Neurology International 2011; volume 3:e14

Evoked potentials in pediatriccerebral malaria Minal Bhanushali,1 Terrie E. Taylor,2Malcolm E. Molyneux,3 Monica Sapuwa,4Eunice Mwandira,4 Gretchen L. Birbeck51US National Institute of Health, 10-CRCHatfield Research Center, Bethesda, USA;2Department of Internal Medicine,College of Osteopathic Medicine,Michigan State University, West Fee HallEast Lansing, USA; 3Malawi-Liverpool-Wellcome Trust Clinical ResearchProgramme, Malawi; College of Medicine,Malawi & The Liverpool School ofTropical Medicine, University ofLiverpool, UK; 4Blantyre Malaria Project,Queen Elizabeth Central Hospital,Blantyre, Malawi; 5InternationalNeurologic & Psychiatric EpidemiologyProgram. Michigan State University, EastLansing, MI, USA

Abstract

Cortical evoked potentials (EP) providelocalized data regarding brain function andmay offer prognostic information and insightsinto the pathologic mechanisms of malaria-mediated cerebral injury. As part of a prospec-tive cohort study, we obtained somatosensoryevoked potentials (SSEPs) and brainstemauditory EPs (AEPs) within 24 hours of admis-sion on 27 consecutive children admitted withcerebral malaria (CM). Children underwentfollow-up for 12 months to determine if theyhad any long term neurologic sequelae. EPswere obtained in 27 pediatric CM admissions.Two children died. Among survivors followedan average of 514 days, 7/25 (28.0%) had atleast one adverse neurologic outcome. Only asingle subject had absent cortical EPs onadmission and this child had a good neurolog-ic outcome. Among pediatric CM survivors,cortical EPs are generally intact and do not pre-dict adverse neurologic outcomes. Furtherstudy is needed to determine if alterations incortical EPs can be used to predict a fatal out-come in CM.

Introduction

Cerebral malaria (CM) is a common causeof mortality and morbidity among children,especially in those younger than 5 years.1-5CM is traditionally defined as being unarous-able coma in the presence of P. falciparum par-asitemia with no other coma etiology evident.6

A CM-specific retinopathy has recently beendescribed that further enhances diagnosticcertainty.1,6-9 Of children with CM who reachcare, 15-25% die. Risk factors for death includemore profound coma, younger age, seizures,hypoglycemia and hyperparasitaemia.10,11Neurologic sequelae, including cortical blind-ness, gross motor deficits, ataxia and languageregression are also common and occur in~30% of survivors.11-12 No prior studies of pedi-atric CM have included evoked potentials (EP)during the acute coma. Despite extensiveresearch, the pathogenetic mechanisms ofCM-induced coma, CNS injury, and deathremain unclear.13 We obtained cortical EPs,specifically somatosensory evoked potentials(SSEPs) and auditory evoked potentials(AEPs), in children with CM coma to deter-mine if the presence or absence of cortical EPspredicts adverse neurological outcomes.EPs are the electrical responses to sensory

stimulation. The SSEPs are presynaptic andpostsynaptic responses recorded over thelimbs, spine and scalp following the stimula-tion of peripheral nerve trunks (median and/orposterior tibial nerves). They provide a meas-ure of sensory conduction and thereby detectlesions in proximal peripheral nerves, spinalcord, brainstem and the brain.14 AEPs consistof auditory (click) stimuli delivered to each earfollowing which responses are recorded in thebrainstem and cortex. They are mainly used forevaluation of peripheral and central auditorycircuits in the brainstem. Cortical responses obtained on SSEPS and

AEPs have been widely used to prognosticateneurological outcome and survival in patientswith coma due to hypoxic, anoxic, traumaticand ischemic brain injury.15-18 The absence ofcortical responses of SSEPs and AEPs (in theabsence of peripheral nervous system or audi-tory system dysfunction) is indicative of irre-versible cerebral damage and poor prognosis.15EPs are obtained quickly and easily at the

bedside with inexpensive equipment, provideinformation on brainstem function and couldbe readily used in endemic areas if shown tocontribute usefully to the diagnosis, manage-ment or prognosis in patients with CM. malar-ia endemic regions, CT technology is the mostcommonly available brain imaging option butroutine protocols provide very limited views ofbrainstem anatomy due to bony artifact.19

Materials and Methods

From January to June 2008 (the malariaseason), children admitted to Queen ElizabethCentral Hospital (QECH) with CM underwentSSEPs and AEPs as part of their clinical assess-ment. Inclusion criteria for this study wereadmission the Pediatric Research Ward, a

Blantyre Coma Score (BCS) of <3, P. falci-parum parasitemia, and the presence of CMretinopathy identified by an ophthalmologist.EPs were generally only available during day-time hours. Children who died or regainedconsciousness before EPs could be obtainedwere not eligible for inclusion in this analysis. AEPs and SSEPs were completed using an

XLTEK Neuromax 1004 System. AEPs were per-formed by inserting small ear buds into theexternal auditory canal for delivery of auditorystimulus. The auditory stimuli consisted ofclicks delivered at a rate of 10/sec at stimulusintensity of 60 dB per SPL (decibels peakequivalent sound pressure level) and durationof 0.1 microseconds. The contralateral ear wasmasked with white noise. The responses wererecorded between the vertex and ipsilateral

Correspondence: Gretchen L. Birbeck, #324 WestFee Hall East Lansing, MI 48824, USATel. +1.517.884.0277 - Fax: +1.517.884.0275.E-mail: Birbeck@msu.edu

Key words: cerebral malaria, evoked potentials,AEP, SSEP, outcome, mortality.

Acknowledgements: many thanks to ClaraAntonio and Juliet Simwinga whose contribu-tions through patient follow-up made this workpossible. We are grateful to the children and theirparents and guardians who took part in the study.The Department of Paediatrics of the College ofMedicine and the Queen Elizabeth CentralHospital provided ward accommodation andessential support for these studies.

Contributions: MB, study design, conception, EPinterpretation, review and editing; TET, studydesign and conception, patient enrollment andcare, staff supervision, review and editing; MEM,study design and conception, patient enrollmentand care, staff supervision, review and editing;MSO, data collection, logistics and design, reviewand editing; GLB, study conception and design,staff training and oversight, data analysis, manu-script writing.

Conflict of interest: the authors report no con-flicts of interest.

Funding: for this work was provided by:NIH/NINDS K23 NS046086-01(GB), NIH/NIAIDR01 AI034969-10AI (TT). The Wellcome Trust(MM) 074125/Z/04/Z

Received for publication: 9 September 2011.Accepted for publication: 28 September 2011.

This work is licensed under a Creative CommonsAttribution NonCommercial 3.0 License (CC BY-NC 3.0).

©Copyright M. Bhanushali et al., 2011Licensee PAGEPress, ItalyNeurology International 2011; 3:e14doi:10.4081/ni.2011.e14

[Neurology International 2011; 3:e 14] [page 57]

mastoid processes. The right and left ear werestimulated independently and at least two sep-arate trials were given consisting of 2000 stim-uli that were amplified and averaged with bandpass filters at 100 and 3000Hz. The waveformswere analyzed for the presence or absence ofwaves III and V.14 SSEPs were obtained afterstimulation of the median and tibial nervesbilaterally. Median nerves were stimulatedusing a surface cathode 3 cm proximal to thewrist crease and anode 2 cm distal to the cath-ode. The electrical stimulus consisted ofsquare-wave pulses at 7 per second. The inten-sity of the stimulus was adjusted to produce avisible thumb twitch. The responses wererecorded at the elbow, Erb’s point (N9), overthe seventh cervical spine process (N13), andthe contralateral parietal cortex (N20) corre-sponding to C3 or 4 of the 10-20 internationalsystem. A common reference electrode wasattached at Fz of the 10-20 system. The groundelectrode was placed on the arm. Each studyconsisted of 500 trials averaged and filteredwith a band width of 30-3000 Hz. Similarly, tib-ial SSEPs were obtained by placing the stimu-lating electrode (cathode) at the anklebetween the medial malleolus and Achilles ten-don. The anode was place 3 cm distal to thecathode and the ground was placed on the calf.The stimulus intensity was adjusted to producea small plantar flexion of the toes. Theresponses were recorded at the T12 spinousprocess (LP), C5 spinous process (N34), ipsi-lateral cortex between C3 or C4 and P3 or P4 ofthe 10-20 system (CPi) and midline betweenCz and Pz (CPz). A common reference elec-trode was placed at the Fpz position of the 10-20 system. The waveforms were recorded andaveraged over 1000 trials and filtered withbandpass of 30-3000 Hz. The presence orabsence of cortical responses for the medianstimulation was based upon the N20 responsesand for the tibial stimulation it was based uponthe P37 responses.14Survivors were followed up for at least 12

months after discharge, to assess for anyadverse neurological outcome. The discharg-ing physician completed a neurologic exami-nation and subsequent assessments werecompleted at 1 month post discharge and quar-terly thereafter by study nurses. These follow-up assessments included The EpilepsyScreening Questionnaire and The TenQuestions. The Epilepsy ScreeningQuestionnaire is a nine-item instrument thathas been previously used to screen for epilep-sy in the developing world with 79.3% sensitiv-ity and 92.9% specificity.20 The Ten Questionsinstrument has been shown to be valid foridentifying moderate neurodisabilities in chil-dren as young as two years with good reliabil-ity (kappa=0.67) with 85% sensitivity fordetecting moderate to severe neurodevelop-mental disabilities.21 Both instruments were

forward and back translated into the local lan-guage with discrepancy resolution prior to use.Any child screening positive for potential prob-lems by the nurses was seen by a neurologistto confirm and characterize the nature of theneurologic sequelae. This study was approved by the University of

Malawi College of Medicine Research EthicsCommittee and Michigan State University’sBiomedical IRB. Written informed consent wasobtained from the parent or guardian of allchildren included in this study.

Results

Twenty-seven children met inclusion crite-ria and underwent EP studies during theiracute admission. The study population wascharacterized by a mean age of 4.2 years(median 2.7; IQR 2.3-5.8) and 13 were male(48.1%). The average time from admission toregaining a BCS ≥3 was 20.4 hours (median10.5; IQR 6.0-25.5). Two children died andamong survivors 7/25 (28.0%) had at least oneadverse neurologic outcome including epilepsy(3 children), behavioral disorders (3 children)and/or gross neurodisabilities (4 children)characterized by language regression, motoror sensory deficits or ataxia. Cortical respons-es were present on EPs in 26 patients (96.3%),including the two who later died. Only a singlesubject had absent EPs during the acute CMinfection and this child had a good neurologicoutcome.

Discussion

The presence or absence of cortical respons-es on SSEPs and AEPs during acute coma dueto CM does not predict long term neurologicsequelae. Some limitations to this studyinclude technical challenges such as the lackof age specific normative data and documenta-tion of limb temperature. More sophisticatedassessments including changes in absolute orinter-peak latencies need to be furtherassessed. Neurodiagnostic staff were availableonly during daytime hours, so we were not ableto assess some children, who recovered or diedbefore EPs could be obtained. This likelyexcluded a higher than random proportion ofpatients with fatal CM, which is reflected bythe fact that the mortality rate in our study was7% in comparison to the pediatric researchward’s overall rate of 16%. Further studies areneeded that include a greater number of CMfatalities to determine whether EPs offer prog-nostic information for survival.

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