Abstracts

Rationale: Progressive myoclonus epilepsy (PME) is a rare generalised epilepsy syndrome, clinically characterized by progressively worsening myoclonus and seizures, with variable associated neurological, cognitive and psychiatric manifestations.  Although PME is one of the best genetically characterised epilepsy syndromes, exact mechanisms or networks driving the characteristic PME phenotype remain poorly understood. We thus aimed to identify differences in patterns of structural connectivity in PME compared to controls utilising advanced diffusion MRI techniques, and also to identify differences in structural volumes in PME through advanced volumetric analysis.

Methods: Eleven individuals with PME with a confirmed genetic diagnosis were recruited and imaged. Age- and sex- matched healthy control data was obtained (n= 22). Whole brain fixel-based analysis of diffusion MRI data was performed to identify regions with significant reductions in fibre density, fibre bundle cross-section, and a combined metric of fibre density and cross-section (FDC). White matter bundle segmentation was performed, and tract-of-interest analysis conducted to determine which white matter tracts were most affected in PME patients. Region-of-interest volumetric analysis was also conducted. Within the PME cohort, exploratory post-hoc analysis investigated relationships between FDC and disease duration, as well as Unified Myoclonus Rating Scale.

Results: Patients with PME demonstrated widespread significantly reduced structural connectivity, particularly involving projection (thalamic radiations, thalamocortical, corticothalamic and corticospinal tracts) and commissural fibres (splenium of corpus callosum) (Figure 1). Tract-of-interest analysis revealed highly affected tracts were predominantly posterior projection fibres in the cerebello-thalamo-cortical network. Cortico-cortical association pathways, such as superior longitudinal fasciculus, arcuate, cingulate and uncinate, were relatively spared. Lateral thalamic nuclei, anterior cerebellar lobes, superior cerebellar peduncles and splenium of the corpus callosum were areas of particular involvement. Region-of-interest volumetric analysis reflected involvement of similar structures, with significantly reduced volumes seen in cerebellar cortex and white matter, thalamus, brainstem and mid-anterior corpus callosum. Post-hoc analysis revealed a significant relationship between mean FDC across all significantly affected fixels and duration of disease (t= -2.519, p= 0.03).

Conclusions: Patients with PME have diffusely reduced structural connectivity, however the magnitude and pattern of involvement of cerebellar, cerebello-thalamic and thalamo-cortical tracts suggest that cerebello-thalamic network dysfunction may be an important driver of the clinical phenotype seen in PME. This pattern of cerebello-thalamic network involvement may distinguish PME from the other more common Genetic Generalised Epilepsy syndromes. Overall, this study provides insight into the underlying pathophysiology of this devastating epilepsy syndrome.

Funding: Not applicable