CEREBRAL MALARIA

mechanisms of brain injury

(pathogenesis), treatment and neuro-

cognitive outcome.

introductory

Malaria is a mosquito-borne infectiousdisease of humans and other animalscaused by parasitic protozoans of thegenus Plasmodium. Commonly, thedisease is transmitted by a bite from aninfected female Anopheles mosquito,which introduces the organisms from itssaliva into a person's circulatory system.In the blood, the parasites travel to theliver to mature and reproduce.

Five species of Plasmodium can infect and be

transmitted by humans.

I. Plasmodium malariae

II. Plasmodium ovale

III. Plasmodium vivax

IV. Plasmodium falciparum

V. Plasmodium knowlesi

General pathophysiology

Malaria infection develops via two phases: 1. exoerythrocytic phase: involving the

liver and2. erythrocytic phase: involving red blood

cells, or erythrocytes.When an infected mosquito pierces aperson's skin to take a blood meal,sporozoites in the mosquito's saliva enterthe bloodstream and migrate to the liverwhere they infect hepatocytes, multiplyingasexually and asymptomatically for aperiod of 8–30 days.

After a potential dormant period inthe liver, these organismsdifferentiate to yield thousands ofmerozoites, which, following ruptureof their host cells, escape into theblood and infect red blood cells tobegin the erythrocytic stage of thelife cycle. The parasite escapes fromthe liver undetected by wrappingitself in the cell membrane of theinfected host liver cell.

Within the red blood cells, the parasites

multiply further, again asexually,

periodically breaking out of their host

cells to invade fresh red blood cells.

Several such amplification cycles occur.

Thus, classical descriptions of waves of

fever arise from simultaneous waves of

merozoites escaping and infecting red

blood cells.

Pathogenesis of cerebral

malaria

It is likely that the pathologies

underlying CM in humans are

highly variable and reflect a

range of attributes, including

parasite virulence, host

susceptibility and comorbidities

ranging from malnutrition to

coinfection.

Most observations of the

pathophysiology of disease come

from postmortem observations of

Plasmodium falciparum (Pf)

infections, which are thought to

account for the vast majority of CM

cases, and show a common feature

of vascular sequestration of infected

erythrocytes (IE) in the brain.

The standard clinical definition of CM

centers on:

1. a state of unarousable coma

partnered with

2. the presence of malaria infected

red blood cells(parasitized red

blood cells (pRBCs)) in the

peripheral circulation and

3. a lack of other potential causes of

coma such as other infections or

hypoglycemia

Parasite sequestration in the

brain

Vascular sequestration of infected

erythrocytes (IE) in the brain is a

common feature of Cerebral Malaria.

The resulting pathophysiological

changes in tissue around the

sequestered parasites, which may

explain why an intravascular parasite

may cause neural dysfunction and

why some patients may have a poor

outcome.

Sequestration results from adherence of

pRBCs to the endothelial lining

(cytoadherence) using parasite derived

proteins exposed on erythrocyte surface.

A group of parasite antigens including

Plasmodium falciparum erythrocyte

membrane protein-1 (PfEMP-1) mediate

binding to host receptors of which,

intercellular adhesion molecule-1 (ICAM-

1) is the most important and whose

expression is upregulated in areas adjacent

to sequestered parasites.

Sequestration impairs perfusion and

may aggravate coma through hypoxia.

Furthermore, the ability of pRBCs to

deform and pass through the

microvasculature is decreased.

Therefore, hypoxia and inadequate

tissue perfusion may be major

pathophysiological events.

Cytokines, chemokines and

excitotoxicity

Cytokines and chemokines play acomplex role in pathogenesis andhave both protective and harmfuleffects. Parasite antigens released atschizogony trigger the release of bothpro- and anti-inflammatory cytokines.Although the balance between thesemediators is critical for parasitecontrol, their role in pathogenesis ofthe neuronal damage is unclear.

Tumour necrosis factor (TNF), the most

extensively studied cytokine in cerebral

malaria, upregulates ICAM-1 expression

on the cerebral vascular endothelium

increasing the cytoadhesion of pRBCs.

Near areas of sequestration, there is

increased local synthesis.

The timing of this is important since early

in disease, TNF may be protective but

prolonged high levels contribute to

complications.

Endothelial injury, apoptosis, blood-brain

barrier (BBB) dysfunction and

intracranial hypertension

Cytoadherence of pRBCs to theendothelium initiates a cascade ofevents beginning with thetranscription of genes involved ininflammation, cell-to-cell signallingand signal transduction, whichresult in endothelial activation,release of endothelial micro-particles (EMPs) and apoptosis ofhost cells.

There is widespread

endothelial activation in

vessels containing pRBCs

and compared to other

complications of falciparum

malaria, significant increases

in circulating EMPs are seen

in patients in coma

Interactions between pRBCs

and platelets (which produce

platelet microparticles) cause

further injury to endothelial

cells through a direct

cytotoxic effect.

treatment

Cerebral malaria is a

syndrome of severe

malaria and therefore its

treatment falls under the

regime of treatment for

severe malaria.

objectives of treatment

The primary objective of antimalarialtreatment in severe malaria is to preventdeath.

In treating cerebral malaria, preventionof neurological deficit is an importantobjective. In the treatment of severemalaria in pregnancy, saving the life of themother is the primary objective. In all casesof severe malaria, prevention ofrecrudescence and avoidance of minoradverse effects are secondary.

Clinical features

impaired consciousness or unrousable

coma

prostration, i.e. generalized weakness

so that the patient is unable walk

or sit up without assistance

failure to feed

multiple convulsions – more than two

episodes in 24 h

Clinical features

– deep breathing, respiratory distress(acidotic breathing)

– circulatory collapse or shock, systolicblood pressure < 70 mm Hg in adults

and < 50 mm Hg in children

– clinical jaundice plus evidence of othervital organ dysfunction

– haemoglobinuria

– abnormal spontaneous bleeding

– pulmonary oedema (radiological)

Laboratory findings

hypoglycaemia (blood glucose < 2.2 mmol/l or <40 mg/dl)

– metabolic acidosis (plasma bicarbonate < 15mmol/l)

– severe normocytic anaemia (Hb < 5 g/dl,packed cell volume < 15%)

– haemoglobinuria

– hyperparasitaemia (> 2%/100 000/μl in lowintensity transmission areas or > 5%

or 250 000/μl in areas of high stable malariatransmission intensity)

– hyperlactataemia (lactate > 5 mmol/l)

– renal impairment (serum creatinine > 265μmol/l).

differential diagnosis

Coma and fever may result from

meningo-encephalitis or malaria.

Cerebral malaria is not associated with

signs of meningeal irritation (neck

stiffness, photophobia or Kernig sign),

but the patient may be opistotonic. As

untreated bacterial meningitis is almost

invariably fatal, a diagnostic lumbar

puncture should be performed to

exclude this condition.

Specific antimalarial treatment

It is essential that effective, parenteral

(or rectal) antimalarial treatment in full

doses is given promptly in severe

malaria. Two classes of medicines are

available for the parenteral treatment of

severe malaria:

the cinchona alkaloids (quinine and

quinidine) and the

artemisinin derivatives (artesunate,

artemether and artemotil).

Parenteral Chloroquine is no

longer recommended for the

treatment of severe malaria,

because of widespread

resistance. Intramuscular

sulfadoxine-pyrimethamine

is also not recommended.

Artemisinin derivatives

Various artemisinin derivatives have

been used in the treatment of severe

malaria, including

1. artemether

2. artemisinin

3. artemotil

4. artesunate

In treatment, artesunate 2.4 mg/kg BW IV orIM given on admission (time = 0), then at 12 hand 24 h, then once a day is therecommended treatment.

Artemether, or quinine, is an acceptablealternative if parenteral artesunate is notavailable: artemether 3.2 mg/kg BW IM givenon admission then 1.6 mg/kg BW per day ;

or quinine 20 mg salt/kg BW on admission(IV infusion or divided IM injection), then 10mg/kg BW every 8 h; infusion rate should notexceed 5 mg salt/ kg BW per hour.

neuro-cognitive complications

and outcome Cognitive sequelae - Risk factors for

cognitive impairment included

1. Hypoglycemia

2. Seizures

3. depth and duration of coma

4. hyporeflexia

Speech and language impairment

- Cerebral malaria is a leading

cause of acquired language

disorder in the tropics; 11.8% of

surviving children have deficits

especially in vocabulary, receptive

and expressive speech, word

finding and phonology.

Epilepsy - Epilepsy develops in about 10% of

exposed children months to years after

exposure and the cumulative incidence

increases with time.

Behavior and neuro-psychiatric disorders

In children, behavior problems include:

1. Inattention

2. impulsiveness and hyperactivity

3. conduct disorders and impaired social

development

4. Obsessive, self injurious and destructive

behaviors are also observed