Gotowa bibliografia na temat „Kernicteru”

This historical overview of kernicterus in prematurity, from the 1950s to the present, provides a unique perspective on this clinical conundrum. Three separate periods of pediatric history are detailed in relationship to our understanding of kernicterus in the preterm newborn: (1) the pre-intensive care era (1950 to 1965); (2) the low bilirubin kernicterus era (1965 to 1982); and (3) the 1980s. Each period demonstrates selected insights regarding kernicterus in prematurity, and together with recent reports suggest that premature newborns are now at extremely low risk of developing kernicterus when managed using current standards of care. However, the current conservative empiric guidelines for preventing kernicterus are questioned, and it is suggested that additional study is needed to clarify this issue in the 1990s.

Bilirubin encephalopathy/kernicterus is relatively rare, but continues to occur despite universal newborn screening. What is more interesting is the spectrum of clinical and even neuropathological findings that have been reported in the literature to be associated with bilirubin encephalopathy and kernicterus. In this review, the authors discuss the array of clinicopathological findings reported in the context of bilirubin encephalopathy and kernicterus, as well as the types of diagnostic testing used in patients suspected of having bilirubin encephalopathy or kernicterus. The authors aim to raise the awareness of these features among both pediatric neurologists and neuropathologists.

A severe increase in total bilirubin coincided with a decline in neurologic status to comatose in a 9 yr old spayed female mixed-breed dog being treated for immune-mediated hemolytic anemia. MRI of the brain was performed to investigate potential causes for the neurologic signs. MRI revealed bilaterally symmetrical hyperintensities within the caudate nuclei, globus pallidus, thalamus, deep cerebellar nuclei, and cortical gray matter on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences, which coincided with areas of bilirubin deposition and neuronal necrosis (kernicterus) identified on necropsy examination. This is the second case report of an adult dog exhibiting kernicterus, and the first report to document MRI findings associated with that condition. Kernicterus is an uncommonly reported complication of hyperbilirubinemia in dogs, but is potentially underreported due to difficulties in recognizing subtle lesions and distinguishing kernicterus from other potential causes of neurologic abnormalities with readily available antemortem tests. MRI may be helpful in supporting the diagnosis of kernicterus.

Neonatal hyperbilirubinaemia, or jaundice, is common and sometimes can cause lifelong neurodevelopmental disability or kernicterus which may result in cerebral palsy and profound hearing deficit. In recent times, international concern has been raised regarding the possible re-emergence of this devastating but usually entirely preventable condition, particularly in high-income countries such as Australia. Possible associations with an increased incidence include changes in clinical management guidelines, infant feeding practices and trends towards shorter postnatal hospital stays. This body of work reviews the severe neonatal hyperbilirubinaemia international incidence literature to ascertain whether local concern is warranted. Subsequently, the findings of our prospective population-based surveillance study to determine the contemporary incidence in Australia are presented. International neurodevelopmental outcomes are reviewed and described followed by the findings of our long-term prospective national follow-up study of the Australian cohort. Furthermore, screening strategies and published clinical guidelines to prevent kernicterus are appraised, with recommendations made for future prevention approaches in Australia and globally in terms of suggested guideline amendments, practice changes and future research.

Dissertação para obtenção do Grau de Mestre em Genética Molecular e Biomedicina
Kernicterus is a neuropathological condition characterized by deposition of unconjugated bilirubin (UCB) in specific brain regions that can lead to permanent sequelae and death, particularly in premature infants. UCB-induced toxicity has been studied in nerve and glial cells and, more recently, in brain microvascular endothelial cells. However, the effects of UCB on pericytes or on the basement membrane were never reported. We performed in vitro studies to assess apoptotic death, nitrosative stress and inflammatory reaction elicited by human brain vascular pericytes exposed to UCB. We also assessed the basement membrane component, collagen type IV, in brain sections of cortex, basal nuclei,hippocampus and cerebellum, collected at autopsy of a kernicteric preterm newborn. Using the pericyte marker, α-smooth muscle actin, we characterized the cells and confirmed the normal outgrowth towards a typical morphology with long processes. UCB induced an early secretion of interleukin-6, followed by that of vascular endothelial growth factor. mRNA upregulation preceded the secretion and confirmed the precocious profile of IL-6. UCB also caused the release of nitrites, which was maximum at 72 h incubation. The earlier upregulation of endothelial nitric oxide synthase expression confirmed the induction of nitric oxide production by UCB, although not excluding that other isoforms of the enzyme are also involved. Probably as a corolary of all these events, apoptotic cell death occurs in a time- and concentration-dependent manner. Through immunohistochemistry we examined the area occupied and the immunoreactivity of collagen type IV, which were reduced in the kernicterus case as compared with a non-icteric control. These findings are the first to demonstrate the compromise of pericytes and the impairment of collagen IV by hyperbilirubinemia and raise some basis for creation of possible target-directed therapy against pericyte and basement membrane damages as a result of UCB exposure.

Kernicterus causes damage to the auditory system and the basal ganglia in humans. Although the Gunn rat model of kernicterus has been extensively used to characterize the auditory features, this model has not been utilized to systematically investigate the movement disorder. In the present study, spontaneously jaundiced (jj) 16 day old Gunn rat pups were treated with sulfadimethoxine to exacerbate bilirubin neurotoxicity and compared to saline treated jjs and non-jaundiced (Nj) littermates. Electromyographic (EMG) activity was recorded from antagonistic hip muscles in dystonic and in normal appearing rats. Raw EMG signals were decomposed using the Discrete Wavelet Transform based multi-resolution analysis, and signal coefficients corresponding to the dominant EMG frequency band were chosen. Gunn rats exposed to sulfadimethoxine developed a stable clinical state characterized by prolonged abnormal axial and appendicular postures. Coherence plots revealed 4-7 Hz co-activation in antagonistic muscles that was significantly more prominent in jj sulfa treated dystonic compared to normal rats. The EMG findings support the presence of dystonia in sulfadimethoxine exposed jj Gunn rats.

Objetivos: A deficiência de glicose-6-fosfato desidrogenase (G6PD) está associada a um maior risco de encefalopatia bilirrubínica e de crise hemolítica aguda grave desencadeada por drogas como a primaquina e a dapsona. Conhecer a prevalência dessa deficiência enzimática em área onde a malária e a hanseníase ainda estão presentes e conhecer a prevalência das principais mutações traz subsídios para planejamento de estratégias com vistas à redução de riscos associados a esta deficiência enzimática. Métodos: Estudo descritivo transversal conduzido em uma região do centro-oeste do Brasil. Exame de triagem para deficiência de G6PD foi realizado em 3573 recémnascidos. Exame confirmatório foi necessário em 188 crianças triadas como possíveis portadores de deficiência. Nas crianças em que foi confirmada a deficiência de G6PD foi feita pesquisa das mutações G202A (G6PD A-) e C563T (G6PD Mediterrâneo) por PCR. Resultados: A deficiência de G6PD foi confirmada em 63 crianças, sendo 60 meninos (95,2%) e três meninas (4,8%). O percentual de exames falso-positivos na fase de triagem foi de 66,5%, estando o percentual de falso-positivos associado à temperatura e tempo de transporte das amostras. Entre as crianças que confirmaram deficiência de G6PD, foi mais frequente a história de anemia em familiares e de icterícia neonatal. Houve associação entre hematócrito baixo e deficiência enzimática, mas não com hemoglobina, contagem de reticulócitos ou neutrófilos. A prevalência da deficiência de G6PD (IC95%) foi de 1,76% (1,37; 2,24) entre os recém-nascidos triados e de 3,34% entre os meninos (2,58; 4,25). A mutação C563T não foi identificada em nenhuma criança, mas a mutação G202A estava presente em 58 crianças - 92,06% (IC95%: 83,29 - 97,03): 56/60 meninos e em 2/3 meninas homozigotas. Foi identificado um menino com Kernicterus portador da mutação G202A em hemizigose. Conclusão: O elevado percentual de falso-positivos na etapa de triagem, o tempo necessário entre coleta e confirmação da presença de deficiência enzimática, associado ao alto custo da triagem universal, não apoiam a inclusão da triagem de deficiência de G6PD no programa de triagem neonatal brasileiro. Na região avaliada, a prevalência observada em meninos indica que a triagem de deficiência de G6PD deva ser realizada antes do uso de drogas como a primaquina e a dapsona somente em meninos. Foi elevada a prevalência da mutação G202A, de classe III, sendo esta mutação associada a uma menor morbidade. A identificação de um menino com Kernicterus com deficiência de G6PD indica que há necessidade de se planejar estratégias para minimizar o risco dessa morbidade associada à deficiência enzimática
Objective: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with an increased risk of bilirubin encephalopathy in neonates and acute hemolytic crisis triggered by drugs such as primaquine and dapsone. In an area where malaria and Hansen\'s disease are still present, knowing the prevalence of this enzyme defect and determining the prevalence of major mutations is important for planning strategies for reducing the risks associated with this enzyme deficiency. Methods: Sectional study was conducted in a Midwestern region of Brazil. Screening for G6PD deficiency was performed in 3,573 neonates. Confirmatory tests were necessary for 188 positively screened children. After confirmation, PCR investigation was utilized to identify the mutations. Results: G6PD deficiency was confirmed in 63 children: 60 boys (95.2%) and 3 girls (4.8%). The percentage of false-positive cases in the screening phase, 66.5% and was associated with the temperature and transportation time of the samples. Family history of anemia and jaundice was more frequent among the children with confirmed G6PD deficiency. An association between a low hematocrit and enzyme deficiency was observed. However, there was no association with hemoglobin reticulocyte or neutrophils counts. The prevalence of G6PD deficiency (CI95%) was 1.76% (1.37; 2.24) among all screened neonates and 3.34% (2.58; 4.25) among male children. The C563T mutation was not identified in any child. The G202A mutation was present in 58 children - 92.06% (CI95%: 83.29 - 97.03), 56/60 boys and 2/3 homozygous girls. One boy with a hemizygous G202A mutation was identified as having Kernicterus. Conclusion: The high percentage of false-positive results when first screening for G6PD deficiency; the long delay time between the test and result; along with the high cost of the this screening test, are all factors that do not support adding this test to the already established Brazilian neonatal screening programs. The prevalence observed among boys does indicate that screening for G6PD deficiency should be performed in this region before the use of drugs such as primaquine and dapsone only in boys. This study found a high prevalence of the G202A mutation, a Class III variant associated with lower morbidity. The identification of a G6PD deficient boy with Kernicterus reinforces the necessity for strategies to abolish the morbidity associated with this enzyme deficiency

2006/2007
INTRODUZIONE A basse concentrazioni la bilirubina non coniugata (unconjugated bilirubin, UCB) prodotta dalla degradazione dell’emoglobina, sembra essere un potente anti-ossidante, mentre è estremamente dannosa ad alte concentrazioni, causando encefalopatia nei neonati con severo ittero. Il 70% dei bambini che presentano kernittero muoiono entro sette giorni di vita, mentre il 30% dei sopravvissuti manifesta irreversibili conseguenze come sordità, ritardo mentale e danni cerebrali permanenti. L’encefalopatia dovuta ad alti livelli di bilirubina rappresenta oggi la maggior causa di riammissione ospedaliera nei neonati entro il primo mese di vita. Storicamente gli studi riguardanti le modalità di ingresso della bilirubina nel sistema nervoso centrale si sono concentrati sulla barriera emato-encefalica (blood brain barrier, BBB), costituita dai microvasi e dai capillari del cervello (micro vessels, MV). Tali studi hanno dimostrato come solamente la bilirubina non coniugata e non legata all’albumina del sangue, definita “bilirubina libera” (free bilirubin, Bf) sia capace di attraversare le membrane cellulari e diffondere nel tessuto. Tuttavia i microvasi non sono l’unica interfaccia sangue-tessuto presente nel cervello. Una seconda barriera è costituita dai plessi coroidei (CP). Questi, collocati nei ventricoli del cervello, mediano il passaggio delle molecole dal sangue al liquido cefalorachidiano e viceversa, posseggono una ampia superficie di scambio, il più alto flusso sanguigno del sistema nervoso centrale ed un fenotipo barriera meno restrittivo rispetto ai microvasi del parenchima. L’ingresso della bilirubina nel cervello sembra essere attivamente controllato da due trasportatori appartenenti alla famiglia delle “ATP dependent transporters”, Mrp1 e Pgp. Tali trasportatori potrebbero mantenere bassa la concentrazione della bilirubina limitandone l’ ingresso a livello di barriere o agendo direttamente a livello delle cellule del parenchima. Nonostante l’ impatto di questi trasportatori sulla disponibilità nel sistema nervoso centrale non solo della bilirubina ma egualmente di atre molecole potenzialmente tossiche, così come dei principi attivi, la loro espressione e localizzazione nelle interfacce sangue-cervello non sono del tutto chiare. Per tali motivi il lavoro di questi tre anni di tersi è stato incentrato a: Ia) chiarire il livello di espressione proteica relativa di Mrp1 e Pgp nelle due principali barriere cerebrali, la BBB (blood brain barrier, barriera emano encefalica) e la BCSFB (blood CerebroSpinal Fluid barrier, barriera emato liquorale); Ib) Definire l’andamento della loro espressione nel corso dello sviluppo post-natale in situazione fisiologica. II) Valutare l’effetto di elevati livelli serici di bilirubina sull’espressione di Mrp1 e Pgp nelle barriere emato encefaliche, come prima linea di difesa verso la bilirubina nel kernittero. Per raggiungere questo secondo obiettivo abbiamo utilizzato il ratto Gunn, considerato il modello in vivo per la sindrome di Crigler-Najjar e il kernittero. I ratti Gunn presentano elevati livelli di bilirubina serica ed un quadro clinico simile a quanto si riscontra nell’uomo. L’iperbilirubinemia, nel ratto, è dovuta ad una mutazione nell’enzima responsabile della coniugazione del pigmento, passaggio fondamentale per la sua successiva eliminazione. Nell’omozigote (jj) la bilirubina totale nel sangue (TBS) è molte volte più alta che nell’eterozigote (Jj) in cui l’allele non mutato codifica per l’enzima nella sua forma attiva, sufficiente a mantenere livelli di bilirubina normali. RISULTATI Ia) Attraverso una quantificazione relativa dell’ espressione proteica, ottenuta tramite Western blot, abbiamo dimostrato una espressione speculare dei due trasportatori nelle interacce sangue cervello. Mentre i microvasi sono caratterizzati dalla forte espressione di Pgp, ed i livelli di Mrp1 sono 15-20 volte inferiori rispetto ai plessi, questi ultimi presentano una elevata espressione di Mrp1 ed una quasi completa assenza di Pgp. Per quanto riguarda l’espressione di Mrp1 nei plessi coroidei (CP), abbiamo potuto evidenziare una differenza, con la massima espressione nel plesso del 4° ventricolo rispetto ai ventricoli laterali. Tramite immunofluorescenza abbiamo poi evidenziato per entrambe i trasportatori una localizzazione lato sangue, con Pgp luminale nei vasi e Mrp1 baso-laterale nel plessi coroidei. Ib) Anche l’andamento dell’espressione durane lo sviluppo post-natale differisce. Mentre Mrp1 è sin dalla nascita (2 giorni di vita) altamente espresso in entrambe le barriere, Pgp è inizialmente espresso a livelli più bassi (4,6 volte meno) rispetto all’ adulto (60 giorni). Contemporaneamente anche la densità dei vasi nel parenchima aumenta. II) Nel modello iperbilirubinemico rappresentato dal ratto Gunn, la TBS (jj) e molte volte più alta che nell’ eterozigote (Jj) e tale differenza permane per tutto l’arco di tempo esaminato (0-60 giorni dalla nascita). Al contrario la bilirubina libera (calcolata) è elevata solo nelle prime due settimane di vita, quando il rapporto bilirubina-albumina nel sangue è superiore all’unità. Poi, il rapido aumento della concentrazione ematica di albumina determina un significativo calo della Bf. Mentre l’analisi degli effetti (macroscopici) dell’iperbilirubinemia sullo sviluppo degli emisferi cerebrali non evidenzia differenze tra Jj e jj; in questi ultimi la crescita del cervelletto è severamente inibita. Già a 17 giorni di vita l’ipoplasia del cervelletto si manifesta con una differenza nel peso del 50% nei jj rispetto agli animali normo bilirubinemici di pari età. Durante tale periodo anche l’espressione dei due trasportatori nelle barriere è modificata. L’espressione proteica di Pgp nella BBB degli animali iperbilirubinemici è aumentata ad ogni età presa in esame. Tuttavia tale incremento non modifica in maniera importante la quantità del trasportatore nei MV durante lo sviluppo post natale, rimanendo quindi poco espresso (5 volte meno rispetto all’adulto) almeno fino ai 17 giorni di vita. Contemporaneamente la presenza Mrp1 nella BCSFB è inibita. Già a 9 giorni nel plesso del 4° ventricolo Mrp1 è il 50% rispetto al controllo (pari età, Jj). Anche se nei plessi dei ventricoli laterali l’inibizione dell’espressione è inferiore, nell’insieme la quantità di Mrp1 è fortemente ridotta negli animali iperbilirubinemici. Contrariamente, nei ratti Jj, Mrp1 ha un andamento simile a quello descritto nella sezione (Ib). CONCLUSIONI I risultati da noi ottenuti sottolineano importanti differenze tra le due barriere. La barriera emato-encefalica si sviluppa durante il primo periodo post-natale, in un ambiente caratterizzato dalla forte presenza di membrane cellulari. Similarmente l’espressione di Pgp è inizialmente bassa ed incrementa molto durante lo sviluppo post-natale. Al contrario I plessi coroidei appaiono precocemente in età embrionale, contribuiscono allo sviluppo del cervello e posseggono il più alta espressione di enzimi di fase II, coinvolti nel metabolismo di potenziali sostanze tossiche, del cervello. Un alto livello di Mrp1 sin dalla nascita suggerisce un suo coinvolgimento nel trasporto di qualche sostanza importante nello sviluppo del cervello o in un suo precoce coinvolgimento nel mantenimento dello stato ossido riduttivo, o nell’eliminazione di metabolici dal sistema nervoso centrale. Elevati livelli di bilirubina, come nel modello Gunn, modulano sia l’espressione di Pgp nella BBB, che di Mrp1 nella BCSFB. Tuttavia l’incremento nell’espressione di Pgp nei microvasi non sembra essere sufficiente a contrastare efficacemente l’ingresso della bilirubina libera, molto elevata fino al 17 giorno di vita. La simultanea riduzione di Mrp1 nei plessi coroidei, può facilitare l’ingresso o ridurre l’efflusso della bilirubina nel liquido cefalo rachidiano, consentendo l’accumulo e conseguente danno dei tessuti esposti.
................................................................ ....................... .. .BACKGROUND The unconjugated bilirubin (UCB), a heme degradation product, has been suggested to be a potent antioxidant at low concentration while it seems to be extremely dangerous at higher concentrations, causing encephalopathy in severely jaundiced neonates. Around 70% of children with kernicterus die within seven days, while the 30% survivors usually suffer irreversible sequels, including hearing loss, paralysis of upward gaze, mental retardation, and cerebral palsy with athetosis. Bilirubin encephalopathy is actually the leading cause of hospital readmission of newborns within the first month after birth. Historically the studies concerning the bilirubin entry the central nervous system have focused on the blood brain barrier (BBB), located at the level of the endothelial cells forming the brain micro vessels (MV), leading to the “free bilirubin theory”. It consists in the idea that only the free unconjugated bilirubin, the part of bilirubin exceeding the binding ability of the serum albumin, is able to cross the cell membranes and diffuse in tissue. In brain a second blood brain barrier is present. It is located at the level of the epithelial cells forming the choroids plexuses, between the blood and the cerebrospinal fluid (blood-cerebrospinal fluid barrier, BCSFB). Despite the largest surface area available for the exchanges, the high blood flux, the strategically position between two circulating fluids and the more leaky phenotype, limited studies have been made concerning its role in limiting the bilirubin entry the brain. Two ATP dependent transporters, the Multidrug Resistance-associated Protein 1 (Mrp1) and the MultiDrug resistance Protein (Pgpor MDR1), appear to be actively involved in UCB trafficking. The transporters play an important role in keeping extra cellular bilirubin concentration, such as potentially toxic compounds, below toxic levels by limiting the entry of UCB from blood to brain, or else in controlling intracellular bilirubin levels in parenchyma cells. Despite the importance of Mrp1 and Pgp on BBI their pattern of expression and cellular localization remains still unsettled. Based on these considerations - The first aim of the thesis was clarify the relative protein expression of these transporters at the two major BBI protecting the brain from toxic insults (Ia), and to identify their post-natal developmental profile of expression and cellular localisation (Ib). Similarly, no data about the Mrp1 and Pgp expression on BBI during the bilirubin encephalopathy are available. - The second aim of the thesis was investigate a relation between the high level of blood bilirubin and Mrp1 and Pgp expression in brain barriers in vivo using the Gunn rat (II), in witch the symptoms closely correlate to the human kernicterus and Crigler-Najjar syndrome type I. In this animal model, a mutation in the enzyme responsible for the conjugation and subsequent elimination of bilirubin, leads to the total absence of the enzymatic activity in the homozygous animals (jj), causing a severe life long hyperbilirubinemia. In the heterozygous Gunn rats (Jj), the enzymatic activity, until if reduced, is present and result in normal serum bilirubin levels. RESULTS Ia) By quantitative Western blot, we have demonstrated a mirroring expression of the two transporters at the blood brain interfaces in the adult rat. On the BBB the Pgp is strongly expressed and the Mrp1 amount is 15-20 times lower than in CPs. At the contrary, the CPs are characterized by the high expression of Mrp1, with a difference between the lateral ventricle (LV) and the 4th ventricle (4thV) CP, the former being a lower Mrp1 expression than in the last. In both LV and 4thV CPs, Pgp is virtually absent. By immunofluorescence we revealed that both ABC transporters are located at the blood side, the Pgp luminal on MV, and Mrp1 basal on CPs. Ib) With respect to the post-natal development, the Mrp1 expression is high since the early post-natal age and do not change significantly from birth to adult life in both barriers. By contrast, Pgp expression is weak a P9 and increase 4.6 fold with maturation on MV. Synchronously the density of Pgp stained MV in parenchyma seems increasing. II) In the homozygous Gunn rat (jj) the total bilirubin in serum is several time higher than in the heterozygous (Jj) animals all life long. By contrast the (calculated) free bilirubin is extremely elevated until the first week of life, when the bilirubin-albumin ratio exceed the unit, then drop due to the developmental increasing albumin concentration in blood. While no differences in Cx weight have been found between Jj and jj rat at every postnatal age, the cerebellum development is strongly impaired by the bilirubin toxic effect, displaying a Summarymarked hypoplasia, with about the 50% of weight loss respect the Jj control at 17 days after the birth. Concerning the ABC transporters, the differential pattern of expression between blood brain interfaces is maintained. But, in jj Gunn rats, the Pgp expression at the BBB is up-regulated at every post natal age analysed, also if this increase do not seems to be sufficient to confer protection at list until P17, when the amount of the transporter in the MV is about 5 times lower than in adult (P60). At the same time the Mrp1 expression on the BCSFB is down regulated. Since P9 the amount of Mrp1 in the 4thV CP of jj rats drops around to the 50% respect the amount in the littermates. In the LV CP the decrease is less marked, but in any case the Mrp1expression in both CPs is strongly impaired. This down regulation seems to be post-transcriptional. In the Jj animals, the Mrp1 relative expression is already high in both plexuses at early postnatal stages. A significant difference was noted only between LV CP (76%) and 4thV CP at P60 (100%). CONCLUSIONS All together these results indicate that the two barriers differ: The BBB develops after the birth and is surrounded by the lipid rich parenchyma environment, in agreement with the transporter preference for the lipid compounds and the strong post-natal developmental increase of the Pgp amount on MV. The CPs develops early in the foetal life, are involved in the guidance of the brain development and posses the highest phase II metabolising enzymes in the brain. The Mrp1 amount in CPs is similar to the adult level since the birth and may be involved in the transport of some compounds important in the brain development, in the detoxification or in the maintenance of the redox state (GS- sulfo- conjugates, LC4, etc.). In Gunn rats, as model for Kernicterus and Crigler-Najjar syndrome type I, the Pgp offered protection is not sufficiently modulate until P17, when the amount of the free bilirubin is elevated and could cross the brain barriers. The simultaneously down regulation of Mrp1 at the BCSFB may facilitate the entry of the bilirubin or strongly impair their clearance in the central nervous system, leading to the accumulation in brain and subsequent damage of tissue.
1974

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014
Classical Kernicterus is a clinical triad of abnormal motor control, movements and muscle tone, an auditory processing disturbance with or without hearing loss, and oculomotor impairments, especially impairment of upward vertical gaze. It’s a rare disease with severe neurologic consequences that is due to severe neonatal hyperbilirubinemia. With early identification, prevention and treatment of severe hyperbilirubinemia, kernicterus is a cerebral palsy preventable cause, happening in the neonatal period. Nowadays, newborns are often discharged before 48 hours of life. Once that most of the times, bilirubin peak level happens around 96 hours of life, when many newborns have already been discharged from the hospital, pediatricians often have to predict the risk of developing subsequent severe hyperbilirubinemia. Like this, it’s necessary to improve the diagnosis and to promote the early treatment of neonatal jaundice when necessary.
O kernicterus clássico consiste na seguinte tríade: controlo motor anormal dos movimentos e do tónus muscular, distúrbios auditivos com ou sem perda de audição e paralisia ocular, predominantemente no olhar vertical. É uma doença rara com graves consequências neurológicas secundárias a uma hiperbilirrubinemia neonatal. Com a prevenção, detecção precoce e tratamento desta hiperbilirrubinemia o kernicterus é uma das causas evitáveis de PC que ocorre no período neonatal. Actualmente, os RN tem alta muitas vezes antes de perfazerem as 48 horas de vida. Uma vez que o pico de bilirrubina é muitas vezes atingido por volta das 96 horas de vida, altura em que grande parte dos RN já obtiveram alta hospitalar, esta situação força os pediatras a tentar prever o risco de hiperbilirrubinemia grave quando ponderam a alta hospitalar. É necessário conhecer os factores de risco para a ocorrência de kernicterus para saber em que situações o tratamento da icterícia neonatal é necessário.

Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2014
Crigler-Najjar Syndrome is a rare disease characterized by an unconjugated hyperbilirrubinemia since birth. This disease is classified into two distinct forms: Crigler-Najjar type 1 and Crigler-Najjar type 2. The Crigler-Najjar type 1 is a rare autosomal recessive disorder with a complete deficiency of bilirubin uridine diphosphate-5'-glucuronosyltransferase type 1 enzyme (UGT1A1) activity, resulting in a total loss of bilirubin glucuronidation. This condition can be fatal due to the permanent and severe unconjugated hyperbilirrubinemia associated with kernicterus. Patients with Crigler-Najjar disease type 2 have residual UGT1A1 activity, resulting in a milder phenotype. These patients are still able to conjugate and excrete bilirubin via the bile. Bile of type 2 patients contains mono-conjugates and some bi-conjugates, although the bile of type 1 patients contains essentially no conjugated bilirubin. Patients with Crigler-Najjar type 2 can be treated with phenobarbital, which enhances the residual UGT1A1 activity and decreases plasma UCB concentrations by approximately 30%. In order to decrease plasma UCB levels, Crigler- Najjar type 1 patients rely on lifelong phototherapy, the routine treatment for unconjugated hyperbilirubinemia. However, it becomes less effective with age and eventually fails to prevent bilirubin-induced brain damage in several patients. This fact suggests the call for the development of alternative treatment strategies for severe unconjugated hyperbilirubinemia.

In hierdie studie word die etiologiese verband tussen verstadigde neurologiese integrasie en latere leerproblematiek by kinders met klinies betekenisvolle neonatale bilirubienmetings ondersoek. Resente navorsing dui aan dat kinders met klinies betekenisvolle bilirubienmetings tydens die neonatale fase ‘n groter risiko loop om later verstadigde neurologiese integrasie te vertoon, veral weens die kwesbaarheid van die neonatale brein vir toksiene. Hierdie navorsingsresultate suggereer ‘n verband tussen klinies betekenisvolle neonatale bilirubienmetings en latere leerproblematiek, aangesien spesifieke breinareas wat deur neonatale bilirubien aangetas word ook vaardighede medieer wat belangrik is vir prestasie in sekere leerareas, te wete lees, skryf en reken. Neonatale fisiologiese geelsug is nie altyd met die blote oog sigbaar nie, en derhalwe word simptome soos oormatige slaperigheid en ingekorte behoefte aan voeding dikwels deur onervare moeders geïgnoreer, omdat die baba nie opmerklik “geel” is nie. Verder word neonatale fisiologiese geelsug nie altyd as sodanig gediagnoseer nie, weens verskeie faktore soos ontoereikende primêre gesondheidsorgdienste op die afgeleë platteland, tuisgeboortes en vroeë ontslag van moeders en babas uit klinieke en hospitale, veral gesien in die lig daarvan dat neonatale geelsug piekvlak tussen dag drie en dag sewe bereik. Bilirubienmeting is nie standaard prosedure by afgeleë klinieke nie, en waar ‘n rowwe skatting deur die klinieksuster op ‘n klinies betekenisvolle bilirubientelling dui, word moeders dan dikwels aangeraai om natuurlike fototerapie (sonlig) toe te pas. Verdermeer vind opvolgkonsultasies by ‘n klinieksuster dikwels eers plaas nadat die baba ongeveer een maand oud is, en voorligting aan die moeder rakende moontlike kwesbaarhede wat verband hou met klinies betekenisvolle neonatale bilirubienmetings is gebrekkig. Sodanige ouers kan dus heeltemal onbewus wees van die potensiële skade wat aangerig kan word aan die ontwikkelende brein, en intervensie vind gevolglik nie tydig plaas nie. Betekenisvolle duidinge wat uit hierdie navorsingsprojek mag voortvloei, kan derhalwe benut word ten einde spesifieke kwesbaarhede in kinders met klinies betekenisvolle neonatale bilirubienmetings tydig te kan identifiseer; en hoë-risiko leerders se moontlike latere leerproblematiek deur tydige intervensie tydens die voorskoolse jare te ondervang, voordat pobleme in die grondslagfase manifesteer. ‘n Empiriese ondersoek is uitgevoer waarby 37 deelnemers betrek is. Gebaseer op die resultate van die data-analise en interpretasie van die resultate word die hipotese aanvaar. Relevante aanbevelings met betrekking to praktykverbetering en verdere navorsing word gemaak. ENGLISH: With this study the etiological link between delayed neurological integration, high neonatal bilirubin measures and learning difficulties were investigated. Recent research findings suggest that children with high neonatal bilirubin measures are at a greater risk for delayed neurological integration later on, especially because of the susceptibility of the neonatal brain for toxins. The results of this research project suggest an etiological link between neonatal hyperbilirubinemia and learning difficulties at a later stage, since specific brain-areas which are affected by the bilirubin do mediate skills important for performance in certain learning areas, e.g. reading, writing and arithmetic. It is not always possible to notice neonatal physiological jaundice; hence, inexperienced mothers tend to ignore symptoms like sleepiness and lack of appetite, merely because their babies do not appear “yellowish”. Neonatal physiological jaundice is often misdiagnosed due to various factors like inadequate primary health care services in rural areas, home births and early discharge from hospitals - particularly in light of the fact that jaundice peaks between day three and day seven after birth. Measurement of neonatal bilirubin levels is not a standard procedure at rural clinics, and mothers are often advised to make use of natural phototherapy (sunlight) when the baby appears “yellowish”. Follow-up consultation often occurs when the baby is already one month old; hence mothers often receive inadequate information concerning neonatal hyperbilirubinemia. Parents might therefore be totally unaware of the potential vulnerability and harm to the developing brain, and intervention often does not take place. Significant indicators of this research project can be used to identify well in advance specific vulnerabilities in learners with neonatal hyperbilirubinemia, as well as potentially high-risk learners during the pre-school years, before such vulnerabilities escalate during the foundation phase. An empirical study with 37 participants was conducted. Based on the data analyses and interpretation of the results, the hypothesis was accepted. Relevant recommendations concerning best practice and further research were done.
Thesis (PhD)--University of Pretoria, 2008.
Educational Psychology
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