Microscopic disorders of cortical development of the brain and its etiopathogenic importance for detection in patients with temporal epilepsy associated with hippocampal sclerosis

Hippocampal sclerosis represents a common structural basis of temporal lobe epilepsy. However, the etiological factors and mechanisms leading to its development still remain unexplained. In our study, we present neuropathological findings in the resected hippocampus and the pole of the temporal lobe in 15 patients with hippocampal sclerosis. "Initial precipitating injuries" that are thought to cause the development of hippocampal sclerosis (febrile seizures in early childhood, head injury or meningoencephalitis) were present in the history of 12 patients. In the remaining 3 cases, no predisposing factors were found. Attention was paid to the histopathological identification of disturbed neuronal migration and differentiation in the temporal lobe. These defects were observed in 7 cases; in three of these, no predisposing factors were stated in the patients' histories. We suggest that in these cases, hippocampal sclerosis arises due to previously undetected disorders of cortical development. A latent neocortical malformation may also contribute to the development of hippocampal sclerosis in patients with an initial precipitating injury in anamnensis. Histopathological examination of resected epileptic brain tissue can provide insights into the individual pathogenesis of epileptic disorders, especially by the detection of microscopic disorders of cortical development.     

GABA uptake and heterotransport are impaired in the dentate gyrus of epileptic rats and humans with temporal lobe sclerosis

In vivo dialysis and in vitro electrophysiological studies suggest that GABA uptake is altered in the dentate gyrus of human temporal lobe epileptics characterized with mesial temporal sclerosis (MTLE). Concordantly, anatomical studies have shown that the pattern of GABA-transporter immunoreactivity is also altered in this region. This decrease in GABA uptake, presumably due to a change in the GABA transporter system, may help preserve inhibitory tone interictally. However, transporter reversal can also occur under several conditions, including elevations in [K(+)]o, which occurs during seizures. Thus GABA transporters could contribute to seizure termination and propagation through heterotransport. To test whether GABA transport is compromised in both the forward (uptake) and reverse (heterotransport) direction in the sclerotic epileptic dentate gyrus, the physiological effects of microapplied GABA and nipecotic acid (NPA; a compound that induces heterotransport) were examined in granule cells in hippocampal slices from kainate (KA)-induced epileptic rats and patients with temporal lobe epilepsy (TLE). GABA- and NPA-induced responses were prolonged in granule cells from epileptic rats versus controls (51.3 and 31.3% increase, respectively) while the conductance change evoked with NPA microapplication was reduced by 40%. Furthermore the ratio of GABA/NPA conductance, but not duration, was significantly >1 in epileptic rats but not controls, suggesting a compromise in transporter function in both directions. Similar changes were observed in tissue resected from epileptic patients with medial temporal sclerosis but not in those without the anatomical changes associated with MTLE. These data suggest that the GABA transporter system is functionally compromised in both the forward and reverse directions in the dentate gyrus of chronically epileptic tissue characterized by mesial temporal sclerosis. This alteration may enhance inhibitory tone interically yet be permissive for seizure propagation due to a decreased probability for GABA heterotransport during seizures.     

Astrocytic expression of cannabinoid type 1 receptor in rat and human sclerotic hippocampi

Cannabinoid type 1 receptor (CB1R), which is traditionally located on axon terminals, plays an important role in the pathology of epilepsy and neurodegenerative diseases by modulating synaptic transmission. Using the pilocarpine model of chronic spontaneous recurrent seizures, which mimics the main features of mesial temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS) in humans, we examined the expression of CB1R in hippocampal astrocytes of epileptic rats. Furthermore, we also examined the expression of astrocytic CB1R in the resected hippocampi from patients with medically refractory mesial TLE. Using immunofluorescent double labeling, we found increased expression of astrocytic CB1R in hippocampi of epileptic rats, whereas expression of astrocytic CB1R was not detectable in hippocampi of saline treated animals. Furthermore, CB1R was also found in some astrocytes in sclerotic hippocampi in a subset of patients with intractable mesial TLE. Detection with immune electron microscopy showed that the expression of CB1R was increased in astrocytes of epileptic rats and modest levels of CB1R were also found on the astrocytic membrane of sclerotic hippocampi. These results suggest that increased expression of astrocytic CB1R in sclerotic hippocampi might be involved in the cellular basis of the effects of cannabinoids on epilepsy.     

AMPA receptor alterations precede mossy fiber sprouting in young children with temporal lobe epilepsy

Following neurological injury early in life numerous events, including excitotoxicity, neural degeneration, gliosis, neosynaptogenesis, and circuitry reorganization, may alone or in concert contribute to hyperexcitability and recurrent seizures in temporal lobe epilepsy. Our studies provide new evidence regarding the temporal sequence of key elements of hippocampal reorganization, mossy fiber sprouting and glutamate receptor subunit up-regulation, in a subset of young temporal lobe epileptic patients. Without evidence of mossy fiber sprouting, the youngest age group (3-10 years old) of mesial temporal lobe epileptic patients demonstrated enhanced glutamate receptor subunit profiles, suggesting that the dendritic change precedes axonal sprouting. However, sclerotic hippocampal specimens from epileptic patients ages 12-15 years old had the characteristic features of glutamate receptor up-regulation and mossy fiber sprouting first identified in the adult, indicating that reconstructed circuits appear early in the course of the disease. Non-sclerotic hippocampal specimens from lesion associated temporal lobe epileptic patients of all age groups showed minimal cell loss, sparse staining of glutamate receptor subunits in the dentate gyrus, and little or no mossy fiber sprouting. These compelling findings suggest a progressive sequence of events in the reorganization of the dentate gyrus of sclerotic hippocampal specimens. We suggest that cell loss and up-regulation of glutamate receptor subunits appear early in temporal lobe epilepsy and contribute to the synaptic plasticity that may facilitate the subsequent sprouting of mossy fiber collaterals which compound an already precipitous state of decline. The combination of pre-synaptic and post-synaptic changes serves as a potential substrate for hyperexcitability.     

Hippocampal Sclerosis in Feline Epilepsy

Hippocampal sclerosis (HS) refers to loss of hippocampal neurons and astrogliosis. In temporal lobe epilepsy (TLE), HS is a key factor for pharmacoresistance, even though the mechanisms are not quite understood. While experimental TLE models are available, there is lack of models reflecting the natural HS development. Among domestic animals, cats may present with TLE‐like seizures in natural and experimental settings. With this study on the prevalence, segmental pattern and clinicopathological correlates of feline HS, we evaluated the translational value for human research. Evaluation schemes for human brains were applied to epileptic cats. The loss of neurons was morphometrically assessed and the degree of gliosis was recorded. Hippocampal changes resembling human HS were seen in about one third of epileptic cats. Most of these were associated with infiltrative diseases such as limbic encephalitis. Irrespective of the etiology and semiology of seizures, total hippocampal sclerosis was the most prevalent form seen in epileptic animals. Other HS types also occur at varying frequencies. Segmental differences to human HS can be explained by species‐specific synaptic connectivities and a different spectrum of etiologies. All these variables require consideration when translating results from feline studies regarding seizure‐associated changes of the temporal lobe and especially HS.     

Septal GABAergic neurons are selectively vulnerable to pilocarpine-induced status epilepticus and chronic spontaneous seizures

The septal region of the basal forebrain plays a critical role modulating hippocampal excitability and functional states. Septal circuits may also play a role in controlling abnormal hippocampal hyperexcitability in epilepsy. Both lateral and medial septal neurons are targets of hippocampal axons. Since the hippocampus is an important epileptogenic area in temporal lobe epilepsy, we hypothesize that excessive excitatory output will promote sustained neurodegeneration of septal region neurons. Pilocarpine-induced status epilepticus (SE) was chosen as a model to generate chronic epileptic animals. To determine whether septal neuronal populations are affected by hippocampal seizures, immunohistochemical assays were performed in brain sections obtained from age-matched control, latent period (7 days post-SE) and chronically epileptic (more than one month post-SE survival) rats. An anti-NeuN (neuronal nuclei) antibody was used to study total neuronal numbers. Anti-ChAT (choline acetyltransferase), anti-GAD (glutamic acid decarboxylase) isoenzymes (65 and 67), and anti-glutamate antibodies were used to reveal cholinergic, GABAergic and glutamatergic neurons, respectively. Our results revealed a significant atrophy of medial and lateral septal areas in all chronically epileptic rats. Overall neuronal density in the septum (medial and lateral septum), assessed by NeuN immunoreactivity, was significantly reduced by approximately 40% in chronically epileptic rats. The lessening of neuronal numbers in both regions was mainly due to the loss of GABAergic neurons (80-97% reduction in medial and lateral septum). In contrast, populations of cholinergic and glutamatergic neurons were spared. Overall, these data indicate that septal GABAergic neurons are selectively vulnerable to hippocampal hyperexcitability, and suggest that the processing of information in septohippocampal networks may be altered in chronic epilepsy.     

Damage to the amygdalo-hippocampal projection in temporal lobe epilepsy: a tract-tracing study in chronic epileptic rats

Both the amygdala and hippocampus are damaged in drug-resistant temporal lobe epilepsy (TLE), suggesting that amygdalo-hippocampal interconnectivity is compromised in TLE. Therefore, we examined one of the major projections from the amygdala to the hippocampus, the projection from the amygdala to the CA1 subfield of the hippocampus/subiculum border region, and assessed whether it is preserved in rats with spontaneous seizures. Male Wistar rats were injected with kainic acid (9 mg/kg, i.p.) to induce chronic epilepsy. The occurrence of spontaneous seizures was monitored 5 or 15 weeks later by video-recording the rats for up to 5 days. Saline-injected animals served as controls. Thereafter, the retrograde tracer Fluoro-gold was injected into the border region of the temporal CA1/subiculum. Rats were perfused for histology 1-2 weeks later and sections were immunohistochemically processed to detect Fluoro-gold-positive cells. Comparison of the labeling in control and epileptic tissue indicated that a large cluster of retrogradely labeled cells in the parvicellular division of the basal nucleus was well preserved in epilepsy, even when the neuronal damage in the amygdala was substantial. Another large cluster of retrogradely labeled cells in the lateral division of the amygdalo-hippocampal area, the posterior cortical nucleus (part of the vomeronasal amygdala), and the periamygdaloid cortex (part of the olfactory amygdala), however, had disappeared in epileptic brain in parallel to severe neuronal loss in these nuclei. These data demonstrate that a projection from the parvicellular division of the basal nucleus to the temporal CA1/subiculum region is resistant to status epilepticus-induced neuronal damage and provides a candidate pathway by which seizure activity can spread and propagate from the amygdala to the hippocampal formation.     

Localization of KCNQ5 in the normal and epileptic human temporal neocortex and hippocampal formation

The KCNQ family of voltage-dependent non-inactivating K+ channels is composed of five members, four of which (KCNQ2-5) are expressed in the CNS and are responsible for the M-current. Mutations in either KCNQ2 or KCNQ3 lead to a hereditary form of dominant generalized epilepsy. Using specific antisera to the KCNQ2, KCNQ3 and KCNQ5 subunits, we found that KCNQ3 co-immunoprecipitated with KCNQ2 and KCNQ5 subunits, but no association was detected between KCNQ2 and KCNQ5. Intense KCNQ5 immunoreactivity was found to be widely distributed throughout the temporal neocortex and the hippocampal formation. In these structures, both pyramidal and non-pyramidal neurons and a population of glial cells in the white matter expressed the KCNQ5 subunit. In the sclerotic areas of the CA fields of epileptic patients, a marked loss of KCNQ5 immunoreactive pyramidal neurons was found in relation with the loss of neurons in these regions. However, in the regions adjacent to the sclerotic areas, the distribution and intensity of KCNQ5 immunostaining was apparently normal. The widespread distribution of KCNQ5 subunits, its persistence in pharmacoresistant epilepsy, along with the significant role of the M-current in the control of neuronal excitability, makes this protein a possible target for the development of anticonvulsant drugs.     

Alzheimer's disease: is the decrease of the cholinergic innervation of the hippocampus related to intrinsic hippocampal pathology?

Consistent findings in the hippocampi of patients with Alzheimer's disease are the presence of neurofibrillary tangles in pyramidal neurons and the loss of choline acetyltransferase activity due to degeneration of hippocampal cholinergic terminals. The present study sought to clarify, in the brains of five patients with Alzheimer's disease and four controls, whether the loss of cholinergic terminals in the hippocampal stratum pyramidale in Alzheimer's disease is related to degenerative changes in hippocampal pyramidal cells. A polyclonal antibody to human choline acetyltransferase was employed to visualize immunohistochemically cholinergic terminals. Hippocampal neurons were stained with Cresyl Violet, neurofibrillary tangles with thioflavin S and a monoclonal antibody against phosphorylated neurofilament (RT97). Quantification of the stained structures was performed in CA4, CA1 and the subiculum, on five sections selected from the entire anteroposterior extent of each hippocampus. In the group of Alzheimer patients, the densities of cholinergic terminals were homogeneously diminished in the three hippocampal subregions in comparison with the controls (32-33%). In contrast, a significant loss of pyramidal neurons was found only in CA1, and the density of neurofibrillary tangles was markedly increased only in CA1 and the subiculum in Alzheimer's disease. These findings suggest that there is no relationship between the loss of cholinergic terminals and the degeneration of pyramidal cells in the hippocampus of patients with Alzheimer's disease.     

Distribution of voltage-dependent calcium channel beta subunits in the hippocampus of patients with temporal lobe epilepsy.

Voltage-dependent Ca2+ channels constitute a major class of plasma membrane channels through which a significant amount of extracellular Ca2+ enters neuronal cells. Their pore-forming alpha1 subunits are associated with cytoplasmic regulatory beta subunits, which modify the distinct biophysical and pharmacological properties of the alpha1 subunits. Studies in animal models indicate altered expression of alpha1 and/or beta subunits in epilepsy. We have focused on the regulatory beta subunits and have analysed the immunoreactivity patterns of the beta1, beta2, beta3 and beta4 subunits in the hippocampus of patients with temporal lobe epilepsy (n = 18) compared to control specimens (n = 2). Temporal lobe epilepsy specimens were classified as Ammon's horn sclerosis (n = 9) or focal lesions without alteration of hippocampal cytoarchitecture (n = 9). Immunoreactivity for the beta subunits was observed in neuronal cell bodies, dendrites and neuropil. The beta1, beta2 and beta3 subunits were found mainly in cell bodies while the beta4 subunit was primarily localized to dendrites. Compared to the control specimens, epilepsy specimens of the Ammon's horn sclerosis and of the lesion group showed a similar beta subunit distribution, except for beta1 and beta2 staining in the Ammon's horn sclerosis group: in the severely sclerotic hippocampal subfields of these specimens, beta1 and beta2 immunoreactivity was enhanced in some of the remaining neuronal cell bodies and, in addition, strongly marked dendrites. Thus, hippocampal neurons apparently express multiple classes of beta subunits which segregate into particular subcellular domains. In addition, the enhancement of beta1 and beta2 immunoreactivity in neuronal cell bodies and the additional shift of the beta1 and beta2 subunits into the dendritic compartment in severely sclerotic hippocampal regions indicate specific changes in Ammon's horn sclerosis. Altered expression of these beta subunits may lead to increased currents carried by voltage-dependent calcium channels and to enhanced synaptic excitability.     

Sprouting and synaptic reorganization in the subiculum and CA1 region of the hippocampus in acute and chronic models of partial-onset epilepsy

Repeated seizures induce permanent alterations in the hippocampal circuitry in experimental models and patients with intractable temporal lobe epilepsy (TLE). Most studies have concentrated their attention on seizure-induced reorganization of the mossy fiber pathway. The present study examined the projection pathway of the CA1 pyramidal neurons to the subiculum, which is the output of the hippocampal formation in five models of TLE. We examined the laminar pattern of Timm's histochemistry in the stratum lacunosum-moleculare of CA1 in three acute and two chronic models of TLE: intraventricular kainic acid (KA), systemic KA, systemic pilocarpine, chronic electric kindling and chronic i.p. pentylenetetrazol. The laminar pattern of Timm histochemistry in the stratum moleculare of CA1 was permanently remodeled in epileptic models suggesting sprouting of Timm containing terminals from the adjacent stratum lacunosum. Ultrastructural examination confirmed that Timm granules were localized in synaptic terminals. As the source of Timm-labeled terminals in this region was not known, sodium selenite, a selective retrograde tracer for zinc-containing terminals, was iontophoretically injected in vivo in rats exposed to systemic pilocarpine, systemic KA or chronic pentylenetetrazol. The normal projection of CA1 pyramidal neurons to the subiculum is topographically organized in a lamellar fashion. In normal rats, the extent of the injection site (terminals) and the retrogradely labeled pyramidal neurons (cell soma) corresponded to the same number of lamellas. In epileptic rats, the retrograde labeling extended 42-67% farther than the normal dorso-ventral extent including lamellas above and below the expected. This is direct evidence for sprouting of CA1 pyramidal axons into the subiculum and stratum lacunosum-moleculare of the CA1 region confirming the alterations of the laminar pattern of Timm's histochemistry. Sprouting of the CA1 projection to subiculum across hippocampal lamellas might lead to translamellar hyperexcitability, and to amplification and synchronization of epileptic discharges in the output gate of the hippocampal formation.     

Non-invasive detection of hippocampal sclerosis: correlation between metabolite alterations detected by (1)H-MRS and neuropathology

We assessed (1)H-MRS as a screening tool for detection of hippocampal sclerosis in patients with temporal lobe epilepsy (TLE). (1)H-MRS was carried out in the hippocampus of 23 patients with unilateral TLE. Metabolite alterations detected by (1)H-MRS correlated with degree of segmental neuronal cell loss and amount of astrogliosis. Positive correlation was found between total N-Acetylaspartate (tNAA) reduction and neuronal density in hippocampal CA1 (P < 0.001), CA3 (P = 0.015), and CA4 subfields (P = 0.031) and the dentate gyrus (P = 0.006). Neuronal cell loss in CA1 turned out to be the most predictive and only significant variable for tNAA reduction (P = 0.027). The association between myo-inositol (m-Ins) and astroglial glial fibrillary acidic protein (GFAP) expression revealed significantly increased m-Ins concentrations associated with diffuse astrogliosis (m-Ins = 6.4 +/- 1.1 institutional units) compared with gliosis restricted to isolated sectors of the hippocampus (i.e. hilus) (m-Ins = 5.2 +/- 1.2 institutional units) (P = 0.039). A negative correlation was found between m-Ins and neuronal loss in the CA4 subfield of the hippocampus (P = 0.028). Our results support (1)H-MRS as a suitable non-invasive method for preoperative identification of hippocampal sclerosis in patients with TLE. The extent of tNAA reduction correlates with hippocampal neuronal cell density. Furthermore, m-Ins is associated with the extent of hippocampal astrogliosis.     

Increased expression of gamma-aminobutyric acid type B receptors in the hippocampus of patients with temporal lobe epilepsy

Malfunctioning of the GABA-ergic system has been postulated as a possible cause of epilepsy. We investigated changes in the mRNA expression of the GABA(B) receptor subtypes GABA(B)-R1 and GABA(B)-R2 and of GABA(B) receptor binding in the hippocampus of patients with temporal lobe epilepsy (TLE) compared with post-mortem controls. In patients with Ammon's horn sclerosis, significant decreases in [3H]CG54626A binding were observed in subfields CA1 and CA3 of the hippocampus proper and the dentate hilus. On the other hand, both GABA(B) receptor mRNAs and receptor binding were enhanced after correction for neuronal loss in dentate granule cells and in the molecular layer, respectively, and the subiculum of patients with and without hippocampal sclerosis. These increases were even more pronounced when correcting the values for cell losses in the respective areas and indicated also increased expression of GABA(B)-R in the dentate hilus. Increased expression of both subtypes of GABA(B) receptors indicates augmented presynaptic inhibition of glutamate release as a possible protective mechanism in TLE.     

Consequences of Epileptic Activity in vitro

Hippocampal sclerosis: a cause or consequence of epileptic activity? This question has concerned neurologists and pathologists for over 150 years. This paper reviews data from an in vitro model system regarding the consequences of epileptic activity of known origin. Exposure of organotypic hippocampal slice cultures to convulsants, such as bicuculline or picrotoxin for three days leads to pronounced neuronal degeneration and a reversible loss of dendritic spines. A similar pathology has been described in hippocampal tissue removed from patients suffering from severe, drug refractory epilepsy. The consequences of such pathological changes are not self-sustaining epileptic activity, as might be expected if such sclerosis caused epilepsy, but rather a selective decrease in synaptic excitation. Inhibitory synaptic transmission and GABAergic interneurons, in contrast, are preserved. At (east two mechanisms contribute to the depression of synaptic excitation: morphological changes in dendritic spines and a decrease in the expression of genes for some glutamatergic receptors. It is hoped that this model will allow the characterization of the mechanisms underlying the pathological consequences of epileptic activity, and lead to useful therapeutic strategies.     

Neurofibrillary pathology - correlation with hippocampal formation atrophy in Alzheimer disease

The three-dimensionally reconstructed hippocampal formations in three patients with very severe, immobile Alzheimer disease (AD) and three age-matched nondemented individuals were examined for a correlation between atrophy of hippocampal formation subdivisions and neurofibrillary changes, neuronal loss, and extent of amyloid deposition in plaques and vessels. In AD, a similar severe volume loss was observed in both cellular layers and layers composed of fibers. A strong correlation between the decrease in the volume of hippocampal formation subdivisions and the decrease in the total number of neurons suggests a causative role for neuronal loss in hippocampal formation volumetric loss. Strong regional correlations between the relative decreases in the total number of neurons and the relative increases in the total number of neurofibrillary tangles implicates neurofibrillary pathology as a possible etiologic proximate factor in neuronal and volumetric loss in the hippocampal formation of AD patients.     

Microtubule-associated protein 2 phosphorylation is decreased in the human epileptic temporal lobe cortex.

Microtubule-associated protein 2 (MAP2) is an abundant component of the neuronal cytoskeleton whose function is related to the outgrowth and stability of neuronal processes, to synaptic plasticity and neuronal cell death. We have sought to study whether abnormal patterns of neuronal activity which are characteristic of epileptic patients are associated to alterations of MAP2 phosphorylation. An antibody (305) that selectively recognizes a phosphorylated epitope in a proline-rich region of the MAP2 molecule has been used to analyze neocortical biopsy samples from temporal lobe epileptic patients, whose electrocorticogram activity had been previously monitored. Immunoblot analysis showed that samples with greater spiking activity displayed significantly diminished MAP2 phosphorylation. Immunocytochemical analysis revealed the occurrence of discrete areas in the neocortex with highly decreased or no immunostaining for antibody 305, which showed a clear, although non-significant, tendency to appear more frequently in areas with greater spiking activity. To further support an association between epileptiform activity and MAP2 dephosphorylation an experimental model of epileptiform activity in cultures of rat hippocampal neurons was used. Neurons were cultured during 15 days in the presence of kynurenic acid, an antagonist of glutamate receptors. At this time, kynurenic acid was removed from the culture medium and neurons developed seizure-like activity. Using antibody 305, we found a decrease of MAP2 phosphorylation that was already visible after 15 min of kynurenic acid withdrawal.We therefore propose that MAP2 phosphorylation is decreased in the neocortex of epileptic patients and that this decrease is a likely consequence of seizure activity. Also, MAP2 dephosphorylation may lead to alterations of the neuronal cytoskeleton and eventually to neuronal damage and loss, which is typical of epileptic patients.     

Hippocampal neurons in pre-clinical Alzheimer's disease

In a previous study of hippocampal neurons in aging and AD [Lancet 344 (1994) 769], we demonstrated that the loss of neurons in the CA1 region was disease-specific and not related to aging. In the present study, we examined for loss of hippocampal neurons in preclinical AD, a period during which there are abundant amyloid deposits in the brain but no evidence of cognitive decline. We examined the postmortem brains of 33 subjects from the Baltimore Longitudinal Study of Aging and the Johns Hopkins Alzheimer's Disease Research Center. Using unbiased stereology, we estimated the total number of neurons in the granule cell layer, hilus, CA3-2, CA1, and subiculum of AD (n = 14) preclinical AD (n = 8), and age-matched control subjects (n = 11). The results from the present study confirm our previous finding of significant neuronal losses in the CA1 (48%), hilus (14%), and subiculum (24%) in AD [Lancet 344 (1994) 769]. However, we did not observe a significant loss of neurons in CA1 or any of the other subdivisions of the hippocampus in preclinical AD.     

New clinicopathological associations and histoprognostic markers in ILAE types of hippocampal sclerosis

Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE‐HS) is a heterogeneous syndrome. Surgery results in seizure freedom for most pharmacoresistant patients, but the epileptic and cognitive prognosis remains variable. The 2013 International League Against Epilepsy (ILAE) histopathological classification of hippocampal sclerosis (HS) has fostered research to understand MTLE‐HS heterogeneity. We investigated the associations between histopathological features (ILAE types, hypertrophic CA4 neurons, granule cell layer alterations, CD34 immunopositive cells) and clinical features (presurgical history, postsurgical outcome) in a monocentric series of 247 MTLE‐HS patients treated by surgery. NeuN, GFAP and CD34 immunostainings and a double independent pathological examination were performed. 186 samples were type 1, 47 type 2, 7 type 3 and 7 samples were gliosis only but no neuronal loss (noHS). In the type 1, hypertrophic CA4 neurons were associated with a worse postsurgical outcome and granule cell layer duplication was associated with generalized seizures and episodes of status epilepticus. In the type 2, granule cell layer duplication was associated with generalized seizures. CD34+ stellate cells were more frequent in the type 2, type 3 and in noHS. These cells had a Nestin and SOX2 positive, immature neural immunophenotype. Patients with nodules of CD34+ cells had more frequent dysmnesic auras. CD34+ stellate cells in scarce pattern were associated with higher ratio of normal MRI and of stereo‐electroencephalographic studies. CD34+ cells were associated with a trend for a better postsurgical outcome. Among CD34+ cases, we proposed a new entity of BRAF V600E positive HS and we described three hippocampal multinodular and vacuolating neuronal tumors. To conclude, our data identified new clinicopathological associations with ILAE types. They showed the prognostic value of CA4 hypertrophic neurons. They highlighted CD34+ stellate cells and BRAF V600E as biomarkers to further decipher MTLE‐HS heterogeneity.     

Shape analysis of hippocampal surface structure in patients with unilateral mesial temporal sclerosis

Structural hippocampal magnetic resonance (MR) imaging-based analysis is helpful in the diagnosis and treatment of mesial temporal epileptic seizures. Computational anatomic techniques provide a framework for objective assessment of three-dimensional hippocampal structure. We applied a previously validated technique of deformation-based hippocampal segmentations in 20 subjects with documented unilateral mesial temporal sclerosis (MTS) and temporal lobe epilepsy. Using composite images, we then measured shape differences between the epileptogenic, smaller hippocampus, and contralateral hippocampus. Final shape differences were projected on the contralateral “normal” side. We calculated results for the left MTS group (10 patients) and right MTS group (10 patients) separately. Both groups showed similar regions of maximal inward deformation in the affected hippocampus, which were the medical and lateral aspect of the head, and posterior aspect of the tail. These results suggest that there are specific three-dimensional patterns of volume loss in patients with mesial temporal epilepsy.