mechanisms of brain injury (pathogenesis), treatment and neuro-cognitive outcome.

1. CEREBRAL MALARIA
mechanisms of brain injury
(pathogenesis), treatment and neuro-
cognitive outcome.

2. introductory
Malaria is a mosquito-borne infectious
disease of humans and other animals
caused by parasitic protozoans of the
genus Plasmodium. Commonly, the
disease is transmitted by a bite from an
infected female Anopheles mosquito,
which introduces the organisms from its
saliva into a person's circulatory system.
In the blood, the parasites travel to the
liver to mature and reproduce.

3. 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

4. General pathophysiology
Malaria infection develops via two phases:
1. exoerythrocytic phase: involving the
liver and
2. erythrocytic phase: involving red blood
cells, or erythrocytes.
When an infected mosquito pierces a
person's skin to take a blood meal,
sporozoites in the mosquito's saliva enter
the bloodstream and migrate to the liver
where they infect hepatocytes, multiplying
asexually and asymptomatically for a
period of 8–30 days.

5. After a potential dormant period in
the liver, these organisms
differentiate to yield thousands of
merozoites, which, following rupture
of their host cells, escape into the
blood and infect red blood cells to
begin the erythrocytic stage of the
life cycle. The parasite escapes from
the liver undetected by wrapping
itself in the cell membrane of the
infected host liver cell.

6. 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.

8. 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.

9. 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.

10. 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

11. 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.

12.  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

13.  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.

14. Cytokines, chemokines and
excitotoxicity
 Cytokines and chemokines play a
complex role in pathogenesis and
have both protective and harmful
effects. Parasite antigens released at
schizogony trigger the release of both
pro- and anti-inflammatory cytokines.
Although the balance between these
mediators is critical for parasite
control, their role in pathogenesis of
the neuronal damage is unclear.

15. 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.

16. Endothelial injury, apoptosis, blood-brain
barrier (BBB) dysfunction and
intracranial hypertension
Cytoadherence of pRBCs to the
endothelium initiates a cascade of
events beginning with the
transcription of genes involved in
inflammation, cell-to-cell signalling
and signal transduction, which
result in endothelial activation,
release of endothelial micro-
particles (EMPs) and apoptosis of
host cells.

17. 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

18. Interactions between pRBCs
and platelets (which produce
platelet microparticles) cause
further injury to endothelial
cells through a direct
cytotoxic effect.

20. treatment
Cerebral malaria is a
syndrome of severe
malaria and therefore its
treatment falls under the
regime of treatment for
severe malaria.

21. objectives of treatment
The primary objective of antimalarial
treatment in severe malaria is to prevent
death.
In treating cerebral malaria, prevention
of neurological deficit is an important
objective. In the treatment of severe
malaria in pregnancy, saving the life of the
mother is the primary objective. In all cases
of severe malaria, prevention of
recrudescence and avoidance of minor
adverse effects are secondary.

22. 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

23. Clinical features
 – deep breathing, respiratory distress
(acidotic breathing)
 – circulatory collapse or shock, systolic
blood pressure < 70 mm Hg in adults
 and < 50 mm Hg in children
 – clinical jaundice plus evidence of other
vital organ dysfunction
 – haemoglobinuria
 – abnormal spontaneous bleeding
 – pulmonary oedema (radiological)

24. Laboratory findings
 hypoglycaemia (blood glucose < 2.2 mmol/l or <
40 mg/dl)
 – metabolic acidosis (plasma bicarbonate < 15
mmol/l)
 – severe normocytic anaemia (Hb < 5 g/dl,
packed cell volume < 15%)
 – haemoglobinuria
 – hyperparasitaemia (> 2%/100 000/μl in low
intensity transmission areas or > 5%
 or 250 000/μl in areas of high stable malaria
transmission intensity)
 – hyperlactataemia (lactate > 5 mmol/l)
 – renal impairment (serum creatinine > 265
μmol/l).

25. 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.

26. 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).

27. Parenteral Chloroquine is no
longer recommended for the
treatment of severe malaria,
because of widespread
resistance. Intramuscular
sulfadoxine-pyrimethamine
is also not recommended.

28. Artemisinin derivatives
Various artemisinin derivatives have
been used in the treatment of severe
malaria, including
1. artemether
2. artemisinin
3. artemotil
4. artesunate

29. In treatment, artesunate 2.4 mg/kg BW IV or
IM given on admission (time = 0), then at 12 h
and 24 h, then once a day is the
recommended treatment.
Artemether, or quinine, is an acceptable
alternative if parenteral artesunate is not
available: artemether 3.2 mg/kg BW IM given
on 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 10
mg/kg BW every 8 h; infusion rate should not
exceed 5 mg salt/ kg BW per hour.

30. 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

31.  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.

32.  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