JOURNAL READING

Human Cerebral Malaria : 2019 Mini Review

 ABSTRACT
During severe malaria, both in endemic and non-endemic areas, cerebral malaria is strongly associated with
mortality and morbidity. The main mechanisms of cerebral malaria combine sequestration of parasitized red
blood cells in brain capillaries, production of cytokines, immune cell/platelet accumulation, and release of
microparticules, finally resulting in endothelial lesions of the blood brain barrier, which contribute to
various brain injuries (oedema, ischemia, haemorrhages). The neurological clinical findings range from
simple delirium to profound coma. Fundoscopy, reflect of the brain microcirculation, is now currently
realized in endemic areas, and should be recommended during imported cerebral malaria. Likewise, cerebral
imaging should be systematically realized in patients with cerebral malaria. Intravenous artesunate is now
firmly established as the treatment of choice for severe malaria worldwide in adults, children and during
pregnancy. General care and supportive treatment are crucially important and supportive treatment of
cerebral malaria should be better standardized. Finally, experimental and clinical research has a key role in
cerebral malaria, so as to identify possible therapeutic targets in order to develop innovative therapies
 INTRODUCTIO
N
Severe malaria, one of the most serious infectious emergencies, is mostly
related to Plasmodium falciparum, and cerebral malaria is common and
strongly related to mortality and morbidity.

Around 93% of patients who die from malaria live in sub Saharan Africa,
mainly related to P. falciparum (99%), and many are children younger
than 5 years of age. France is the first country concerning imported
malaria with about 4000-5000 cases diagnosed each year, including 10 to
15% of severe malaria episodes and 10-20 deaths annually.
DEFINITION
Cerebral malaria is the first clinical criterion and corresponds to an
‘‘impaired consciousness’’ defined as a coma with a Glasgow Coma Scale
(GCS) score < 11 in adults and a Blantyre score < 3 in children.

Sequestration of IE and endothelial
activation
• Mediated by cytoadherence of IE
• Parasite adhesins : PfEMP-1, HRP,
RESA Ag, RIFINS
• Endothelial receptors : CD36, EPCR,
ICAM-1, E-selectine, thrombospondin,
ELAM-1, V-CAM 1, PECAM-1.
• Sequestration & rosetting phenomenon
 capilary obstruction reducing blood
flow
PATHOPHYSIOLOGY
Immune cell accumulation
• IE, NPE, endothelial cells, mononuclear
cells, platelets  induce immune and
coagulation mechanisms
• Secretion of proinflammatory cytokines
(TNF, IFN, lymphotoxin)
• TNFMO activation, increased
sequestration, up-regulated ROS
• CD8+ T cells  cytotoxic local damage
to endothelium of BBB cytotoxic
oedema brain swelling
Coagulation, platelets and
microparticules
• PfEMP1 binds to EPCR inducing
procoagulant pathway by decreasing the
synthesis of both EPCR and activated
protein C & decreasing the endothelial
cytoprotection by blocking the
interaction between APC and EPCR 
thrombin-induced permeability of BBB
 brain swelling
• Platelets bind to IE, to endothelial, to
rosettesexpress cytokines and
chemokines vaskular leakage and
microvascular damage
 CLINICAL & IMAGINING ASPECTS OF CEREBRAL
MALARIA
Clinical symptoms and
funcuscopy Brain imaging

●Uncomplicated malaria : asthenia, fever, chills, headache, ●MRI  cerebral swelling

myalgia, abdominal pain, diarrhea, and cough. ●28 adults  cortical infarcts in 3 pts, cerebral oedema in
●CM  neurologic manifests : delirium to coma, 3 pts, hematoma in 2 pts, abnormalities of the deep white
convulsions matter in 3, meningeal enhancement in 1 pts
●Funduscopy  retinal whitening, discoloration of retinal
vessel, retinal hemorrhages, papilledema, cotton-like
nodules and retinal exudates
●Funcduscopy  may help in diagnosing intracranial HTN
(bilateral papilledema)
 Management of Cerebral Malaria
Specific antimalarial
treatments
● Since 2010 in Europe and worldwide, IV artesunate (an hemi-synthetic
derivative of artemisinin) is the new reference treatment of severe malaria in
adults, children and during pregnancy.
● In Asian adults  IV artesunate was clearly superior over IV quinine (less
mortality and better safety profile)
● WHO guidelines recommend artesunate as the first choice in severe malaria
 Management of Cerebral Malaria
Supportive care of
neurological disturbances
• ICU should be considered to patiens with severe complicated malaria. Patient’s state of consciousness must be
closely monitored with repeated GCS Score measurement

• Hypoglycemia must be ruled out in patients presenting with neurological failure, and the consciousness must
be reassessed after correction

• Lumbal puncture may be considered in coma patients to rule out bacterial meningitis

• CT scan/MRI  case of focal signs, seizures, or consciousness disorders

• Management coma  orotracheal intubation to preventing cerebral oedema and secondary brain lesions of
systemic origin. Prevention  rising the patient’s head at 30– 45, maintaining normonatremia, normocapnia,
normothermia, normoglycemia, normo-pH, and SpO2 > 95%.

• Repeated transcranial Doppler imaging  monitored intracranial hypertension

• Mannitol for cerebral oedema is not recommended (except in case of brain herniation)
 Management of Cerebral Malaria
Adjuvant treatments

• High dose steroid therapy is not recommended, except for exceptional cases of acute disseminated
encephalomyelitis associated with malaria or with post malaria neurological syndrome

• No other adjunctive treatments (anti-TNF antibodies, iron chelators, pentoxifylline, IV immunoglobulins,

ciclosporin A, N-acetylcysteine, heparin, aspirin, ibuprofen. . .) has proved clinically effective

• Treatments have recently been suggested  cytoadherence and/or rosetting inhibitors (high-affinity ligands to
inhibit binding between PfEMP1 and endothelial cells, levamisole, glycosaminoglycans), immunomodulators
(rosigli- tazone, pantethine, statins), anti-apoptosis molecules (fasudil), nitric oxide modulators (L-arginine,
inhaled NO), or neuro- protectors (erythropoietin, citicoline)
 CONCLUSION

Cerebral malaria is a frequent presentation of severe malaria both in endemic and non-endemic
industrialized areas. The fascinating and complex pathophysiology is centered by the sequestration of
infected erythrocytes in the brain microvasculature. The mortality and morbidity of cerebral malaria
are high, making a challenge for intensivists. To progress, we must both increase the quality of
prevention and improve the management of cerebral malaria. Finally, experimental and clinical
research play a key role to unravel the pathophysio- logy of cerebral malaria, to identify new
therapeutic targets and develop new therapies.