Hippocampus, hippocampal sclerosis and epilepsy

doi:10.1016/S1734-1140(13)71033-8

Pharmacological Reports

Volume 65, Issue 3, May–June 2013, Pages 555-565

https://doi.org/10.1016/S1734-1140(13)71033-8 Get rights and content

Abstract

Hippocampal sclerosis (HS) is considered one of the major pathogenic factors of drug-resistant temporal lobe epilepsy. HS is characterized by selective loss of pyramidal neurons – especially of sectors CA1 and CA3 of the hippocampus – pathological proliferation of interneuron networks, and severe glia reaction. These changes occur in the course of long-term and complex epileptogenesis. The authors, on the basis of a review of the literature and own experience, present the pathomechanisms leading to hippocampal sclerosis and epileptogenesis, including various morphological and functional elements of this structure of the brain and pharmacological possibilities of preventing these processes.

Section snippets

Pathophysiology of epilepsy

Epilepsy is one of the most common neurological diseases and affects about 1% of the population [7]. An epileptic seizure is the result of functional disorders of the brain and is formed as a result of abnormal, excessive bioelectrical discharge in the nerve cells [21]. This disorder can theoretically occur in every population of neurons, but it is often observed in the immediate vicinity of organic brain damage, such as a scar or a tumor. A group of changed, overly excitable nerve cells is

Epileptogenesis

The process of epileptogenesis is usually explained in the literature by the two-hit hypothesis. The term epileptogenesis commonly refers to a period of time from the first hit, such as trauma or stroke, to the occurrence of the first epileptic seizure. It is a chronic process, in which a series of biochemical and structural changes take place in the nerve tissue. Experimental and clinical studies have shown that nerve tissue in experimental animals and in patients with epilepsy, although it

Anatomy of hippocampus

The hippocampus is an essential part of the archeocortex. In mammals, it is three-layered structure located on the medial surface of the temporal lobe in the back of each cerebral hemisphere. The name hippocampus is derived from Greek and means sea horse, which it resembles in shape. In the literature, it is often referred to as Ammon's horn (cornu Ammonis), which is derived from the distinctive image of an Egyptian god. The hippocampus is an important part of the limbic system, which plays

HS: cause or effect of epilepsy?

Despite the well-studied histological and ultrastructural basis of HS, its pathophysiology remains unclear. Whether HS is a primary cause of focal epilepsy or maybe the result of repeated epileptic seizures is still an unanswered question [47].

In generally accepted theory and aforementioned epileptogenesis two-hit hypothesis, the initial insult of even a small area of nerve tissue of the brain caused by various etiological factors leads to a stretched over time sequence of histological and

HS and antiepileptic drugs

HS is characterized by three pathological histological changes: loss of neurons, glial reaction (gliosis), and remodeling of neuronal networks especially interneurons (sprouting). Therefore, it is interesting to question whether and how antiepileptic drugs (AEDs) may prevent HS. AED mechanisms of action are mainly based on their effects on ion channels (sodium and calcium), excitatory and inhibitory amino acid receptors, inhibition of GABA metabolism and synaptic transmission [58]. All of these

References (105)

W. Baer-Dubowska et al.
Pharmacoepigenetics: a new approach to predicting individual drug responses and targeting new drugs
Pharmacol Rep
(2011)
D. Boison
The adenosine kinase hypothesis of epileptogenesis
Prog Neurobiol
(2008)
A. Bordey et al.
Distinct electrophysiological alterations in dentate gyrus versus CA1 glial cells from epileptic humans with temporal lobe sclerosis
Epilepsy Res
(2004)
J.E. Cavazos et al.
Progressive neuronal loss induced by kindling: a possible mechanism for mossy fiber synaptic reorganization and hippocampal sclerosis
Brain Res
(1990)
A. Crespel et al.
Increased number of neural progenitors in human temporal lobe epilepsy
Neurobiol. Dis
(2005)
D.J. Cross et al.
Synaptic reorganization in subiculum and CA3 after early-life status epilepticus in the kainic acid rat model
Epilepsy Res
(2007)
T. Eid et al.
Loss of glutamine synthetase in the human epileptogenic hippocampus: Possible mechanism for raised extracellular glutamate in mesial temporal lobe epilepsy
Lancet
(2004)
M. Fukuchi et al.
Valproic acid induces up- or down-regulation of gene expression responsible for the neuronal excitation and inhibition in rat cortical neurons through its epigenetic actions
Neurosci Res
(2009)
K. Heuser et al.
Variants of the genes encoding AQP4 and Kir4.1 are associated with subgroups of patients with temporal lobe epilepsy
Epilepsy Res
(2010)
R. Kalviainen et al.
Do recurrent seizures cause neuronal damage?. A series of studies with MRI volumetry in adults with partial epilepsy
Prog Brain Res
(2002)

W. Lasoń et al.

Basic mechanisms of antiepileptic drugs and their pharmacokinetic/pharmacodynamic interactions: an update

Pharmacol Rep

(2011)

W. Lasoń et al.

Effects of pentylenetetrazol kindling on glutamate receptor genes expression in the rat hippocampus

Brain Res

(1998)

W. Lasoń et al.

Effects of pilocarpine and kainateinduced seizures on N-methyl-D-aspartate receptor gene expression in the rat hippocampus

Neuroscience

(1997)

K. Łukasiuk et al.

Epileptogenesis-related genes revisited

Prog Brain Res

(2006)

R.C. Malenka et al.

NMDA-receptor-dependent synaptic plasticity: multiple forms and mechanisms

Trends Neurosci

(1993)

G. Marucci et al.

Neurogenesis in temporal lobe epilepsy: Relationship between histological findings and changes in dentate gyrus proliferative properties

Clin Neurol Neurosurg

(2013)

G.W. Mathern et al.

Hippocampal neuron damage in human epilepsy: Meyer's hypothesis revisited

Prog Brain Res

(2002)

A. Pitkanen et al.

Mechanisms of epileptogenesis and potential treatment targets

Lancet Neurol

(2011)

E.F. Sperber et al.

Resistance of the immature hippocampus to seizure-induced synaptic reorganization

Brain Res Dev Brain Res

(1991)

G. Sperk et al.

Altered GABA_A Receptor Subunit Composition in Temporal Lobe Epilepsy. Encyclopedia of Basic Epilepsy Research

(2009)

D. Amaral et al.

Chapter 3. Hippocampal Neuroanatomy

M.C. Angulo et al.

Glutamate released from glial cells synchronizes neuronal activity in the hippocampus

J Neurosci

(2004)

J.I. Arellano et al.

Histopathology and reorganization of chandelier cells in the human epileptic sclerotic hippocampus

Brain

(2004)

M. Avoli et al.

Cellular and molecular mechanisms of epilepsy in the human brain

Prog Neurobiol

(2007)

S.B. Bausch et al.

Plasticity of both excitatory and inhibitory synapses is associated with seizures induced by removal of chronic blockade of activity in cultured hippocampus

J Neurophysiol

(2006)

G.S. Bell et al.

The epidemiology of epilepsy: the size of the problem

Seizures

(2001)

V. Benfenati et al.

An aquaporin-4/transient receptorpotential vanilloid 4 (AQP4/TRPV4) complex is essential for cell-volume control in astrocytes

Proc Natl Acad Sci USA

(2011)

A.T. Berg et al.

Childhood-onset epilepsy with and without preceding febrile seizures

Neurology

(1999)

R. Bianchi et al.

Cellular plasticity for group I mGluR-mediated epileptogenesis

J Neurosci

(2009)

J. Bidziński

Hippocampus – anatomical substrate of temporal lobe epilepsy

Epileptologia

(2007)

D.K. Binder et al.

Functional changes in astroglial cells in epilepsy

Glia

(2006)

J.L. Bizon et al.

Production of new cells in the rat dentate gyrus over the lifespan: relation to cognitive decline

Eur J Neurosci

(2003)

I. Blümcke et al.

Ammon's horn sclerosis: a maldevelopmental disorder associated with temporal lobe epilepsy

Brain Pathol

(2002)

D. Boison

Adenosine dysfunction in epilepsy

Glia

(2012)

R.A. Bronen et al.

Imaging findings in hippocampal sclerosis: correlation with pathology

Am J Neuroradiol

(1991)

G.D. Casino et al.

Magnetic resonance imaging-based volume studies in temporal lobe epilepsy: pathological correlations

Ann Neurol

(1991)

J.E. Cavazos et al.

Neuronal loss induced in limbic pathways by kindling: evidence for induction of hippocampal sclerosis by repeated brief seizures

J Neurosci

(1994)

J.E. Cavazos et al.

Pathophysiology of seizures and epilepsy

Neurol Dis Ther

(2004)

F. Cendes et al.

Early childhood febrile convulsions, atrophy and sclerosis of mesial structures, and temporal lobe epilepsy: an MRI volumetric study

Neurology

(1993)

F. Cendes et al.

Frequency and characteristics of dual pathology in patients with lesional epilepsy

Neurology

(1995)

S.-C. Chuang et al.

Group I mGluR activation turns on a voltage-gated inward current in hippocampal pyramidal cells

J Neurophysiol

(2000)

C.W. Cotman et al.

Anatomical organization of excitatory amino acid receptors and their properties

R. Covolan et al.

Cell damage and neurogenesis in the dentate granule cell layer of adult rats after pilocarpine- or kainite-induced status epilepticus

Hippocampus

(2000)

C.M. DeGiorgio et al.

Hippocampal pyramidal cell loss in human status epilepticus

Epilepsia

(1992)

T. Eid et al.

Glutamate and astrocytes-key players in human mesial temporal lobe epilepsy?

Epilepsia

(2008)

J. Engel

Mesial temporal lobe epilepsy: what have we learned?

Neuroscientist

(2001)

S. Engelborghs et al.

Pathophysiology of epilepsy

Acta Neurol Belg

(2000)

P.S. Eriksson et al.

Neurogenesis in the adult human hippocampus

Nat Med

(1998)

C.J. Gibson et al.

Traumatic brain injury and the effects of diazepam, diltiazem, and MK-801 on GABA-A receptor subunit expression in rat hippocampus

J Biomed Sci

(2010)

E. Gould et al.

Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress

Proc Natl Acad Sci USA

(1998)

Cited by (61)

Association between serum apolipoprotein E and cognitive function in Chinese patients with temporal lobe epilepsy
2024, Epilepsy and Behavior
To investigate the effect of serum apolipoprotein E (APOE) levels on cognitive function in patients with temporal lobe epilepsy (TLE).
Clinical data were collected from 190 subjects including 110 TLE patients and 80 healthy people. Cognitive function was assessed using the Addenbrooke’s Cognitive Examination Revised (ACE-R) scale. Serum levels of APOE were measured using ELISA kits. Genotyping of APOE in peripheral blood was detected by microarray hybridization.
Patients with TLE had significantly lower ACE-R total score, memory and verbal fluency scores compared to the healthy group. Serum levels of APOE were significantly higher in TLE patients than in the healthy subjects. Serum APOE levels were significantly negatively correlated with ACE-R total score, memory and verbal fluency scores. The cognitive function score of TLE with APOE ε4 allele was lower than that of TLE without APOE ε4 allele.
Our study showed that serum APOE levels were higher in TLE patients than in the healthy population. And serum APOE levels were associated with cognitive dysfunction in TLE patients. APOE ε4 allele carriers have poor cognitive function in TLE patients.
Epilepsy is more than a simple seizure disorder: Causal relationships between epilepsy and its comorbidities
2024, Veterinary Journal
This review draws connections between the pathogenesis of canine epilepsy and its most commonly recognised comorbidities: cognitive impairment (CI), attention deficit hyperactivity disorder (ADHD)-like behaviour, fear and anxiety. Uni/bidirectional causalities and the possibility of a common aetiology triggering both epilepsy and the associated diseases are considered. Research on this topic is sparse in dogs, so information has been gathered and assessed from human and laboratory animal studies. Anatomical structures, functional connections, disrupted neurotransmission and neuroinflammatory processes collectively serve as a common foundation for epilepsy and its comorbidities. Specific anatomical structures, especially parts of the limbic system, such as the amygdala and the hippocampus, are involved in generating seizures, as well as cognitive- and behavioural disorders. Furthermore, disturbances in inhibitory and excitatory neurotransmission influence neuronal excitability and networks, leading to underlying brain dysfunction. Functional magnetic resonance imaging (fMRI), interictal epileptiform discharges (IEDs), and electroencephalography (EEG) have demonstrated functional brain connections that are related to the emergence of both epilepsy and its various comorbidities. Neuroinflammatory processes can either cause or be a consequence of seizures, and inflammatory mediators, oxidative stress and mitochondrial dysfunction, can equally evoke mood disorders. The extensive relationships contributing to the development and progression of seizures and comorbid cognitive and behavioural conditions illustrate the complexity of the disease that is epilepsy.
Is depression in patients with temporal lobe epilepsy related to hippocampal sclerosis? A meta-analysis
2023, Clinical Neurology and Neurosurgery
To systematically evaluate the association between hippocampal sclerosis (HS) and depression in patients with temporal lobe epilepsy (TLE) through a meta-analysis.
Chinese and English databases, such as the China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals (VIP), WanFang, the Chinese Biomedical Literature Service System (SinoMed), PubMed and the Web of Science, were searched.
Two evaluators independently screened the literature, extracted data and evaluated the risk of bias in the included studies in accordance with the inclusion and exclusion criteria. RevMan 5.1 was used to analyze the data. A total of 786 patients with epilepsy were included in the study, including 82 depressive patients with HS and 64 depressive patients without HS. The results showed that the TLE patients with HS were more likely to develop depression than those without HS (odds ratio (OR)= 2.14, 95% confidence interval (CI) [1.45, 3.16], Z = 3.85, p = 0.0001).
HS can be considered a high-risk factor for depression in patients with TLE, and the correlation is significant. However, the sample size included in the study was small; additional high-quality studies are needed in the future.
Psychiatric symptoms predict drug-resistant epilepsy in newly treated patients
2022, Seizure
Citation Excerpt :
Evidence indicates a relationship between the extent of hippocampal dysfunction with the severity of depression symptoms in epilepsy [43]. Hippocampal sclerosis has also been reported to be one of the major pathogenic factors of DRE [44]. Additionally, cognitive function in major depression disorders may be related to aberrant functional connectivity in cognitive networks, and patterns of alternate brain networks could influence cognitive processes [45].
Literature on the complex interrelationships between psychiatric symptoms and drug resistance in newly treated patients with epilepsy (PWE) is lacking. We aimed to determine whether psychiatric symptoms are predictive of the development of drug-resistant epilepsy (DRE) in newly treated patients.
Newly treated PWE were psychiatrically evaluated at enrolment and were followed for 24 months to determine the occurrence of DRE. The impacts of depressive and anxiety symptoms on the development of DRE were investigated using the Cox proportional hazard model.
A total of 217 patients were included in the final analysis. DRE was diagnosed in 26.7% of patients (n=58). In univariate analysis, depressive and anxiety symptoms were identified as risk factors for the development of DRE. In multivariate analyses, depressive symptoms were a significant independent predictor of DRE (HR: 3.253, 95% CI: 1.643-6.441; p = 0.001). Additionally, the probability of developing DRE was 5.219 times higher in patients with both depressive and anxiety symptoms than in patients without depressive or anxiety symptoms (HR: 5.219, 95% CI: 2.716-10.029; p<0.001).
In conclusion, psychiatric symptoms provide prognostic information regarding the occurrence of DRE in patients newly treated with ASMs. Our findings support the need for prospective studies to investigate whether psychiatric treatment reduces the risk of developing DRE in these patients.
Nuclear translocation of GluA2/ GAPDH promotes neurotoxicity after pilocarpine-induced epilepsy
2022, Epilepsy Research
Recent studies have identified that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) exerts multiple functions besides its role in energy metabolism. It can form a protein complex with GluA2 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), translocate into nucleus and confer neurotoxicity in a cerebral ischemia model. We postulate that GAPDH may also induce neurotoxicity by forming a coupling with GluA2 in pilocarpine-induced epileptic model, and disruption of the GluA2/GAPDH coupling can protect against neuronal injury. In this study, induced status epilepticus (SE) in rats by the systemic administration of pilocarpine, collected hippocampal tissues at different time points after SE, and assessed the relationship between GluA2/GAPDH coupling and neuronal apoptosis in SE rats. Then, we interrupted the GluA2/GAPDH coupling by a special interfering peptide and determined whether neuronal injury can be rescued and hippocampus-depended memory function can be improved. We also evaluated the concentrations of GAPDH in nuclear and cytoplasmatic proteins in SE group, non-SE group and after interruption of GluA2/GAPDH coupling, to verify the nuclear translocation of GAPDH in SE model. We found that the apoptosis of hippocampal neurons was most significant at 72 h after SE, which was also the peak time of GluA2/GAPDH coupling expression and GluA2 consumption. After interruption of GluA2/GAPDH coupling, the apoptosis and memorial function of hippocampal neurons were improved and nuclear translocation of GluA2/GAPDH coupling was reduced. In conclusion, GAPDH can be translocated into nucleus in the form of GluA2/GAPDH, which plays an important role in regulating pilocarpine-induced epilepsy via neurotoxicity pathway.
A mathematical model of neuroimmune interactions in epileptogenesis for discovering treatment strategies
2022, iScience
The development of epilepsy (epileptogenesis) involves a complex interplay of neuronal and immune processes. Here, we present a first-of-its-kind mathematical model to better understand the relationships among these processes. Our model describes the interaction between neuroinflammation, blood-brain barrier disruption, neuronal loss, circuit remodeling, and seizures. Formulated as a system of nonlinear differential equations, the model reproduces the available data from three animal models. The model successfully describes characteristic features of epileptogenesis such as its paradoxically long timescales (up to decades) despite short and transient injuries or the existence of qualitatively different outcomes for varying injury intensity. In line with the concept of degeneracy, our simulations reveal multiple routes toward epilepsy with neuronal loss as a sufficient but non-necessary component. Finally, we show that our model allows for in silico predictions of therapeutic strategies, revealing injury-specific therapeutic targets and optimal time windows for intervention.

View all citing articles on Scopus

View full text

ReviewHippocampus, hippocampal sclerosis and epilepsy

Abstract

Section snippets

Pathophysiology of epilepsy

Epileptogenesis

Anatomy of hippocampus

HS: cause or effect of epilepsy?

HS and antiepileptic drugs

Pharmacol Rep

Prog Neurobiol

Epilepsy Res

Brain Res

Neurobiol. Dis

Epilepsy Res

Lancet

Neurosci Res

Epilepsy Res

Prog Brain Res

Pharmacol Rep

Brain Res

Neuroscience

Prog Brain Res

Trends Neurosci

Clin Neurol Neurosurg

Prog Brain Res

Lancet Neurol

Brain Res Dev Brain Res

Chapter 3. Hippocampal Neuroanatomy

Glutamate released from glial cells synchronizes neuronal activity in the hippocampus

J Neurosci

Histopathology and reorganization of chandelier cells in the human epileptic sclerotic hippocampus

Brain

Cellular and molecular mechanisms of epilepsy in the human brain

Prog Neurobiol

Plasticity of both excitatory and inhibitory synapses is associated with seizures induced by removal of chronic blockade of activity in cultured hippocampus

J Neurophysiol

The epidemiology of epilepsy: the size of the problem

Seizures

An aquaporin-4/transient receptorpotential vanilloid 4 (AQP4/TRPV4) complex is essential for cell-volume control in astrocytes

Proc Natl Acad Sci USA

Childhood-onset epilepsy with and without preceding febrile seizures

Neurology

Cellular plasticity for group I mGluR-mediated epileptogenesis

J Neurosci

Hippocampus – anatomical substrate of temporal lobe epilepsy

Epileptologia

Functional changes in astroglial cells in epilepsy

Glia

Production of new cells in the rat dentate gyrus over the lifespan: relation to cognitive decline

Eur J Neurosci

Ammon's horn sclerosis: a maldevelopmental disorder associated with temporal lobe epilepsy

Brain Pathol

Adenosine dysfunction in epilepsy

Glia

Imaging findings in hippocampal sclerosis: correlation with pathology

Am J Neuroradiol

Magnetic resonance imaging-based volume studies in temporal lobe epilepsy: pathological correlations

Ann Neurol

Neuronal loss induced in limbic pathways by kindling: evidence for induction of hippocampal sclerosis by repeated brief seizures

J Neurosci

Pathophysiology of seizures and epilepsy

Neurol Dis Ther

Early childhood febrile convulsions, atrophy and sclerosis of mesial structures, and temporal lobe epilepsy: an MRI volumetric study

Neurology

Frequency and characteristics of dual pathology in patients with lesional epilepsy

Neurology

Group I mGluR activation turns on a voltage-gated inward current in hippocampal pyramidal cells

J Neurophysiol

Anatomical organization of excitatory amino acid receptors and their properties

Cell damage and neurogenesis in the dentate granule cell layer of adult rats after pilocarpine- or kainite-induced status epilepticus

Hippocampus

Hippocampal pyramidal cell loss in human status epilepticus

Epilepsia

Glutamate and astrocytes-key players in human mesial temporal lobe epilepsy?

Epilepsia

Mesial temporal lobe epilepsy: what have we learned?

Neuroscientist

Pathophysiology of epilepsy

Acta Neurol Belg

Neurogenesis in the adult human hippocampus

Review
Hippocampus, hippocampal sclerosis and epilepsy