Cerebral Malaria is a form of severe (complicated) malaria in which there are alterations in the neurologic functions of the individual (evidenced by multiple convulsion and unarousable coma) usually due to Plasmodium falciparum. It was a descriptive,cross-sectional study, conducted at a tertiary health facility in Southwest Nigeria over a 6-month period during which consecutive children, aged 6 months to 15 years with confirmed features of severe malaria according to the World Health Organisation (WHO) criteria were recruited. Subsequently, those with defining features of cerebral malaria were identified and focused on. Sixty-eight participants (out of a total of 165 children with severe malaria i.e 41.2%) met the defining criteria for cerebral malaria. Sixty-three (92.3%) survived while 5 children (7.4%) died. Two study participants among the survivors (2.9%) had persisting neurologic deficits (hemiparesis and visual impairment) at discharge. Cerebral malaria is rife in the west, sub-Saharan Africa. Needless mortalities are still being recorded. The attendant neurologic sequelae limits the potentials of the affected children and also disrupts the socio-economic functioning and stability of the families where these children belong to.

Cerebral Malaria is a form of severe (complicated) malaria in which there are alterations in the neurologic functions of the individual (multiple convulsion and unarousable coma) usually due to Plasmodium falciparum.1–5Research has shown however, that other species of the Plasmodium species, notablyP. vivax and P. ovale,6 can also cause complicated malaria. P. falciparum however still accounts for >95% of cases of severe malaria because it is indiscriminate in its parasitization of red blood cells (RBCs); it parasitizes all stages of the erythrocyte development whereas P. vivax and P. ovalehave predilection for younger (immature) RBCs.7Multiple convulsion is defined as >2 episodes of seizures within 24hrs.4Chiabiet al8in a review of studies on severe malaria in African children concluded that while those with simple febrile seizures usually undergo complete resolution, multiple seizures (>2 episodes in 24hrs) have been shown to be a significant risk factor for mortality and in survivors, persisting neurologic and cognitive impairments following cerebral malaria. Coma (or impaired consciousness) is defined as inability to localise a painful stimulus at least an hour after termination of a seizure or correction of hypoglycaemia, detection of asexual forms of P. falciparum malaria parasites on peripheral blood smears, and exclusion of other causes of encephalopathy.9,10Idroet al11 in their study showed that the depth of the coma (impaired consciousness) is an important prognostic factor in complicated malaria. Impaired consciousness in combination with seizures have been shown to be associated

with a higher risk of mortality in children with severe malaria.8,12–14About 70% of malaria cases occur in Africa with as many as 80-90% of malaria deaths.15 Nigeria contributes the largest percentage of these cases.3 Hence, this study set out to describe the epidemiology of cerebral malaria and its outcome among Nigerian children.

Materials And Methods

It was a descriptive,cross-sectional study, conducted at the University College Hospital, Ibadan, Nigeria over a 6-month period (July-December, 2022). The study protocol was approved by the University of Ibadan (UI)/University College Hospital (UCH) Joint Ethics Review Committee prior to the commencement of the study (Approval Number: UI/EC/21/0629). Written informed consentwas obtained from the participants’ caregivers prior to recruitment into the study.

Consecutive children, aged 6 months to 15 years with confirmed features of severe malaria according to the World Health Organisation (WHO) criteria were recruited. Subsequently, those with defining features of cerebral malaria (multiple convulsion and unarousablecoma) were identified. The care of this group was in a high dependency ward. Some of them were subsequently transferred to the Paediatric Intensive Care Unit when the need for such arose. Theirsocio-demographic, clinical, laboratory and treatment information were obtained via a semi-structured questionnaire. The study participants were followed upuntil an outcome measure (survival or death) was obtained.

Sample size determination:

The minimum samplesize was calculated using the formulafor a single proportion in a cross-sectional study.16

[0.05]2

n              =             150

Allowing for 10% attrition (i.e 15), a total of 165 subjects was studied. Of the larger cohort of 165 participants with severe malaria, 68 met the defining criteria for cerebral malaria and this group was subsequently focused on.

Inclusion Criteria:

•              Children aged 6months -15years with confirmed features of severe malaria including either (or both) of the following:

             Multiple convulsion (>2 episodes in 24hrs)

             Coma (impaired consciousness)

Exclusion Criteria:

•              Children aged 6months -15years with other co- morbidities e.g meningitis

•              Children with pre-existing neurologic condition e.g hemiparesis from previous cerebrovascular accident, cerebral palsy, epilepsy

•              Children who died shortly after presentation before the clinical cause of death could be determined

Malaria diagnosis was done via Malaria Rapid Diagnostic Test (mRDT) kits and Blood film for Malaria Parasites. On admission, about 5ml of venous blood was drawn (while ensuring strict asepsis) to obtain a full blood count, blood culture and blood film for malaria parasites (to determine the parasite species and density). Blood samples for packed cell volume and mRDT were collected via capillary tubes.Randomblood glucose was done using handheld Accu- Chek® Active glucometer, Model GB (Serial No: GB19325136; Reference No: 06993770001) and Accu- Chek® Active glucometer strips. Lumbar puncture (LP) was doneexcept whenthere were clinical contraindications. The cerebrospinal fluid (CSF) obtained from the LP procedure was analysed (CSF Glucose compared with Blood Glucose,

Cell count, Gram’s staining and Culture) to rule out meningitis.

History of multiple convulsion was ascertained from the parents/caregivers or observed on presentation. The degree of impairment of consciousness (depth of coma) was assessed using either theGlasgow Coma Scale or the BlantyreComa scale. The WHO recommends the use of Glasgow coma score of ≤ 8 in children older than 3 years or a Blantyre score of ≤ 2 in children younger than 3 years.3,18,19

The treatment of severe malaria (specific and appropriate supportive care) was according to the Nigeria national malaria treatment guidelines 2020.7,20Thestudy participants were followed up (while on admission) until an outcome measure (survival or death) was obtained. The survivors had full neurologic evaluation at discharge and those with neurologic deficits were referred to the Paediatric Neurology Clinic of the study centre for follow up care.

Results

Sixty-eight participants (out of a total of 165 children with severe malaria i.e 41.2%) met the defining criteria for cerebral malaria. The male:female ratio was 1.4:1.0. There was an equal distribution between the under-fives and the children aged at least 5 years (1.0:1.0). The median duration of coma was 34.0hrs for survivors (range: 6.0-96.0hrs). Majority of the participants with cerebral malaria (57.4%) spent at least five days on admission. The survival rate was 92.6%. Sixty-one (i.e 89.7%) were discharged without neurologic sequelae whiletwo participants (2.9%) had persisting neurologic deficits (hemiparesis and visual impairment) at discharge. Five participants (7.4%) died.

Table 1: Summary of findings

Discussion

From the larger pool of children with severe malaria, about two-fifths were diagnosed with cerebral malaria. Its distribution was equal between the under-fives and the older children withslight male preponderance. This implies how common this disease is among children of all age groups; its fatality and attendant persisting neurologic sequelae cannot be overemphasised.19,21,22

That the incidence of cerebral malaria was equal in both the under-fives and the older children (as revealed by this study) has public health implications. This differs from previous studies17,23,24 in which the proportion of under-fives was significantly greater. This change (as observed in this study) has been attributed in part to the changing epidemiology of the disease25–27 and suggests prioritisation of intervention measures in all age-groups.28

In this study, the burden of the diseases was more among the males. This was similar to the finding of Msezaet al.22 The reason for this differential affliction of the male gender with the diseasehas not been clearly elucidated; however, some researchers have shown that high levels of dehydroepiandrosterone especially in the adolescent females confers some protection against malaria.28 Other possible reasons that have been alluded to include differences in exposure risksdue to outdoor activities and genetic variations in immune response genes.29–31

More episodes of convulsion and longer duration of coma have been shown to be contributory to neurologic deficits in children with Cerebral Malaria.8,19According to Boivinet al19andChandyet al32 most neurologic deficits observed at discharge usually resolve at 6months post discharge, however, the findings of Idroet al11,33,34and Opokaet al35 show that cerebral malaria is a leading cause of persistingneuro-disability in sub-Saharan Africa.

Neurologic deficits identified (hemiparesis and visual impairment) are comparable to those in previous studies11,33although other possible deficits following cerebral malaria (e.g hearing impairment, speech

impairment and behavioural disturbances) were not identified in this study in the participants at discharge. Also, other studies34have reported multiple neurologic sequelae in a single patient following cerebral malaria but no participant was identified with multiple neurologic sequelae in this study. The explanation could be due to the cross-sectional nature of this study compared with those other studies which were longitudinal.

Although, the estimated mortality rate of cerebral malaria in sub-Saharan Africa is between 18.0-20.0% among hospitalized children,19,34,36–38 the value obtained in this study was much lower (less than half of the quoted value) but comparable to the finding of Idroet al.39 The reason for the lower mortality rate recorded could be attributable (among others) to: ready availability of artemisinin-based therapy (which has significantly improved outcomes in the management of children with complicated malaria),38,40,41 administration of pre-referral artesunate,42,43 prompt referrals and prompt response of the medical team on participants’ arrival at the study centre.

Beyond the childhood mortality attributable to cerebral malaria, the severe socio-economic disruptions and the family dysfunction occasioned by having to care for a previously healthy child now limited by the sequelae of the disease (cerebral malaria) also calls for attention.37 Frequent visits to the Paediatric Neurology Clinic, the seemingly poor outlook combined with the financial demands puts enormous psychological strain, emotional distress and physical caregiver fatigue on the families of these children.37,44

Conclusion

Despite the advances in medical care, Cerebral malaria is still rife in the west, sub-Saharan Africa with Nigeria accounting for the largest number of cases. Needless mortalities are still being recorded. The attendant neurologic sequelae not only limits the potentials of the affected children but also serves as a major disruptive factor in the socio-economic functioning of the families where these children belong to.

Limitations

The authors acknowledged that the cross-sectional nature of this research could have limited the findings observed in the study. Fundoscopy (to diagnose participants with malaria retinopathy) and neuroimaging (computed tomography scans and serial magnetic resonance imaging to assess cerebral oedema) would probably have enhanced the diagnostic accuracy of cerebral malaria in children enrolled in the research.31,38

Acknowledgements

The authors are grateful to all the children who participated in this study as well as their parents/caregivers. The authors also appreciate the physicians, nurses and other members of the medical team who provided excellent care to these children while on admission.

Declaration of Helsinki

The study was conducted according to the principles of Helsinki declaration.

Author Contributions

All the authors were involved in the conceptualisation of the study, data collection and analyses. All the authors contributed to the manuscript write-up. All the authors approved the final draft of the manuscript.

Disclosures

The authors have no disclosures to make. There are no conflicts of interest to declare.

Informed Consent

Written informed consentwas obtained from the participants’ parents or caregivers prior to recruitment into the study

Ethical Approval

The study protocol was approved by the University of Ibadan (UI)/University College Hospital (UCH) Joint Ethics Review Committee prior to the commencement of the study (Approval Number: UI/EC/21/0629).