Cerebral Malaria

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.

See Pathology

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.

Malarial Retinopathy:

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

Cerebral malaria in children

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:

  1. 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
  2. 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

Severe Malaria

Severe falciparum malaria is defined by the demonstration of asexual forms of P. falciparum in a patient with a potentially fatal manifestation or complication of malaria in whom other diagnoses have been excluded.

Even though the complications are almost unique to P. falciparum infection, that DOES NOT mean that all cases of P. falciparum malaria invariably develop complications. The case fatality of P. falciparum malaria is around 1 per cent and this accounts for more than half a million deaths per year all over the world; 80% of these deaths are caused by cerebral malaria.

In 1990, the World Health Organization (WHO) established criteria for severe malaria and these were revised in the year 2000 to include other clinical manifestations and laboratory values that portend a poor prognosis based on clinical experience in semi-immune patients (Table 1). The major complications of severe malaria include cerebral malaria, pulmonary edema, acute renal failure, severe anemia, and/or bleeding. Acidosis and hypoglycemia are the most common metabolic complications. Any of these complications can develop rapidly and progress to death within hours or days.[1]

The presentation of severe malaria varies with age and geographical distribution. In areas of high malaria transmission, severe malaria mainly affects children under five years of age. The mortality rate is higher in adults than in children but African children develop neuro-cognitive sequelae following severe malaria more frequently. In children, the complications include metabolic acidosis (often caused by hypovolaemia), hypoglycaemia, hyperlacticacidaemia, severe anaemia, seizures and raised intracranial pressure and concomitant bacterial infections occur more frequently. In adults, renal failure and pulmonary oedema are more common causes of death.[2]

In many patients, several of these complications exist together or evolve in rapid succession within a few hours. In clinical practice, patients must be assessed for any of these signs or symptoms that suggest an increased risk for developing complications and must be treated immediately. In various studies risk factors for severe malaria and death include age greater than 65 years, female sex (especially when associated with pregnancy), nonimmune status, coexisting medical conditions, no antimalarial prophylaxis, delay in treatment, and severity of the illness at admission (coma, acute renal failure, shock, pulmonary edema, coagulation disorders). In tropical countries with a high transmission of malaria (hyperendemic areas), severe malaria is predominantly a disease of young children (1 month to 5 years of age).[1]

Predisposing factors for complications and death from P. falciparum malaria:

In various studies, risk factors for severe malaria and death include age greater than 65 years, female sex (especially when associated with pregnancy), nonimmune status, coexisting medical conditions, no antimalarial prophylaxis, delay in treatment, and severity of the illness at admission (coma, acute renal failure, shock, pulmonary edema, coagulation disorders). In tropical countries with a high transmission of malaria (hyperendemic areas), severe malaria is predominantly a disease of young children (1 month to 5 years of age).[1]

Lab. abnormalities:

Thrombocytopenia is the most common laboratory abnormality (60% of cases), followed by hyperbilirubinemia (40%), anemia (30%), and elevated hepatic aminotransferase levels (25%). The leukocyte count is usually normal or low, but neutrophilia with a marked increase in band forms (left shift) is present in the majority of cases. The erythrocyte sedimentation rate, C-reactive protein, and procalcitonin are almost invariably elevated. The severity of malaria corresponds to the degree of the laboratory abnormalities. In one study of travelers who returned from the tropics, thrombocytopenia and hyperbilirubinemia had a positive predictive value of 95% for malaria.[1]

Severe manifestations and complications of P. falciparum malaria

In a patient with falciparum malaria in whom other diseases have been excluded, the presence of one or more of the following manifestations is sufficient for a diagnosis of severe falciparum malaria.

Table 1: Indicators of severe malaria and poor prognosis [1,3-5]
Manifestation Features
Initial World Health Organization criteria from 1990 [3]
1. Cerebral malaria: Unarousable coma not attributable to any other cause, with a Glasgow Coma Scale score ≤9; Coma should persist for at least 30 min after a generalized convulsion
2. Severe anemia Hematocrit <15% or hemoglobin < 50 g/l in the presence of parasite count >10000/µl
3. Renal failure Urine output <400 ml/24 hours in adults (<12 ml/kg/24 hours in children) and a serum creatinine >265 µmol/l (> 3.0 mg/dl) despite adequate volume repletion
4. Metabolic (Lactic) Acidosis/acidosis Metabolic acidosis is defined by an arterial blood pH of <7.35 with a plasma bicarbonate concentration of <22 mmol/L; hyperlactatemia is defined as a plasma lactate concentration of 2-5 mmol/L and lactic acidosis is characterized by a pH <7.25 and a plasma lactate >5 mmol/L.
5. Pulmonary edema or acute respiratory distress syndrome (ARDS) Breathlessness, bilateral crackles, and other features of pulmonary oedema. The acute lung injury score is calculated on the basis of radiographic densities, severity of hypoxemia, and positive end-expiratory pressure
6. Hypoglycemia Whole blood glucose concentration of less than 2.2 mmol/l (less than 40 mg/dl).td
7. Hypotension and shock (algid malaria) Systolic blood pressure <50 mmHg in children 1-5 years or <70 mm Hg in patients ≥5 years; cold and clammy skin or a core-skin temperature difference >100C
8. Abnormal bleeding and/or disseminated intavascular coagulation Spontaneous bleeding from the gums, nose, gastrointestinal tract, retinal haemorrhages and/or laboratory evidence of disseminated intravascular coagulation.
9. Repeated generalised convulsions ≥3 generalized seizures within 24 hours
10. Haemoglobinuria Macroscopic black, brown or red urine; not associated with effects of oxidant drugs or enzyme defects (like G6PD deficiency)
Added World Health Organization criteria from 2000 [4]
11. Impaired consciousness Various levels of impairment may indicate severe infection although not falling into the definition of cerebral malaria. These patients are generally arousable
12. Prostration Extreme weakness, needs support
13. Hyperparasitemia 5% parasitized erythrocytes or > 250 000 parasites/µl (in nonimmune individuals)
14. Hyperpyrexia Core body temperature above 400C
15. Jaundice (Hyperbilirubinemia) Serum bilirubin of more than 43m mol/l (2.5 mg/dl).
Other
16. Fluid and electrolyte disturbances [5] Dehydration, postural hypotension, clinical evidence of hypovolemia
17. Vomiting of oral drugs Patients with persistent vomiting may have to be admitted for parenteral therapy.
18. Complicating or associated infections Aspiration bronchopneumonia, septicemia, urinary tract infection etc.
19. Other indicators of poor prognosis [5] Leukocyte count >12,000/cumm; high CSF lactate (>6 mmol/l)and low CSF glucose; more than 3-fold elevation of serum enzymes (aminotransferases); increased plasma 5′-nucleotidase; low antithrombin III levels; peripheral schizontemia; papilloedema/retinal oedema
20. Malarial Retinopathy A large, prospective autopsy study of children dying with cerebral malaria in Malawi found malarial retinopathy to be a better indicator of malarial coma. Similar retinopathy in an adult has also been reported.

Differential Diagnosis: The differential diagnosis of fever in a severely ill patient is broad. Coma and fever may result from meningoencephalitis or malaria. Cerebral malaria is not associated with signs of meningeal irritation (neck stiffness, photophobia, Kernig sign) but the patient may be opisthotonic. As untreated bacterial meningitis is almost invariably fatal, a diagnostic lumbar puncture should be performed to exclude this condition. There is also considerable clinical overlap between septicaemia, pneumonia and severe malaria – and these conditions may coexist. In malaria endemic areas particularly, where parasitaemia is common in the young age group, it is often impossible to rule out septicaemia in a shocked or severely ill obtunded child. Where possible, blood should always be taken on admission for culture, and if there is any doubt, empirical antibiotic treatment should be started immediately along with antimalarial treatment.[6]

Evaluation of the Patient

Malaria is a very simple disease to diagnose and treat; yet it claims more lives than any other infectious disease in the world. It is therefore very essential that every case of malaria be assessed thoroughly.

Clinical examination:

General: Functional status, prostration, breathlessness, level of consciousness, hydration, toxicity, puffiness of face and lids, etc.

Vital signs: Pulse rate, blood pressure (hypotension), temperature (hyperpyrexia), respiratory rate (tachypnoea, acidotic breathing).

Other signs: Pallor, Jaundice, Cyanosis, Edema, etc.

Abdomen: Liver, spleen, bowel sounds – Tender hepato/ splenomegaly is more common in acute malaria.

Respiratory system: Basal crackles, wheezes; sometimes, associated pneumonia and its bronchial breath sounds.

C.N.S.: Level of sensorium, convulsions, neck stiffness, ocular fundii, any focal deficits.

Investigations:

Hemoglobin: Anemia is common in malaria. Rapid reduction in level of hemoglobin is seen in falciparum malaria and less than 7 g/ dl should be a warning.

Total leukocyte count: It can vary from low to high, and neutrophilic leukocytosis is common in severe malaria with or without associated bacterial infection. Leukopenia is seen in severe malaria with septicemia, and chronic hypersplenism.

Platelet count: Thrombocytopenia is common in P. falciparum and P. vivax malaria, but it does not correlate with the severity of the infection.

Parasite count: This is a simple yet very important and useful method of assessing the severity of infection in falciparum malaria. It should be done routinely in all cases of falciparum malaria.

How to do a parasite count?

Thick film: The density of malarial parasites can be read against the leukocytes and an approximate parasite count can be calculated.

  1. Count the number of asexual forms of the parasite ( rings, trophozoites and schizonts) against 100 leukocytes and multiply by 75, this gives an approximate total per micro liter (mm3).
  2. The average leukocyte count per microscopic field is about ten. Therefore, multiply the average number of parasites per field by 750, this also gives an approximate total per micro liter.

Thin film: Count the number of parasites within 1000 red blood cells and divide this by 10. This gives the percentage of parasitemia.

A parasite count of 100000 or more per mm3 (or 5% and more) is considered as severe infection.

See details

Blood Glucose: Hypoglycemia is a common problem encountered in malaria and may remain undetected because the symptoms and signs of hypoglycemia viz. sweating, tachycardia etc., are even otherwise seen in malaria. It is very important to monitor the blood glucose levels once at least 6 hours in falciparum malaria, particularly if the patient is pregnant or is receiving quinine.

Other investigations:

Moderate elevation in blood urea and creatinine are common. Significant increase is suggestive of renal impairment.

Hyperbilirubinemia is common in malaria, particularly due to hemolysis. Some patients with falciparum malaria may have very high levels of conjugated bilirubin due to associated hepatocyte dysfunction.

Serum albumin levels may be reduced, some times markedly.

Serum aminotransferases, 5′ – nucleotidase and lactic dehydrogenase are elevated.

Prothrombin time and partial thromboplastin time are elevated in 20% of patients with cerebral malaria. Some may have features of disseminated intravascular coagulation.

Hyponatremia is common and needs careful management.

Lactic acidosis is seen in severely ill patients, especially in patients with hypoglycemia and renal dysfunction. It can be suspected if there is a wide anion gap.

Urine examination may show albuminuria, microscopic hematuria, hemoglobinuria and red cell casts. With massive intravascular hemolysis, urine may be black in colour.

Indications for hospitalisation of malarial cases:

  1. Persistence of fever even after 48 hours of initial treatment.
  2. Continuously worsening headache.
  3. Persistent vomiting.
  4. Any complications of P. falciparum malaria– altered sensorium, convulsions, anemia, jaundice, hyperpyrexia, bleeding and clotting disorders, breathlessness, high coloured urine etc.
  5. Patients who are at higher risk for development of complications of P. falciparum malaria-extremes of age, pregnancy etc.
  6. Patients who appear sick and prostrated
  7. Significant dehydration

References:

  1. 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
  2. Njuguna PW, Newton CR. Management of severe falciparum malaria. J Postgrad Med [serial online] 2004;50:45-50. Available at http://www.jpgmonline.com/text.asp?2004/50/1/45/6653
  3. World Health Organization: Severe and complicated malaria. Trans R Soc Trop Med Hyg 1990;84(suppl 2):S1-S65.
  4. World Health Organization: Severe falciparum malaria. Trans R Soc Trop Med Hyg 2000;94(suppl 1):S1-S90.
  5. Management of Severe Malaria: A practical handbook. Second edition. World Health Organization. Geneva, 2000. Available at http://apps.who.int/malaria/docs/hbsm.pdf
  6. Guidelines for the treatment of malaria. World Health Organization. Geneva, 2006. pp 41-61. Available at http://apps.who.int/malaria/docs/TreatmentGuidelines2006.pdf
  7. Jagannath Sarkar et al. Risk factors for malaria deaths in Jalpaiguri district, West Bengal, India: evidence for further action. Malaria Journal 2009;8:133 Available at
    http://www.malariajournal.com/content/pdf/1475-2875-8-133.pdf

 

©malariasite.com ©BS Kakkilaya | Last Updated: Mar 11, 2015