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Title: A longitudinal study of brain structure and function in Rolandic epilepsy between active epilepsy and seizure remission
Author: Smith, Stuart David Whitson
ISNI:       0000 0004 8505 455X
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2019
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Introduction: Rolandic Epilepsy (RE), an idiopathic focal epilepsy, is one of the most common epilepsies in school-age children, which frequently co-occurs with a heterogeneous mix of cognitive impairments (Pellock et al. 2016). These cognitive deficits predominantly involve reading disability, developmental language disorder and developmental coordination disorder (Overvliet et al. 2011, Smith et al. 2015, Vega et al. 2015). The seizures of this epilepsy spontaneously remit when the child reaches adolescence. However, it is unclear whether the same occurs with the cognitive impairments (Camfield and Camfield 2014, D'Alessandro et al. 1990, Garcia-Ramos 2015, Metz-Lutz and Fillipini 2006, Northcott 2006, Overvliet 2010). Furthermore, it is unknown how brain structure and function changes in respect to remission of seizures and whether this differs from the development of healthy children, which could provide a better understanding of the process to seizure remission. Methods: In this longitudinal study, children with active Rolandic epilepsy and healthy children were invited to have structural neuroimaging and neuropsychological testing at baseline and 4.5 years later at follow-up, in seizure remission. Furthermore, at follow-up, a non-clinical sleep electroencephalogram (EEG) was performed. Details of the investigations are below: Neuroimaging: Longitudinal structural magnetic resonance imaging (MRI) scans were used to assess cortical thickness and subcortical volumes. The a priori hypothesis proposed at baseline increased cortical thickness within the inferior frontal gyrus, supramarginal gyrus and inferior parietal lobe and the transverse temporal and superior temporal gyrus at baseline with reduced thinning at follow-up. Furthermore, the putamen would be larger in volume at baseline and would increase in volume at follow-up. Also included, were exploratory investigations of cortical thickness within the whole brain and parcellated regions. Neuropsychology: Longitudinal neuropsychological assessments were used to assess fluid intelligence, single-word reading, central auditory processing, indication for developmental coordination disorder (DCD) and attention deficit hyperactivity disorder (ADHD). At follow-up, additional tasks were included to investigate phonological processing and the nature of fine-motor deficits. The a priori hypothesis proposed that DCD would be the most prevalent disorders, and there would be additional layers of cognitive problems. The first layer would be epilepsy specific, and the second layer suspected to be familial in origin. In seizure remission, it was proposed that the epilepsy-specific cognitive problems, which include motor and attentional issues, would reduce, whereas familial features such as dyslexia would remain. Electroencephalography: Clinical EEG reports were reviewed, and the appearance of Rolandic spikes (RS) and their location were recorded. At follow-up, a non-clinical, sleep-deprived EEG was recorded to see if there was any evidence of RS in seizure remission. Furthermore, using global power analysis and topographic power maps, sections of awake resting-state EEG were compared with similar EEG samples from clinical EEG recordings during active epilepsy. The a priori hypothesis derived from Bouma et al. (1997), proposed that RS would be apparent in 10% of the cohort in seizure remission. An additional, exploratory component investigated changes in global EEG power and peak-dominant frequency between active epilepsy and seizure remission. Results: Neuroimaging: The longitudinal neuroimaging data demonstrates patchy regions of cortical thinning across the cortex; however, in the areas where thinning occurred, there was a greater reduction in cortical thickness compared to controls. The greatest thinning occurred in the bilateral frontal lobes, insular and anterior temporal regions. The cross-sectional analysis shows regions of predominantly thinner cortex at baseline, whereas, at follow-up, altered regions were likely to have thicker cortex compared to controls. In particular, a large region of thicker cortex was identified around the right post-central gyrus. There was no difference in the size of putamen at baseline or follow-up, whereas the longitudinal analysis found an increase in the volume of the putamen over time. In the control group, putamen size decreased with time. Neuropsychology: At baseline, an indication for DCD was the predominant cognitive problem; this frequently co-occurred with evidence for dyslexia and ADHD. At follow-up, the number of participants with an indication for DCD was reduced compared to baseline, but the numbers at follow-up were greater than the controls. The longitudinal analysis found an improvement in group cognition, in particular in the processing of filtered words; there was one exception, a deterioration in matrix reasoning scores. Despite group improvements, specific cognitive problems persisted in some individuals, and in some, new ones appeared in seizure remission. Electroencephalography: The review of clinical EEG reports found a predominance for spikes over the right hemisphere. Furthermore, there were individuals with spikes before seizures and no spikes recorded during active epilepsy. At follow-up, in seizure remission, 50% had evidence of EEG abnormalities, of which, 28.6% had evidence of RS. In the remaining individuals with abnormalities, there was evidence of poorly formed, short duration, generalised spike and slow-wave discharges. Quantitative analysis of EEG resting state between active epilepsy and seizure remission found a relationship between relative delta power and time to final seizure furthermore; there was a significant difference in the topography of absolute delta power between active epilepsy and seizure remission. Conclusions: This longitudinal controlled study has demonstrated altered cortical thickness and abnormal cognition in both active epilepsy and seizure remission. In those individuals with cognitive problems, the cognitive profile of RE is predominantly based on motor and coordination problems which co-occur in with dyslexia and ADHD. Specific cognitive problems can persist or appear in seizure remission, and thus a rethink of the educational assessment of individuals with RE is proposed. Furthermore, large amounts of thinning occur in the frontal lobes in seizure remission; this would suggest that the maturity of this structure is required for seizure remission, and this presents a new therapeutic target. The appearance of new generalised spike and waves discharges in seizure remission needs to be replicated and investigated to see how prevalent they are and whether they influence cognition. Finally, the EEG evidence lessens the role of the RS and implicates the power of resting delta wave activity in the generation of seizures; which could improve our understanding and treatment of this common childhood epilepsy.
Supervisor: Pal, Deb Kumar ; Richardson, Mark Philip Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available