Cerebral malaria is the most common complication and cause of death in severe P. falciparum infection. In falciparum malaria, 10% of all admissions and 80% of deaths are due to the CNS involvement. On the other hand, CNS manifestations are fairly common in malaria and it could be due to not only severe P. falciparum infection, but also high-grade fever and antimalarial drugs. Therefore, it is extremely important to differentiate between these so as to avoid unnecessary anxiety and improper treatment.
Manifestations of cerebral dysfunction include any degree of impaired consciousness, delirium, abnormal neurological signs, and focal and generalized convulsions. In severe P. falciparum malaria, the neurological dysfunction can manifest suddenly following a generalized seizure or gradually over a period of hours.
Causes of neurological manifestations in malaria:
- High-grade fever alone can produce impairment of consciousness, febrile convulsions (in children) and psychosis. These manifestations subside with the decrease in the body temperature. Such cases and patients with unimpaired consciousness after seizures tend to have good prognosis.
- Antimalarial drugs like chloroquine, quinine, mefloquine and halofantrine also can cause altered behaviour, convulsions, hallucinations and even psychosis. Absence of high-grade fever and of falciparum parasitemia may suggest such a possibility.
- Hypoglycemia, either due to severe malaria or due to drugs like quinine, may also present with similar manifestations. Hypoglycemia is more common in pregnancy. It may be worthwhile considering this possibility in ALL cases and to administer 25-50% dextrose intravenously.
- Hyponatremia, most often in the elderly and caused by repeated vomiting, is another important cause for neurological manifestations.
- Severe anaemia and hypoxemia can also cause cerebral dysfunction, particularly in children.
- There could be other causes for neurological dysfunction in patients with malaria like vascular disease, other neurological infections and diseases. Focal neurological deficits, neck rigidity, photophobia, papilloedema and neurological sequelae are very rare in falciparum malaria and such a picture would therefore suggest these other possibilities.
A strict definition of cerebral malaria has been recommended for sake of clarity and this requires the presence of unarousable coma, exclusion of other encephalopathies and confirmation of P. falciparum infection. This requires the presence of P. falciparum parasitemia and the patient to be unrousable with a Glasgow Coma Scale score of 9 or less, and other causes (e.g. hypoglycemia, bacterial meningitis and viral encephalitis) ruled out. To distinguish cerebral malaria from transient postictal coma, unconsciousness should persist for at least 30 min after a convulsion. The deeper the coma, the worse is the prognosis. If necessary, a lumbar puncture should be performed to rule out bacterial meningitis. However, all patients with P. falciparum malaria with neurological manifestations of any degree should be treated as cases of cerebral malaria.[1]
Pathophysiology: Cerebral malaria is the most important complication of falciparum malaria. However, its pathophysiology is not completely understood. The basic underlying defect seems to be clogging of the cerebral micocirculation by the parasitized red cells. These cells develop knobs on their surface and develop increased cytoadherent properties, as a result of which they tend to adhere to the endothelium of capillaries and venules. This results in sequestration of the parasites in these deeper blood vessels. Also, rosetting of the parasitized and non-parasitized red cells and decreased deformability of the infected red cells further increases the clogging of the microcirculation. It has been observed that the adhesiveness is greater with the mature parasites. Obstruction to the cerebral microcirculation results in hypoxia and increased lactate production due to anaerobic glycolysis. The parasitic glycolysis may also contribute to lactate production. In patients with cerebral malaria, C.S.F. lactate levels are high and significantly higher in fatal cases than in survivors. The adherent erythrocytes may also interfere with gas and substrate exchange throughout the brain. However, complete obstruction to blood flow is unlikely, since the survivors rarely have any permanent neurological deficit.
Vascular permeability is found to be mildly increased, however, no definite evidence of cerebral edema has been found on imaging studies. 80% children with cerebral malaria have raised ICT, due to increased cerebral blood volume and biomass rather than increased permeability. The mechanism of coma is not clearly known. Increased cerebral anaerobic glycolysis, intereference with neurotransmission by sequestered and highly metabolically active parasites have been blamed. Cytokines induce nitric oxide synthesis in leukocytes, smooth muscle cells, microglia and endothelium and NO is a potent inhibitor of neurotransmission.
Neurological signs in cerebral malaria:
As per the definition, patient should have unarousable coma, not responding to noxious stimuli with a Glasgow coma scale of <7/15. Mild neck stiffness may be seen, however, neck rigidity and photophobia and signs of raised intracranial tension are absent. Retinal haemorrhages occur in about 15% of cases, exudates are rare. Pupils are normal. Papilloedema is rare and should suggest other possibilities. A variety of transient abnormalities of eye movements, especially dysconjugate gaze, are observed. Fixed jaw closure and tooth grinding (bruxism) are common. Pouting may occur or a pout reflex may be ellicitable, but other primitive reflexes are usually absent. The corneal reflexes are preserved except in case of deep coma. Motor abnormalities like decerebrate rigidity, decorticate rigidity and opisthotonus can occur. Deep jerks and plantar reflexes are variable. Abdominal and cremasteric reflexes are not ellicitable. These signs help in distinguishing from behavioural problems due to fever of other causes.
These patients may also have anemia, jaundice and hepatosplenomegaly.
Investigations: Lumbar puncture and CSF analysis may have to be done in all doubtful cases and to rule out associated meningitis. In malaria, CSF pressure is normal to elevated, fluid is clear and WBCs are fewer than 10/µl; protein and lactic acid levels are elevated.
EEG may show non-specific abnormalities. CT scan of the brain is usually normal.
A large, prospective autopsy study of children dying with cerebral malaria in Malawi found that malarial retinopathy was better than any other clinical or laboratory feature in distinguishing malarial from non-malarial coma. The malarial retinopathy consists of four main components: retinal whitening, vessel changes, retinal hemorrhages, and papilledema. The first two of these abnormalities are specific to malaria, and are not seen in other ocular or systemic conditions.
See Beare NAV, Taylor TE, Harding SP, Lewallen S, Molyneux ME. Malarial Retinopathy: A Newly Established Diagnostic Sign in Severe Malaria. Am. J. Trop. Med. Hyg. 2006;75(5):790-797. Full Text Available at http://www.ajtmh.org/cgi/content/full/75/5/790
A case of severe retinal whitening has also been reported in an adult with cerebral malaria.
See Maude RJ, Hassan MU, Beare NAV. Severe Retinal Whitening in an Adult with Cerebral Malaria. Am. J. Trop. Med. Hyg., 2009;80(6):881. Available at http://www.ajtmh.org/cgi/reprint/80/6/881
Management:
1. Nursing care: Meticulous nursing is the most important aspect of management in these patients.
- Maintain a clear airway. In cases of prolonged, deep coma, endotracheal intubation may be indicated.
- Turn the patient every two hours.
- Avoid soiled and wet beds.
- Comatose patients should be placed in a semirecumbent position to reduce the risk for aspiration.
- Naso-gastric aspiration to prevent aspiration pneumonia.
- Maintain strict intake/output record. Observe for high coloured or black urine.
- Monitor vital signs every 4-6 hours.
- Changes in levels of sensorium, occurrence of convulsions should also be observed.
- If the temperature is above 390 C, tepid sponging and fanning must be done.
- Serum sodium concentration, arterial carbon dioxide tension, blood glucose, and arterial lactate concentration should be monitored frequently.
2. Urethral catheter can be inserted for monitoring urine output.
3. Seizures should be treated promptly with anticonvulsants, but their prophylactic use is still in dispute.[1] Diazepam by slow intravenous injection, (0.15 mg/kg, maximum of 10 mg), or intrarectally (0.5-1.0 mg/kg), or intramuscular paraldehyde are the drugs of choice.
4. Do not administer the following: Corticosteroids; other anti inflammatory drugs; anti oedema drugs like mannitol, urea, invert sugar; low molecular weight dextran; adrenaline; heparin; pentoxifylline; hyperbaric oxygen; ciclosporin etc. The efficacy of hypertonic mannitol in treatment of cerebral edema is not proven. Therapy with monoclonal antibodies against TNF-a shortens the duration of fever, but has no impact on mortality in patients with severe and complicated malaria, and may increase morbidity due to neurologic sequelae. Although corticosteroids were used in the past to treat patients with cerebral malaria, a controlled trial has shown that they are harmful. Those who received dexamethasone had a longer duration of coma and worse outcome than did patients who received antimalarial chemotherapy alone. Results of studies of antipyretics, pentoxifylline, hyperimmune serum, and iron chelators (deferoxamine) have shown no effect on outcome.[1]
5. Antimalarial treatment: Parenteral Quinine has been traditionally the treatment of choice for cerebral malaria. Artemisinin derivatives have been proved to be equally, if not more, effective in treating cerebral malaria. (For details see Treatment of Severe P. falciparum malaria)
Prognosis: Cerebral malaria carries a mortality of around 20% in adults and 15% in children. Residual deficits are unusual in adults (<3%). About 10% of the children (particularly those with recurrent hypoglycemia, severe anemia, repeated seizures and deep coma), who survive cerebral malaria may have persistent neurological deficits.
Cerebellar dysfunction: Rarely, cases of falciparum malaria may present with cerebellar ataxia with unimpaired consciousness. It may even occur 3-4 weeks after an attack of falciparum malaria. It completely recovers over 1-2 weeks.
Malarial psychosis: Occasionally patients with malaria may present with organic brain syndrome. More often it can develop due to drugs like chloroquine and mefloquine. It can also develop during convalescence after attacks of otherwise uncomplicated malaria. Malaria can also exacerbate pre-existing psychiatric illness. Patients can manifest with depression, paranoia, delusions and personality changes. Most of these are self-limiting and improve in a matter of days.
In a study of 118 cases of malaria in Mangalore, Nagesh Pai, Satish Rao and B.S. Kakkilaya found varied psychiatric manifestations. Most of these patients were already on antimalarial treatment at the time of referral to the psychiatric service (unpublished data).
| Feature | (n=118) | Feature | (n=118) |
| Delirium | 22 | Organic hallucinosis | 12 |
| Organic catatonic disorder | 4 | Organic delusional disorder | 9 |
| Organic mania | 7 | Organic Depressive disorder | 13 |
| Organic anxiety | 26 | Organic dissociative disorder | 2 |
| Mild cognitive disorder | 4 | Multiple vague complaints > 7days | 8 |
| Headache >7 days | 11 |
References:
- Andrej Trampuz, Matjaz Jereb, Igor Muzlovic, Rajesh M Prabhu. Clinical review: Severe malaria Critical Care 2003;7:315-323 Available at http://ccforum.com/content/7/4/315
- Guidelines for the treatment of malaria. World Health Organization. Geneva, 2006. pp 41-61. Available at http://apps.who.int/malaria/docs/TreatmentGuidelines2006.pdf
©malariasite.com ©BS Kakkilaya | Last Updated: Mar 11, 2015