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TOUCH MEDICAL MEDIA
66
Editorial Epilepsy
Publication Date: 7 February 2020
Temporal Lobe Epilepsy – Pathophysiology
and Mechanisms
Leong Tung Ong
Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Temporal lobe epilepsy (TLE) is a disorder of the nervous system due to unprovoked seizures originating from the temporal lobe.
The main cause of TLE is neuronal hyperexcitability due to the presence of pathological changes in the temporal lobe of the brain
such as neuronal loss, mutation, granule cell dispersion and malformations of cortical development. This editorial discusses important
aspects of the pathogenesis underlying TLE.
Keywords
Temporal lobe epilepsy, seizures,
pathophysiology
Disclosure: Leong Tung Ong has nothing to disclose in
relation to this article.
Review Process: Double-blind peer review.
Compliance with Ethics: This article is an opinion
piece and does not report on new clinical data, or any
studies with human or animal subjects performed by
the author.
Authorship: The named author meets the International
Committee of Medical Journal Editors (ICMJE) criteria
for authorship of this manuscript, takes responsibility
for the integrity of the work as a whole, and has given
nal approval for the version to be published.
Access: This article is freely accessible at
touchNEUROLOGY.com. © Touch Medical Media 2020.
Received: 15 November 2019
Accepted: 2 December 2019
Published Online: 17 January 2020
Citation: European Neurological Review.
2019;14(2):66–7
Corresponding Author: Leong Tung Ong, Department
of Medicine, Faculty of Medicine, University of Malaya,
50603 Kuala Lumpur, Malaysia. E: leotungong@gmail.com
Support: No funding was received in the publication of
this article.
Seizure is a paroxysmal event caused by the excessive, hypersynchronous discharge of neurons
in the brain, which causes alteration in neurologic function.1 Seizures can occur when there is a
distortion between the normal balance of excitation and inhibition in the brain. The factors that
cause this alteration in the balance of excitation and inhibition can be genetic or acquired.1 The
definition of epilepsy, based on the International League Against Epilepsy (ILAE), is a disease of the
brain causing at least two unprovoked or reflex seizures occurring more than 24 hours apart or, if
after one seizure, the risk of recurrence is ‘high’ (>60%).2
Temporal lobe epilepsy (TLE) is a disorder of the nervous system which describes unprovoked
seizures originating from the temporal lobe, and is further classified by the ILAE, as mesial TLE
(MTLE) and lateral TLE (LTLE).3,4 MTLE is the more common form of TLE, accounting for two-thirds
of cases,3 and within this classification, hippocampal sclerosis (HS) is a common pathology.4,5
The ILAE classification has several advantages in the diagnosis of TLE: it is based on typical
clinical features, it recognises the localisation of seizures (e.g., those originating from the
amygdalo-hippocampal area and seizures coming from the lateral temporal lobe), and the
addition of MTLE with HS to the classification.2 There are, however, some limitations to the ILAE
classification, which include the exclusion of diagnostic modalities such as, magnetic resonance
imaging and electroencephalography.6
The ILAE defines HS as severe segmental loss of pyramidal neurons in the CA1 region, and less
prominent neuronal loss can be seen in the areas CA3 and CA4.7,8 Experimental models show that
activation of N-methyl-d-aspartate (NMDA) receptors can produce neuronal loss in TLE.9 Electrical
stimulation of the afferent pathway to the hippocampus of healthy animal brains replicates the
cell loss that is associated with TLE, and has shown that repetitive seizures cause a persistent loss
of recurrent inhibition and irreversibly damaged adjacent interneurons.10 Gamma-aminobutyric
acid (GABA) is the main inhibitory neurotransmitter that inhibits neuronal firing by activating two
different classes of receptors, GABAA and GABAB, through Cl–-influx into the central nervous system.
Therefore, damage of GABAergic interneurons will cause continuous unregulated neuronal firing,
which will lead to seizures.11 However, growing evidence shows that TLE can develop even with
minimal neuronal loss.9
Mutation of the neuron-specific type 2 K+/Cl− cotransporter (KCC2) in some of the subicular
pyramidal cells, which leads to loss of function, is one of the causes of HS-associated MTLE.12
KCC2 maintains the Cl– homeostasis by active extrusion of Cl– and K+, and mutation of KCC2 causes
accumulation of intracellular Cl– which leads to positive shifts in GABA-mediated currents.13 An
increase in intracellular Cl– concentration causes efflux of Cl– through GABA receptors, resulting in
depolarisation and hyperexcitability, and subsequently leading to seizures.
Granule cell dispersion (GCD) in the dentate gyrus is observed in HS, which may be a consequence
of enhanced proliferation of granule cell precursors as a result of seizures.14 Dentate granule cells
function as a high-resistance gate, which inhibits the propagation of seizures from the entorhinal
cortex to the hippocampus in the normal brain.15 In TLE, the granule cell stomata are extended from
the normal granule-cell layer into the molecular layer to varying extents compared with granule
cells in the normal brain, which exhibit a densely packed granule cell layer.16,17 GCD causes changes
DOI: https://doi.org/10.17925/ENR.2019.14.2.66
Temporal Lobe Epilepsy – Pathophysiology and Mechanisms
67
EUROPEAN NEUROLOGICAL REVIEW
in both the afferent and efferent connections in neurons, which may
alter the circuitry of the hippocampal formation.16 Axons of granule cells
are known as ‘mossy fibres’ and the hippocampal mossy fibre pathway
connects between the granule cells and the pyramidal cells of the CA3
region.18 GCD causes neuroplasticity of granule cell axons into their own
dendritic field, a reorganisation process known as mossy fibre sprouting.19
This then creates de novo recurrent excitatory circuits, and thus increases
excitation that can reduce the threshold for granule cell synchronisation,
resulting in epilepsy due to the increase in excitatory signals.15,19
Malformations of cortical development (MCD) represent abnormalities
in the development of the cortex which involves processes such
as regionalisation, cell proliferation, neuronal migration and cortical
organisation.7 Focal cortical dysplasia (FCD) is a subtype of MCD which
causes chronic medically refractory epilepsy in the paediatric population,
and is a frequent cause of epilepsy in adults.20 FCD is classified into
three categories: FCD type I, which is cortical dyslamination; FCD type II,
which is with the addition of dysmorphic neurons and/or balloon cells,
commonly seen in children; and FCD type III, which is associated with
another principal lesion such as a tumour or vascular malformation.7,20
FCD can cause hyperactivation of the rapamycin (mTOR) pathway, which
is involved in regulation of protein and lipid synthesis, cell growth, and
metabolism.21 The mTOR pathway forms two distinct protein complexes,
mTORC1 which is rapamycin-sensitive and promotes protein synthesis
by activating downstream signalling cascades, and mTORC2 which acts
as a cytoskeletal regulator and is rapamycin-insensitive.22 Tuberous
sclerosis complex (TSC) is a disorder caused by mutations of mTOR
regulatory genes TSC1 or TSC2. Cell overgrowth and synaptogenesis
disruptions occur with TSC1 or TSC2 mutations due to abnormal
activation of mTORC1, and TSC2 mutation causes hyperexcitability of
glutamate-mediated neurons which will lead to seizures.22,23
In conclusion, the pathophysiology of TLE is complex and not
well-understood; to-date there are several pathological findings in TLE.
However, thorough understanding of the mechanism of the disease is
crucial in developing new pharmacological therapies. New experimental
models, designed by understanding the different defects in TLE are
warranted in order to develop new drugs, which are more efficient in
managing the condition and improving the quality of life of patients with
this form of epilepsy.
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