Cerebral Malaria

Key facts:

Authors: Chaturaka Rodrigo, Deepika Fernando, Senaka Rajapakse

Top Tips: Suspect diagnosis in any patient with fever and drowsiness/coma with a recent travel history to a malaria endemic area. Manage on ITU

Key Differential Diagnoses

• Viral encepahalitis
• Meningitis
• Other causes of coma

Key Investigations

• Thick and thin blood films for malaria parasite
• Rapid malaria antigen detection test
• FBC, CRP, Clotting
• U+E, LFT, Bone, Glucose
• CXR, ECG  
• CT followed by lumbar puncture
  Note: there is no one key investigation

Key Treatment

• IV (or IM) ARTESUNATE 2.4 mg/kg or IV QUININE 20 mg/kg (diluted in 5% dextrose + infused over 4h, max 1.4g)
  Note: start treatment as soon as diagnosis is considered

Key Management Decisions

• Differentiate cerebral malaria from viral encephalitis or bacterial meningitis
• In many occasions this cannot be done immediately. So it’s wise to treat all three

Background

Cerebral malaria often co-exists with other severe complications of malaria: AKI, DIC, ARDS etc 

Introduction

• Cerebral malaria is a form of acute severe malaria
• It is caused mainly by infection with Plasmodium falciparum species
• Cerebral malaria may be the most common non-traumatic encephalopathy in the world
• Malaria affects 5% of the world's population at any one time
• Severe malaria is a multi-systems disease; cerebral malaria can co-exist with other manifestations of severe malaria, namely: metabolic imbalances (hypoglycaemia, hyponatraemia), anaemia, AKI and multi-organ dysfunction
• So patients may have other signs eg, jaundice and Kussmaul's breathing (AKI or lactic acidosis), acute pulmonary oedema
• Cerebral involvement in infection with benign tertian malaria (caused by Plasmodium vivax) have been reported rarely
• Should be suspected in any one with high fever and confusion, especially if has returned from malaria-endemic area; the key to diagnosis is suspicion
• Symptoms (except malarial retinopathy) are not specific. In fact the definition itself requires elimination of other encephalopathies (metabolic and infective)
• As well as specific treatments (above and below), control seizures, correct hypoglycaemia, hypoxia, shock, and anaemia (transfuse if necessary)
• Start treatment as soon as the diagnosis is considered; do not wait for all investigations to come back
• Mortality is 20% in adults

Definitions

• (Adults) Presence of unousable coma with exclusion of other encephalopathies in a patient with P.falciparum malaria 
• (Children) Blantyre Coma Score ≤ 2 with asexual Plasmodium falciparum parasitaemia and no other cause for coma

Blantyre Coma Scale

• A modification of the paediatric Glasgow Coma Scale, designed to assess malarial coma in children. It was designed by Drs. Terrie Taylor and Malcolm Molyneux in 1987, and named after the Malawian city of Blantyre, site of the Blantyre Malaria Project
• All scores under 5 are considered abnormal:
  Eye movements
  1 - Watches or follows
  0 - Fails to watch or follow
  Best motor response
  2 - Localizes painful stimulus
  1 - Withdraws limb from painful stimulus
  0 - No response or inappropriate response
  Best verbal response
  2 - Cries appropriately with pain, or, if verbal, speaks
  1 - Moan or abnormal cry with pain
  0 - No vocal response to pain

Etymology

• Probably first used by Italian physician Francisco Torti (1658-1741)
• The mosquito-borne disease was once thought to have been caused by foul air in marshy districts
• Cerebral malaria can occur at any age but extremes of age are more susceptible to death. However infants can be protected due to passive immunity up to 6 months of age. Pregnancy also increases susceptibility to complications of acute severe malaria
• Approximately 80% of deaths from P. falciparum malaria occur due to cerebral malaria
• It is estimated that 785,000 children under age of nine in sub-Saharan Africa die annually due to cerebral malaria
• The situation in endemic areas in Asia and South America is better, because of effective preventive and curative strategies

Pathophysiology

• The exact pathophysiology of cerebral malaria is unclear
• Changes in the red cell membrane including knob formation and reduced deformability; resulting in adherence of the red blood cells to the endothelial cells of the cerebral microvasculature (cytoadherence)
• The process of removal of the infected red blood cells from the circulating blood to the capillary beds is known as sequestration
• Rosetting (the phenomenon of infected RBCs adhering to uninfected RBCs leading to  microvascular obstruction), auto-agglutination (the ability of the infected red blood cells to stick together) and platelet clumping contribute to the process of sequestration
• Sequestration causes microvascular obstruction, resulting in a relative lack of oxygen (hypoxia) which is ideal for parasite growth. This results in anaerobic glycolysis with excessive lactate production and lactic acidosis
• Parasite derived exo-antigens stimulate the production of cytokines which causes pyrexia, bone marrow suppression, liver dysfunction and inhibition of glycolysis. Cytokines also stimulate nitric oxide production; which is associated with the development of complications such as coma, lactic acidosis, hypotension and hypoglycaemia
• This change in the cerebral neuronal microenvironment is thought to cause disrupted neurotransmission and neuronal cell death

Risk factors

• Older infants and children
• Elderly
• Pregnant women
• Patients with underlying severe illness
• Malnourished patients

Symptoms

• High fever with or without seizures (80% children, 20% adults)
• Altered sensorium
• Drowsiness or coma
• Prostration
  Note: hypoglycaemia occurs (10% adults, 20% children) but its traditional symptoms and signs do not

Key questions

• "Have you recently been to an area where malaria is common?"
• "Have you recently had a blood transfusion?"

Signs

• As per definition: unrousable coma (GCS < 7/15, Blantyre coma score ≤ 2)
• No neck stiffness or mild neck stiffness; no rash or lymphadenopathy
• Usually focal neurological signs are absent and pupils are of normal size (rarely patients can have dysconjugate gaze, opisthotonus, decorticate rigidity and decerebrate rigidity)
• However certain retinal appearances on fundoscopy (collectively named malarial retinopathy) carry a sensitivity of 90% and specificity of 95% to diagnose cerebral malaria. Occur in 15% of patients. These include: macular and peripheral whitening, vessel whitening including capillary whitening, retinal haemorrhages (white centered) and papilloedema. The first two are only observed in cerebral malaria
  Note: all other systems must be carefully examined as severe malaria can affect all other systems. The signs to look for include; pallor, icterus, hepatosplenomegaly, evidence of DIC, dark urine (black water fever) and features of acute respiratory distress syndrome (ARDS)

Malarial retinopathy

Characteristic features include whitening of the macula (that spares the central fovea), peripheral retina, retinal vessels, papilloedema, and multiple retinal haemorrhages (often with pale centres)

Investigation

There is no one key investigation. Peripheral parasitaemia may not always be present in P. falciparum infection

Blood

• Thick and thin blood film for malaria parasite
• Rapid malaria antigen detection test
• FBC, CRP, Clotting, Blood culture
• U+E, LFT, Bone, Glucose (and recheck 4-hourly), Ammonia

Other

• CXR, ECG, ECHO
• CT, followed by
• Lumbar puncture (samples should be sent for gram stain, viral PCR, bacterial culture, CSF sugar, cytology, AFB stain and AFB culture)

Gross sagittal section of brain with acute cerebral malaria

Petechial haemorrhages occur in white matter, particularly in the subcortical rim and corpus callosum

Key investigations

• Thick and thin (peripheral) blood films for malaria parasite repeated on three consecutive days (or more if the history is strongly suggestive of malaria)
  Notes: though these investigations are useful in confirming a diagnosis, peripheral parasitaemia may not always be present in P. falciparum infections. Many physicians would start treatment on suspicion if no alternate cause is found for the encephalopathy

Specialist investigation

• Rapid Antigen Detection Test (RDT)

Differential diagnoses

• Viral encephalitis (HSV, Japanese encephalitis virus, echoviruses, HIV)
• Bacterial meningitis
• Meninigoencephalitis
• Other causes of coma, eg metabolic encephalopathies (poisoning, uraemia, hepatic encephalopathy)
• Cerebral abscess

Treatment

Do not use glucocorticoids, mannitol, NSAIDs. Consider starting treatment on suspicion if no alternate cause is found for the encephalopathy 

WHO guidelines

• According to WHO recommendations, severe malaria including cerebral malaria can be treated with artesunate, artemether or quinine
• Deaths from cerebral malaria is known to occur hours after admission; therefore treat immediately if suspected
• In all regions and especially in low transmission areas, artemisinins (artesuanate and artemether) are preferred to quinine in treatment of both adults and children

Treatment (first line)

• IV (or IM) ARTESUNATE 2.4 mg/kg on admission; then at 12h and 24h; then once a day for at least 24h, followed by full course of artemisinin combination therapy (ACT; eg artemether plus lumefantrine; see local guidelines) plus a single dose of PO PRIMAQUINE 0.75mg/kg unless contraindicated (children under 4 years, pregnancy, G6PD deficiency)
• (Or) IM ARTEMETHER 3.2 mg/kg on admission; then 1.6 mg/kg per day for at least 24 hours, followed by full course of artemisinin combination therapy
  In areas where artemisinins are not available IV quinine can be used:
• (Or) IV QUININE 20 mg/kg loading dose (diluted in 5% dextrose and infused over 4h; max 1.4g) followed by maintenance doses of IV QUININE 10 mg/kg; max 700 mg) administered at 8h intervals, starting 8h after the first dose
  • After 3d, if the patient can tolerate oral drugs a full course of ACT should be given. After ACT a single dose of PO PRIMAQUINE 0.75mg/kg is given
  • The follow up therapy after the initial IV phase also depend on local guidelines. In the UK it is recommended that quinine treatment should always be accompanied by a second drug. This can either be PO DOXYCYCLINE 200 mg (or PO CLINDAMYCIN 450 mg tds for pregnant women; 7-13 mg/kg tds for children), given orally for total of 7 days from when the patient can swallow

Supportive measures

• Protect airway, assess breathing and correct any hypovolaemia
• Skin, bladder and bowel care
• Transfuse if necessary (the role of exchange transfusion is debated)
• Correct any other metabolic derangement such hypoglycaemia, other electrolyte disturbances and AKI; correct hyper/hypothermia
• Careful monitoring of vital signs
• Seizures should be treated with IV LORAZEPAM 2-4 mg. There is no place for prophylactic anti-epileptics. If status epilepticus occurs, follow standard guideline protocol
• Carefully maintain fluid balance charts and monitor U+E daily

Key Management Decision

• Differentiate cerebral malaria from viral encephalitis or bacterial meningitis
• In many occasions it cannot be done immediately, so it’s wise to treat all three

Treatment (second line)

• Complications involving other organ systems (eg AKI, DIC, ARDS, lactic acidosis) should be treated as they arise

Prescribing issues

• Do not use glucocorticoids, mannitol, NSAIDs
• Artemisinins are not recommended for use in first trimester of pregnancy. These patients should be treated with IV QUININE 20 mg/kg followed by PO QUININE SULPHATE 10mg/kg tds for 7 days
• The loading dose of IV QUININE should not be used if the patient has received quinine, quinidine or mefloquine during the previous 12h

Admit?

• Always

Bed plan

• ITU

Referrals

• ITU
• Microbiology
• Infectious Diseases (or ring nearest ID unit, if your hospital does not have one)

The Rest

Maxim

• "If you think of cerebral malaria, treat it"

Complications

• Seizures
• Hypoglycaemia
• Other complication of Falciparum malaria

Risk stratification

• High risk: prolonged seizures, deep coma, delay in treatment, hypoglycaemia, multiorgan dysfunction

Follow-up

• Neurology (including cognitive assessment, rehabilitation)

Prognosis

• Mortality ≈ 20% in adults (50% if associated with AKI and metabolic acidosis) and 15% in children; most deaths occur in first 48h
• Neurological impairment ≈ 5% in adults and 10% in children

2° Prevention
+ Health promotion

• Chemoprophylaxis when travelling to endemic areas

Don't forget

• Peripheral parasitaemia may not always be present in P. falciparum infection
• So, if you are not sure, treat empirically. Early treatment saves lives
• If you cannot differentiate it from bacterial meningitis and HSV encephalitis, treat them as well
• Monitor for hypoglycaemia and hyponatraemia
• They can have other complications of severe malaria too

Red flags

• Absence of focal neurological signs in presence of deep coma
• Hypoglycaemia
• Seizures
• AKI, DIC, ARDS, multi-organ failure

References