Se realizó un estudio de isoenzimas de Adenosina Deaminasa (Adenosina Aminohidrolasa, EC 3.5.4.4), en líquido cefalorraquídeo de pacientes con Tuberculosis Meníngea y otras enfermedades del sistema nervioso central con actividad ADA incrementado; utilizando la técnica estandarizada de electroforesis en gel de poliacrilamida (método electroforético de Laemmli modificado), una técnica de revelado enzimático y la densitometria para distinguir las isoenzimas en cada grupo. Se evaluaron 19 muestras de LCR de pacientes con cuadro clínico de TBC meníngea. al momento de obtener las muestras, los pacientes no tenían diagnóstico confirmatorio; posteriormente se realizó la correlación c1ÍPjca respectiva. Para corroborar la baja frecuencia de esta enfermedad se realizó la revisión de las historias clínicas desde un año antes (setiembre 1998 - agosto 1999). Para el ensayo se consideró las muestras que tenían actividad ADA mayor de 9 UIL, determinado por el método espectrofométrico de Giusti y Galanti, las cuales fueron conservadas a - 40°C hasta la corrida electroforética. Para cada carril se aplicó 120 ul de muestra, y la corrida fue realizada en un sistema de electroforesis vertical usando buffer fosfato 0.1 M a pH 6.7. Se encontró que las medianas de las actividades de adenosina deaminasa totales en LCR de pacientes con TBC meníngea son mayores que ei LCR de otras enfermedades parainfectivas del SNC. De otro lado ADA1m tuvo muy poca contribución a la actividad ADA total tanto en TBC meníngea como en otras patologías; ADA1cp tuvo mayor contribución de la actividad ADA total para ambos grupos, mostrándose mayor en las enfermedades no TBC meníngea y la contribución ADA2 mostró un incremento en tuberculosis meníngea respecto de otras enfermedades del SNC. Se concluye que la electroforesis de LCR es una herramienta que permite distinguir las isoenzimas ADA; evidenciando la presencia de niveles elevados de isoenzima ADA2 en TBC meníngea, como consecuencia del incremento de la línea celular monocito-macrófago en LCR.

Thesis (MMed)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: BACKGROUND: Tuberculous meningitis (TBM) research remains important but obtaining adequate sample sizes of microbiologically-confirmed TBM cases is difficult, therefore clinical cases of TBM need to be included. A uniform research case definition for TBM was developed to assist diagnostic standardization. METHODS: Our study evaluated the proposed uniform research case definition in a group of children diagnosed with TBM. A subgroup of 66 children with cultureconfirmed TBM was compared to culture-confirmed bacterial meningitis controls. RESULTS: The uniform case definition was applied to 554 TBM patients. Sixty-six (11.9%) patients had definite TBM, 408 (73.6%) had probable TBM and 72 (13.0%) had possible TBM. Symptom duration >5 days, weight loss or persistent cough >2 weeks, recent TB contact, focal neurological deficit, clear cerebrospinal fluid (CSF) appearance and basal meningeal enhancement predicted TBM when compared to definite bacterial meningitis with a sensitivity and specificity of 97.0% and 93.7%, respectively. When using a probable TBM score as the diagnostic measure, sensitivity was 86% and specificity was 100%. When using a possible TBM score as the diagnostic measure, sensitivity was 100% but specificity was 56%. CONCLUSION: The uniform research case definition for TBM performed well when using a probable TBM score as the diagnostic marker. A regression model also differentiated TBM from bacterial meningitis with good accuracy, but caution is needed in its application to early TBM.

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Compara la eficacia y seguridad de los regímenes de tratamiento largo de 12 meses y el corto de 6 meses en el tratamiento de la meningitis tuberculosa. Realiza un estudio es de tipo analítico, comparativo, retrospectivo y observacional. La muestra estuvo comprendida por todos los pacientes con meningitis tuberculosa diagnosticados en el Hospital Nacional Dos de Mayo (HNDM) y del Instituto Especializado en Ciencias Neurológicas IECN ”Oscar Trelles Montes” durante el período comprendido entre enero 2000 - diciembre 2003 que cumplieron con todos los criterios de inclusión y ninguno de exclusión. Los pacientes fueron asignados al grupo 1 (pacientes con indicación de curso largo de 12 meses de tratamiento con isoniazida, rifampicina, pirazinamida y etambutol los primeros 2 meses, luego Isoniazida, rifampicina por 10 meses) y el grupo 2 (todos los pacientes con indicación de curso corto de 6 meses de tratamiento con isoniazida, rifampicina, pirazinamida y etambutol los primeros 2 meses, luego isoniazida, rifampicina por 4 meses). Se revisaron las historias clínicas de los pacientes de ambos grupos de estudio y se evaluó las variables clínicas, epidemiológicas, exámenes de laboratorio, presencia de recaídas, fracaso terapéutico, mortalidad, curación y secuelas luego de concluir el tratamiento completo por lo menos hace dos años. Los datos fueron llenados en un instrumento de recolección de datos. Se realizó una visita domiciliaria a los pacientes de ambos grupos de tratamiento (grado II), los cuales fueron entrevistados y se les realizó una evaluación neurológica integral. Luego se comparó la mortalidad, recaídas, efectos adversos y secuelas en los pacientes con meningitis tuberculosa sometidos a los regímenes de tratamiento largo de 12 meses y corto de 6 meses. Para determinar si existió asociación estadística entre variables cualitativas se empleó la prueba Chi cuadrado de Mantel-Haenzel con ajuste para las variables edad y sexo; para las variables cualitativas se empleó la prueba t de Student. En el archivo del Programa Nacional de Tuberculosis (PCT) del IECN se registraron durante el período de estudio (enero 2000 – diciembre 2003) 72 casos de meningitis tuberculosa en inmunocompetentes, de los cuales se ubicaron 69 historias clínicas y 55 cumplieron los criterios de inclusión. En el archivo del PCT del HNDM se registraron durante el período de estudio 133 pacientes con meningitis tuberculosa en inmunocompetentes, de los cuales se ubicaron 76 historias clínicas y 53 cumplieron con los criterios de inclusión. Se presentaron 26 pacientes con meningoencefalitis grado I de los cuales 10 habían sido asignados al esquema de tratamiento largo y 16 al esquema corto; 51 pacientes con meningoencefalitis grado II, 27 de los cuales habían sido asignados al esquema de tratamiento largo y 24 al esquema corto; y 31 pacientes con meningoencefalitis grado III siendo 13 asignados al esquema de tratamiento corto y 18 al esquema largo. Los grupos asignados a los esquemas largo y corto en términos generales no difirieron significativamente en cada grado de la enfermedad siendo estadísticamente comparables. Al evaluarse la eficacia de los regímenes de tratamiento largo y corto no se encontró diferencia estadísticamente significativa en los grados I, II y III; tampoco existió diferencia estadísticamente significativa en la frecuencia de reacciones adversas a fármacos antituberculosos (RAFAs), en la mortalidad, en la frecuencia de secuelas así como discapacidad (grado II). Concluye que los esquemas de tratamiento antituberculoso largo (12 meses) y corto (6 meses) en el tratamiento de la meningoencefalitis tuberculosa tienen similar eficacia y seguridad y el esquema de tratamiento corto no está asociado a mayor frecuencia de recaídas en comparación a el esquema de tratamiento largo. / Trabajo académico

Made available in DSpace on 2015-06-17T19:34:00Z (GMT). No. of bitstreams: 0 Previous issue date: 2014-03-13. Added 1 bitstream(s) on 2015-06-18T12:47:36Z : No. of bitstreams: 1 000823248.pdf: 1366369 bytes, checksum: b17228d9ed70968327d9e51b0d6dc3d6 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Introdução O alívio da dor é uma das atribuições do anestesiologista. Dentre os fármacos utilizados com esta finalidade inclui-se a cetamina (bloqueador do receptor Nmetil D aspartato). Ela pode ser administrada por diversas vias dentre as quais a subaracnoidea e a peridural. Resultados de pesquisas clínicas e experimentais mostraram que a cetamina S (+) foi eficaz no alívio da dor pós-operatória quando introduzida no espaço peridural. Contudo, ainda pouco se sabe sobre sua administração no espaço subaracnoideo. Foram descritas lesões neurológicas no tecido medular de seres humanos e animais quando se utilizou a cetamina com conservantes, no espaço subaracnoideo e, as mesmas lesões foram descritas, em animais, com o fármaco desprovido de conservantes. Objetivo: avaliar os efeitos que a cetamina S (+) a 5% sem conservantes, administrada pela via subaracnoidea em punção única, determina sobre a medula espinal e as meninges de coelhos. Método: Vinte coelhos adultos jovens, fêmeas, pesando entre 3500 a 5000 gr com comprimento de coluna vertebral entre 34 e 38 cm foram divididas, por sorteio, em dois grupos (G): G1 solução fisiológica 0,9%, G2 cetamina S (+) 5% em volume de 5μg por cm de coluna (1,8 μl). Após anestesia venosa com cetamina e xilazina foi realizada punção subaracnoidea em S1-S2 guiada por ultrassom e injetada a solução sorteada. Os animais permaneceram em cativeiro por 21 dias sob observação clínica e foram sacrificados por decapitação e retirada a porção lombo-sacral da medula espinal para exame histológico [Hematoxilina e eosina (HE) e imuno-histoquímica para proteína glial fibrilar ácida (GFAP)]. Resultados: nenhum animal apresentou lesão histológica de tecido nervoso (raizes e medula) e meninges. Conclusão: Neste modelo experimental em coelhos a cetamina S (+) 5% sem conservante não desencadeou lesão neurológicas ou histológica na medula espinal e meninges / Background: Pain relief is one of the tasks of the anesthesiologist . Among the drugs used for this purpose include the ketamine (blocker of N-methyl D aspartate receptor). It can be administered by various routes among which spinal and epidural. Results of clinical and experimental studies have shown that ketamine S (+) was effective in relieving postoperative pain when introduced into the epidural space. Almost nothing is known about his administration in the subarachnoid space. Neurological lesions were described in the medullary tissue of humans and animals when using ketamine S(+) 5% preservative free, the subarachnoid space, the same lesions have been reported in animals with the drug devoid of preservatives. Objective: To evaluate the effects of ketamine S (+) 5% preservative free, administered by the intrathecal route in single puncture , determines on the spinal cord and meninges of rabbits. Method: Twenty young adult female rabbits, weighing 3500-5000 g with entre34 spine length and 38 cm were divided by lot into two groups (G ): 0.9% saline G1 , G2 ketamine S (+) 5% by volume of 5μg per cm column (1,8 μl). After intravenous anesthesia with ketamine and xylazine spinal puncture was performed in S1 - S2 ultrasound guided and injected a random solution. The animals remained in captivity for 21 days under medical observation and were sacrificed by decapitation and removal of the lumbosacral portion of the spinal cord for histologic examination [hematoxylin and eosin (HE)] and immunohistochemistry for glial fibrillary acidic protein (GFAP). Results: No animal showed histological lesions of nerve tissue (roots and cord) and meninges. Conclusions: In this experimental model in rabbits ketamine S (+) 5% preservative free triggered no neurological or histological lesions in the spinal cord and meninges

Orientador: Eliana Marisa Ganem / Banca: Guilherme Antonio Moreira de Barros / Banca: Simone Maria D'Angelo Vanni / Resumo: Clicar acesso eletrônico abaixo. / Abstract: Click electronic access below. / Mestre

Orientador: Eliana Marisa Ganem / Coorientador: Lais Helena Navarro / Banca: Norma Sueli Pinheiro Modolo / Banca: Angélica de Fátima de Assunçao Braga / Resumo: O hábito de tatuar o corpo faz parte da cultura de muitos povos no mundo. A partir de 1990, passou a ser utilizado como forma de arte no corpo. Os pigmentos da tatuagem podem conter componentes orgânicos e inorgânicos, metais e solventes. Pouco se conhece sobre as implicações da realização de anestesia regional sobre pele tatuada. Não existem evidências documentadas ou provas científicas de que os pigmentos da tatuagem possam causar aracnoidite ou outras complicações neurológicas. Objetivos: avaliar se a punção subaracnoidea realizada sobre a pele tatuada de coelhos determinaria alterações histológicas no tecido nervoso medular e nas meninges. Analisar presença de fragmentos de tinta no interior das agulhas de punção. Metodologia: foram utilizados 36 coelhos randomizados em 3 grupos (G): G1 punção sobre tatuagem, G2 punção subaracnoidea sobre tatuagem e injeção de solução fisiológica e G3 punção subaracnoidea e injeção de solução fisiológica. A punção (agulha de Quincke 22G 21/2) foi realizada sob anestesia no espaço entre a primeira e a segunda vértebra sacral guiada por ultrassom. Os animais de G2 e G3 receberam soluções em volume de 5 μL/cm de coluna vertebral (0,2 mL) e nos de G1 foi realizado somente punção sacral e, após esta, foi injetado, através da agulha, 1 mL de solução fisiológica sobre lâmina histológica para realização de esfregaço para possível identificação do tecido. Os animais foram avaliados clinicamente por 6 meses, após os quais foram decaptados sob anestesia e retiradas as porções lombar e sacral da medula espinhal para exame histológico por microscopia óptica. Resultados: presença de pigmentos de tinta em todos os esfregaços dos materiais das agulhas de punção do G1. Infiltrado linfoplasmocitário perivascular em áreas focais das meninges em 33% dos coelhos de G2. Tecido nervoso, meninges e vasos sanguíneos normais em G3. Conclusão: a punção ... / Abstract: Body tattooing is part of many peoples culture in the world. Since 1990, it has been used as a body art. The tattoo pigments may contain organic and inorganic compounds, metals and solvents. The implications of performing regional anesthesia on tattooed skin are poorly known. There are no documented evidence or scientific proof that tattoo pigments can cause arachnoiditis or other neurological complications. Objectives: to assess whether spinal puncture performed on the tattooed skin of rabbits determine histological changes in the spinal nerve tissue and meninges. To analyze the presence of fragments of ink inside of needles. Methods: 36 rabbits were randomized in 3 groups (G). G1 puncture on tattoos, G2 spinal puncture on tattoos and injection of saline, G3 spinal puncture and injection of saline. The spinal puncture was ultrasound guided and performed under anesthesia in the space between the first and second sacral vertebra (a 22G 21/2 Quincke needle was used). The animals in the groups 2 and 3 received a 5 μl/cm spine volume solution (0,2 cc). The animals in the group 1 underwent only sacral puncture and, after that, was injected through the needle 1 cc of saline. The goal was to obtain histological material for conducting smear and possible identification of the tissue. The animals were evaluated clinically for 6 months. After this time they were sacrificed and have the lumbar and sacral portions of the spinal cord removed under anesthesia for histological examination by light microscopy. Results: pigments of ink was noted in all G1 smears material of needles. Perivascular lymphocytic infiltrate was noted in focal areas of the meninges in 33% of rabbits in group 2. Nervous tissue, meninges and blood vessels were normal in G3. Conclusion: subarachnoid puncture on the tattooed skin caused histological changes in the meninges, but not in the spinal nervous tissue. Fragments of tattoo ink were found inside of needles, despite the ... / Mestre

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.

BACKGROUND:Migraine headache is one of the most common neurological disorders, but the pathophysiology contributing to migraine is poorly understood. Intracranial interleukin-6 (IL-6) levels have been shown to be elevated during migraine attacks, suggesting that this cytokine may facilitate pain signaling from the meninges and contribute to the development of headache.METHODS:Cutaneous allodynia was measured in rats following stimulation of the dura with IL-6 alone or in combination with the MEK inhibitor, U0126. The number of action potentials and latency to the first action potential peak in response to a ramp current stimulus as well as current threshold were measured in retrogradely-labeled dural afferents using patch-clamp electrophysiology. These recordings were performed in the presence of IL-6 alone or in combination with U0126. Association between ERK1 and Nav1.7 following IL-6 treatment was also measured by co-immunoprecipitation.RESULTS:Here we report that in awake animals, direct application of IL-6 to the dura produced dose-dependent facial and hindpaw allodynia. The MEK inhibitor U0126 blocked IL-6-induced allodynia indicating that IL-6 produced this behavioral effect through the MAP kinase pathway. In trigeminal neurons retrogradely labeled from the dura, IL-6 application decreased the current threshold for action potential firing. In response to a ramp current stimulus, cells treated with IL-6 showed an increase in the numbers of action potentials and a decrease in latency to the first spike, an effect consistent with phosphorylation of the sodium channel Nav1.7. Pretreatment with U0126 reversed hyperexcitability following IL-6 treatment. Moreover, co-immunoprecipitation experiments demonstrated an increased association between ERK1 and Nav1.7 following IL-6 treatment.CONCLUSIONS:Our results indicate that IL-6 enhances the excitability of dural afferents likely via ERK-mediated modulation of Nav1.7 and these responses contribute to migraine-related pain behavior in vivo. These data provide a cellular mechanism by which IL-6 in the meninges causes sensitization of dural afferents therefore contributing to the pathogenesis of migraine headache.

Mortality and morbidity rates associated with tuberculous meningitis (TBM) are substantial. The average duration of the untreated disease from onset to death is about 17 days. The prognosis of TBM is known to correlate with the stage of the disease at the time of diagnosis and commencement of chemotherapy. Early diagnosis improves the chances of recovery without neurological sequelae. Early diagnosis is a problem because the presenting symptoms are non-specific and the onset of the disease is typically insidious. To date no single test is available that is totally reliable and specific for TBM. I have attempted to develop a reliable and easily applicable test for the diagnosis of TBM. In fulfilling this objective, the work undertaken may be divided into three major sections:- 1. Detection of soluble Mycobacterium tuberculosis antigens in the cerebrospinal fluid (CSF) of patients with TBM and in control groups by using Mycobacterium bovis BCG antigens. The technique used was that of inhibition enzyme-linked immunosorbent assay (ELISA). The principle of this technique is illustrated in Fig. 5. 2. Detection of soluble M. tuberculosis antigens in the CSF of tuberculous and control groups of patients by using antibodies raised against M.bovis BCG. The technique used was that of the double antibody sandwich ELISA. An outline of this ELISA is given in Fig. 6. 3. Correlation of chloride levels in the blood and CSF of patients with tuberculous and other forms of meningitis. It has been established that the SERUM/CSF ratio of bromide tends towards unity in patients with TBM because the permeability of the blood-brain barrier is impaired. Since both bromide and chloride are chemically similar (both being halides), it was thought that a similar pattern may exist for BLOOD/CSF chloride ratios; and this was investigated. The method used for the INHIBITION ELISA had to be standardized before the samples could be tested. This involved investigating the acceptability of various microtitre plates; determination of the optimal working dilutions for the coating solution and conjugate; and determination of optimal conditions for the various incubation periods, both in terms of time and temperature. A total of 70 specimens was tested. These consisted of 25 normal CSF controls; 25 pleural and ascitic fluid samples; 10 TBM samples, and 10 bacterial meningitis CSF samples. It was found that a distinction existed between the absorbance values obtained from positive TBM CSF samples (Mean 0,658 + 0,043) and that from normal CSF samples (Mean 1,089 + 0,224). The mean absorbance of the culture-positive bacterial CSF's also differed significantly from the other 2 groups (Tables VII; IX). Some overlap occurred amongst the absorbance values of bacterial culture positive CSF's (Range 0,975-0,879) and normal CSF's (Range 1,486-0,934). The mean absorbance value for bacterial positive CSF samples (0,920 _+ 0,029) differed significantly (p <0,01) from those of normal CSF (1,089 + 0,224) and TBM CSF's (0,658 + 0,043). The difference between the mean values obtained with tuberculous and non-tuberculous groups of pleural and ascitic fluid was also significant (p < 0,01). The method used for the DOUBLE ANTIBODY SANDWICH ELISA was that of Sada et al. (1983). Before the samples could be tested, the method had to be standardized and similar investigations to those for the INHIBITION ELISA were performed. In addition, antibodies raised against M.bovis BCG were conjugated to alkaline phosphatase since no commercial preparation was available. Unfortunately no distinction was recorded between negative and positive test specimens, even on repetition of the entire procedure. Measurement of chloride was done by a fully automated procedure using the BECKMAN ASTRA-8. A total of 149 samples were tested. Of these 10 were tuberculous, 34 were viral, and the remainder were bacterial meningitis. No pattern was established that could differentiate TBM from viral or bacterial meningitis. The results obtained are tabulated in Table III and illustrated in Figures 9, 10, and 11. In summarizing, the use of the INHIBITION ELISA technique for the accurate diagnosis of TBM seems promising. However, its validity in the clinical situation will have to be assessed further and with greater numbers of specimens before it can be adopted as a diagnostic procedure for TBM. OBJECTIVE. To determine 1. The ability and reliability of the INHIBITION ELISA1 technique to detect mycobacterial antigens in pleural, ascitic, and cerebrospinal fluids. 2. The accuracy and reproducibility of the double antibody sandwich ELISA in the detection of mycobacterial antigens in CSF of patients with tuberculous meningitis (TBM). 3. Whether a correlation exists between blood and CSF chloride levels in patients with tuberculous and other forms of meningitis. / Thesis (M.Med.Sc.)-University of Natal, Durban, 1985.