Cerebral Malaria severe complication of falciparum malaria mortality of 30-50% associated with sequestration in micro- vasculature of brain a diffuse.

Disease Severity Pv Po Pm Pf Average (per mm3)

20,000 9,000 6,000 50,000-500,000

Maximum (per mm3)

50,000 30,000 20,000 2,500,000

Paroxysm Severity

moderate to severe

mild mild to

moderate severe

Duration Disease Infection

3-8 w 5-8 y

2-3 w 12-20 m

3-24 w >20 y

2-3 w 6-17 m

Anemia ++ + ++ ++++ Complications renal cerebral

Cerebral Malaria•severe complication of falciparum malaria

• mortality of 30-50%•associated with sequestration in micro-vasculature of brain

•a diffuse encephalopathy with loss of consciousness• consciousness ranges from stupor to coma• unresponsive to pain, visual, and verbal stimuli• convulsions frequently observed• onset can be gradual or sudden

Complications Associated with Falciparum Malaria

• cerebral malaria• anemia• hyperpyrexia• hypoglycemia • acidosis• GI and liver syndromes• pulmonary edema• blackwater fever• algid malaria (shock)

Features Indicating Poor Prognosis in Severe Malaria• impaired consciousness• repeated convulsions• respiratory distress• shock• acidosis/hyperlactemia• hypoglycemia• jaundice or other liver malfunctions• renal impairment• high parasitemia (>500,000/mm3)

• all erythrocytes invaded• Pv/Po = reticulocytes• Pm = senescent RBC

• up to 36 merozoites• sequestration of

infected erythrocytes • trophozoite and schizont

stages• primarily in brain, heart,

lungs, and gut• complications• immune evasion

Higher Parasitemias in Falciparum Malaria

• avoidance of spleen• low oxygen tensions• better invasion

P. falciparum expresses ‘knobs’ on the surface of infected erythrocytes. Knobs mediate cytoadherence to endothelial cells.

Several Parasite Proteins Are Associated with Knobs

• KAHRP and PfEMP2 are believed to interact with the submembrane cytoskeleton of the host erythrocyte

• reorganization of the membrane skeleton may result in knob formation

• PfEMP1 crosses the erythrocyte membrane and is exposed on the surface

• family of 40-50 var genes• conserved intracellular C-terminus

• acidic terminal segment (ATS)• binds cytoskeleton + KAHRP

• transmembrane domain• variable extracellular domain

composed of modules• 2-7 copies of Duffy-binding like

domains • 5 sequence types ()

• 1-2 cys-rich interdomain regions• all have DBL1 + CIDR

• participates in cytoadherence

PfEMP-1 Structure

• CD36• Ig super-family

• ICAM-1• VCAM-1• PECAM-1

• E-selectin• thrombospondin• chondroitin sulfate A• hyaluronic acid

• Rosetting Receptors• CR-1• glycosaminoglycan• blood group A

Possible Host Receptors

Binding SitesDomain ReceptorCIDR CD36

DBL rosetting

DBL ICAM-1

DBL CSA

SequestrationHypothesis

cytoadherence

cerebral ischemia

hypoxia, metabolic effects

coma

death

Neurological Sequelae AmongSurvivors of Cerebral Malaria

at discharge 23.3%

at 1 month 8.6%

at 6 months 4.4%van Hansbroek et al (1997) J. Pediatrics 131:125

Problems with Sequestration Hypothesis

• rapid reversibility• lack of ischemic damage• low levels of permanent

neurological damage• sequestration occurs in

non-cerebral malaria cases

Cytokine Theoryexo-

antigens TNF +

IL-1 nitric

oxide coma,

death

Cytokine Theory Problem• minimal lymphocyte infil-

tration or inflammation

Severe falciparum malaria

• potentially high parasitemias• sequestration• complex (and not fully understood)

host-parasite interactions