Neurological sequelae in survivors of cerebral malaria

Introduction Cerebral malaria is a common cause of neurological sequelae and death in childhood. Information on persistent neurological sequelae post hospital discharge and their predisposing factors are scarce. Methods This is a prospective study describing persisting neurological impairments post discharge among children treated for cerebral malaria. In addition the study was designed to investigate the frequency of persistent neurologic deficits and the risk factors for their persistence in these patients. The case records of 160 patients treated for CM at the Paediatrics Department of University College Hospital, Ibadan from January 2004 to November 2006 were reviewed to recruit cases. Recruited survivors were then followed up for information concerning the presence and persistence of neurological sequelae. Results A total of 160 children aged 9 months to 134 months were admitted and treated for CM during the study period. One hundred and thirty one (81.9%) survived while 29 (18.1%) died. The 131 survivors of cerebral malaria consisted of 64 boys and 67 girls. Neurological sequelae occurred in 13.7% of survivors of cerebral malaria at discharge and 4.6% at follow up. Six children with neurological deficits at discharge had persistence of deficits 6 months post-hospital discharge and one at 24 months. No associations were found between hypoglycemia, anemia, age, sex and multiplicity of convulsions, and persistence of neurologic sequelae. The persisting neurologic deficits among survivors at follow up were: memory impairment (1.5%), seizure disorders (0.8%), visual impairment (0.8%), speech impairment (0.8%), monoparesis (0.8%) and hyperactivity (0.8%) at follow up. The longest persisting sequelae lasted for at least 24 months. Conclusion Neurologic deficits are not uncommon complications of CM. Neurologic sequelae may persist for as long as 24 months or more in survivors of childhood CM. There is no association between the risk factors for neurologic deficits and persistent neurologic sequelae.


Introduction
Plasmodium falciparum is the most common cause of malaria worldwide [1]. It is responsible for almost all the mortality from malaria and affects the central nervous system causing neurological deficits and cognitive sequelae [1][2][3]. The social and economic burden of malaria in malaria-endemic countries is immense [4].
Cerebral malaria is the most severe neurological presentation of acute falciparum malaria, the clinical hallmark of which is the presence of coma [3]. It is a diffuse encephalopathy associated with seizures in at least 80% and status epilepticus, in up to a third of cases [5][6][7]. Multiple or prolonged seizures in cerebral malaria have been reported to be associated with epilepsy later in life [8][9][10]. The case fatality rate of cerebral malaria ranges between 5 and 50 percent [5]. Although most survivors make a full recovery, neurological sequelae such as hemiplegia, speech problems, cortical blindness and epilepsy occur in 3-31 percent [6,8,9] Despite the growing recognition that Plasmodium falciparum malaria significantly threatens child survival and long-term impairment of cognition often follows early insult and injury to growing brains, inadequate attention has been given to the impact of malaria on general cognitive and behavioural development of children after discharge from the hospital by previous reports [9,11]. Most of the previous studies report neurological sequelae in the acute phase or at discharge from the hospital in cerebral malaria [5,[12][13][14]. There are very few reports on the long term neurological sequelae in survivors of childhood cerebral malaria [8,9,11]. This study therefore focuses on describing persisting neurological impairments among children treated for cerebral malaria after a period of at least six months from the time of diagnosis. The study was carried out at the Paediatric Department of the University College Hospital, Ibadan, Nigeria and the homes of the patients in Ibadan community.

Methods
The present study is a cross sectional study. The subjects were children who were previously admitted and treated for cerebral malaria at least six months before the time of study, who were then followed up for presence or persistence of neurological sequelae.
Ethical clearance was obtained from The Joint University of Ibadan and University College Hospital Ibadan Ethical Committee. Informed verbal consent was obtained from the parents or guardians of the children and explanation was made to the children as much as possible to ensure their optimal cooperation. All children with cerebral malaria admitted into Children Emergency Data was analyzed using SPSS 11.0 for Windows (SPSS Inc., Chicago, USA). The patients were grouped based on age and the presence or absence of neurological deficit. Data was presented as frequency tables and mean ± standard deviations (x ± SD).
Selected clinical and laboratory factors such as duration of coma, nutritional status, multiple seizures, anaemia and hypoglycemia were compared in those with and without sequelae. Analysis for significance was by use of Chi square or Fishers exact test, where counts were less than 5. P values less than 0.05 was regarded as significant.
Neurologic sequelae were defined as impairment of neurologic or cognitive function. Specifically they include: impairment or loss of function in musculoskeletal system, these includes paralysis or paresis manifesting as inability to walk, staggering, monoparesis,  Four of the 18 survivors with neurological deficits at discharge were lost to follow up in the community while 6 (4.6%) survivors had persisting neurological sequelae for more than 6 months after discharge from the hospital.

Age and sex distribution
The 131 survivors were made up of 64 males and 67 females giving a male to female ratio (M:F) of 1:1.05. The age distribution of survivors shown in Table 1 reveals increasing frequency from infancy with a peak in the 36 -47 months age group. The majority (71.8%) of children were under 5 years of age.  Table 3).

Pattern of neurological sequelae in CM survivors
The 18 children with neurologic impairment at discharge had 38 neurologic deficits. The commonest neurological deficits at discharge were movement disorder and speech impairment in 9 children each, followed by visual impairment and memory impairment in 5 children each. Seizure disorder, hearing impairment, hemiparesis and quadriparesis occurred in one child each.  [6,8,9]. The reduction in the proportion of survivors who continued to have neurological deficit at discharge in the same centre over the space of 30years has been previously attributed to improved standard of health and case management which is commendable. The difference could also be due to a longer duration between discharge and follow up assessment in this study (6 -33 months) compared to 12 -16 months in the earlier study by Bondi [8].

Potential risk factors for neurological deficit in CM
There was no statistically significant association between selected factors such as hypoglycaemia, severe anaemia, multiple seizures, under-nutrition, age, duration of coma and the presence or absence of neurologic deficits at follow up. These are at variance to the commonly reported findings in other studies [8,12,17]. This

Conclusion
It is concluded that, the present study shows that neurological sequelae is common among survivors of CM. A minority have neurological deficits persisting beyond 6 months with memory Page number not for citation purposes 5 impairment being the most common. The most vulnerable age groups were the under-five.

Competing interests
The authors declare that they have no competing interests.

Authors' contributions
Isaac Oludare Oluwayemi (IOO) designed the study and actively involved in recruiting and obtaining information from the subjects.

Acknowledgments
We wish to sincerely appreciate the children, their parents, members of Records and Paediatrics Department of the University College Hospital, Ibadan, Nigeria, and Mrs. Adebisi whose collective contributions helped in making this work a reality. Table 1: Age distribution of survivors of cerebral malaria