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Cerebral malaria

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mechanisms of brain injury (pathogenesis), treatment and neuro-cognitive outcome.

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Cerebral malaria

  1. 1. CEREBRAL MALARIA mechanisms of brain injury (pathogenesis), treatment and neuro- cognitive outcome.
  2. 2. introductory Malaria is a mosquito-borne infectious disease of humans and other animals caused by parasitic protozoans of the genus Plasmodium. Commonly, the disease is transmitted by a bite from an infected female Anopheles mosquito, which introduces the organisms from its saliva into a person's circulatory system. In the blood, the parasites travel to the liver to mature and reproduce.
  3. 3. Five species of Plasmodium can infect and be transmitted by humans. I. Plasmodium malariae II. Plasmodium ovale III. Plasmodium vivax IV. Plasmodium falciparum V. Plasmodium knowlesi
  4. 4. General pathophysiology Malaria infection develops via two phases: 1. exoerythrocytic phase: involving the liver and 2. erythrocytic phase: involving red blood cells, or erythrocytes. When an infected mosquito pierces a person's skin to take a blood meal, sporozoites in the mosquito's saliva enter the bloodstream and migrate to the liver where they infect hepatocytes, multiplying asexually and asymptomatically for a period of 8–30 days.
  5. 5. After a potential dormant period in the liver, these organisms differentiate to yield thousands of merozoites, which, following rupture of their host cells, escape into the blood and infect red blood cells to begin the erythrocytic stage of the life cycle. The parasite escapes from the liver undetected by wrapping itself in the cell membrane of the infected host liver cell.
  6. 6. Within the red blood cells, the parasites multiply further, again asexually, periodically breaking out of their host cells to invade fresh red blood cells. Several such amplification cycles occur. Thus, classical descriptions of waves of fever arise from simultaneous waves of merozoites escaping and infecting red blood cells.
  7. 7. Pathogenesis of cerebral malaria It is likely that the pathologies underlying CM in humans are highly variable and reflect a range of attributes, including parasite virulence, host susceptibility and comorbidities ranging from malnutrition to coinfection.
  8. 8. Most observations of the pathophysiology of disease come from postmortem observations of Plasmodium falciparum (Pf) infections, which are thought to account for the vast majority of CM cases, and show a common feature of vascular sequestration of infected erythrocytes (IE) in the brain.
  9. 9. The standard clinical definition of CM centers on: 1. a state of unarousable coma partnered with 2. the presence of malaria infected red blood cells(parasitized red blood cells (pRBCs)) in the peripheral circulation and 3. a lack of other potential causes of coma such as other infections or
  10. 10. Parasite sequestration in the brain  Vascular sequestration of infected erythrocytes (IE) in the brain is a common feature of Cerebral Malaria.  The resulting pathophysiological changes in tissue around the sequestered parasites, which may explain why an intravascular parasite may cause neural dysfunction and why some patients may have a poor outcome.
  11. 11.  Sequestration results from adherence of pRBCs to the endothelial lining (cytoadherence) using parasite derived proteins exposed on erythrocyte surface.  A group of parasite antigens including Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP-1) mediate binding to host receptors of which, intercellular adhesion molecule-1 (ICAM- 1) is the most important and whose expression is upregulated in areas adjacent
  12. 12.  Sequestration impairs perfusion and may aggravate coma through hypoxia.  Furthermore, the ability of pRBCs to deform and pass through the microvasculature is decreased.  Therefore, hypoxia and inadequate tissue perfusion may be major pathophysiological events.
  13. 13. Cytokines, chemokines and excitotoxicity  Cytokines and chemokines play a complex role in pathogenesis and have both protective and harmful effects. Parasite antigens released at schizogony trigger the release of both pro- and anti-inflammatory cytokines. Although the balance between these mediators is critical for parasite control, their role in pathogenesis of the neuronal damage is unclear.
  14. 14. Tumour necrosis factor (TNF), the most extensively studied cytokine in cerebral malaria, upregulates ICAM-1 expression on the cerebral vascular endothelium increasing the cytoadhesion of pRBCs. Near areas of sequestration, there is increased local synthesis. The timing of this is important since early in disease, TNF may be protective but prolonged high levels contribute to complications.
  15. 15. Endothelial injury, apoptosis, blood-brain barrier (BBB) dysfunction and intracranial hypertension Cytoadherence of pRBCs to the endothelium initiates a cascade of events beginning with the transcription of genes involved in inflammation, cell-to-cell signalling and signal transduction, which result in endothelial activation, release of endothelial micro- particles (EMPs) and apoptosis of host cells.
  16. 16. There is widespread endothelial activation in vessels containing pRBCs and compared to other complications of falciparum malaria, significant increases in circulating EMPs are seen in patients in coma
  17. 17. Interactions between pRBCs and platelets (which produce platelet microparticles) cause further injury to endothelial cells through a direct cytotoxic effect.
  18. 18. treatment Cerebral malaria is a syndrome of severe malaria and therefore its treatment falls under the regime of treatment for severe malaria.
  19. 19. objectives of treatment The primary objective of antimalarial treatment in severe malaria is to prevent death. In treating cerebral malaria, prevention of neurological deficit is an important objective. In the treatment of severe malaria in pregnancy, saving the life of the mother is the primary objective. In all cases of severe malaria, prevention of recrudescence and avoidance of minor adverse effects are secondary.
  20. 20. Clinical features  impaired consciousness or unrousable coma  prostration, i.e. generalized weakness so that the patient is unable walk  or sit up without assistance  failure to feed  multiple convulsions – more than two episodes in 24 h
  21. 21. Clinical features  – deep breathing, respiratory distress (acidotic breathing)  – circulatory collapse or shock, systolic blood pressure < 70 mm Hg in adults  and < 50 mm Hg in children  – clinical jaundice plus evidence of other vital organ dysfunction  – haemoglobinuria  – abnormal spontaneous bleeding  – pulmonary oedema (radiological)
  22. 22. Laboratory findings  hypoglycaemia (blood glucose < 2.2 mmol/l or < 40 mg/dl)  – metabolic acidosis (plasma bicarbonate < 15 mmol/l)  – severe normocytic anaemia (Hb < 5 g/dl, packed cell volume < 15%)  – haemoglobinuria  – hyperparasitaemia (> 2%/100 000/μl in low intensity transmission areas or > 5%  or 250 000/μl in areas of high stable malaria transmission intensity)  – hyperlactataemia (lactate > 5 mmol/l)  – renal impairment (serum creatinine > 265 μmol/l).
  23. 23. differential diagnosis Coma and fever may result from meningo-encephalitis or malaria. Cerebral malaria is not associated with signs of meningeal irritation (neck stiffness, photophobia or Kernig sign), but the patient may be opistotonic. As untreated bacterial meningitis is almost invariably fatal, a diagnostic lumbar puncture should be performed to exclude this condition.
  24. 24. Specific antimalarial treatment It is essential that effective, parenteral (or rectal) antimalarial treatment in full doses is given promptly in severe malaria. Two classes of medicines are available for the parenteral treatment of severe malaria:  the cinchona alkaloids (quinine and quinidine) and the  artemisinin derivatives (artesunate, artemether and artemotil).
  25. 25. Parenteral Chloroquine is no longer recommended for the treatment of severe malaria, because of widespread resistance. Intramuscular sulfadoxine-pyrimethamine is also not recommended.
  26. 26. Artemisinin derivatives Various artemisinin derivatives have been used in the treatment of severe malaria, including 1. artemether 2. artemisinin 3. artemotil 4. artesunate
  27. 27. In treatment, artesunate 2.4 mg/kg BW IV or IM given on admission (time = 0), then at 12 h and 24 h, then once a day is the recommended treatment. Artemether, or quinine, is an acceptable alternative if parenteral artesunate is not available: artemether 3.2 mg/kg BW IM given on admission then 1.6 mg/kg BW per day ; or quinine 20 mg salt/kg BW on admission (IV infusion or divided IM injection), then 10 mg/kg BW every 8 h; infusion rate should not exceed 5 mg salt/ kg BW per hour.
  28. 28. neuro-cognitive complications and outcome  Cognitive sequelae - Risk factors for cognitive impairment included 1. Hypoglycemia 2. Seizures 3. depth and duration of coma 4. hyporeflexia
  29. 29.  Speech and language impairment - Cerebral malaria is a leading cause of acquired language disorder in the tropics; 11.8% of surviving children have deficits especially in vocabulary, receptive and expressive speech, word finding and phonology.
  30. 30.  Epilepsy - Epilepsy develops in about 10% of exposed children months to years after exposure and the cumulative incidence increases with time.  Behavior and neuro-psychiatric disorders In children, behavior problems include: 1. Inattention 2. impulsiveness and hyperactivity 3. conduct disorders and impaired social development 4. Obsessive, self injurious and destructive behaviors are also observed

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