'Innocent bystander' or active participant in the induction of immunopathology? Isabelle M Medana, Geeta Chaudhri, Tailoi Chan-Ling and Nicholas H Hunt Newton CR, Warrell DA. Neurological manifestations of falciparum malaria. Ann. Neurol. 1998; 43: 695–702. Berendt AR, Turner GDH, Newbold CI. Cerebral malaria: the sequestration hypothesis. Parasit. Today 1994; 10: 412–4. Clark IA, Rockett KA. The cytokine theory of human cerebral malaria. Parasit. Today 1994; 10: 410–2 Riley EM, Rowe P, Allen SJ, Greenwood BM. Soluble plasma IL-2 receptors and malaria. Clin. Exp. Immunol. 1993; 91: 495–9. Zaman V, Keong LA. Handbook of Medical Parasitology. New York: ADIS Health Science Press, 1982. What is the prognosis for a child whose malarial infection has localized in the blood vessels of the brain? If not immediately treated, cerebral malaria is likely to be fatal. What other pathological processes may be seen? Bone marrow Bone marrow may show evidence of dyserythropoeisis, iron sequestration and erythrophagocytosis in the acute phase of falciparum malaria. Maturation defects may be present in the marrow for 3 weeks after the clearance of parasitemia. Large, abnormal looking megakaryocytes have been found in the marrow and the circulating platelets may also be enlarged, suggesting dysthrombopoeisis. Spleen Spleen plays an important role in the immune response against malarial infection and splenectomy invariably activates a latent infection. Enlargement of the spleen is one of the early and constant signs of malarial infection. Spleen may become palpable as early as the first paroxysm. Spleen may be palpable at the early stages of infection in the right lateral position or even in supine position. Its edge is usually round and hard to palpate and it may be tender. As the disease progresses, the spleen becomes harder, less sensitive and readily palpable. In falciparum malaria, spleen may not be palpable if the patient presents very early (due to severity). Otherwise, splenomegaly is common in all types of malaria. The early enlargement of the spleen is due to engorgement, oedema of the pulp and later due to lymphoid and reticulo-endothelial hyperplasia with an increased hemolytic and phagocytic function of the organ. Frequent relapses and re-infections lead to pulp sclerosis and dilated sinuses. Following treatment, spleen regresses in size, usually completely, within two weeks. In cases of large, fibrotic spleen due to repeated malaria, regression is slower, but complete involution with treatment is common. Rapid and considerable enlargement of spleen may sometimes result in splenic rupture, which is a serious complication of malaria. This is more common in primary attack of malaria. Due to fibrosis and perisplenitis, rupture is less likely in case of chronic splenomegaly. A small proportion of adults in Africa and India and a high proportion of adults from New Guinea have been found to suffer from huge enlargement of the spleen. This condition has been termed as the Tropical Splenomegaly Syndrome. Its nature still remains unclear. It is characterized by marked enlargement of the spleen whose weight may reach 2000-4400 g. The splenic sinuses are dilated and there is marked lymphoid hyperplasia. There is increased phagocytosis of red and white blood cells. The liver is also enlarged and shows lymphoreticular infiltration of the sinusoids. High levels of Ig G and Ig M antibodies against malaria have been demonstrated in these patients. These patients also have anemia, leucopenia, and thrombocytopenia with fairly well maintained general health. Prolonged anti malarial treatment may reduce the size of the spleen in these patients. Liver Enlargement of the liver also occurs early in malaria. The liver is enlarged after the first paroxysms, it is usually firm and may be tender. It is oedematous, coloured brown, grey or even black as a result of deposition of malaria pigment. Hepatic sinusoids are dilated and contain hypertrophied Kupffer cells and parasitized red cells. Small areas of centrilobular necrosis may be seen in severe cases and these may be due to shock or disseminated intravascular coagulation. Prolonged infection may be associated with stromal induration and diffuse proliferation of fibrous connective tissue. However, changes of cirrhosis are not seen. In falciparum malaria, in addition to the involvement of the mesenchyma, the hepatocytes may also be involved, causing functional changes as well (malarial hepatitis). Malarial hepatitis is characterized by hyperbilirubinemia with elevation of conjugated bilirubin, increased levels of transaminases and alkaline phosphatase. Being part of the severe falciparum infection, it may be associated with renal failure, anemia or other complications of falciparum malaria. Liver involvement in severe falciparum malaria is due to impairment of local microcirculation associated with hepatocellular damage. In patients with repeated attacks of malaria, liver also enlarges significantly along with a large and hard spleen. However, there is no functional abnormality of the liver in these patients. Malaria is not a proven cause for cirrhosis of the liver. Lungs Involvement of the lungs occurs in P. falciparum malaria and is secondary to the changes in the red blood cells and the microcirculation. Acute pulmonary oedema is an infrequent but nearly fatal complication of P. falciparum malaria, largely due to capillary endothelial lesions and perivascular oedema. Fluid overload and blood transfusion may also contribute to this problem. Pulmonary capillaries and venules are packed with inflammatory cells and parasitized red cells. The vascular endothelium is oedematous with narrowing of the lumen. Interstitial oedema and hyaline-membrane formation is also seen. Focal or lobar pneumonia and bronchopneumonia can also complicate malaria. Cardiovascular system Malaria is commonly associated with cardiovascular function abnormalities. The most frequent changes during a paroxysm include decrease in blood pressure, tachycardia, muffled heart sounds, transient systolic murmur at the apex and occasional cardiac dilation. Also there is peripheral vasodilation, leading to postural hypotension. In P. falciparum malaria, there could be microcirculatory changes in the coronary vessels. The myocardial capillaries are congested with parasitized red cells, pigment laden macrophages, lymphocytes and plasma cells. Malaria may aggravate a pre-existing cardiac dysfunction and may prove fatal to patients already suffering from significant cardiac failure or valvular obstruction. Gastro-intestinal tract Malaria is often accompanied by nausea and vomiting, mainly central in origin. In the acute phase, patient may have anorexia, abdominal distention, and pain in the epigastrium. Some times the abdominal colics may be so severe as to mimic acute abdomen or appendicitis. Some patients may have watery diarrhoea and the condition may mimic gastro-enteritis or cholera. Acute colitis may be associated with malaria. Bacillary dysentery, amoebiasis, etc. may complicate malaria. In falciparum malaria, involvement of splanchnic microcirculation can lead to ischaemia of the gut, mucosal oedema, necrosis and ulceration. This may hamper absorption. Further these changes in the gut may also lead absorption of toxins, precipitating septic shock. Kidneys Malaria can cause varied problems in the kidneys. During the acute attack, albuminuria may be seen commonly. Acute diffuse malarial nephritis with hypertension, albuminuria and oedema may also be seen rarely. In P. malariae infection, nephrotic syndrome may be seen (Quartan malaria nephropathy). This immune complex mediated nephropathy develops weeks after the malarial illness and is characterized by albuminuria, oedema and hypertension. It may be progressive and may require treatment with steroids or immunesuppressants. In severe P. falciparum malaria, acute renal failure may develop in 0.1-0.6% of the patients. Microcirculation disorders, anoxia and subsequent necrosis of the glomeruli and renal tubules are responsible for this serious complication. Disseminated intravascular coagulation also may cause or aggravate this problem.