Cerebral Malaria

Introduction and Definition

Cerebral malaria is the most common and severe complication of Plasmodium falciparum infection in children, contributing significantly to mortality. It is defined as a clinical syndrome characterized by:

• Unarousable Coma: Blantyre Coma Score <3 (in pre-verbal children) or Glasgow Coma Scale <11 (in adults), persisting for more than 1 hour after termination of a seizure or correction of hypoglycemia.
• Parasitemia: Presence of asexual forms of P. falciparum in peripheral blood.
• Exclusion: Exclusion of other causes of encephalopathy (e.g., bacterial meningitis, viral encephalitis, hypoglycemia).

Epidemiology

• Age: In high-transmission areas (e.g., sub-Saharan Africa), it typically affects children aged 3 to 6 years (mean 3.5 years). In lower transmission areas, it affects older children and adults.
• Risk Factors: Non-immune status (young children, travelers), lack of chemoprophylaxis, and delay in treatment.

Pathophysiology

The pathogenesis involves a complex interaction of mechanical obstruction and immune-mediated damage:

• Sequestration and Cytoadherence: Infected red blood cells (iRBCs) develop “knobs” on their surface, allowing them to adhere to the vascular endothelium (cytoadherence) of deep vascular beds, particularly in the brain.
• Microvascular Obstruction: The sequestration of iRBCs leads to congestion, obstruction of blood flow, and tissue anoxia/ischemia.
• Inflammatory Mediators: Excessive production of pro-inflammatory cytokines, particularly Tumor Necrosis Factor (TNF-alpha) and Interleukin-1, contributes to endothelial activation and damage.
• Cerebral Edema: Brain swelling with increased intracranial pressure (ICP) is a major feature in children and is strongly associated with fatal outcomes due to herniation.
• Metabolic Derangement: Hypoglycemia and lactic acidosis (anaerobic metabolism) exacerbate neuronal injury.

Clinical Features

The onset may be gradual (following 1–2 days of fever) or precipitous (especially in young children).

• Altered Consciousness: Ranges from confusion/drowsiness to deep unarousable coma.
• Seizures: Occur in 50–70% of children; often generalized, repeated, or status epilepticus.
• Abnormal Posturing: Decerebrate (extensor) or decorticate (flexor) posturing and opisthotonus are common.
• Brainstem Signs: Abnormalities in pupillary reflexes (constricted or unequal), dysconjugate gaze, and irregularities in breathing patterns (e.g., Cheyne-Stokes).
• Malarial Retinopathy: A highly specific sign for cerebral malaria consisting of retinal whitening (macular/peripheral), vessel discoloration (orange/white vessels), and retinal hemorrhages. Its presence confirms the diagnosis; its absence in a comatose child with parasitemia should prompt a search for other causes.
• Associated Systemic Signs: Fever, severe anemia (pallor), splenomegaly, hepatomegaly, and respiratory distress (acidotic breathing).

Diagnosis

• Parasitology:
  • Thick and Thin Smear: Gold standard. Demonstrates P. falciparum asexual forms. Note: Peripheral parasitemia may be low due to sequestration.
  • Rapid Diagnostic Tests (RDTs): Useful if microscopy is unavailable; detects HRP-2 or pLDH antigens.
• CSF Examination: Essential to rule out bacterial meningitis.
  • Opening Pressure: Often elevated.
  • Analysis: Usually normal or shows mild pleocytosis (10–20 cells/µL), slightly elevated protein, and normal glucose. High WBC counts suggest meningitis.
• Blood Glucose: Mandatory to rule out hypoglycemia (<40 mg/dL or <2.2 mmol/L), which mimics cerebral malaria.
• Neuroimaging (CT/MRI): Typically shows brain swelling/edema. Useful to rule out other intracranial lesions but not required for diagnosis.

Management

Severe malaria is a medical emergency requiring admission to an intensive care unit (ICU).

1. General Supportive Care

• Airway/Breathing: Protect the airway in comatose patients; manage respiratory distress.
• Circulation: Assess for shock. Fluid resuscitation should be careful to avoid pulmonary edema (a risk in adults and some children).
• Hypoglycemia: Correct immediately with IV dextrose (e.g., 2–5 mL/kg of 10% dextrose). Monitor blood glucose every 4 hours.
• Nursing Care: Frequent position changes, eye care, and monitoring of vital signs/coma score.

2. Antimalarial Therapy

Parenteral therapy is mandatory initially.

• First Line: Intravenous Artesunate.
  • Dose: 2.4 mg/kg IV at 0, 12, and 24 hours, then once daily.
  • Pediatric (<20kg): Some guidelines suggest 3.0 mg/kg per dose.
  • Efficacy: Reduces mortality by ~22-25% compared to quinine in children.
• Alternative: Intravenous Quinine.
  • Dose: Loading dose of 20 mg salt/kg infused over 4 hours, followed by maintenance of 10 mg salt/kg every 8 hours.
  • Precaution: Cardiac monitoring (QT prolongation) and glucose monitoring (stimulates insulin release) are required.
• Follow-up: Switch to a full course of oral Artemisinin-based Combination Therapy (ACT) (e.g., Artemether-Lumefantrine) once the patient can tolerate oral medication.

3. Management of Complications

• Seizures: Treat with IV Benzodiazepines (Diazepam 0.3-0.5 mg/kg or Lorazepam 0.1 mg/kg). If persistent, use Phenytoin (18 mg/kg load) or Phenobarbitone (15-20 mg/kg load). Note: Prophylactic anticonvulsants are not recommended.
• Severe Anemia: Transfuse packed red blood cells if Hb <5 g/dL (or <7 g/dL with respiratory distress).
• Adjunctive Therapies:
  • Contraindicated: Corticosteroids (harmful), Mannitol (no benefit for edema), Heparin, Aspirin, and prophylactic Phenobarbital.
  • Exchange Transfusion: No longer recommended based on surveillance data showing no added benefit.

Complications and Sequelae

• Mortality: 15–30% with treatment; nearly 100% without treatment.
• Neurologic Sequelae: Occur in 10–25% of survivors.
  • Motor: Hemiplegia, ataxia, spasticity.
  • Sensory: Cortical blindness (often transient), deafness.
  • Cognitive/Behavioral: Mental retardation, learning disabilities, attention deficits, speech disorders.
  • Epilepsy: Can develop as a long-term complication.
• Predictors of Sequelae: Prolonged coma, multiple seizures, hypoglycemia, and severe anemia.