Journal of Infection (2004) 48, 86–90

www.elsevierhealth.com/journals/jinf

Cerebral venous and dural sinus thrombosis in
severe falciparum malaria
A. Krishnana, D.R. Karnada,*, U. Limayeb, W. Siddharthb
a

Medical Neurology Neurosurgery Intensive Care Unit, Department of Medicine, King Edward Memorial
Hospital, Parel, Mumbai 400 012, India
b
Department of Radiology, King Edward Memorial Hospital, Parel, Mumbai 400 012, India
Accepted 1 July 2003

KEYWORDS
Plasmodium falciparum;
Cerebral malaria;
Cortical venous
thrombosis; Superior
sagittal sinus;
Coagulation;
Hypercoagulable state;
Cerebral infarction;
Cerebral haemorrhage

Summary Common causes of coma in falciparum malaria are cerebral malaria,
hypoglycaemia and electrolyte disturbances. Focal deficits due to arterial infarcts may
sometimes occur in children, but are rare in adults. Three adults with falciparum
malaria who had fever, altered consciousness and focal neurological deficits (one of
whom also had seizures) are being reported here. CT scan of the brain revealed
haemorrhagic infarction of the cerebral cortex and subcortical white matter with
surrounding oedema suggestive of venous infarction in all three patients. The diagnosis
of cerebral venous thrombosis was missed in the first patient, and was detected only at
autopsy. In the next two patients, superior sagittal sinus thrombosis was confirmed
angiographically. Only one patient survived; the other two died of increased
intracranial pressure. Two of the three patients also had Plasmodium vivax coinfection. A hypercoagulable state resulting from severe malaria may be responsible
for this rare and potentially fatal complication. Cerebral malaria may be associated
with raised intracranial pressure due to cerebral oedema. Cerebral venous thrombosis
may worsen this and adversely affect outcome. This diagnosis should be suspected in
patients with severe malaria who develop focal neurological deficits and confirmed by
appropriate imaging; judicious use of local thrombolytic therapy may help improve
outcome.
Q 2003 The British Infection Society. Published by Elsevier Ltd. All rights reserved.

Cerebral venous and dural sinus
thrombosis in severe falciparum malaria
Cerebral venous thrombosis can complicate several
intracranial infections like bacterial meningitis,
subdural empyema and suppurative otitis media.1
It may also occur in conditions that increase blood
viscosity like dehydration, polycythaemia vera and
thrombocytosis. 1 Hypercoagulable states like
antithrombin III, protein C or protein S deficiency
*Corresponding author.
E-mail address: karnad@vsnl.net

may be present in some patients with cerebral
venous thrombosis.1 In women, it may also complicate the course of pregnancy or puerperium.1
A hypercoagulable state has been demonstrated
in patients with falciparum malaria.2 – 8 Excess
activation of platelets and the coagulation cascade
may give rise to disseminated intravascular coagulation or thrombocytopenia. Studies on brain
imaging in cerebral malaria have shown cerebral
oedema, bithalamic and cerebellar hypodensities,
small areas of haemorrhagic cortical infarcts and
diffuse white matter changes.9 – 11 However. intracranial venous thrombosis has not been reported in

0163-4453/$30.00 Q 2003 The British Infection Society. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/S0163-4453(03)00130-0

Cerebral venous and dural sinus thrombosis in severe falciparum malaria

patients with malaria. Of the 497 patients with
severe falciparum malaria admitted to the medical
intensive care unit during a 3-year period; three
patients had cortical venous thrombosis and are
reported in this paper.

Case 1
A 45-year-old man was admitted to another hospital
for intermittent fever with chills and rigors.
Peripheral blood smear showed trophozoites of
Plasmodium vivax. He was treated with oral
chloroquine but continued to remain febrile. Two
days later he developed sudden onset of unconsciousness and left hemiparesis for which he was
transferred to our hospital. On admission he was
febrile, had mild splenomegaly and was unconscious (Glasgow Coma Scale (GCS) ¼ 6) with dense
left hemiplegia. Deep tendon reflexes were absent
in the left limbs and the left plantar reflex was
extensor. Laboratory tests revealed a haematocrit
of 32%, total leukocyte count of 5.6 £ 109/L and
platelet count was 1.81 £ 109/L. Peripheral blood
smear revealed mixed infection with P. vivax as
well as Plasmodium falciparum. BUN was 18 mg%
and serum electrolytes, prothrombin time (PT) and
activated partial thromboplastin time (aPTT) were
normal. CT scan revealed a haematoma in the right
parietal lobe with surrounding oedema, midline
shift and subfalcine herniation (Fig. 1(A)). Central
venous pressure (CVP) was recorded to be 4 –6 cm of
water. Intravenous quinine was administered and
mannitol was also added in view of raised intracranial pressure. His consciousness deteriorated progressively to GCS 3, and he developed signs of
transtentorial herniation; neurosurgical evacuation
of the clot was done. After initial transient
improvement he worsened and died of brainstem
dysfunction due to raised intracranial pressure 6 h
later. Post-mortem examination revealed extensive
thrombosis of the cerebral cortical veins, posterior
part of the superior sagittal sinus (SSS) and the
superficial cerebral veins with haemorrhagic infarction of the right parietal lobe. This diagnosis was
missed ante mortem.

Case 2
This 48-year-old male had intermittent high grade
fever since 2 days and three episodes of left focal to
secondary generalized seizures followed by unconsciousness 2 h before admission. On examination,
GCS was 6 and he had left hemiplegia with left

87

upper motor neuron facial palsy. The haematocrit
was 40%, total leukocyte count 8.7 £ 109/L and the
platelet count was 0.8 £ 109/L. PT, aPTT and blood
glucose levels were normal. Peripheral blood smear
showed trophozoites of P. falciparum with a
parasitic index of 2%. BUN was 12 mg%, uric acid
4.0 mg% and electrolytes were within normal range.
CVP on admission was 6 – 8 cm of water. Intravenous
quinine was started. CT scan showed right frontal
haemorrhagic infarction and absence of contrast in
the posterior end of the SSS (Fig. 1(B)). Digital
subtraction angiography (DSA) confirmed thrombosis of the SSS along its entire extent (Fig. 2).
Transcatheter thrombolytic therapy was initiated
with urokinase. This was continued for 36 h,
followed by anticoagulation with heparin. He
gradually improved and 4 days later GCS was 13
and power in left limbs was grade 2/5. A repeat DSA
showed recanalisation of almost the entire SSS
except a small segment in the middle third. He was
discharged after 17 days in hospital on oral anticoagulation. One year later, there was mild stiffness in the left side of the body and the CT scan
showed gliotic changes in the right frontal area.

Case 3
This 35-year-old man was treated for mixed infection with P. vivax and P. falciparum with oral
chloroquine and intramuscular artesunate. He
became afebrile with this treatment but 48 h later
he became drowsy and developed right hemiparesis. On examination, vital signs were normal.
Power in the right upper limb was grade 3/5 and
grade 4/5 in the right lower limb with upper motor
neuron right facial paresis. The haematocrit was
45% with normal platelet and leukocyte counts, PT
and aPTT. Blood urea nitrogen was 14 mg% and
electrolytes normal. CT scan showed haemorrhagic
infarction in the left frontoparietal region with
surrounding oedema. DSA showed extensive thrombosis of the SSS and transverse sinus. However, as
an angiography catheter could not be negotiated to
the site of thrombosis, local thrombolysis was not
feasible. Intravenous quinine and mannitol were
given, but the patient developed progressive signs
of transtentorial herniation with brainstem dysfunction and died 24 h after the onset of focal
deficits.

Discussion
Activation of the intrinsic coagulation cascade

88

A. Krishnan et al.

Figure 1 Non-enhanced CT scan of the brain of patient 1 (Panel A) showing a large right temporoparietal haemorrhagic
infarct with surrounding cerebral oedema, midline shift and brain stem compression. Contrast enhanced CT scan (brain)
of patient 2 (Panel B) showing a large area of hemorrhagic infarction in the right frontoparietal cortex with surrounding
oedema. Absence of contrast is seen as a hypodense area in the posterior aspect of the superior sagittal sinus—the
‘empty delta’ sign (arrow).

Figure 2 Venous phase of digital subtraction angiogram in right anterior oblique view. Note the normal filling of the
entire length of the superior sagittal sinus (solid arrowheads) in Panel A. The angiogram of patient 2 (Panel B) showing
absence of opacification of the anterior portion of the superior sagittal sinus (SSS) and multiple irregular filling defects
(open arrowheads) in the posterior part of the SSS. The superficial cerebral veins that drain the anterior part of the SSS
too are not opacified unlike the posterior veins that are clearly seen.

Cerebral venous and dural sinus thrombosis in severe falciparum malaria

may occur in falciparum malaria as a result of
endothelial damage resulting from adhesion of
parasitized RBCs and marginated mononuclear
cells to the walls of capillaries and venules.2,3
Release of tissue factor from monocytes and
changes in the lipid structure of the cell membrane
of infected erythrocytes activate the extrinsic
coagulation pathway as well.4 – 6 Simultaneously,
there is activation of the antithrombotic systems
with increased levels of circulating thrombin –
antithrombin III complexes.2,4,7,8,12 Ultimately,
there is depletion of antithrombotic plasma proteins like antithrombin III, protein C and protein S
while levels of fibrinogen and other clotting factors
may remain unchanged.4,7,8 Circulating levels of
fibrin degradation products, fibrinopeptide-A and
D-dimer are increased in many patients with severe
malaria due to fibrinolytic activity4,14,15 which may
explain why fibrin clots are demonstrable in only
some but not all patients dying of cerebral
malaria.15,16 A recent study has shown that tissue
plasminogen activator in blood is severely depleted
while plasminogen activator inhibitor (PAI-1) level
is increased with increasing severity of malaria.4
The net effect of these abnormalities is a hypercoagulable state, which manifests as disseminated
intravascular coagulation in 16 – 26% of patients with
severe falciparum malaria, although overt bleeding
is seen in only 5% of patients.13 Thrombocytopenia
due to intravascular platelet activation too may add
to the capillary clogging as well as to the bleeding
diathesis.2,17 While several studies have demonstrated that coagulopathy increases in parallel with
the severity of P. falciparum infection,2 coagulation disturbances are extremely rare in vivax
malaria.4,18,19 Hence, the significance of P. vivax
co-infection in two of our three patients is unclear.
While microvascular thrombosis in the cerebral
capillaries and venules is an important mechanism
of neurological affection in cerebral malaria,3,20
thrombosis in larger vessels is rare. Brewster et al.21
found cerebral infarction due to arterial occlusion
in five out of 11 African children with severe
malaria. Obama et al.22 found that cerebral malaria
was responsible for 14% of all strokes in children in
Cameroon. Seven patients with gangrene of the
extremities and digits have been reported to date,
one of whom was successfully treated with thrombolytic therapy.23 – 25 However, intracranial venous
thrombosis has not been reported before. It is not
clear as to why thrombosis should occur in the
intracerebral venous system. During the later
phases of the lifecycle of P. falciparum, adhesion
of parasitized RBCs to capillary and post-capillary
venular endothelium seems to be essential.19,20
This sequestration of RBCs is maximum in the brain

89

and MacPherson et al.26 have shown that 45% of
RBCs in the smaller cerebral vessels are parasitized
compared to 4 – 19% in other organs. It is therefore
possible that the resulting derangement of coagulation may be most pronounced in cerebral venules
and could result in spontaneous thrombosis in the
veins and dural sinuses, which drain these vascular
beds. Further studies are needed to investigate this
hypothesis.
Thus, cerebral venous and dural sinus thrombosis
may rarely complicate the course of severe falciparum malaria. As the hypercoagulable state can
persist for 7 – 10 days after initiation of antimalarial
therapy4 venous thrombosis could occur even after
clearance of parasitaemia (as in our patient 3). The
major cause of convulsions and coma in patients
with falciparum infection is cerebral malaria
itself.27 Hypoglycaemia, which occurs in 20 – 32%
of patients with severe malaria, may also cause
coma and seizures.15,16 However, neither of these
causes focal neurological deficits. Cerebral venous
and dural sinus thrombosis should be suspected if a
focal neurological deficit develops in a patient with
cerebral malaria and the CT scan reveals haemorrhagic cerebral infarction. The diagnosis was
missed in Patient 1. However, past experience led
to prompt diagnosis in patients 2 and 3. Intracranial
venous thrombosis may substantially increase mortality in cerebral malaria by further increasing
intracranial pressure due mass effect caused by
parenchymal haemorrhage and perilesional oedema
as well as by impeding the venous drainage.

Acknowledgements
The authors are grateful to Dr Tufail Patankar for
providing imaging and clinical details of patient 1.

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