Childhood tuberculous meningitis : challenging current management strategies

Van Toorn, Ronald (2015-04)

Thesis (PhD)--Stellenbosch University, 2015.


ENGLISH ABSTRACT: Tuberculous meningitis (TBM) continues to be an important cause of mortality and neurological disability in resource-limited countries. Many questions remain about the best approaches to prevent, diagnose, and treat TBM, and there are still too fewanswers. The aim of this dissertation was to challenge current management strategies in childhood TBM. Accurate prediction of outcome in TBM is of critical importance when assessing the efficacy of different interventions. I conducted a retrospective cohort study of 554 children with TBM less than 13 years of age admitted to Tygerberg Children’s Hospital over a 20 year period (1985-2005) and reclassified all patients according to the criteria of all the currently available staging systems in childhood TBM (chapter 4). In this study, I found that the “Refined Medical Research Council (MRC) staging system after 1 week” had the highest predictive value of all TBM staging systems. It is created by subdivision of stage 2 (2a and 2b) of the existing MRC staging system. Additionally, I proposed and validated a simplified TBM staging system which is less dependent on clinical ability and neurological expertise than current staging systems. The simplified staging system was termed the “Tygerberg Children’s Hospital Scale” (TCH) and relies solely on the patient’s ability to visually fixate and follow and the motor response to pain on both sides. It demonstrated excellent predictive power of outcome after 1 week and did not differ significantly from the “Refined MRC staging system” in this regard. The optimal anti-TB drug regimen and duration of treatment for TBM is unknown. It has been suggested that intensive short-course (6 months) anti-TB therapy may be sufficient and safe. I conducted a prospective descriptive study of 184 consecutively treated children with TBM and found that short-course intensified anti-TB therapy aimed at treating TBM patients (anti-TBM therapy) is sufficient and safe in both HIV-uninfected and HIVinfected children with drug susceptible TBM (chapter 5). The overall study mortality of 3.8% at completion of treatment compares favourably with the median mortality rate of 33% (range 5-65%) reported in a recent review describing outcome in TBM treatmentstudies. TB-immune reconstitution inflammatory syndrome (IRIS) is a potentially life-threatening complication in HIV-infected children with TB of the central nervous system. Little is known about the incidence, case fatality, underlying immunopathology and treatment approaches in HIV-infected children with neurological TB-IRIS. In a case series, I found that neurological TB-IRIS should be considered when new neurological signs develop after initiation of antiretroviral therapy (ART) in children with TBM (chapter 6.1). Manifestations of neurological TB-IRIS include headache, seizures, meningeal irritation, a decreased level of consciousness, ataxia and focal motor deficit. I also discussed the rational for using certain treatment modalities, includingthalidomide. Neurological tuberculous mass lesions (tuberculomas and pseudo-abscesses) may develop or enlarge in children on anti-TBM treatment. These lesions respond poorly to therapy, and may require surgical excision, but may be responsive to thalidomide, a potent inhibitor of tumour necrosis factor-alpha (TNF-alpha). The optimal dose and duration of thalidomide therapy and the correlation with magnetic resonance imaging (MRI) is yet to be explored. The primary objective of our next study was to investigate whether serial MRI is useful in evaluating treatment response and duration of thalidomide therapy (chapter 6.2). A secondary objective was to determine the value of thalidomide in the treatment of these lesions. In a prospective observational study over three years, serial MRI was performed in 16 consecutive children compromised by TB pseudo-abscesses who were treated with thalidomide. The rapid clinical response of most patients suggests that thalidomide provides substantial clinical benefit in this clinical context. I also identified a MRI marker of cure that is evolution of lesions from early stage “T2 bright” with edema to “T2 black.” This finding could be useful in the future management of these patients. Transcranial Doppler imaging (TCDI) is potentially a valuable investigational tool in children with TBM, a condition often complicated by pathology relevant to Doppler imaging such as raised intracranial pressure (ICP) and cerebral vasculopathies. Serial TCDI was performed on 20 TBM children with the aim of investigating cerebral haemodynamics and the relationship between pulsatility index (PI) and ICP (chapter 6.3). In this study, I found that TCDI-derived pulsatility index (PI) is not a reliable indicator of raised ICP in children with tuberculous hydrocephalus which I attributed this to individual variation of tuberculous vascular disease, possibly compromising cerebral vascular compliance and resistance. The study did confirm the efficacy of medical therapy in children with tuberculous communicating hydrocephalus. In all cases, the ICP normalized within 7 days after initiation of acetazolamide and furosemide. In the same cohort of children with TBM I also measured cerebral blood flow velocities (BFV) in the anterior cerebral artery (ACA), middle cerebral artery (MCA) and posterior cerebral artery (PCA) on admission and after day 3 and 7. I found persistent high BFV in all the basal cerebral arteries suggesting stenosis due to vasculitis rather than functional vasospasm. Additionally, I found that complete MCA occlusion, subnormal mean MCA velocities (less than 40 cm/s) and a reduced PI (less than 0.4) correlated with radiological proven large cerebral infarcts. No side-to-side differences in MCA BFV or subnormal PI’s were detected in four TBM children with territory infarcts on admission. I attributed this to the occlusion of a limited number (one or two) of the 9 MCA perforators which has been shown not to affect the hemodynamics of the MCA. I concluded by highlighting the many questions that remain about the best approaches to prevent, diagnose, and treat TBM (chapter 2). In a second literature review, aimed at clinicians working in resource-limited countries, I describe novel approaches to the management of childhood TBM, including a treatment algorithm for tuberculous hydrocephalus, the role for short-course intensified anti-TBM treatment and home-based anti-TBM treatment (chapter 3). Even with the best diagnostic and treatment modalities, outcome in childhood TBM will remain poor if diagnosis is delayed. Our efforts should be on increased awareness and earlier diagnosis.

AFRIKAANSE OPSOMMING: Tuberkuleuse meningitis (TBM) bly ‘n belangrike oorsaak van mortaliteit en neurologiese ongeskiktheid in lande met beperkte hulpbronne. Baie vrae oor die beste benaderings tot voorkoming, diagnose en behandeling van TBM bly bestaan en daar is steeds te min antwoorde. Die doel van die verhandeling was om huidige behandelingstrategieë van tuberkuleuse meningitis (TBM) in kinders uit te daag. Akkurate voorspelling oor die uitkoms van TBM is van kritieke belang wanneer doeltreffendheid van verskillende ingrypings beoordeel word. Ek het ‘n retrospektiewe kohort studie van 554 kinders jonger as 13 jaar met TBM wat in Tygerberg Kinderhospitaal toegelaat is oor `n tydperk van twintig jaar (1985 tot 2005) uitgevoer en al die pasiënte volgens die kriteria van al die huidig beskikbare stadiëringsisteme vir kinder TBM geherklassifiseer (hoofstuk 4). Die waarde van die verskillende stadiëringsisteme in die voorspelling van neurologiese uitkoms is toe bepaal. In hierdie studie het ek bevind dat die “Verfynde Mediese Navorsings Raad (MNR) stadiëringsisteem na 1 week” die TBM stadiëringsisteem met die hoogste voorspellende waarde was om neurolgiese uitkoms te voorspel. Dit is geskep deur onderverdeling van stadium 2 (2a en 2b) van die bestaande gemodifiseerde MNR stadiëringsisteem. Daarbenewens het ek ’n vereenvoudigde stadiëringsisteem vir TBM wat minder afhanklik van kliniese vermoëns en neurologiese kundigheid sal wees as die bestaande stadiëringsisteme daargestel en getoets. Die vereenvoudigde stadiëringsisteem is die “Tygerberg Kinderhospitaal Skaal (TKH)” genoem en dit is slegs gebaseer op `n pasiënt se vermoë om visueel te fikseer en te volg en die motoriese respons tot pyn aan beide kante van die ligaam. Dit het uitstekende voorspellingswaarde gehad vir uitkoms na die eerste week van siekte en het in hierdie verband nie betekenisvol verskil van die “Verfynde MNR stadiëringsisteem” nie. Die optimale anti-TB middel regimen en duurte van behandeling vir TBM is onbekend. Sommige kenners stel voor dat ‘n intensiewe kort-kursus (6 maande) van anti-TB behandeling veilig en voldoende mag wees. Ek het ‘n prospektiewe beskrywende studie op 184 opeenvolgende kinders met TBM uitgevoer en bevind dat intensiewe kort-kursus anti-TB behandeling gemik op die behandeling van kinders met TBM (anti-TBM behandeling) in beide menslike immuniteitgebrekvirus (MIV)-ongeïnfekteerde en MIV-geïnfekteerde kinders met middel-gevoelige TBM voldoende en veilig was (hoofstuk 5 ). Die mortaliteit in my studie met voltooing van behandeling vergelyk gunstig met die mediane mortaliteit van 33% (reikwydte 5-65%) wat onlangs in ‘n oorsig van uitkoms in TBM gerapporteer is. TB immuun rekonstitusie inflammatoriese sindrome (IRIS) is ‘n potensieël lewensbedreigende komplikasie in MIV-geïnfekteerde kinders met TB van die sentrale senuwee sisteem (SSS). Min is oor die voorkoms, mortaliteit, onderliggende immunopatologie en behandelingsbenaderings in MIV-geïnfekteerde kinders met neurologiese TB-IRIS bekend. In `n gevalle-reeks het ek gevind dat neurologiese TB-IRIS oorweeg moet word as nuwe neurologiese tekens na aanvang van antiretrovirale terapie (ART) in MIV-geïnfekteerde kinders met TBM ontwikkel (hoostuk 6.1). Simptome en tekens van neurologies TB-IRIS behels hoofpyn, konvulsies, meningiale prikkeling, ‘n verlaagde vlak van bewussyn, ataksie en fokale motoriese uitval. Ons bespreek ook die rasionaal vir die gebruik van sekere behandelingsmodaliteite, insluitende thalidomied. Neurologiese tuberkuleuse massaletsels (tuberkulome en pseudo-absesse) mag ontwikkel of vergroot in kinders op anti-TBM behandeling. Hierdie letsels reageer swak op terapie, vereis soms chirurgiese verwydering, maar kan op talidomied behandeling reageer, ‘n kragtige inhibeerder van tumor nekrose faktor-alfa (TNF-α). Die optimale dosis en duurte van thalidomide behandeling en die korrelasie met magnetiese resonansbeelding (MRB) moet nog ondersoek word. Die primêre doel van my volgende studie was om te bepaal of seriële MRB van waarde is om die respons op behandeling te evalueer asook die duurte van talidomied behandeling. Die sekondêre doelwit was om die waarde van talidomied in die behandeling van hierdie letsels te bepaal. In ‘n prospektiewe waarnemingstudie wat oor 3 jaar gestrek het is seriële MRB uitgevoer op 16 opeenvolgende kinders met TB pseudo-absesse wat behandel is met talidomied (hoofstuk 6.2). Die spoedige kliniese verbetering van die meeste pasiënte dui daarop dat thalidomied `n aansienlike kliniese voordeel bied in hierdie kliniese konteks. Verder het ek `n MRB merker van genesing geïdentifiseer naamlik evolusie van die letsel van vroeë stadium “T2 helder” met edeem na “T2 swart”. Hierdie bevinding is van groot waarde in die toekomstige behandeling van TBM pasiënte wat hierdie komplikasie ontwikkel. Transkraniale Doppler beelding (TKDB) is potensieël `n waardevolle ondersoekmetode in kinders met TBM, `n toestand wat dikwels gekompliseer word deur patologie verwant aan Doppler beelding soos verhoogde intrakraniale druk (IKP) en serebrale vaskulopatieë. Seriële TKBD is op 20 TBM kinders uitgevoer om serebrale hemodinamika en die verband tussen die pulsatiele indeks (PI) en IKP te ondersoek (hoofstuk 6.3). In hierdie studie het ek gevind dat TKDB-afgeleide PI nie `n betroubare aanduiding van verhoogde IKD in kinders met tuberkuleuse hidrokefalus is nie en dit aan individuele variasies van tuberkuleuse vaskulêre siekte toegeskryf, wat serebrale vaskulêre toegeeflikheid en weerstand benadeel. Die studie het die doeltreffendheid van mediese behandeling in kinders met kommunikerende tuberkuleuse hidrokefalus bevestig. In alle gevalle het die IKP binne 7 dae na aanvang van asetosoolamied en furosemied genormaliseer. In dieselfde groep TBM kinders het ek die serebrale bloedvloei-snelhede (BVS) in die anterior serebrale arterie (ASA), middel serebrale arterie (MSA) en posterior serebrale arterie (PSA) met toelating en na dag 3 en 7 gemeet. Ek het volgehoue hoё BVS in al die basale arteries gevind wat op stenose sekondêr tot vaskulitis eerder as funksionele vasospasma dui. Daarbenewens het ek gevind dat volledige MSA afsluiting, subnormale gemiddelde MSA snelhede (minder as 40 sentimeter per sekonde) en `n verminderde PI (minder as 0.4) met radiologies-bewysde groot serebrale infarksies gekorreleer het. Geen kant-tot-kant verskille in MSA BVS of subnormale PI’s is in vier TBM kinders met kleiner infarksies met toelating bespeur nie. Ek skryf dit toe aan die afsluiting van `n beperkte aantal (een of twee) van die nege MSA perforators wat nie nie die hemodinamika van die MSA beïnvloed nie. Ek het afgesluit om al die vrae wat nog bestaan oor die beste benadering ten opsigte van voorkoming, diagnose and behandeling van TBM uit te wys (hoofstuk 2). In die tweede literatuuroorsig, wat gemik is op dokters wat werk in hulpbron-beperkte lande, beskryf ek nuwe benaderings tot die hantering van pediatriese TBM, insluitend `n behandelingsalgoritme vir tuberkuleuse hidrokefalus, die rol van kort- kursus versterkte anti-TB behandeling vir TBM en tuis-gebaseerede anti-TBM behandeling (hoofstuk 3). Selfs met die beste diagnostiese en behandelingsmodaliteite, is die uitkoms van kinder TBM swak indien diagnose vertraag word. Ons pogings moet daarom op groter bewustheid en vroeёr diagnose berus.

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