Human enteroviruses are not the cause of neurological impairments in children at the Korle-Bu Teaching Hospital

Introduction Convulsions associated with fever and acute onset of unknown aetiology with case fatalities have become a long observed medical condition at the Child Health Department of the Korle-Bu Teaching Hospital. Children admitted to the department with seizures of undetermined origin and fever has been a source of diagnostic confusion. Studies from the Asia Pacific region suggest a link with non-polio enteroviruses. The aim of the study was to investigate the association between non-polio enterovirus and acute encephalopathy causing neurological morbidity in children. Methods One hundred and fifty cerebrospinal fluid (CSF), throat swab and serum samples were collected from participants at the Child Health Department of the Korle-Bu Teaching Hospital for virus isolation and characterization. Samples were cultured on cells and positive culture assayed by microneutralisation. Direct PCR as well as multiplex PCR were used to detect other viral agents present. Results Enterovirus isolation rate was approximately 0.67%. Intratypic differentiation by molecular characterization identified a poliovirus from vaccine origin. Further screening by real-time RT-PCR identified the virus as normal Sabin and not vaccine-derive poliovirus. No arbovirus was however detected. Conclusion Non-polio enteroviruses and chikugunya virus were found not to be the etiologic agent responsible for the convulsion with neurologic morbidity observed in the Ghanaian children. Investigation for other viral agents is recommended.


Introduction
Convulsion with acute onset in general is a common cause of admission in paediatric emergency wards and risk for neurological, cognitive impairment and epilepsy. Early diagnosis for the etiological cause and immediate clinical management is crucial to the survival of the child [1][2][3][4]. Clinical and experimental data suggest that prolonged seizures can have immediate and long-term adverse consequences on the immature and developing brain [5]. It is estimated that about 4% to 6% of all children will have a seizure in the first 16 years of life [6]. The incidence is predominant in children under the age of 3 years, with a declining frequency in older children [7]. Epidemiologic investigations have revealed that approximately 150,000 children will sustain a first-time, unprovoked seizure each year, and of those, 30,000 will develop epilepsy5 with the highest risk being among children with prior condition of neurodevelopmental abnormality and family history of afebrile seizures [6,8]. The incidence of convulsions in developing countries including Ghana is higher than developed countries because of high infection rates [9][10][11][12]. Convulsion denotes a clinical symptom of an underlying pathologic condition with many possible causes.
Convulsion may be caused by genetic and metabolic factors, fever, head injury, excessive alcohol intake, ischaemic stroke, intracranial haemorrhage, use of illicit drugs, meningitis, encephalitis and infection with parasites, bacteria or viruses [9,13,14]. Some of the viruses implicated in cases of convulsion include Human herpesvirus 6 [15,16], influenza A [17,18], Chikungunya virus [19,20] and Human enterovirus 71 [21,22]. Cases include children between the ages of one day and twelve years with presentations of convulsion and fever, with occasional rashes. Many of the patients without any history of neurological problem were found to have developed temporal or permanent neurological impairment. Isolation of the causative agent would help to curtail unnecessary investigations, rationalise treatment, improve reliability of prognosis and prevent overuse of antimicrobial agents with consequent antimicrobial resistance.
In the Asian-Pacific regions, this manifestation of childhood convulsion associated with fever and neurological complication observed at the Child Health Department of the KBTH is usually associated with the non-polio enterovirus known as Human enterovirus 71 (HEV71) [23][24][25][26][27]. Currently, there is very little literature supporting the circulation of HEV71 in Africa which include the isolation of HEV71-like virus from children with acute flaccid paralysis in Central Africa Republic [28] and two small institutional outbreaks of HEV71 infection in HIV orphanages in Nairobi, Kenya [29]. However, the circulation of other enteroviruses is prevalent, which include poliovirus, Coxsackievirus, echovirus, hepatitis A virus and enterovirus 70 (5) [30,31]. Although HEV71 is yet to be isolated in Ghana, migration, travel, tourism and pilgrimage of Muslims from Ghana to HEV71 endemic regions, may get infected and become a source of infection for others.
Epidemics of viral infections causing central nervous system effects are continuously being reported from around the world and clinicians are challenged to be abreast with local epidemiology. This study therefore aimed to investigate whether non-polio enterovirus was the etiological cause of the neurological disorders observed in the children.

Study population:
The study population comprised children between the ages of one day and twelve years old admitted to the hospital having clinical diagnosis of convulsion associated with fever and rash. Convulsions includes seizures lasting for at least half an hour, or convulsions followed by coma lasting two hours or more or convulsions followed by paralysis or other neurological signs not previously present and lasting 24 hours or more and convulsions that presented as encephalitis [32][33][34]. Only children with fever, convulsion, skin rash, herpangina, viral meningitis, viral encephalitis and other neurological manifestations were considered for the study.  The clinical presentations as shown in Figure 1 indicates that the most frequent symptoms recorded in decreasing order were fever accelerates the development of antimicrobial resistance [37,38].
Antimicrobial resistance, as it is already known, inflates the patient's budget, prolonging stay in hospital and also pressurizes drug manufacturing companies to make available new drugs that these agents would be susceptible to [39,40].
To many emergency room physicians, the threat of antimicrobial resistance has not sunk in yet. It has been apparent through this study that emergency department physician's fundamental and principal concern in an emergency situation is how possible he could resuscitate his patient and that, the issue of the impact of antimicrobial use on the prevalence of resistance was not a crucial consideration at that moment. Many physicians and patients do not see antimicrobial resistance as a reason to abstain from its use [41,42]. Emergency department physicians may therefore not be different from other physicians in their frequent prescription of antimicrobials for conditions that do not appear to profit from their use. This raises a general concern if the principle of prudent use of antimicrobials is being adhered to.
The findings from this study could not establish non-polio  [43,44]. It is also a way of gaining natural immunity when a person has not received the OPV. The OPV is unstable and can revert to neurovirulence in some instances.
Further investigation to determine whether the Sabin  viruses. Solving this puzzle will save the Government a lot of money that is spent on antibiotics, antimalarial and other drugs which in future will lead to drug resistance in the children.

Conclusion
The findings from this study indicate that the aetiological agent for the observed convulsions in the children was neither due to nonpolio enteroviruses nor chikugunya. We recommend that other viral agents capable of causing convulsion in children be investigated.
The use of drugs to manage convulsions should be minimized and efforts should be made toward identifying the aetiological agent.

Competing interests
Competing