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Associated findings with hippocampal sclerosis
(i) Dispersion of granule cells into the molecular layer, associated with hippocampal sclerosis
was first described by Houser39. This phenomenon appears peculiar to seizure-induced
hippocampal damage and is encountered in 4050% of HS cases in surgical series40–43. In the
presence of dispersion, granule cells often appear enlarged and more fusiform in shape, with
increased cytoplasm and neuropil separating neurones. In some cases ectopic neurones within the
molecular layer have their long axis orientated more horizontally41,44. The border of the granule
cell layer with the molecular layer, as a consequence of this neo-migration, becomes more ill-
defined. In some cases distinct clusters of granule cells are seen in the molecular layer and in a
smaller number (about 10% of surgical cases) a bi-laminar granule cell layer is noted (see Figure).
The extent and pattern of dispersion may vary both within and between cases and may alternate
with regions of granule cell depletion. There is no precise definition for granule cell dispersion
(GCD); a granule

cell layer thicker than 10 cells42 or 120 m has been proposed. In many cases the thickness may
in fact reach 200 m or greater45, compared to mean control widths of around 100 m. There is
a sub-classification system for types of dispersion46, although no correlation with outcome
following surgery has been demonstrated in any study46,47. There is an association between GCD
and early onset of seizures.

The functional significance as well as the mechanism for granule cell dispersion is unclear.
Dispersion of granule cells has also been demonstrated in experimental models of TLE. For
example, granule cell dispersion is observed in the kainate models, first appearing at about four
days following seizures, increasing over eight weeks and persisting for at least six months48. GCD
is almost invariably associated with gliosis in the granule cell layer and it has been proposed that
persistent radial glial processes guide this neo-migration of granule cells through the dentate
gyrus44. It may relate to local reelin deficiency49,50, altered rates of neurogenesis stimulated by
seizures or differential expression of miRNA51.

(ii) Mossy fibre sprouting. In animal models of MTLE (e.g. the kainate model), and in
hippocampal sclerosis in humans, extensive recurrent projection of mossy fibre collaterals into
the molecular layer occurs, a process more commonly known as mossy fibre spouting (MFS).
The majority (over 90%) of these sprouted mossy fibres appear to make synaptic contact
(excitatory asymmetric synapses)52 with apical dendrites and spines of granule cells in the inner
molecular layer, and a smaller proportion with inhibitory interneurones52. This therefore creates
a recurrent excitatory circuit, potentially a pro-epileptogenic ‘short-circuit’. However, recent post
mortem studies in humans support the notion that MFS is more likely an epiphenomenon of,
rather than directly provoking, seizures53. Mossy fibre sprouting is best visualised (in both
experimental and human tissue) with Timm silver method (as mossy fibre boutons contain high
levels of zinc). MFS can also be demonstrated with immunohistochemistry for dynorphin A, an