End Folium Sclerosis Research Articles

Persistent reduction of hippocampal glutamine synthetase expression after status epilepticus in immature rats.

Mesiotemporal sclerosis (MTS), the most frequent form of drug-resistant temporal lobe epilepsy, often develops after an initial precipitating injury affecting the immature brain. To analyse early processes in epileptogenesis we used the juvenile pilocarpine model to study status epilepticus (SE)-induced changes in expression of key components in the glutamate-glutamine cycle, known to be affected in MTS patients. SE was induced by Li(+) /pilocarpine injection in 21-day-old rats. At 2-19 weeks after SE hippocampal protein expression was analysed by immunohistochemistry and neuron damage by FluoroJade staining. Spontaneous seizures occurred in at least 44% of animals 15-18 weeks after SE. As expected in this model, we did not observe loss of principal hippocampal neurons. Neuron damage was most pronounced in the hilus, where we also detected progressive loss of parvalbumin-positive GABAergic interneurons. Hilar neuron loss (or end-folium sclerosis), a common feature in patients with MTS, was accompanied by a progressively decreased glutamine synthetase (GS)-immunoreactivity from 2 (-15%) to 19 weeks (-33.5%) after SE. Immunoreactivity for excitatory amino-acid transporters, vesicular glutamate transporter 1 and glial fibrillary acidic protein was unaffected. Our data show that SE elicited in 21-day-old rats induces a progressive reduction in hilar GS expression without affecting other key components of the glutamate-glutamine cycle. Reduced expression of glial enzyme GS was first detected 2 weeks after SE, and thus clearly before spontaneous recurrent seizures occurred. These results support the hypothesis that reduced GS expression is an early event in the development of hippocampal sclerosis in MTS patients and emphasize the importance of astrocytes in early epileptogenesis.

Surgical pathology of epilepsy‐associated non‐neoplastic cerebral lesions: A brief introduction with special reference to hippocampal sclerosis and focal cortical dysplasia

Among epilepsy-associated non-neoplastic lesions, mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE-HS) and malformation of cortical development (MCD), including focal cortical dysplasia (FCD), are the two most frequent causes of drug-resistant focal epilepsies, constituting about 50% of all surgical pathology of epilepsy. Several distinct histological patterns have been historically recognized in both HS and FCD, and several studies have tried to perform clinicopathological correlations. However, results have been controversial, particularly in terms of post-surgical seizure outcome. Recently, the International League Against Epilepsy constituted a Task Forces of Neuropathology and FCD within the Commission on Diagnostic Methods, to establish an international consensus of histological classification of HS and FCD, respectively, based on agreement with the recognition of the importance of defining a histopathological classification system that reliably has some clinicopathological correlation. Such consensus classifications are likely to facilitate future clinicopathological studies. Meanwhile, we reviewed the neuropathology of 41 surgical cases of mTLE, and confirmed three type/patterns of HS along with no HS, based on the qualitative evaluation of the distribution and severity of neuronal loss and gliosis within hippocampal formation, that is, HS type 1 (61%) equivalent to "classical" Ammon's horn sclerosis, HS type 2 (2%) representing CA1 sclerosis, HS type 3 (17%) equivalent to end folium sclerosis, and no HS (19%). Furthermore, we performed a neuropathological comparative study on mTLE-HS and dementia-associated HS (d-HS) in the elderly, and confirmed that neuropathological features differ between mTLE-HS and d-HS in the distribution of hippocampal neuronal loss and gliosis, morphology of reactive astrocytes and their protein expression, and presence of concomitant neurodegenerative changes, particularly Alzheimer type and TDP-43 pathologies. These differences may account, at least in part, for the difference in pathogenesis and epileptogenicity of HS in mTLE and senile dementia. However, the etiology and pathogenesis of most epileptogenic lesions are yet to be elucidated.

Clinico‐pathological investigations of Rasmussen encephalitis suggest multifocal disease progression and associated focal cortical dysplasia

Rasmussen encephalitis is a devastating neurological disorder characterised by seizures, brain inflammation, and progressive hemispheric atrophy. The objective of the current study was to systematically characterise patterns of structural lesions in children with Rasmussen encephalitis, referred for modified anatomical hemispherectomy at the Tsinghua University Epilepsy Center in Beijing. Seven consecutive patients were investigated with a mean age at operation of 4.5 years, who suffered from medically intractable seizures for a mean of 1.6 years. Foci of abnormally increased T2 signal intensity were observed in all patients. With the exception of one child, all patients presented with progressive unilateral cerebral atrophy. FDG-PET imaging revealed extensive regions of hypometabolism within the affected cerebral hemisphere in 3 of 4 patients. Diagnosis of Rasmussen encephalitis was confirmed histologically, demonstrating CD68 positive microglial nodules, as well as CD3 and CD8 positive Tlymphocytes invading the cerebral parenchyma. An intriguing observation was the heterogenous distribution of patterns of lesions throughout the affected hemisphere, suggesting multifocal manifestation and distinct sequences of disease progression, from discrete foci of inflammatory infiltrates (stage 1) to extensive cortical destruction (stage 4). Atypical hippocampal sclerosis (HS), with neuronal cell loss affecting most prominently the CA4 region (HS type 3 or end folium sclerosis), was evident in 5 of 7 cases. Four hippocampi also showed chronic inflammation. In addition, we observed associated focal cortical dysplasia (FCD; ILAE type IIId) in 4 of 7 children, supporting the concept of acquired and postmigratory FCD pathomechanisms. Postsurgical seizure freedom was achieved in all children with a mean follow-up period of 2.7 years and continuous antiepileptic medication.

The Presynaptic Active Zone Protein RIM1α Controls Epileptogenesis following Status Epilepticus

To ensure operation of synaptic transmission within an appropriate dynamic range, neurons have evolved mechanisms of activity-dependent plasticity, including changes in presynaptic efficacy. The multidomain protein RIM1α is an integral component of the cytomatrix at the presynaptic active zone and has emerged as key mediator of presynaptically expressed forms of synaptic plasticity. We have therefore addressed the role of RIM1α in aberrant cellular plasticity and structural reorganization after an episode of synchronous neuronal activity pharmacologically induced in vivo [status epilepticus (SE)]. Post-SE, all animals developed spontaneous seizure events, but their frequency was dramatically increased in RIM1α-deficient mice (RIM1α(-/-)). We found that in wild-type mice (RIM1α(+/+)) SE caused an increase in paired-pulse facilitation in the CA1 region of the hippocampus to the level observed in RIM1α(-/-) mice before SE. In contrast, this form of short-term plasticity was not further enhanced in RIM1α-deficient mice after SE. Intriguingly, RIM1α(-/-) mice showed a unique pattern of selective hilar cell loss (i.e., endfolium sclerosis), which so far has not been observed in a genetic epilepsy animal model, as well as less severe astrogliosis and attenuated mossy fiber sprouting. These findings indicate that the decrease in release probability and altered short- and long-term plasticity as present in RIM1α(-/-) mice result in the formation of a hyperexcitable network but act in part neuroprotectively with regard to neuropathological alterations associated with epileptogenesis. In summary, our results suggest that presynaptic plasticity and proper function of RIM1α play an important part in a neuron's adaptive response to aberrant electrical activity.

Reliability of patterns of hippocampal sclerosis as predictors of postsurgical outcome

Around one-third of patients undergoing temporal lobe surgery for the treatment of intractable temporal lobe epilepsy with hippocampal sclerosis (HS) fail to become seizure-free. Identifying reliable predictors of poor surgical outcome would be helpful in management. Atypical patterns of HS may be associated with poorer outcomes. Our aim was to identify atypical HS cases from a large surgical series and to correlate pathology with clinical and outcome data. Quantitative neuropathologic evaluation on 165 hippocampal surgical specimens and 21 control hippocampi was carried out on NeuN-stained sections. Neuronal densities (NDs) were measured in CA4, CA3, CA2, and CA1 subfields. The severity of granule cell dispersion (GCD) was assessed. Comparison with control ND values identified the following patterns based on the severity and distribution of neuronal loss: classical HS (CHS; n = 60) and total HS (THS; n = 39). Atypical patterns were present in 30% of cases, including end-folium sclerosis (EFS; n = 5), CA1 predominant pattern (CA1p; n = 9), and indeterminate HS (IHS, n = 35). No HS was noted in 17 cases. Poorest outcomes were noted for no-HS, and CA1p groups with 33-44% International League Against Epilepsy (ILAE) class I at up to 2 years follow-up compared to 69% for CHS (p < 0.05). GCD associated with HS type (p < 0.01), but not with outcome. These findings support the identification and delineation of atypical patterns of HS using quantitative methods. Atypical patterns may represent distinct clinicopathologic subtypes and may have predictive value following epilepsy surgery.

Beyond hippocampal sclerosis

Hippocampal atrophy is now routinely detected in MRI studies of patients at the onset of seizures and during presurgical evaluation for intractable temporal lobe epilepsy (TLE). The classic lesion of hippocampal sclerosis (HS) was described in 1880 by Sommer. Subsequent postmortem and surgical pathologic studies revealed that patterns of neuronal loss in TLE are considerably more diverse than the “classic” lesion, are frequently bilateral, are sometimes limited to the hilus of the dentate gyrus without prominent loss in CA1 (endfolium sclerosis), and may involve all hippocampal subfields.1 Neuronal loss in the epileptic hippocampus is accompanied by sprouting and reorganization of surviving synaptic connections, essentially rewiring hippocampal circuits.2–4 As surgical resection of the sclerotic rewired hippocampus and temporal lobe is frequently curative in cases with unilateral alterations, it has been presumed that more extensive bilateral hippocampal circuit rewiring may contribute to seizure susceptibility and influence prognosis. In this issue of Neurology ®, a postmortem study by Thom et al.5 revealed that synaptic reorganization is frequently bilateral and appears to be a long-term, essentially permanent hippocampal …

Endfolium sclerosis in temporal lobe epilepsy diagnosed preoperatively by 3-tesla magnetic resonance imaging

A 34-year-old man presented with intractable temporal lobe epilepsy. Three-tesla magnetic resonance imaging revealed increased T2 signal intensity and volume loss limited to the CA4 region of the right hippocampus. A right anterior temporal lobectomy and amygdalohippocampectomy were performed. Histological examination of the hippocampus disclosed severe neuron loss limited to the CA4 region, consistent with the preoperative imaging, which is a pattern known as endfolium sclerosis. Close inspection of the internal hippocampal anatomy with high-field MR imaging is useful in patients with temporal lobe epilepsy, because endfolium sclerosis may be associated with less chance of seizure freedom after temporal lobectomy.

Pathophysiological implications of focal cortical dysplasia of end folium for hippocampal sclerosis

Dual pathology is a well-known cause of temporal lobe epilepsy (TLE), but TLE associated with dual pathology within the hippocampus has rarely been reported. We describe a patient with medically refractory TLE due to a focal cortical dysplasia of the end folium of the left hippocampus (i.e. CA4) and left hippocampal sclerosis (HS) that was successfully treated with left anterior temporal lobectomy and speculate on the interaction between end folium sclerosis and HS.

PROPELLER MRI visualizes detailed pathology of hippocampal sclerosis

Purpose:Hippocampal sclerosis (HS) is the most common cause of refractory temporal lobe epilepsy. Histopathologically, HS is characterized by neuron loss and gliosis. HS can be identified on MRI by signal increase on T2-weighted images and volume loss on T1-weighted volume images. The Periodically Rotated Overlapping Parallel Lines with Enhanced Reconstruction (“PROPELLER”) sequence has excellent contrast between grey and white matter and compensates for subjects moving during the scan. The aim of the current report was to explore PROPELLER image quality of the hippocampus compared to routine sequences.Methods:Routine sequences (T1 volume, T2-weighted, PD and FLAIR images) and PROPELLER images were acquired in four presurgical patients with HS using a GE 3T Excite HD scanner (General Electric). Resected tissue was stained with LFB, and for GFAP, NeuN and dynorphin immunohistochemistry. Hippocampal sections were compared with PROPELLER images.Results:PROPELLER images were T2-weighted and had superior tissue contrast compared to routine sequences. PROPELLER images showed the internal hippocampal structures and tissue changes associated with HS. This corresponded to changes seen on histopathological sections confirming that the sequence could distinguish between different strata and subfields of the hippocampus.Discussion:The PROPELLER sequence shows promise for detailed in vivo imaging of the hippocampus in patients who did not move overtly, negating the inevitable subtle movements during scans. More detailed in vivo studies of the hippocampal formation, investigating subtle abnormalities such as end folium sclerosis, and the neocortex are now possible and may increase the diagnostic yield of MRI.

Temporal Lobe Epilepsy

Abstract Object. The syndrome of medial temporal lobe epilepsy (MTLE) may occur in patients in whom magnetic resonance (MR) images demonstrate normal findings. In these patients, there is no evidence of hippocampal sclerosis on neuroimaging, and histopathological examination of the resected hippocampus does not reveal significant neuron loss. In this paper the authors describe the distinct clinical features of this MTLE subtype, referred to as paradoxical temporal lobe epilepsy (PTLE). Methods. The authors selected 12 consecutive patients with preoperative findings consistent with MTLE in whom MR imaging did not demonstrate any hippocampal abnormality. Onset of hippocampal seizure was confirmed by long-term intracranial monitoring. There were six female and six male patients with a mean age of 32 ± 11 years (mean ± standard deviation [SD]) at presentation. These patients' seizure histories, available hippocampal volumetric measurements, and hippocampal cell densities in different subfields were reviewed. Sharp electrode recordings from dentate granule cells that had been maintained in hippocampal slices provided a measure of excitation and inhibition in the tissue. We compared these data with those of a cohort of 50 randomly selected patients who underwent anteromedial temporal resection for medial temporal sclerosis (MTS) during the same time period (1987–1999). The durations of follow up (means ± SDs) for the PTLE and MTS groups were 51 ± 59 months and 88 ± 44 months, respectively. A history of febrile seizure was present less frequently in the PTLE group (8%) than in the MTS group (34%). Other risk factors for epilepsy such as trauma, meningoencephalitis, or perinatal injuries were present more frequently in the PTLE group (50%) than in the MTS cohort (36%). In patients in the PTLE group the first seizure occurred later in life (mean age at seizure onset 14 years in the PTLE group compared with 9 years in the MTS group, p = 0.09). Ten patients (83%) in the PTLE cohort and 23 patients (46%) in the MTLE cohort had secondary generalization of their seizures. Among patients with PTLE, volumetric measurements (five patients) and randomized blinded visual inspection (seven patients) of the bilateral hippocampi revealed no atrophy and no increased T2 signal change on preoperative MR images. All patients with PTLE underwent anteromedial temporal resection (amygdalohippocampectomy, in five patients on the left side and in seven on the right side). Electrophysiological studies of hippocampal slices demonstrated that dentate granule cells from patients with PTLE were significantly less excitable than those from patients with MTS. The mean pyramidal cell loss in the CA1 subfield in patients in the PTLE group was 20% (range 0–59%) and that in patients in the MTS group was 75% (range 41–90%) (p &lt; 0.001). Maximal neuron loss (mean loss 38%) occurred in the CA4 region in six patients with PTLE (end folium sclerosis). At the last follow-up examination, six patients (50%) in the PTLE group were seizure free compared with 38 patients (76%) in the MTS group. Conclusions. Clinical PTLE is a distinct syndrome with clinical features and surgical outcomes different from those of MTS.

Normal magnetic resonance imaging and medial temporal lobe epilepsy: the clinical syndrome of paradoxical temporal lobe epilepsy

The syndrome of medial temporal lobe epilepsy (MTLE) may occur in patients in whom magnetic resonance (MR) images demonstrate normal findings. In these patients, there is no evidence of hippocampal sclerosis on neuroimaging, and histopathological examination of the resected hippocampus does not reveal significant neuron loss. In this paper the authors describe the distinct clinical features of this MTLE subtype, referred to as paradoxical temporal lobe epilepsy (PTLE). The authors selected 12 consecutive patients with preoperative findings consistent with MTLE in whom MR imaging did not demonstrate any hippocampal abnormality. Onset of hippocampal seizure was confirmed by long-term intracranial monitoring. There were six female and six male patients with a mean age of 32 +/- 11 years, (mean +/- standard deviation [SD]) at presentation. These patients' seizure histories, available hippocampal volumetric measurements, and hippocampal cell densities in different subfields were reviewed. Sharp electrode recordings from dentate granule cells that had been maintained in hippocampal slices provided a measure of excitation and inhibition in the tissue. We compared these data with those of a cohort of 50 randomly selected patients who underwent anteromedial temporal resection for medial temporal sclerosis (MTS) during the same time period (1987-1999). The durations of follow up (means +/- SDs) for the PTLE and MTS groups were 51 +/- 59 months and 88 +/- 44 months, respectively. A history of febrile seizure was present less frequently in the PTLE group (8%) than in the MTS group (34%). Other risk factors for epilepsy such as trauma, meningoencephalitis, or perinatal injuries were present more frequently in the PTLE group (50%) than in the MTS cohort (36%). In patients in the PTLE group the first seizure occurred later in life (mean age at seizure onset 14 years in the PTLE group compared with 9 years in the MTS group, p = 0.09). Ten patients (83%) in the PTLE cohort and 23 patients (46%) in the MTLE cohort had secondary generalization of their seizures. Among patients with PTLE, volumetric measurements (five patients) and randomized blinded visual inspection (seven patients) of the bilateral hippocampi revealed no atrophy and no increased T2 signal change on preoperative MR images. All patients with PTLE underwent anteromedial temporal resection (amygdalohippocampectomy, in five patients on the left side and in seven on the right side). Electrophysiological studies of hippocampal slices demonstrated that dentate granule cells from patients with PTLE were significantly less excitable than those from patients with MTS. The mean pyramidal cell loss in the CAI subfield in patients in the PTLE group was 20% (range 0-59%) and that in patients in the MTS group was 75% (range 41-90%) (p < 0.001). Maximal neuron loss (mean loss 38%) occurred in the CA4 region in six patients with PTLE (end folium sclerosis). At the last follow-up examination, six patients (50%) in the PTLE group were seizure free compared with 38 patients (76%) in the MTS group. Clinical PTLE is a distinct syndrome with clinical features and surgical outcomes different from-those of MTS.

Correlation of hippocampal neuronal density and FDG-PET in mesial temporal lobe epilepsy.

Interictal [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) reveals regional hypometabolism in 60-80% of patients with mesial temporal lobe epilepsy (MTLE). The extent of hypometabolism generally extends beyond the epileptogenic zone. The pathophysiology underlying this widespread change is unknown. This study evaluated the relation between hippocampal neuronal loss and hypometabolism in patients with MTLE. Forty-three patients with MTLE after anterior temporal lobectomy were included. Pathology demonstrated mesial temporal sclerosis (n = 41) or endfolium sclerosis (n = 2). Interictal FDG-PET scans were graded by visual analysis on a scale ranging from normal (grade 1) to severe (grade 5) hypometabolism. Neuronal counting was performed in the subiculum, hippocampal subfields, and dentate granular cell layer (DG). Neuronal density of patients was compared with that of seven autopsy controls. Data were compared by using Student's t tests and Kruskal-Wallis one-way analysis of variance (ANOVA). Significant neuronal loss in CA1 through CA4 and DG was found in patients compared with controls. Neuronal density in the subiculum, CA1, CA4, and DG did not correlate with severity of hypometabolism. However, patients with abnormal FDG-PET had higher neuronal density in CA2 and CA3 versus patients with normal studies. This study supports a previous observation that degree of FDG-PET hypometabolism does not parallel severity of hippocampal neuronal loss in MTLE.

Quantitative neuropathology and quantitative magnetic resonance imaging of the hippocampus in temporal lobe epilepsy.

The aims of this study were to examine the relationships of hippocampal T2 (HCT2) relaxation time and magnetic resonance (MR)-based hippocampal volume (HCV) to neuronal (ND) and glial cell densities (GD) of hippocampal neuronal cell layers, and to obtain a better clinicopathological definition of hippocampal sclerosis (HS) and end folium sclerosis (EFS). Fifty-three hippocampi with HS, 6 with EFS, and 6 control hippocampi were studied. Pathologically, the HS group had a significantly higher logarithm (log) GD/ND than the controls in all hippocampal subregions, and than the EFS group in all subregions except the granule cell layer of the dentate gyrus (GCDG). The EFS group had a significantly higher log GD/ND than the control group only in the GCDG. Clinical correlations suggested that EFS may be the consequence of temporal lobe seizures and not an epileptogenic entity. Hippocampal atrophy in HS was associated with neuronal cell depletion and concomitant gliosis in the cornu Ammonis (CA) 1, CA2, CA3, and hilus. An increased HCT2 was associated with damage in the CA1 and also the hilus and has a different neuropathological basis than HCV loss. MR-based HCV measurement and HCT2 mapping, therefore, give complementary information in the presurgical evaluation of temporal lobe epilepsy and longitudinal studies.

Quantitative hippocampal MRI and intractable temporal lobe epilepsy.

To evaluate and compare T2 relaxometry and volumetrics of hippocampus in the presurgical evaluation of patients with intractable temporal lobe epilepsy (TLE), and to correlate these quantitative MRI measures with the pathology of the resected hippocampus. Forty patients with intractable TLE who underwent presurgical evaluation and subsequent temporal lobe surgery. Hippocampal T2 (HCT2), volumes of hippocampi and hippocampal volume ratio (HCVR) (volume of hippocampus with higher HCT2 divided by volume of hippocampus with lower HCT2), and qualitative pathology. Thirty-two patients had hippocampal sclerosis, three patients had end-folium sclerosis, one patient had amygdala sclerosis, and four patients had a foreign tissue lesion in the temporal lobe. HCT2 (R/L) correlated inversely with the ratio of hippocampal volumes (R/L) (r = -0.91; p < 0.0001). A high T2 signal in an atrophic hippocampus was characteristic of hippocampal sclerosis. All patients with hippocampal sclerosis had an HCVR below control values, and only one of these had an HCT2 in the normal range. HCVR produced one false-positive result. The patients with end-folium sclerosis had normal HCT2 and HCVR. The patient with amygdala sclerosis had a normal hippocampus on qualitative and quantitative assessment. Of the four patients with a lesion, one had a mildly increased HCT2 and one had mild volume asymmetry. Hippocampal volume asymmetry could be reliably detected on visual inspection of the MRI with an HCVR of 0.85 or less, and an increase of HCT2 with a T2 of 115 msec or higher. Quantitative MRI combining HCT2 and HCVR is a reliable method for diagnosing hippocampal sclerosis noninvasively. End-folium sclerosis and amygdala sclerosis should be considered in patients with intractable TLE and negative findings on MRI studies, including quantitative measures of the hippocampus.

The functional organization of the hippocampal dentate gyrus and its relevance to the pathogenesis of temporal lobe epilepsy.

Temporal lobe seizures are frequently associated with a characteristic pattern of hippocampal pathology (hippocampal sclerosis), as well as pathology in other temporal lobe structures. Despite more than a century of study, the relationship between pathology and epileptogenesis remains unclear. Endfolium sclerosis, which is characterized by the loss of dentate hilar neurons that are presumed to govern dentate granule cell excitability, is evident whenever hippocampal sclerosis exists and is the only temporal lobe pathology in some patients. Because prolonged seizures or head trauma produce endfolium sclerosis and granule cell hyperexcitability in experimental animals, hilar neuron loss may be the common pathological denominator and primary network defect underlying development of a hippocampal seizure "focus." Physiological studies suggest that vulnerable hilar mossy cells normally excite neurons that mediate granule cell inhibition. Recent anatomical studies indicate that the axons of mossy cells project longitudinally, out of the lamellar plane in which their cell bodies lie. If mossy cells in one lamella excite inhibitory neurons in surrounding lamellae, neocortical excitation of one segment of the granule cell layer may produce lateral inhibition and limit neocortical excitation to the targeted lamella. In patients who have had status epilepticus, prolonged febrile seizures, head trauma, or encephalitis, loss of dentate mossy cells may deafferent inhibitory neurons, render them "dormant," and thereby disinhibit an enlarged expanse of the granule cell layer. The selective loss of neurons that normally govern lateral inhibition in the dentate gyrus may cause functional delamination of the granule cell layer and result in synchronous, multilamellar discharges in response to cortical stimuli. Repetitive seizures may ultimately produce the full pattern of hippocampal and mesial temporal sclerosis by destroying cells within the seizure circuit that were not injured irreversibly by the initial insult. Thus, hippocampal pathology may be both the cause and effect of seizures that originate in the temporal lobe.