Migrating partial seizures of infancy: expansion of the electroclinical, radiological and pathological disease spectrum

Abstract

Migrating partial seizures of infancy, also known as epilepsy of infancy with migrating focal seizures, is a rare early infantile epileptic encephalopathy with poor prognosis, presenting with focal seizures in the first year of life. A national surveillance study was undertaken in conjunction with the British Paediatric Neurology Surveillance Unit to further define the clinical, pathological and molecular genetic features of this disorder. Fourteen children with migrating partial seizures of infancy were reported during the 2 year study period (estimated prevalence 0.11 per 100,000 children). The study has revealed that migrating partial seizures of infancy is associated with an expanded spectrum of clinical features (including severe gut dysmotility and a movement disorder) and electrographic features including hypsarrhythmia (associated with infantile spasms) and burst suppression. We also report novel brain imaging findings including delayed myelination with white matter hyperintensity on brain magnetic resonance imaging in one-third of the cohort, and decreased N-acetyl aspartate on magnetic resonance spectroscopy. Putaminal atrophy (on both magnetic resonance imaging and at post-mortem) was evident in one patient. Additional neuropathological findings included bilateral hippocampal gliosis and neuronal loss in two patients who had post-mortem examinations. Within this cohort, we identified two patients with mutations in the newly discovered KCNT1 gene. Comparative genomic hybridization array, SCN1A testing and genetic testing for other currently known early infantile epileptic encephalopathy genes (including PLCB1 and SLC25A22) was non-informative for the rest of the cohort.

Figure 1

(A) EEG recording from Patient 9 illustrating modified hypsarrhythmia at 2 months of age. (B) EEG recording from Patient 9 illustrating migrating epileptic foci within the same recording at 5 months of age.

Figure 2

Axial T₂-weighted MRI of Patient 10 at 16 months of age demonstrating relative hyperintensity of the deep white matter (arrow) suggesting delayed myelination.

Figure 3

T₂-weighted MRI in Patient 7 at 39 months of age reveals bilateral symmetrical signal abnormality of putamen (arrows) and caudate (arrow heads) in addition to cerebral atrophy.

Figure 4

Single voxel magnetic resonance spectroscopy. (A) With short echo time (35 ms) of the right frontal white matter from Patient 2 at 24 months of age demonstrating a relatively high myoinositol (mI) peak and a relatively low N-acetyl aspartate peak (NAA, circled) in relation to the creatine (Cr) and choline (Cho) peaks signifying immaturity. Magnetic resonance spectroscopy obtained with similar acquisition parameters of a normal 24-month-old child is shown (B) for comparison.

Figure 5

(A–C) The images show the abnormal putamen in Patient 7 demonstrated by (A) large perivascular spaces revealing neuronal loss in the putamen (Luxolfastblue/Nissl), (B) depletion of neurons and gliosis with focal calcification (haematoxylin and eosin) and (C) astrocytosis in putamen (GFAP). (D) CA1, CA3, CA4 sectors and the dentate gyrus (DG) of hippocampus show cell depletion, consistent with a form of hippocampal sclerosis in Patient 7.

Figure 6

Hippocampal sections from Patient 12 revealing a pattern of hippocampal sclerosis. Right and left CA4 sectors show depletion of neurons and gliosis (i.e. end folial sclerosis). R-DG (right dentate gyrus) and L-DG (left dentate gyrus) show an extra layer of cells (arrow) due to granule cell dispersion. Right CA3/CA2/CA1 are relatively preserved.