Browsing by Author "Wilmshurst Joanne"

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    Delineation of the genetic causes of complex epilepsies in South African pediatric patients
    (2023) Esterhuizen, Alina; Ramesar, Rajkumar; Wilmshurst Joanne
    Background Sub-Saharan Africa bears the highest burden of epilepsy worldwide. A proportion is presumed to be genetic, but this aetiology is buried under the burden of infections and perinatal insults, in a setting of limited awareness and few options for testing. Children with developmental and epileptic encephalopathies (DEEs), are most severely affected by this diagnostic gap, as the rate of actionable findings is highest in DEE-associated genes. This research study investigated the genetic architecture of epilepsy in South African (SA) children clinically diagnosed with DEE, highlighting the clinical utility of informative genetic findings and relevance to precision medicine for DEEs in a resource-constrained setting. Methods A group of 234 genetically naïve SA children with drug-resistant epilepsy and a diagnosis or suspicion of DEE, were recruited between 2016 and 2019. All probands were genetically tested using a DEE gene panel of 71 genes. Of the panel-negative probands, 78 were tested with chromosomal microarray and 20 proband/parent trios underwent exome sequencing. Statistical comparison of electroclinical features in children with and without candidate variants was performed to identify characteristics most likely predictive of a positive genetic finding. Results Pathogenic/likely pathogenic (P/LP) variants were identified in 41/234(17.5%) * probands. Of these, 29/234(12.4%) * were sequence variants in epilepsy-associated genes and 12/234(5.1%) * were genomic copy number variants (CNVs). Sixteen variants of uncertain significance (VUS) were detected in 12 patients. Of the 41 children with P/LP variants, 26/234(11%) had variants supporting precision therapy. Multivariate regression modelling highlighted neonatal or infantile-onset seizures with movement abnormalities and attention difficulties as predictive of a positive genetic finding. This, coupled with an emphasis on precision medicine outcomes, was used to propose the pragmatic “Think-Genetics” decision tree for early recognition of a possible genetic aetiology, pragmatic testing, and multidisciplinary consultation. Conclusion The findings presented here emphasise the relevance of an early genetic diagnosis in DEEs and highlight the importance of access to genetic testing. The “Think-Genetics” strategy was designed for early recognition, appropriate interim management, and genetic testing for DEEs in resource constrained settings. The outcomes of this study emphasise the pressing need for augmentation of the local genetic laboratory services, to incorporate gene panels and exome sequencing. *These percentages were rounded off to whole numbers in the published articles included in this thesis (i.e., rounded off to 18%, 12% and 5%, respectively).
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    Paediatric epilepsy surgery in a middle-income country: the red cross war memorial children's hospital experience
    (2023) Louw, Lizet; Enslin, Johannes; Wilmshurst Joanne; Fieggen, A G
    Purpose While epilepsy surgery has been shown to reduce seizure frequency and severity and even cures seizures in children with drug-resistant epilepsy, data from middle-income countries (MIC) are lacking. Method This study is a retrospective review of children with drug-resistant epilepsy who underwent surgical treatment at Red Cross War Memorial Children's Hospital (RCWMCH) between 1 January 2000 and 31 December 2021 (HREC: 140/2020). Results During the 21-year study period, 60 patients underwent epilepsy surgery for drugresistant epilepsy. The median age of the children was seven years (IQR 4.81-10.27years) at the time of surgery, with a male predominance of 33 patients. The most common surgical procedure performed was an anterior temporal lobectomy for temporal lobe epilepsy in 19 cases (31.7%), followed by peri-insular hemispherotomy in 9 cases (15.0%) and frontal lobectomy in 8 cases (13.3%). Of the 60 patients, complete records were available for 55 patients noting complications in 11 (20.0%), of which 4 cases (7.3%) had major complications. Notably, 2 patients (3.6%) had new-onset psychiatric symptoms. The long term outcomes after surgery showed 1-year seizure freedom in 32 patients (58.2%); among these, 21 patients (38.2%) could stop ASM one year after surgery, 17 patients (30.9%) had a recurrence of their seizures, and three had to restart ASM after 2-3 years. Eight patients (14.5%) required repeat surgery. The one-year-Modified Engel scoring for the study population was: 1-A in 52.7%, I-B in 3.6%, I-C in 1.8%, II-A in 15.8%, III-A in 10.9%, IV-A in 3.6% and IV-B in 10.9%. The most common histological finding in anterior temporal lobectomy (ATL) was focal cortical dysplasia (FCD), found in 11 patients (57.9%). The periinsular hemispherotomy (PIH) cases had equal numbers of FCD and Rasmussen's encephalitis in 4 patients (44.4%). The number of FCD in this series is much higher than in international data. Conclusion Epilepsy surgery is an effective and attainable intervention for drug-resistant epilepsy in the paediatric population despite limited resources and challenging aetiological profiles. Low complication rates were comparable to international data, with good seizure freedom outcomes.