Cerebral malaria

Definition. A diffuse, potentially reversible encephalopathy complicating Plasmodium falciparum infection, defined strictly as unrousable coma (Glasgow Coma Scale ≤11 in adults; Blantyre ≤2 in children) persisting for more than 30 minutes after a seizure, in the presence of asexual parasitaemia, with no other identifiable cause of coma. It is the commonest lethal complication of falciparum malaria, with mortality of 15–20% even with optimal treatment, and 10–20% of survivors have persistent neurological sequelae. It is rarely reported with P. knowlesi and P. vivax.

Pathogenesis. Parasitised red cells express PfEMP-1 on their surface and cytoadhere to endothelial receptors — ICAM-1, EPCR and CD36 — in cerebral microvessels, producing sequestration and rosetting. The result is microvascular obstruction, endothelial activation, cytokine release (particularly TNF-α), blood–brain barrier breakdown, cerebral oedema and reduced cerebral perfusion. Contributing systemically: lactic acidosis, hypoglycaemia and severe anaemia.

Clinical features. Fever, headache and progressive impairment of consciousness to coma; generalised or focal seizures; symmetrical upper motor neurone signs with decerebrate or decorticate posturing; and malarial retinopathy — retinal whitening, vessel discolouration, retinal haemorrhages and papilloedema, which is the most specific bedside sign and should be sought on fundoscopy. Characteristically there is no meningism and no focal lateralising deficit. Look for the other features of severe malaria: severe anaemia, jaundice, acute kidney injury, ARDS, hypoglycaemia, shock, spontaneous bleeding and DIC. Older adults have a substantially higher risk of renal failure, pulmonary oedema and death.

Diagnosis. Peripheral blood smear — thick film for detection, thin film for species identification and parasite counting (hyperparasitaemia >2–5% indicates severe malaria); repeat 12-hourly if initially negative. Rapid diagnostic tests detect HRP-2 (P. falciparum) and pLDH, but HRP-2 can remain positive for weeks after treatment. PCR where available. Essential adjuncts: blood glucose — hypoglycaemia must be excluded and corrected in every case, lactate, CBC, renal and liver function, coagulation screen and blood cultures. Lumbar puncture is needed to exclude bacterial meningitis unless contraindicated — in cerebral malaria the CSF is essentially normal or shows only a minimally raised protein. CT or MRI to exclude an alternative cause of coma.

Treatment. Intravenous artesunate is the drug of choice — 2.4 mg/kg at 0, 12 and 24 hours, then once daily — and is superior to quinine, having reduced mortality by about 35% in adults in the SEAQUAMAT trial. Give parenteral therapy for at least 24 hours, then switch to a full 3-day course of oral artemisinin-based combination therapy once the patient can swallow. Supportive care is what determines survival: correct hypoglycaemia with 25% dextrose, treat seizures with a benzodiazepine followed by a maintenance anticonvulsant, maintain careful fluid balance avoiding both under-filling and pulmonary oedema, provide ventilation and dialysis as required, nurse the unconscious patient appropriately, and treat concurrent bacterial sepsis (common). Do NOT give prophylactic phenobarbitone (it increased mortality), dexamethasone, routine mannitol, heparin or adrenaline — all are ineffective or harmful. Watch for post-artesunate delayed haemolysis at 1–3 weeks, and check the haemoglobin at follow-up.

The WHO Guidelines for Malaria (2024–2025 updates) reaffirm intravenous artesunate for a minimum of 24 hours as first-line treatment for all severe malaria, followed by a complete ACT course, and recommend pre-referral rectal artesunate where parenteral treatment cannot be started immediately — directly relevant to rural India. India's National Framework for Malaria Elimination and the NCVBDC national drug policy follow the same. The important current concern is that artemisinin partial resistance (Kelch13 mutations), long established in the Greater Mekong subregion, is now confirmed in East Africa, which makes a full ACT course after parenteral therapy and follow-up parasite clearance monitoring mandatory rather than optional.