1. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk Severe and complicated malaria Jørgen Kurtzhals Centre for Medical Parasitology Rigshospitalet, Copenhagen, Denmark

2. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk Cerebral malaria kills ½-1 million children every year

3. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk Correct treatment: 85% survival – most without sequelae

4. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk 15% of cerebral malaria patients die

5. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk The asexual parasite multiplication cycle Ring-stage trophozoite Mature trophozoite Schizont (segmenter) Free merozoites Trophozoite maturation Schizogony Rupture Re-invasion

6. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk Spleen Vascular endothelium Sequestration interferes with splenic removal of schizont-infected erythrocytes

7. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk Sequestration of erythrocytes in the brain

8. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk Cerebral malaria – clinical features P. falciparum – often (not always) high parasitaemia High temperature – (or hypothermia) Impaired consciousness From prostration and convulsions -> deep coma Convulsions Partial motor seizures Convulsions is a bad sign Classical definition of cerebral malaria Unrousable coma Mortality 5-15%

9. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk Cerebral malaria - diagnosis Exclusion diagnosis Other manifestations of malaria (may co-exist) Hypoglycaemia Hyponatriaemia Multi-organ failure Prolonged post-ictal state Other infections (may co-exist!) Meningitis Sepsis Metabolic diseases (e.g. DM) Neurologic diseases Head trauma

10. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk Cerebral malaria – treatment Effective anti-malarial – i.v. quinine Alternative: artemisinin, artesunate… i.v. or rectal Anti-convulsive therapy Only when clinically indicated (respiration depression) Avoid hypoglycaemia Ensure vital functions Correct electrolyte derangement

11. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk Severe anaemia - pathogenesis Erythrocyte destruction during schizogony Erythrophagocytosis in spleen Hypersplenism Immune mediated Bone marrow suppression TNF/IL-10 ratio Reversible Spleen

12. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk Severe anaemia P. falciparum – often, not always, high parasitaemia Often prolonged duration Hb < 5 g/dl (3 mmol/l) Lactic acidosis – ’respiratory distress’ Hypovolaemia Haemolysis Hyperbilirubinaemia Haemoglobinuria

13. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk Severe anaemia – treatment Effective anti-malarial treatment Parasite clearance restores bone marrow function Blood transfusion At >20% parasitaemia ~ exchange transfusion Optimise circulation and oxygenation Keep high urinary output Caveat: do not precipitate pulmonary oedema General supportive treatment

14. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk Other severe complications Pulmonary oedema ARDS Renal insufficiency Haemolysis Thrombocytopaenia, DIC Superinfections Septicaemia

15. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk Recommended laboratory investigations Blood film (x3) Blood culture Hb, thrombocytes, WBC and differential count Na, K, creatinine Bilirubin, ASAT, factor II-VII-X, LDH Glucose (Arterial blood gas, lactate)

16. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk Case 1 53 year old male civil engineer, resident in Ghana for 6 years. No malaria prophylaxis due to fear of side effects (and general opposition toward doctors) During field work feeling feverish, treated with aspirin Returned after 5 days. Wife finds the patient extremely ill looking and rushes him to hospital

17. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk Case 1 (ctd.) On arrival pale, acutely ill, tp. 41.2 o C, slow cerebrated Blood film: 17% P. falciparum (ring stages) Hb 8.2 g/dl, thrombocyte count 46, WBC normal range Creatinine 320  mol/l, Na 120 mmol/l, K 4.0 mmol/l Glucose 3.8 mmol/l Treatment suggestion?

18. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk Case 1 (ctd.) Quinine 10 mg/kg infusion in 5% dextrose/saline over 4 h stat. Quinine 10 mg/kg infusion tds After parasite clearance (marked reduction) continue oral quinine at same dosage for 7 days Alternatively doxycycline 100 mg/day for 7 days CAVE! Never use mefloquine after quinine Other necessary measures?

19. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk Case 1 (ctd.) Hyponatraemia treated with isotonic saline and frusemide Renal function did not deteriorate but was normalised after rehydration Follow blood glucose carefully Thrombocytes normalised after parasite clearance

20. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk Theories about pathogenesis of cerebral malaria Impaired cerebral blood flow? Sequestration of infected RBC in blood vessels Histological picture Ophthalmoscopy

21. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk Near infrared spectrophotometry (NIRS)

22. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk ScO 2 on admission

23. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk Theories about pathogenesis of cerebral malaria Impaired cerebral blood flow? Regional blood flow changes

24. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk Theories about pathogenesis of cerebral malaria Generalised excessive inflammation High TNF levels Association with TNF promoter polymorphism Animal experiments

25. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk Clin Exp Immunol 1998; 112: 303-307 Increased levels of inflammation markers in cerebral malaria

26. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk Theories about pathogenesis of cerebral malaria Impaired cerebral blood flow? Regional blood flow changes Excessive inflammation Regional inflammation

27. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk Theories about pathogenesis of severe malarial anaemia Destruction of erythrocytes Schizogony Infected cells removed in spleen Uninfected cells removed in spleen

28. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk Complement binding to erythrocytes - direct Coombs’ test

29. e-mail: jkcmp@rh.dk Internet: http://www.cmp.dk Pathogenesis of severe malaria Cerebral malaria – too much Excessive inflammation Localised in the brain Local neuronal excitation Possible focal impairment of micro- circulation Redirection of circulation Severe anaemia – too little Insufficient inflammation Long term infection Low grade inflammation Bone marrow suppression Erythrocyte destruction