SEARCH

SEARCH BY CITATION

Keywords:

  • Temporal lobe epilepsy;
  • Epilepsy surgery;
  • Neuropathology;
  • Magnetic resonance imaging

Summary

  1. Top of page
  2. Summary
  3. Background and History of Hippocampal Sclerosis Based on Postmortem Studies
  4. Hippocampal Anatomy
  5. Hippocampal Sclerosis and Clinical Features of Mesial Temporal Lobe Epilepsy
  6. Structural Imaging
  7. Functional Imaging
  8. Temporal Lobe Resection in Patients with Drug-Resistant MTLE with HS
  9. Neuropathology
  10. Seizure Outcome after TLR in Relation to Imaging and Resection Type
  11. Conclusions
  12. Acknowledgments
  13. Disclosures
  14. References

The association between hippocampal sclerosis (HS) and epilepsy has been known for almost two centuries. For many years, HS was studied in postmortem series; however, since the mid-20th century, surgical specimens from temporal lobe resections have provided important new knowledge. HS is the most common pathology underlying drug-resistant mesial temporal lobe epilepsy (MTLE), a syndrome with a characteristic history and seizure semiology. In the early 1990s, it was recognized that magnetic resonance imaging (MRI) could detect HS. The standard MRI protocol for temporal lobe abnormalities uses coronal slices perpendicular to the long axis of the hippocampus. The MRI features of HS include reduced hippocampal volume, increased signal intensity on T2-weighted imaging, and disturbed internal architecture. The histopathologic diagnosis of HS is usually straightforward, with neuronal loss and chronic fibrillary gliosis centered on the pyramidal cell layer. There are several patterns or subtypes of HS recognized from surgical series based on qualitative or quantified assessments of regional neuronal loss. The pathologic changes of HS include granule cell dispersion, mossy fiber sprouting, and alterations to interneurons. There may also be more extensive sclerosis of adjacent structures in the medial temporal lobe, including the amygdala and parahippocampal gyrus. Subtle cortical neuropathologies may accompany HS. The revised classification of dysplasias in epilepsy denotes these as focal cortical dysplasias type IIIa. Sometimes, HS occurs with a second lesion, either in the temporal lobe or extratemporal, most often ipsilateral to the HS. HS on preoperative MRI strongly predicts good seizure outcome following temporal lobe resection (TLR). If adequate MRI shows no structural correlate in patients with MTLE, functional imaging studies are valuable, especially if they are in agreement with ictal electroencephalography (EEG) findings. Focal hypometabolism on 18F-fluorodeoxyglucose–positron emission tomography (FDG-PET) ipsilateral to the symptomatic temporal lobe predicts a good surgical outcome; the added value of 11C-Flumazenil-PET (FMZ-PET) and proton magnetic resonance spectroscopy (MRS) is less clear. Surgical methods have evolved, particularly resecting less tissue, aiming to preserve function without compromising seizure outcome. Around two thirds of patients operated for MTLE with HS obtain seizure freedom. However, the best surgical approach to optimize seizure outcome remains controversial.


Background and History of Hippocampal Sclerosis Based on Postmortem Studies

  1. Top of page
  2. Summary
  3. Background and History of Hippocampal Sclerosis Based on Postmortem Studies
  4. Hippocampal Anatomy
  5. Hippocampal Sclerosis and Clinical Features of Mesial Temporal Lobe Epilepsy
  6. Structural Imaging
  7. Functional Imaging
  8. Temporal Lobe Resection in Patients with Drug-Resistant MTLE with HS
  9. Neuropathology
  10. Seizure Outcome after TLR in Relation to Imaging and Resection Type
  11. Conclusions
  12. Acknowledgments
  13. Disclosures
  14. References

Hippocampal sclerosis (HS) underlying epilepsy has been recognized for more than 180 years. Initially termed Ammon’s horn sclerosis, the first detailed neuropathologic studies by Sommer and Bratz were based on postmortem series (see (Thom, 2009) for review). They identified relatively consistent patterns of neuronal loss, largely restricted to a section of the hippocampal pyramidal cell layer immediately adjacent to the temporal horn of the lateral ventricle; this vulnerable region became known as Sommer’s sector (now termed CA1). Jackson in 1889 associated the clinical symptoms of temporal lobe epilepsy (TLE) with focal lesions in the hippocampus (Jackson & Beevor, 1889). In the mid-20th century, with the dawn of electroencephalography (EEG), Sano and Malamud associated HS (confirmed histologically at autopsy) with electrophysiologic evidence of temporal lobe seizures (Sano & Malamud, 1953). More recent epilepsy postmortem series, including patients with TLE, have explored the variability in the patterns and severity of neuronal loss between cases (Margerison & Corsellis, 1966), and speculated on different stages in the disease process. Postmortem studies have shown bilateral sclerosis in 48–56% of cases (Thom et al., 2011a). Other studies have addressed the variability of neuronal loss along the longitudinal hippocampal axis (Dam, 1980; Mouritze Dam, 1982). HS represents the most common pathologic finding in adult epilepsy surgery series (Blumcke, 2009), and surgical specimen studies in the last 20 years have underpinned the major advances in our understanding of the cellular and molecular pathology of HS.

Hippocampal Anatomy

  1. Top of page
  2. Summary
  3. Background and History of Hippocampal Sclerosis Based on Postmortem Studies
  4. Hippocampal Anatomy
  5. Hippocampal Sclerosis and Clinical Features of Mesial Temporal Lobe Epilepsy
  6. Structural Imaging
  7. Functional Imaging
  8. Temporal Lobe Resection in Patients with Drug-Resistant MTLE with HS
  9. Neuropathology
  10. Seizure Outcome after TLR in Relation to Imaging and Resection Type
  11. Conclusions
  12. Acknowledgments
  13. Disclosures
  14. References

The hippocampus, located in the medial temporal lobe, is formed by the interlocking neuronal bands of the dentate gyrus and the hippocampus proper (syn. cornu ammonis; CA). The laminar structure of the hippocampus from outside–in comprises the alveus (outgoing axons), stratum oriens (crossing axons and interneurons), stratum pyramidale (the main cellular elements, the pyramidal cells), stratum radiatum (apical dendrites of pyramidal cells), and stratum lacunosum/moleculare (axon bundles, dendrites, and interneurons) (Fig. 1A). Several schemes have subdivided the hippocampal subfields, and here we use the one most widely adopted in human epilepsy studies, the system of Lorente de No; for detail see (Duvernoy, 2005) (Fig. 1A,B). The pyramidal cell layers have four subfields (CA1–4); CA1 is the largest region and broadest part of the pyramidal cell layer, and is in continuity with the subiculum; CA2 is narrower with densely packed neurons; CA3 forms the curve of the hippocampus; CA4 is within the concavity of the dentate gyrus, comprising scattered ovoid cells (also termed the endplate or end blade).

image

Figure 1.   Hippocampal subfields and pathways. (A) Postmortem hematoxylin & eosin (H&E) section of the hippocampus from a neurologically normal patient and (B) from a patient with a long history of temporal lobe epilepsy. The subregions of the hippocampus are highlighted from CA4 to CA1 (CA = cornu ammonis), and the subiculum is indicated (SC). The laminar layers of the hippocampus are shown in (A) (see text for details), and (1) marks the position of a normal granule cell and its apical dendrite (the arrow marks the direction of incoming excitatory perforant pathway fibers) and its axonal trajectory to CA3 in the mossy fiber pathway (2). (3) indicates the position and orientation of a normal CA1 pyramidal cell with its apical dendrite extending through the stratum radiatum and into the stratum moleculare and its outgoing axon (arrow) in the alveus; (4) indicates the recurrent Schaffer collateral axons connecting CA1 neurons with SC neurons. In the sclerotic hippocampus in (B), note the sharp cutoff between the atrophied CA1 sector and the intact SC. Figure (C) shows a normal granule cell layer (GCL) inner molecular layer (IML) and outer molecular layer (OML), with the underlying cell-poor subgranular zone (SGZ) and polymorphic cell layer (PL). In comparison, in (D), there is evident granule cells dispersion from the same case as in (B), obscuring the cell-layer boundaries. Bar = approximately 2,000 μm in A, B and 150 μm in C, D.

Download figure to PowerPoint

The dentate gyrus comprises a C-shaped band with three layers: the granule cell layer with an outer cell-poor molecular layer, and a deeper polymorphic cell layer containing interneuronal cell types that merge with the CA4 region (Fig. 1C). Granule cells give rise to the mossy fiber axons that terminate in CA4 and CA3 (Fig. 1A). The range of hippocampal interneuronal populations shows great diversity: for example, CA1 pyramidal cells are supported by more than 16 different GABAergic cell types (Somogyi & Klausberger, 2005). In tissue sections, interneurons have characteristic morphology, location, and immunostaining properties, with some major types being calcium-binding-containing interneurons (parvalbumin, calbindin, and calretinin) and neuropeptidergic neurons. A major excitatory input pathway to the hippocampus (also termed the polysynaptic intrahippocampal pathway) originates in layer II of the entorhinal cortex to the granule cells of dentate gyrus, then via the mossy fiber axons to CA4 and CA3 pyramids, via their Schaffer collateral axons to CA1 and subicular neurons, and the main hippocampal output fibers then pass through the alveus.

Hippocampal Sclerosis and Clinical Features of Mesial Temporal Lobe Epilepsy

  1. Top of page
  2. Summary
  3. Background and History of Hippocampal Sclerosis Based on Postmortem Studies
  4. Hippocampal Anatomy
  5. Hippocampal Sclerosis and Clinical Features of Mesial Temporal Lobe Epilepsy
  6. Structural Imaging
  7. Functional Imaging
  8. Temporal Lobe Resection in Patients with Drug-Resistant MTLE with HS
  9. Neuropathology
  10. Seizure Outcome after TLR in Relation to Imaging and Resection Type
  11. Conclusions
  12. Acknowledgments
  13. Disclosures
  14. References

Following early work with depth electrode recordings and cortical stimulation (Penfield & Jasper, 1954; Bancaud et al., 1965; Escueta et al., 1982), the International Classification of Epileptic Syndromes (Commission, 1989) distinguished medial from lateral temporal lobe epilepsies. The clinical characteristic features of medial temporal lobe seizures include a history of an early initial injury (typically complicated febrile convulsions, but also central nervous system (CNS) infections or head injury) followed by a long-lasting latent period, before refractory chronic epilepsy develops (French et al., 1993). Several studies have analyzed semiologic elements differentiating medial from lateral TLE. In mesial temporal lobe epilepsy (MTLE), there is typically an aura that includes initial viscerosensory sensations (especially epigastric sensation), fear or anxiety and dreamy state. There is then behavioral arrest and a slowly progressing impairment of consciousness, with a motionless stare. Oroalimentary and elementary upper limb automatisms are common (lip smacking, chewing, and fidgeting). Other characteristic features are long seizure duration and prolonged postictal reorientation (Wieser et al., 1993; Williamson et al., 1993Kotagal et al., 1995; Gil-Nagel & Risinger, 1997; Saint-Hilaire & Lee, 2000; Engel, 2001; Maillard et al., 2004; Wieser, 2004). Hippocampal sclerosis is the most common pathology underlying drug-resistant MTLE.

Note, however, that each semiologic element may incorrectly localize the seizure origin (So, 2006). Conversely, clinical features atypical of MTLE are common in patients with HS, especially when severe. Extratemporal features in patients with more severe HS do not negatively affect the postsurgical outcome (Borelli et al., 2008). This is important, since atypical seizure semiology might otherwise be thought to render surgical treatment inappropriate.

Structural Imaging

  1. Top of page
  2. Summary
  3. Background and History of Hippocampal Sclerosis Based on Postmortem Studies
  4. Hippocampal Anatomy
  5. Hippocampal Sclerosis and Clinical Features of Mesial Temporal Lobe Epilepsy
  6. Structural Imaging
  7. Functional Imaging
  8. Temporal Lobe Resection in Patients with Drug-Resistant MTLE with HS
  9. Neuropathology
  10. Seizure Outcome after TLR in Relation to Imaging and Resection Type
  11. Conclusions
  12. Acknowledgments
  13. Disclosures
  14. References

Magnetic resonance imaging – MRI

Neuroimaging is crucial in evaluating patients with focal epilepsy, to identify the structural basis of the seizures. MRI is generally the method of choice. In the last decade, expertise and technical improvements have yielded increased sensitivity in detecting epileptogenic lesions, but even high-resolution qualitative MRI does not reveal significant pathology in 20–30% of patients with chronic focal epilepsy.

The clinical value of MRI depends strongly on the expertise of those obtaining and interpreting the images. Standard MRI based on axial images and read by radiologists unfamiliar with epilepsy investigations fail to detect up to 50% of focal epileptogenic lesions (Von Oertzen et al., 2002). Therefore, a report of “MRI negativity” may mislead, and good candidates for epilepsy surgery may not be referred appropriately (Fig. 2).

image

Figure 2.   MR images of left-sided hippocampal sclerosis. (A) Sagittal T1 with a line demonstrating the orientation of the coronal images perpendicular to the long axis of the hippocampus, corresponding to the level of the coronal T1 in D. (B) Coronal FLAIR image illustrating the atrophy and T2 hyperintensity. (C) Coronal T2 confirming the FLAIR images. (D) T1-weighted image.

Download figure to PowerPoint

Most patients referred for epilepsy surgery have MTLE, and HS is the most common histopathologic finding in the resected tissue. In the early 1990s, it was recognized that MRI could detect HS (Jackson et al., 1990; Berkovic et al., 1991). The standard MRI protocol for temporal lobe abnormalities uses coronal slices perpendicular to the long axis of the hippocampus. The MRI features of HS include reduced hippocampal volume, increased signal intensity on T2-weighted imaging, and disturbed internal architecture (Jackson et al., 1990, 1993; Woermann et al., 1998). Furthermore, temporal lobe atrophy, dilatation of the temporal horn, and blurring of the gray–white matter interface may accompany HS (Meiners et al., 1994; Moran et al., 2001). The hyperintense signal change on T2-weighted images can be enhanced by using FLAIR (a fluid-attenuated inversion recovery pulse sequence), but since this can give false-positive results, FLAIR findings must be confirmed with T2-weighted images. T1-weighted images provide detailed information on hippocampal anatomy and gyral patterns and a clear contrast between gray and white matter.

Reduced hippocampal volumes on MRI correlate with lower neuron cell counts in the hippocampus (Bronen et al., 1991; Lencz et al., 1992; Van Paesschen et al., 1997). The increased T2 signal in HS probably reflects gliosis; one study showed this was influenced mainly by gliosis in the dentate gyrus (Briellmann et al., 2002).

HS may accompany lesions located outside the hippocampus and even outside the temporal lobe—so called “dual pathology.” Early ischemic lesions, hemiatrophy, low-grade tumors, vascular malformations, and malformations of cortical development can be associated with HS and are mostly ipsilateral (Hofman et al., 2011). Neocortical thinning may also accompany HS (Bonilha et al., 2010; Labate et al., 2011a) (Fig. 3).

image

Figure 3.   Dual pathology. (A) Coronal FLAIR image demonstrating right-sided hippocampal sclerosis and hemiatrophy in a 7-year old girl. (B) Coronal T1 images illustrating loss of internal structure in the right temporal pole. After right-sided TLR, histopathology showed hippocampal sclerosis and heterotopic neurons in the white matter. The patient is seizure-free since surgery, now for 9 months.

Download figure to PowerPoint

It is important not to miss bilateral HS: when symmetric, it can be difficult to detect on MR. When suspected, volumetric quantification can help. Hippocampal volumes are measured manually or using automated methods. Manual measurement of hippocampal volume involves segmenting the hippocampus on serial sections of a T1-weighted MR scan acquired perpendicular to the long axis of the hippocampus (Jack et al., 1990; Cook et al., 1992; Watson et al., 1992). Expert manual volumetry is more sensitive than automated methods but requires a trained operator. If not available, automated methods can also be valuable (Pardoe et al., 2009).

MRI features of HS must be carefully assessed and interpreted in their clinical context. Despite the strong relationship between HS and the severity of the epilepsy in MTLE, some patients with well-controlled MTLE have MRI signs of HS (Labate et al., 2011b). Hippocampal hyperintense FLAIR signal occurs in about one third of normal controls (Labate et al., 2010) but is never associated with hippocampal atrophy. A unilateral enlarged temporal horn, common in HS, also occurs frequently in controls and should not be considered pathologic in isolation (Menzler et al., 2010).

Tertiary epilepsy centers are starting to use new MR methods with increased sensitivity. The so-called PROPELLER sequence (Periodically Rotated Overlapping Parallel Lines with Enhanced Reconstruction) has excellent contrast between gray and white matter and compensates for subjects moving during the scan (Eriksson et al., 2008). Higher field-strength MRI scanners (commonly 3T and, for research purposes, 7T) have a higher yield, especially when evaluating malformations of cortical development, but also produce more pronounced artifacts due to greater field inhomogeneity. The added value for diagnosing HS could be through its improved detection of even very small intrahippocampal structural changes and through demonstrating regional differences in hippocampal atrophy (Breyer et al., 2010). However, when MTLE is the likely cause of chronic drug-resistant epilepsy, a standard MRI protocol for temporal lobe abnormalities on a 1.5-T scanner is adequate (Symms et al., 2004; Jeukens et al., 2009; Woermann & Vollmar, 2009; Hashiguchi et al., 2010). Sending MR images to epilepsy centers for second opinion is an underutilized resource, both for checking protocol adequacy and for image interpretation.

Functional Imaging

  1. Top of page
  2. Summary
  3. Background and History of Hippocampal Sclerosis Based on Postmortem Studies
  4. Hippocampal Anatomy
  5. Hippocampal Sclerosis and Clinical Features of Mesial Temporal Lobe Epilepsy
  6. Structural Imaging
  7. Functional Imaging
  8. Temporal Lobe Resection in Patients with Drug-Resistant MTLE with HS
  9. Neuropathology
  10. Seizure Outcome after TLR in Relation to Imaging and Resection Type
  11. Conclusions
  12. Acknowledgments
  13. Disclosures
  14. References

Positron emission tomography – PET

FDG-PET

PET has assisted in localizing the seizure-onset zone for over 25 years, especially in TLE (Engel et al., 1990). Glucose metabolism is the most commonly measured variable, using 18F-fluorodeoxyglucose (18F-FDG). The characteristic interictal finding in TLE is a diffuse regional hypometabolism of both mesial and lateral temporal structures (Henry et al., 1993). The exact reasons for the interictal hypometabolism are not clear. Some data suggest that hypometabolism results from HS in the temporolimbic region (Knowlton et al., 2001), not necessarily affecting other parts of the temporal lobe (Semah et al., 1995). The interictal hypometabolism may reflect the preferential networks involved by ictal discharges and spread pathways (Chassoux et al., 2004).

A meta-analysis focusing on the FDG-PET in preoperative epilepsy surgery evaluation for TLE (Willmann et al., 2007) showed that 46 PET studies from 24 centers fulfilled specified inclusion criteria. The identified studies showed that PET was a confirmatory test, especially valuable in MRI-negative patients. Ipsilateral PET hypometabolism had a predictive value of 86% for good outcome. The predictive value was 80% in patients with normal MRI (28/153 patients). It was not possible to distinguish between localizing and lateralizing findings. The authors concluded that PET is not necessary in patients whose seizure focus is localized by both ictal scalp EEG and MRI. They also underscore that an MRI evaluated as normal 6 years ago might be judged as localizing today, given the better high-resolution MRI. It is therefore difficult to quantify the additional value of FDG-PET in MRI-negative patients (Fig. 4).

image

Figure 4.   PET findings in hippocampal sclerosis. (A) Axial 18F-FDG PET scan. MRI was normal, but FDG-PET showed widespread hypometabolism in the left temporal lobe. (B) Axial 11C-FMZ PET in the same patient shows a more restricted area of hypometabolism in the left temporal lobe. The patient underwent a left TLR and the histopathology was hippocampal sclerosis. In the color scale, red indicates areas of highest uptake, whereas blue indicates areas of lowest uptake. FDG, fluorodeoxyglucose, FMZ, flumazenil. Image courtesy of Eva Kumlien, Department of Neurology, Uppsala Akademiska Hospital, Sweden.

Download figure to PowerPoint

FMZ-PET

11C-Flumazenil (FMZ) is a specific antagonist of central benzodiazepine receptors (cBZR) and is a marker of the complex of GABAA/cBZR using PET scanning. In MTLE with HS, cBZRs numbers in the hippocampus are reduced. In vivo 11C-FMZ binding in presurgical PET correlates with 3H autoradiography in the resected hippocampal tissue ex vivo (Koepp et al., 1998). Moreover, reduced FMZ binding is most prominent in the hippocampal subfields with the most pronounced neuronal loss (Hand et al., 1997). 11C-FMZ-PET may provide useful data to complement FDG-PET in bitemporal epilepsy (Ryvlin et al., 1998). In MRI-negative 11C-FMZ-PET–positive patients, histologic analysis has verified HS (Lamusuo et al., 2000); on the other hand FMZ-PET does not consistently help to localize the epileptic focus in MRI-negative patients with MTLE and HS (Koepp et al., 2000). FMZ-PET is also limited by cost and by limited availability of 11C radiochemistry.

Magnetic Resonance Spectroscopy – MRS

(1) H-MRS can be performed with existing MRI equipment. It detects a series of peaks, representing concentrations of N-acetyl-aspartate (NAA), creatine plus phosphocreatine (Cr) and choline-containing compounds (Cho). NAA is widely used as a neuronal marker sensitive to neuronal loss or dysfunction (Hugg et al., 1993; Connelly et al., 1994; Cendes et al., 1994; Kuzniecky et al., 2001). In MTLE with HS, MRS characteristically shows a localized relative reduction of NAA (Cendes et al., 1994; Connelly et al., 1994; Achten et al., 1998; Kuzniecky et al., 1998; Woermann et al., 1999). However, there is often also a reduction in the contralateral normal-appearing hippocampus (Cendes et al., 1995; Woermann et al., 1999; Simister et al., 2002). A meta-analysis showed great heterogeneity in both methodology and data interpretation among studies. The odds ratio for seizure freedom after TLR was 4.9 times higher in patients with an ipsilateral MRS abnormality concordant with the epileptogenic zone than for patients with bilateral MRS abnormalities. Data for MRI-negative patients were conflicting (Willmann et al., 2006). One study found no difference in MRS abnormalities in different HS subtypes (Hajek et al., 2009). We need more studies of MRS in MRI-negative patients to identify its added value in presurgical evaluation.

Temporal Lobe Resection in Patients with Drug-Resistant MTLE with HS

  1. Top of page
  2. Summary
  3. Background and History of Hippocampal Sclerosis Based on Postmortem Studies
  4. Hippocampal Anatomy
  5. Hippocampal Sclerosis and Clinical Features of Mesial Temporal Lobe Epilepsy
  6. Structural Imaging
  7. Functional Imaging
  8. Temporal Lobe Resection in Patients with Drug-Resistant MTLE with HS
  9. Neuropathology
  10. Seizure Outcome after TLR in Relation to Imaging and Resection Type
  11. Conclusions
  12. Acknowledgments
  13. Disclosures
  14. References

Resective surgery is well-established for drug-resistant epilepsy due to MTLE with HS. Temporal lobe resection (TLR) techniques have evolved, specifically with more limited resections, aiming to preserve function without compromising seizure outcome. The “en bloc” resection, introduced by Falconer (Falconer, 1967), included mesial as well as lateral structures. More recently, the so-called Spencer type of resection combines a small anterior partial lobectomy with a more extensive mesial resection (Spencer et al., 1984). Another more restricted surgical method is the strictly mesial resection, the selective amygdalohippocampectomy (Yasargil et al., 1985). The efficacy of TLR in treating drug-resistant MTLE was shown in a randomized controlled trial in which 58% of surgically treated patients (in the intent-to-treat analysis, 64% of those operated), most of whom had HS, were free from seizures that impaired awareness after 1 year, compared to 8% in the medically treated group (Wiebe et al., 2001). Several systematic reviews of observational studies have shown similar outcomes (Engel et al., 2003; Spencer & Huh, 2008).

Neuropathology

  1. Top of page
  2. Summary
  3. Background and History of Hippocampal Sclerosis Based on Postmortem Studies
  4. Hippocampal Anatomy
  5. Hippocampal Sclerosis and Clinical Features of Mesial Temporal Lobe Epilepsy
  6. Structural Imaging
  7. Functional Imaging
  8. Temporal Lobe Resection in Patients with Drug-Resistant MTLE with HS
  9. Neuropathology
  10. Seizure Outcome after TLR in Relation to Imaging and Resection Type
  11. Conclusions
  12. Acknowledgments
  13. Disclosures
  14. References

The pathologic diagnosis of HS is usually straightforward and based on identifying neuronal loss and chronic fibrillary gliosis, centered on the pyramidal cell layer (Wieser, 2004). The resulting tissue atrophy and hardening may be apparent on macroscopic examination of the surgically resected tissue (Fig. 5A). Surgical series show several patterns or subtypes of HS (Table 1) based on qualitative or quantified assessments of regional neuronal loss (Babb et al., 1984; Bruton, 1988; Davies et al., 1996; de Lanerolle et al., 2003; Blumcke et al., 2007; Thom et al., 2010). The main and most common type is classical hippocampal sclerosis, with neuronal loss primarily involving the CA1 subfield, typically severely depleted, with accompanying neuronal loss from the CA4 region. There is a sharp transition between the neuronal loss and gliosis in CA1 and the adjacent preserved subiculum (Fig. 5B,D); CA2 subfield is also relatively preserved (the “resistant sector”) (Fig. 6A) with variable loss from CA3. In severe or total HS, neuronal loss also involves CA2 and the granule cells of the dentate gyrus. The atypical or “nonclassical” HS patterns include end-folium HS (neuronal loss restricted to CA4) (Fig. 6A) and CA1 HS (neuronal loss restricted to CA1). The atypical cases comprise up to 20%; there is conflicting evidence regarding their association with less favourable surgical outcomes, although they are associated with later onset of seizures (Blumcke et al., 2007; Thom et al., 2010). Cautionary points regarding the histologic diagnosis of atypical HS forms are (1) the extent of HS may vary along the longitudinal axis, risking underestimating HS severity if sampled at only one level (Fig. 6C,D), (2) atypical forms of HS are often associated with a second pathology (see dual pathology below), which may or may not be represented in the surgical resection but could influence outcome, (3) end-plate gliosis commonly occurs in epilepsy patients but should not be overinterpreted as end folium sclerosis, unless there is definite neuronal loss. Most epilepsy surgical series consistently report the poorest outcomes in cases with no HS, with only 40–50% becoming seizure-free (de Lanerolle et al., 2003; Thom et al., 2010); a history of febrile seizures is less common in this group.

image

Figure 5.   Classical hippocampal sclerosis. Surgical specimen of hippocampal sclerosis in a patient with intractable temporal lobe epilepsy. (A) The four sections of the temporal lobe are normal following fixation (bottom row); the three sections of the hippocampus confirm atrophy of the CA1 region visible to the naked eye (arrowhead). (B) Luxol fast blue/cresyl violet preparation of the section shown by arrow in (A) confirms loss of neurons from CA1 and CA4 and the classical pattern of HS. (C) In the same specimen, there is mossy fiber sprouting with a dense band of dynorphin labeling in the molecular layer of the dentate gyrus as well as residual staining in CA4 and CA3; (D) Glial fibrillary acidic protein (GFAP) stain confirms chronic dense gliosis, but note the sharp cutoff between the CA1 and the less gliotic subiculum. Bar in A = 1 cm and in CD = 1,000 μm.

Download figure to PowerPoint

Table 1.   Summary of the pathologic subtypes and associated pathologies of hippocampal sclerosis in epilepsy
  Pathology typeDefinition
  1. DNT, dysembryoplastic neuroepithelial tumor; FCD, focal cortical dysplasia; MCD, malformation of cortical development; PM, postmortem; HS, hippocampal sclerosis.

  2. a Variable reported in human and experimental studies.

  3. b The HS in dual pathology is often less severe or atypical (see text).

Categories of hippocampal sclerosis in surgical practiceSevere hippocampal sclerosisSevere neuronal loss and gliosis from all subfields
Classical hippocampal sclerosisCA1 and CA4 neuronal loss and gliosis; variable loss in CA3
End folium sclerosisCA4 neuronal loss and gliosis
CA1 hippocampal sclerosisCA1 neuronal loss and gliosis
Probable hippocampal sclerosisNot all subfields represented in specimen but neuronal loss present in CA4 or CA1
Indeterminate hippocampal sclerosisNeuronal loss and gliosis is present but does not fit one of the above defined groups (e.g., CA1 + CA3 neuronal loss)
No hippocampal sclerosis/gliosis onlyNo clear qualitative evidence of significant neuronal loss. Gliosis alone does not amount to sclerosis
Mesial temporal sclerosis (MTS)/“HS plus”Amygdala gliosis/sclerosisGliosis ± neuronal loss in amygdala (lateral and basal nuclear groups)
Parahippocampal gyrus/entorhinal cortexLaminar neuronal loss and gliosisa
Temporal neocortical sclerosisNeuronal loss reported in 11% of HS/TLE patients in layer II/III
Widespread cortical atrophySubtle volume loss/cortical thinning reported both ipsilateral (and bilaterally) including temporal, frontal, parietal cortical regions in MRI and PM studies
Thalamic nucleiReported in MRI and postmortem studies
Contralateral hippocampusBilateral hippocampal sclerosis (asymmetrical or symmetrical)
Hippocampal sclerosis and dysplasiaFCD IIIaTemporal lobe sclerosis with layer II dysplasia
Cortical dyslamination (FCD type I-like)
Lentiform heterotopias
Mild malformation of cortical development type IIAn excess of single, mature neurons in the white matter of the temporal lobe
Dual pathologyHippocampal sclerosis in the context of a second temporal/extratemporal epileptogenic pathologybCavernoma Tumor (often low grade tumor as DNT or ganglioglioma) FCD type II (FCD IIIa and mild MCD excluded by definition)
image

Figure 6.   Patterns and variability of hippocampal sclerosis. Surgical specimens of classical hippocampal sclerosis (A), with loss and atrophy of CA1 neurons in this subfield. (B) An example of end-folium sclerosis where neuronal loss was restricted to CA4 and CA1 sector was intact. (C) Illustrates a surgical case where neuronal loss was evident only in the section from the pes hippocampus (head) and not the main body, with CA4 loss and gliosis shown in (D) and with mossy fiber sprouting (not shown). (E) Granule cell dispersion with fusiform morphology of the neurons. (F) Timm’s silver method for mossy fiber sprouting shows a dense band of silver synaptic staining in the molecular layer. Neuropeptide Y: (G) shows a normal pattern with demarcation between labeling in the outer molecular layer, compared to the pale inner molecular layer; (H) shows changes typical of hippocampal sclerosis, with loss of staining between inner and outer molecular layer and sprouted fibers throughout the dentate gyrus. Calbindin: (I) in the normal hippocampus, there is dense staining of granule cells and apical dendrites in the molecular layer; in HS (J) only the dispersed granule cells retain calbindin expression. Calretinin: (K) A normal pattern with dense axons around the granule cell layer on both sides; in HS (L) this pattern is lost with sprouted fibers throughout the hippocampus. Bar in AD = 1,000 μm, EL = 100 μm.

Download figure to PowerPoint

Pathology Changes Associated with HS

Granule cell dispersion (GCD)

Granule cell dispersion (GCD) accompanies HS in 40–50% (Wieser, 2004; Blumcke et al., 2009a). This process is relatively specific to the epileptogenic hippocampus, compared to other causes of hippocampal atrophy, for example, in aging and neurodegeneration. Furthermore, GCD can be replicated in experimental epilepsy models. In GCD, the normally compact cell layer becomes broadened (up to 200 μm wide) with individual granule cells separating from each other and displaying a more elongated, fusiform morphology, reminiscent of migrating neurons (Figs. 1D and 6F). In 10%, there is either a bilaminar arrangement or neuronal clusters in the molecular layer. The extent and pattern of GCD varies within and between cases, and may alternate with regions of granule cell depletion, but is nearly always accompanied by isomorphic radial gliosis of the dentate gyrus. GCD is significantly associated with early seizure onset (Lurton et al., 1998), with the extent of neuronal loss in CA4 but not CA1 (Thom et al., 2010) and with a longer duration of epilepsy (Blumcke, 2009). The mechanisms stimulating GCD and its influence on seizure activity have attracted great interest. Although GCD is similar to the de novo granule cell abnormality in the reeler mutant mouse, in human HS it appears acquired rather than developmental, with “neo-migration” of mature granule cells. Real-time studies in hippocampal slice preparations confirm the migration of mature neurons by “somatic translocation” along their dendrites into the molecular layer (Murphy & Danzer, 2011). The dispersion is promoted by a local reduction of reelin, a secreted migration guidance cue; lower reelin levels occur in HS, probably from loss of specific interneuronal cells (Heinrich et al., 2006). Although there may be increased proliferative activity in the dentate gyrus in epilepsy surgical specimens (Thom et al., 2005), GCD appears independent of altered neurogenesis in the residual stem cell populations in this region (Fahrner et al., 2007; Haas & Frotscher, 2010).

Mossy fiber sprouting (MFS)

Mossy fiber sprouting (MFS) of granule cell axons is common in HS and in experimental epilepsy models. Axonal sprouting, frequently seen in the developing brain, also develops in response to seizures; the con-sequent remodeling of neuronal networks appears proepileptogenic, through enhancing excitability or synchronizing discharges. The mossy fiber axons of the glutamatergic granule cells normally project in the mossy fiber pathway to CA4 and CA3 (Fig. 1A). However, in MFS, recurrent collateral axons make synaptic contact (excitatory asymmetric synapses) with apical dendrites and spines of other granule cells in the molecular layer. This creates a potential recurrent excitatory circuit. MFS is best seen in tissue sections with the Timm silver method (Fig. 3F) or dynorphin immunohistochemistry (Fig. 5C). Although some experimental data support MFS as integral to hippocampal epileptogenesis, suppression of mossy fiber growth with cyclohexamide does not affect the severity of spontaneous seizures in experimental animals (Longo & Mello, 1997), and its presence is not always associated with spontaneous seizures (Nissinen et al., 2001). In human epilepsy postmortem studies, MFS was bilateral, not exclusive to HS/MTLE and persisted despite seizure remission; it may therefore represent axonal sprouting in response to seizures, rather than causing them.

Alterations to interneurons

Hippocampal interneurons play a central role in epileptogenesis in addition to loss of the pyramidal and excitatory neurons. Although initial studies supported their relative resistance in epilepsy, they are reduced in number with reorganization of remaining neurons, including axonal sprouting and new synaptic networks (Magloczky, 2010). For example, in the dentate gyrus, there are distinct alterations of calbindin, calretinin, and neuropeptide-Y interneurons, specific to the epileptic hippocampus (Fig. 6G–L). Local interneuronal alterations could synchronize granule cell firing and start or promote seizures. These stereotypical alterations also help the neuropathologist in diagnosing and evaluating surgical specimens.

“HS Plus”

Hippocampal sclerosis can sometimes be accompanied by more extensive sclerosis of adjacent structures in the medial temporal lobe, including the amygdala and parahippocampal gyrus (mesial temporal lobe sclerosis) (Table 1). Pathologic changes typically manifest as atrophy (neuronal loss and astrocytic gliosis) and may result from the spread of seizures and excitotoxic injury, and could in turn modulate seizure activity. There is electrophysiologic evidence in some cases to support an origin of temporal lobe seizures outside the hippocampus, for example, in the parahippocampal gyrus and amygdala (Graebenitz et al., 2011; Kullmann, 2011). Neuropathologic assessment of the amygdala is often hampered by the incomplete and fragmentary nature of surgical specimens; studies have reported gliosis and neuronal loss in the lateral nucleus (in particular its ventromedial aspects) and basal nuclei (particularly the parvicellular division) (Pitkanen et al., 1998). There may be abnormal patterns of glutamate and GABA receptor densities and synaptic function in the lateral nucleus of the amygdala in patients with TLE, which could correlate with observed interictal discharges from this location (Graebenitz et al., 2011). Cases with severe neuronal loss and gliosis, may be termed “amygdala sclerosis,” although there is no strict definition for this (Wieser, 2004). Amygdala enlargement can also occur in patients with TLE without HS (Kim et al., 2012).

Quantified studies of the entorhinal cortex and parahippocampal gyrus region in patients with hippocampal sclerosis undergoing surgery show subtle and variable patterns of gliosis and neuronal loss (Yilmazer-Hanke et al., 2000; Dawodu & Thom, 2005). Quantified neuroimaging techniques can identify more widespread extra-hippocampal atrophy accompanying HS, involving temporal and extratemporal neocortex and thalamus, in both ipsilateral and contralateral hemispheres (Moran et al., 2001; Bonilha et al., 2007; Keller & Roberts, 2008; Mcdonald et al., 2008); postmortem studies support this (Margerison & Corsellis, 1966; Blanc et al., 2011). Possible explanations include reciprocal atrophy via hippocampal-cortical networks or secondary changes from generalized seizures, including subtle accumulative cerebral trauma. More widespread cortical changes may be relevant to recurrent seizures following temporal lobectomy, as well as comorbid symptoms, including cognitive decline in epilepsy.

HS and cortical dysplasia

Epilepsy surgical series have long reported subtle, presumed developmental, cortical neuropathologies accompanying HS, previously termed “microdysgenesis” or focal cortical dysplasias (FCDs). In the revised classification of dysplasias in epilepsy, these alterations are encompassed within FCD type IIIa (Blumcke et al., 2011) to distinguish them clinically and pathologically from dysplasias in isolation. Within the FCD IIIa spectrum are disordered cortical lamination and small “lentiform” neuronal heterotopias in the subcortical white matter (Table 1). In addition, there is a distinct cortical abnormality associated with HS, also termed “temporal lobe sclerosis,” where there is neuron loss from the superficial cortex accompanied by gliosis and abnormal neuronal clustering. This is present in around 11% of HS surgical patients (Thom et al., 2009). Unlike FCD II, FC IIIa is not clearly defined by MRI (Eriksson et al., 2009; Meroni et al., 2009) and we need further studies to determine its developmental origins, its relationship to the processes of HS and its significance in predicting seizure outcome following surgery. Single neurons in the temporal lobe white matter are normal but they may appear in excess when accompanying HS, for review see Blumcke et al. (2009b); this feature is not included as a subtype FCD IIIa but still regarded, at most, as a mild malformation of cortical development (mild MCD) (Blumcke et al., 2011).

HS and dual pathology

Some patients with HS have a second lesion in the temporal lobe, in particular a low-grade tumor (as dysembryoplastic neuroepithelial tumours, gangliogliomas) and vascular and cortical malformation. Possibly the HS may have been “kindled” by this second pathology. Often the hippocampal atrophy is less severe with dual pathology than in HS alone; for example, end-folium sclerosis patterns may predominate (Thom et al., 2011b).

Seizure Outcome after TLR in Relation to Imaging and Resection Type

  1. Top of page
  2. Summary
  3. Background and History of Hippocampal Sclerosis Based on Postmortem Studies
  4. Hippocampal Anatomy
  5. Hippocampal Sclerosis and Clinical Features of Mesial Temporal Lobe Epilepsy
  6. Structural Imaging
  7. Functional Imaging
  8. Temporal Lobe Resection in Patients with Drug-Resistant MTLE with HS
  9. Neuropathology
  10. Seizure Outcome after TLR in Relation to Imaging and Resection Type
  11. Conclusions
  12. Acknowledgments
  13. Disclosures
  14. References

Many studies have shown circumscribed HS on preoperative MR imaging as a strong predictor of remission after TLR (Wieshmann et al., 2008; Elsharkawy et al., 2009). The prognosis for seizure freedom in MRI-negative patients is generally less good but also more variable. This variability is at least partly explained by varying MRI quality, reflected in the histopathologic findings: HS was diagnosed histopathologically in 8–69% of presumed MRI-negative cases (Siegel et al., 2001; Carne et al., 2004; Chapman et al., 2005; Alarcon et al., 2006; Bien et al., 2009; Smith et al., 2011). Seizure outcome is better in those series with a high proportion of HS.

Structural MRI continues to improve, and patients considered MRI-negative often justify rescanning to identify lesions previously not seen. If adequate MRI still discloses no structural correlate in MTLE, functional imaging is valuable, especially when it concords with ictal EEG findings. Focal hypometabolism on FDG-PET ipsilateral to the temporal lobe to be resected predicts a good surgical outcome and is cost-effective (Willmann et al., 2007; O’brien et al., 2008); the added value of FMZ-PET and proton MRS is less clear (Koepp et al., 2000; Willmann et al., 2006).

Which temporal lobe resection method gives the best seizure outcome (while preserving as much cognitive function as possible, a topic outside the scope of this article) remains controversial. Among 53 studies addressing the extent of surgical resection for TLE, there were seven prospective studies, of which four were randomized (Schramm, 2008). Many were retrospective and did not use postoperative MRI volumetry to assess the extent of resection. Most studies found that a larger extent of mesial resection did not reliably predict a better seizure outcome (for references see Schramm, 2008). One randomized study on the mesial extent of resection found that a larger resection led to better seizure control but that there was no postoperative MRI volumetry (Wyler et al., 1995). In a recent randomized controlled trial of 2.5 cm versus 3.5 cm mesial temporal resection, with the resection volume controlled by postoperative MRI, the intent-to-treat analysis showed no difference in seizure outcomes between the groups. It is therefore possible that it is not maximal volume resection but adequate volume resection that gives seizure freedom (Schramm et al., 2011a,b).

Conclusions

  1. Top of page
  2. Summary
  3. Background and History of Hippocampal Sclerosis Based on Postmortem Studies
  4. Hippocampal Anatomy
  5. Hippocampal Sclerosis and Clinical Features of Mesial Temporal Lobe Epilepsy
  6. Structural Imaging
  7. Functional Imaging
  8. Temporal Lobe Resection in Patients with Drug-Resistant MTLE with HS
  9. Neuropathology
  10. Seizure Outcome after TLR in Relation to Imaging and Resection Type
  11. Conclusions
  12. Acknowledgments
  13. Disclosures
  14. References

HS is the most common pathology in MTLE, and most patients are treated successfully by temporal lobe resection. Some patients with typical MTLE, however, despite circumscribed unilateral HS on MRI and concordant investigation findings, do not achieve seizure control after surgery. There are several pathologic subtypes of HS and also associated additional pathologic changes. More sensitive new imaging methods may disclose subtle changes as well as HS. We need more research to further our understanding of these differences and to help identify patient categories that may need different investigations and different surgical approaches to improve seizure outcome.

References

  1. Top of page
  2. Summary
  3. Background and History of Hippocampal Sclerosis Based on Postmortem Studies
  4. Hippocampal Anatomy
  5. Hippocampal Sclerosis and Clinical Features of Mesial Temporal Lobe Epilepsy
  6. Structural Imaging
  7. Functional Imaging
  8. Temporal Lobe Resection in Patients with Drug-Resistant MTLE with HS
  9. Neuropathology
  10. Seizure Outcome after TLR in Relation to Imaging and Resection Type
  11. Conclusions
  12. Acknowledgments
  13. Disclosures
  14. References
  • Achten E, Santens P, Boon P, De Coo D, De Kerckhove T, De Reuck J, Caemaert J, Kunnen M. (1998) Single-voxel proton MR spectroscopy and positron emission tomography for lateralization of refractory temporal lobe epilepsy. AJNR Am J Neuroradiol 19:18.
  • Alarcon G, Valentin A, Watt C, Selway RP, Lacruz ME, Elwes RD, Jarosz JM, Honavar M, Brunhuber F, Mullatti N, Bodi I, Salinas M, Binnie CD, Polkey CE. (2006) Is it worth pursuing surgery for epilepsy in patients with normal neuroimaging? J Neurol Neurosurg Psychiatry 77:474480.
  • Babb TL, Lieb JP, Brown WJ, Pretorius J, Crandall PH. (1984) Distribution of pyramidal cell density and hyperexcitability in the epileptic human hippocampal formation. Epilepsia 25:721728.
  • Bancaud J, Talairach J, Bonis A, Schaub C, Szikla G, Morel P, Bordas-Ferer M. (1965) La stéréoencéphalographie dans l’épilepsie. Informations neuro-physiopathologiques apportées par l’investigation fonctionnelle stéréotaxique. Masson, Paris.
  • Berkovic SF, Andermann F, Olivier A, Ethier R, Melanson D, Robitaille Y, Kuzniecky R, Peters T, Feindel W. (1991) Hippocampal sclerosis in temporal lobe epilepsy demonstrated by magnetic resonance imaging. Ann Neurol 29:175182.
  • Bien CG, Szinay M, Wagner J, Clusmann H, Becker AJ, Urbach H. (2009) Characteristics and surgical outcomes of patients with refractory magnetic resonance imaging-negative epilepsies. Arch Neurol 66:14911499.
  • Blanc F, Martinian L, Liagkouras I, Catarino C, Sisodiya SM, Thom M. (2011) Investigation of widespread neocortical pathology associated with hippocampal sclerosis in epilepsy: a postmortem study. Epilepsia 52:1021.
  • Blumcke I. (2009) Neuropathology of focal epilepsies: a critical review. Epilepsy Behav 15:3439.
  • Blumcke I, Pauli E, Clusmann H, Schramm J, Becker A, Elger C, Merschhemke M, Meencke HJ, Lehmann T, Von Deimling A, Scheiwe C, Zentner J, Volk B, Romstock J, Stefan H, Hildebrandt M. (2007) A new clinico-pathological classification system for mesial temporal sclerosis. Acta Neuropathol 113:235244.
  • Blumcke I, Kistner I, Clusmann H, Schramm J, Becker AJ, Elger CE, Bien CG, Merschhemke M, Meencke HJ, Lehmann T, Buchfelder M, Weigel D, Buslei R, Stefan H, Pauli E, Hildebrandt M. (2009a) Towards a clinico-pathological classification of granule cell dispersion in human mesial temporal lobe epilepsies. Acta Neuropathol 117:535544.
  • Blumcke I, Vinters HV, Armstrong D, Aronica E, Thom M, Spreafico R. (2009b) Malformations of cortical development and epilepsies: neuropathological findings with emphasis on focal cortical dysplasia. Epileptic Disord 11:181193.
  • Blumcke I, Thom M, Aronica E, Armstrong DD, Vinters HV, Palmini A, Jacques TS, Avanzini G, Barkovich AJ, Battaglia G, Becker A, Cepeda C, Cendes F, Colombo N, Crino P, Cross JH, Delalande O, Dubeau F, Duncan J, Guerrini R, Kahane P, Mathern G, Najm I, Ozkara C, Raybaud C, Represa A, Roper SN, Salamon N, Schulze-Bonhage A, Tassi L, Vezzani A, Spreafico R. (2011) The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia 52:158174.
  • Bonilha L, Rorden C, Halford JJ, Eckert M, Appenzeller S, Cendes F, Li LM. (2007) Asymmetrical extra-hippocampal grey matter loss related to hippocampal atrophy in patients with medial temporal lobe epilepsy. J Neurol Neurosurg Psychiatry 78:286294.
  • Bonilha L, Edwards JC, Kinsman SL, Morgan PS, Fridriksson J, Rorden C, Rumboldt Z, Roberts DR, Eckert MA, Halford JJ. (2010) Extrahippocampal gray matter loss and hippocampal deafferentation in patients with temporal lobe epilepsy. Epilepsia 51:519528.
  • Borelli P, Shorvon SD, Stevens JM, Smith SJ, Scott CA, Walker MC. (2008) Extratemporal ictal clinical features in hippocampal sclerosis: their relationship to the degree of hippocampal volume loss and to the outcome of temporal lobectomy. Epilepsia 49:13331339.
  • Breyer T, Wanke I, Maderwald S, Woermann FG, Kraff O, Theysohn JM, Ebner A, Forsting M, Ladd ME, Schlamann M. (2010) Imaging of patients with hippocampal sclerosis at 7 Tesla: initial results. Acad Radiol 17:421426.
  • Briellmann RS, Kalnins RM, Berkovic SF, Jackson GD. (2002) Hippocampal pathology in refractory temporal lobe epilepsy: T2-weighted signal change reflects dentate gliosis. Neurology 58:265271.
  • Bronen RA, Cheung G, Charles JT, Kim JH, Spencer DD, Spencer SS, Sze G, Mccarthy G. (1991) Imaging findings in hippocampal sclerosis: correlation with pathology. AJNR Am J Neuroradiol 12:933940.
  • Bruton CJ. (1988) The neuropathology of temporal lobe epilepsy. Oxford University Press, Oxford.
  • Carne RP, O’brien TJ, Kilpatrick CJ, Macgregor LR, Hicks RJ, Murphy MA, Bowden SC, Kaye AH, Cook MJ. (2004) MRI-negative PET-positive temporal lobe epilepsy: a distinct surgically remediable syndrome. Brain 127:22762285.
  • Cendes F, Andermann F, Preul MC, Arnold DL. (1994) Lateralization of temporal lobe epilepsy based on regional metabolic abnormalities in proton magnetic resonance spectroscopic images. Ann Neurol 35:211216.
  • Cendes F, Andermann F, Dubeau F, Arnold DL. (1995) Proton magnetic resonance spectroscopic images and MRI volumetric studies for lateralization of temporal lobe epilepsy. Magn Reson Imaging 13:11871191.
  • Chapman K, Wyllie E, Najm I, Ruggieri P, Bingaman W, Luders J, Kotagal P, Lachhwani D, Dinner D, Luders HO. (2005) Seizure outcome after epilepsy surgery in patients with normal preoperative MRI. J Neurol Neurosurg Psychiatry 76:710713.
  • Chassoux F, Semah F, Bouilleret V, Landre E, Devaux B, Turak B, Nataf F, Roux FX. (2004) Metabolic changes and electro-clinical patterns in mesio-temporal lobe epilepsy: a correlative study. Brain 127:164174.
  • Commission on Classification and Terminology of the International League Against Epilepsy. (1989) Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 30:389399.
  • Connelly A, Jackson GD, Duncan JS, King MD, Gadian DG. (1994) Magnetic resonance spectroscopy in temporal lobe epilepsy. Neurology 44:14111417.
  • Cook MJ, Fish DR, Shorvon SD, Straughan K, Stevens JM. (1992) Hippocampal volumetric and morphometric studies in frontal and temporal lobe epilepsy. Brain 115(Pt 4):10011015.
  • Dam AM. (1980) Epilepsy and neuron loss in the hippocampus. Epilepsia 21:617629.
  • Davies KG, Hermann BP, Dohan FC Jr, Foley KT, Bush AJ, Wyler AR. (1996) Relationship of hippocampal sclerosis to duration and age of onset of epilepsy, and childhood febrile seizures in temporal lobectomy patients. Epilepsy Res 24:119126.
  • Dawodu S, Thom M. (2005) Quantitative neuropathology of the entorhinal cortex region in patients with hippocampal sclerosis and temporal lobe epilepsy. Epilepsia 46:2330.
  • de Lanerolle NC, Kim JH, Williamson A, Spencer SS, Zaveri HP, Eid T, Spencer DD. (2003) A retrospective analysis of hippocampal pathology in human temporal lobe epilepsy: evidence for distinctive patient subcategories. Epilepsia 44:677687.
  • Duvernoy HM. (2003) The human hippocampus: functional anatomy, vascularization, and serial sections with MRI. Springer, Berlin.
  • Elsharkawy AE, Alabbasi AH, Pannek H, Oppel F, Schulz R, Hoppe M, Hamad AP, Nayel M, Issa A, Ebner A. (2009) Long-term outcome after temporal lobe epilepsy surgery in 434 consecutive adult patients. J Neurosurg 110:11351146.
  • Engel J Jr. (2001) Mesial temporal lobe epilepsy: what have we learned? Neuroscientist 7:340352.
  • Engel J Jr, Henry TR, Risinger MW, Mazziotta JC, Sutherling WW, Levesque MF, Phelps ME. (1990) Presurgical evaluation for partial epilepsy: relative contributions of chronic depth-electrode recordings versus FDG-PET and scalp-sphenoidal ictal EEG. Neurology 40:16701677.
  • Engel J Jr, Wiebe S, French J, Sperling M, Williamson P, Spencer D, Gumnit R, Zahn C, Westbrook E, Enos B. (2003) Practice parameter: temporal lobe and localized neocortical resections for epilepsy: report of the Quality Standards Subcommittee of the American Academy of Neurology, in association with the American Epilepsy Society and the American Association of Neurological Surgeons. Neurology 60:538547.
  • Eriksson SH, Thom M, Bartlett PA, Symms MR, Mcevoy AW, Sisodiya SM, Duncan JS. (2008) PROPELLER MRI visualizes detailed pathology of hippocampal sclerosis. Epilepsia 49:3339.
  • Eriksson SH, Thom M, Symms MR, Focke NK, Martinian L, Sisodiya SM, Duncan JS. (2009) Cortical neuronal loss and hippocampal sclerosis are not detected by voxel-based morphometry in individual epilepsy surgery patients. Hum Brain Mapp 30:33513360.
  • Escueta AV, Bacsal FE, Treiman DM. (1982) Complex partial seizures on closed-circuit television and EEG: a study of 691 attacks in 79 patients. Ann Neurol 11:292300.
  • Fahrner A, Kann G, Flubacher A, Heinrich C, Freiman TM, Zentner J, Frotscher M, Haas CA. (2007) Granule cell dispersion is not accompanied by enhanced neurogenesis in temporal lobe epilepsy patients. Exp Neurol 203:320332.
  • Falconer MA. (1967) Surgical treatment of temporal lobe epilepsy. N Z Med J 66:539542.
  • French JA, Williamson PD, Thadani VM, Darcey TM, Mattson RH, Spencer SS, Spencer DD. (1993) Characteristics of medial temporal lobe epilepsy: I. Results of history and physical examination. Ann Neurol 34:774780.
  • Gil-Nagel A, Risinger MW. (1997) Ictal semiology in hippocampal versus extrahippocampal temporal lobe epilepsy. Brain 120(Pt 1):183192.
  • Graebenitz S, Kedo O, Speckmann EJ, Gorji A, Panneck H, Hans V, Palomero-Gallagher N, Schleicher A, Zilles K, Pape HC. (2011) Interictal-like network activity and receptor expression in the epileptic human lateral amygdala. Brain 134:29292947.
  • Haas CA, Frotscher M. (2010) Reelin deficiency causes granule cell dispersion in epilepsy. Exp Brain Res 200:141149.
  • Hajek M, Krsek P, Dezortova M, Marusic P, Zamecnik J, Kyncl M, Tomasek M, Krijtova H, Komarek V. (2009) 1H MR spectroscopy in histopathological subgroups of mesial temporal lobe epilepsy. Eur Radiol 19:400408.
  • Hand KS, Baird VH, Van Paesschen W, Koepp MJ, Revesz T, Thom M, Harkness WF, Duncan JS, Bowery NG. (1997) Central benzodiazepine receptor autoradiography in hippocampal sclerosis. Br J Pharmacol 122:358364.
  • Hashiguchi K, Morioka T, Murakami N, Suzuki SO, Hiwatashi A, Yoshiura T, Sasaki T. (2010) Utility of 3-T FLAIR and 3D short tau inversion recovery MR imaging in the preoperative diagnosis of hippocampal sclerosis: direct comparison with 1.5-T FLAIR MR imaging. Epilepsia 51:18201828.
  • Heinrich C, Nitta N, Flubacher A, Muller M, Fahrner A, Kirsch M, Freiman T, Suzuki F, Depaulis A, Frotscher M, Haas CA. (2006) Reelin deficiency and displacement of mature neurons, but not neurogenesis, underlie the formation of granule cell dispersion in the epileptic hippocampus. J Neurosci 26:47014713.
  • Henry TR, Mazziotta JC, Engel J Jr. (1993) Interictal metabolic anatomy of mesial temporal lobe epilepsy. Arch Neurol 50:582589.
  • Hofman PA, Fitt GJ, Harvey AS, Kuzniecky RI, Jackson G. (2011) Bottom-of-sulcus dysplasia: imaging features. AJR Am J Roentgenol 196:881885.
  • Hugg JW, Laxer KD, Matson GB, Maudsley AA, Weiner MW. (1993) Neuron loss localizes human temporal lobe epilepsy by in vivo proton magnetic resonance spectroscopic imaging. Ann Neurol 34:788794.
  • Jack CR Jr, Bentley MD, Twomey CK, Zinsmeister AR. (1990) MR imaging-based volume measurements of the hippocampal formation and anterior temporal lobe: validation studies. Radiology 176:205209.
  • Jackson H, Beevor CE. (1889) Case of tumour of the right temporo-sphenoidal lobe bearing on the localisation of the sense of smell and on the interpretation of a particular variety of epilepsy. Brain 34:6357.
  • Jackson GD, Berkovic SF, Tress BM, Kalnins RM, Fabinyi GC, Bladin PF. (1990) Hippocampal sclerosis can be reliably detected by magnetic resonance imaging. Neurology 40:18691875.
  • Jackson GD, Berkovic SF, Duncan JS, Connelly A. (1993) Optimizing the diagnosis of hippocampal sclerosis using MR imaging. AJNR Am J Neuroradiol 14:753762.
  • Jeukens CR, Vlooswijk MC, Majoie HJ, De Krom MC, Aldenkamp AP, Hofman PA, Jansen JF, Backes WH. (2009) Hippocampal MRI volumetry at 3 Tesla: reliability and practical guidance. Invest Radiol 44:509517.
  • Keller SS, Roberts N. (2008) Voxel-based morphometry of temporal lobe epilepsy: an introduction and review of the literature. Epilepsia 49:741757.
  • Kim DW, Lee SK, Chung CK, Koh YC, Choe G, Lim SD. (2012) Clinical features and pathological characteristics of amygdala enlargement in mesial temporal lobe epilepsy. J Clin Neurosci 19:509512.
  • Knowlton RC, Laxer KD, Klein G, Sawrie S, Ende G, Hawkins RA, Aassar OS, Soohoo K, Wong S, Barbaro N. (2001) In vivo hippocampal glucose metabolism in mesial temporal lobe epilepsy. Neurology 57:11841190.
  • Koepp MJ, Hand KS, Labbe C, Richardson MP, Van Paesschen W, Baird VH, Cunningham VJ, Bowery NG, Brooks DJ, Duncan JS. (1998) In vivo [11C]flumazenil-PET correlates with ex vivo [3H]flumazenil autoradiography in hippocampal sclerosis. Ann Neurol 43:618626.
  • Koepp MJ, Hammers A, Labbe C, Woermann FG, Brooks DJ, Duncan JS. (2000) 11C-flumazenil PET in patients with refractory temporal lobe epilepsy and normal MRI. Neurology 54:332339.
  • Kotagal P, Luders HO, Williams G, Nichols TR, Mcpherson J. (1995) Psychomotor seizures of temporal lobe onset: analysis of symptom clusters and sequences. Epilepsy Res 20:4967.
  • Kullmann DM. (2011) What’s wrong with the amygdala in temporal lobe epilepsy? Brain 134:28002801.
  • Kuzniecky R, Hugg JW, Hetherington H, Butterworth E, Bilir E, Faught E, Gilliam F. (1998) Relative utility of 1H spectroscopic imaging and hippocampal volumetry in the lateralization of mesial temporal lobe epilepsy. Neurology 51:6671.
  • Kuzniecky R, Palmer C, Hugg J, Martin R, Sawrie S, Morawetz R, Faught E, Knowlton R. (2001) Magnetic resonance spectroscopic imaging in temporal lobe epilepsy: neuronal dysfunction or cell loss? Arch Neurol 58:20482053.
  • Labate A, Gambardella A, Aguglia U, Condino F, Ventura P, Lanza P, Quattrone A. (2010) Temporal lobe abnormalities on brain MRI in healthy volunteers: a prospective case–control study. Neurology 74:553557.
  • Labate A, Cerasa A, Aguglia U, Mumoli L, Quattrone A, Gambardella A. (2011a) Neocortical thinning in “benign” mesial temporal lobe epilepsy. Epilepsia 52:712717.
  • Labate A, Gambardella A, Andermann E, Aguglia U, Cendes F, Berkovic SF, Andermann F. (2011b) Benign mesial temporal lobe epilepsy. Nat Rev Neurol 7:237240.
  • Lamusuo S, Pitkanen A, Jutila L, Ylinen A, Partanen K, Kalviainen R, Ruottinen HM, Oikonen V, Nagren K, Lehikoinen P, Vapalahti M, Vainio P, Rinne JO. (2000) [11 C]Flumazenil binding in the medial temporal lobe in patients with temporal lobe epilepsy: correlation with hippocampal MR volumetry, T2 relaxometry, and neuropathology. Neurology 54:22522260.
  • Lencz T, Mccarthy G, Bronen RA, Scott TM, Inserni JA, Sass KJ, Novelly RA, Kim JH, Spencer DD. (1992) Quantitative magnetic resonance imaging in temporal lobe epilepsy: relationship to neuropathology and neuropsychological function. Ann Neurol 31:629637.
  • Longo BM, Mello LE. (1997) Blockade of pilocarpine- or kainate-induced mossy fiber sprouting by cycloheximide does not prevent subsequent epileptogenesis in rats. Neurosci Lett 226:163166.
  • Lurton D, El Bahh B, Sundstrom L, Rougier A. (1998) Granule cell dispersion is correlated with early epileptic events in human temporal lobe epilepsy. J Neurol Sci 154:133136.
  • Magloczky Z. (2010) Sprouting in human temporal lobe epilepsy: excitatory pathways and axons of interneurons. Epilepsy Res 89:5259.
  • Maillard L, Vignal JP, Gavaret M, Guye M, Biraben A, Mcgonigal A, Chauvel P, Bartolomei F. (2004) Semiologic and electrophysiologic correlations in temporal lobe seizure subtypes. Epilepsia 45:15901599.
  • Margerison JH, Corsellis JA. (1966) Epilepsy and the temporal lobes. A clinical, electroencephalographic and neuropathological study of the brain in epilepsy, with particular reference to the temporal lobes. Brain 89:499530.
  • Mcdonald CR, Hagler DJ Jr, Ahmadi ME, Tecoma E, Iragui V, Gharapetian L, Dale AM, Halgren E. (2008) Regional neocortical thinning in mesial temporal lobe epilepsy. Epilepsia 49:794803.
  • Meiners LC, Van Gils A, Jansen GH, De Kort G, Witkamp TD, Ramos LM, Valk J, Debets RM, Van Huffelen AC, Van Veelen CW. (1994) Temporal lobe epilepsy: the various MR appearances of histologically proven mesial temporal sclerosis. AJNR Am J Neuroradiol 15:15471555.
  • Menzler K, Iwinska-Zelder J, Shiratori K, Jaeger RK, Oertel WH, Hamer HM, Rosenow F, Knake S. (2010) Evaluation of MRI criteria (1.5 T) for the diagnosis of hippocampal sclerosis in healthy subjects. Epilepsy Res 89:349354.
  • Meroni A, Galli C, Bramerio M, Tassi L, Colombo N, Cossu M, Lo Russo G, Garbelli R, Spreafico R. (2009) Nodular heterotopia: a neuropathological study of 24 patients undergoing surgery for drug-resistant epilepsy. Epilepsia 50:116124.
  • Moran NF, Lemieux L, Kitchen ND, Fish DR, Shorvon SD. (2001) Extrahippocampal temporal lobe atrophy in temporal lobe epilepsy and mesial temporal sclerosis. Brain 124:167175.
  • Mouritze Dam A. (1982) Hippocampal neuron loss in epilepsy and after experimental seizures. Acta Neurol Scand 66:601642.
  • Murphy BL, Danzer SC. (2011) Somatic translocation: a novel mechanism of granule cell dendritic dysmorphogenesis and dispersion. J Neurosci 31:29592964.
  • Nissinen J, Lukasiuk K, Pitkanen A. (2001) Is mossy fiber sprouting present at the time of the first spontaneous seizures in rat experimental temporal lobe epilepsy? Hippocampus 11:299310.
  • O’brien TJ, Miles K, Ware R, Cook MJ, Binns DS, Hicks RJ. (2008) The cost-effective use of 18F-FDG PET in the presurgical evaluation of medically refractory focal epilepsy. J Nucl Med 49:931937.
  • Pardoe HR, Pell GS, Abbott DF, Jackson GD. (2009) Hippocampal volume assessment in temporal lobe epilepsy: how good is automated segmentation? Epilepsia 50:25862592.
  • Penfield W, Jasper H. (1954) Epilepsy and the functional anatomy of the human brain. Little, Brown, Boston.
  • Pitkanen A, Tuunanen J, Kalviainen R, Partanen K, Salmenpera T. (1998) Amygdala damage in experimental and human temporal lobe epilepsy. Epilepsy Res 32:233253.
  • Ryvlin P, Bouvard S, Le Bars D, De Lamerie G, Gregoire MC, Kahane P, Froment JC, Mauguiere F. (1998) Clinical utility of flumazenil-PET versus [18F]fluorodeoxyglucose-PET and MRI in refractory partial epilepsy. A prospective study in 100 patients. Brain 121(Pt 11):20672081.
  • Saint-Hilaire JM, Lee MA. (2000) Localizing and lateralizing value of epileptic symptoms in temporal lobe epilepsy. Can J Neurol Sci 27(Suppl. 1):S1S5; discussion S20-1.
  • Sano K, Malamud N. (1953) Clinical significance of sclerosis of the cornu ammonis: ictal psychic phenomena. AMA Arch Neurol Psychiatry 70:4053.
  • Schramm J. (2008) Temporal lobe epilepsy surgery and the quest for optimal extent of resection: a review. Epilepsia 49:12961307.
  • Schramm J, Lehmann TN, Zentner J, Mueller CA, Scorzin J, Fimmers R, Meencke HJ, Schulze-Bonhage A, Elger CE. (2011a) Randomized controlled trial of 2.5-cm versus 3.5-cm mesial temporal resection – part 2: volumetric resection extent and subgroup analyses. Acta Neurochir (Wien) 153:221228.
  • Schramm J, Lehmann TN, Zentner J, Mueller CA, Scorzin J, Fimmers R, Meencke HJ, Schulze-Bonhage A, Elger CE. (2011b) Randomized controlled trial of 2.5-cm versus 3.5-cm mesial temporal resection in temporal lobe epilepsy – part 1: intent-to-treat analysis. Acta Neurochir (Wien) 153:209219.
  • Semah F, Baulac M, Hasboun D, Frouin V, Mangin JF, Papageorgiou S, Leroy-Willig A, Philippon J, Laplane D, Samson Y. (1995) Is interictal temporal hypometabolism related to mesial temporal sclerosis? A positron emission tomography/magnetic resonance imaging confrontation. Epilepsia 36:447456.
  • Siegel AM, Jobst BC, Thadani VM, Rhodes CH, Lewis PJ, Roberts DW, Williamson PD. (2001) Medically intractable, localization-related epilepsy with normal MRI: presurgical evaluation and surgical outcome in 43 patients. Epilepsia 42:883888.
  • Simister RJ, Woermann FG, Mclean MA, Bartlett PA, Barker GJ, Duncan JS. (2002) A short-echo-time proton magnetic resonance spectroscopic imaging study of temporal lobe epilepsy. Epilepsia 43:10211031.
  • Smith AP, Sani S, Kanner AM, Stoub T, Morrin M, Palac S, Bergen DC, Balabonov A, Smith M, Whisler WW, Byrne RW. (2011) Medically intractable temporal lobe epilepsy in patients with normal MRI: surgical outcome in twenty-one consecutive patients. Seizure 20:475479.
  • So EL. (2006) Value and limitations of seizure semiology in localizing seizure onset. J Clin Neurophysiol 23:353357.
  • Somogyi P, Klausberger T. (2005) Defined types of cortical interneurone structure space and spike timing in the hippocampus. J Physiol 562:926.
  • Spencer S, Huh L. (2008) Outcomes of epilepsy surgery in adults and children. Lancet Neurol 7:525537.
  • Spencer DD, Spencer SS, Mattson RH, Williamson PD, Novelly RA. (1984) Access to the posterior medial temporal lobe structures in the surgical treatment of temporal lobe epilepsy. Neurosurgery 15:667671.
  • Symms M, Jager HR, Schmierer K, Yousry TA. (2004) A review of structural magnetic resonance neuroimaging. J Neurol Neurosurg Psychiatry 75:12351244.
  • Thom M. (2009) Hippocampal sclerosis: progress since Sommer. Brain Pathol 19:565572.
  • Thom M, Martinian L, Williams G, Stoeber K, Sisodiya SM. (2005) Cell proliferation and granule cell dispersion in human hippocampal sclerosis. J Neuropathol Exp Neurol 64:194201.
  • Thom M, Eriksson S, Martinian L, Caboclo LO, Mcevoy AW, Duncan JS, Sisodiya SM. (2009) Temporal lobe sclerosis associated with hippocampal sclerosis in temporal lobe epilepsy: neuropathological features. J Neuropathol Exp Neurol 68:928938.
  • Thom M, Liagkouras I, Elliot KJ, Martinian L, Harkness W, Mcevoy A, Caboclo LO, Sisodiya SM. (2010) Reliability of patterns of hippocampal sclerosis as predictors of postsurgical outcome. Epilepsia 51:18011808.
  • Thom M, Liu JY, Thompson P, Phadke R, Narkiewicz M, Martinian L, Marsdon D, Koepp M, Caboclo L, Catarino CB, Sisodiya SM. (2011a) Neurofibrillary tangle pathology and Braak staging in chronic epilepsy in relation to traumatic brain injury and hippocampal sclerosis: a post-mortem study. Brain 134:29692981.
  • Thom M, Toma A, An S, Martinian L, Hadjivassiliou G, Ratilal B, Dean A, Mcevoy A, Sisodiya SM, Brandner S. (2011b) One hundred and one dysembryoplastic neuroepithelial tumors: an adult epilepsy series with immunohistochemical, molecular genetic, and clinical correlations and a review of the literature. J Neuropathol Exp Neurol 70:859878.
  • Van Paesschen W, Revesz T, Duncan JS, King MD, Connelly A. (1997) Quantitative neuropathology and quantitative magnetic resonance imaging of the hippocampus in temporal lobe epilepsy. Ann Neurol 42:756766.
  • Von Oertzen J, Urbach H, Jungbluth S, Kurthen M, Reuber M, Fernandez G, Elger CE. (2002) Standard magnetic resonance imaging is inadequate for patients with refractory focal epilepsy. J Neurol Neurosurg Psychiatry 73:643647.
  • Watson C, Andermann F, Gloor P, Jones-Gotman M, Peters T, Evans A, Olivier A, Melanson D, Leroux G. (1992) Anatomic basis of amygdaloid and hippocampal volume measurement by magnetic resonance imaging. Neurology 42:17431750.
  • Wiebe S, Blume WT, Girvin JP, Eliasziw M. (2001) A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med 345:311318.
  • Wieser HG. (2004) ILAE Commission Report. Mesial temporal lobe epilepsy with hippocampal sclerosis. Epilepsia 45:695714.
  • Wieser HG, Engel J Jr, Williamson P, Babb TL, Gloor P. (1993) Surgically remediable temporal lobes syndromes. In: Engel J Jr (Ed) Surgical treatment of the epilepsies. 2nd ed. Raven Press, New York, pp. 4963.
  • Wieshmann UC, Larkin D, Varma T, Eldridge P. (2008) Predictors of outcome after temporal lobectomy for refractory temporal lobe epilepsy. Acta Neurol Scand 118:306312.
  • Williamson PD, French JA, Thadani VM, Kim JH, Novelly RA, Spencer SS, Spencer DD, Mattson RH. (1993) Characteristics of medial temporal lobe epilepsy: II. Interictal and ictal scalp electroencephalography, neuropsychological testing, neuroimaging, surgical results, and pathology. Ann Neurol 34:781787.
  • Willmann O, Wennberg R, May T, Woermann FG, Pohlmann-Eden B. (2006) The role of 1H magnetic resonance spectroscopy in pre-operative evaluation for epilepsy surgery. A meta-analysis. Epilepsy Res 71:149158.
  • Willmann O, Wennberg R, May T, Woermann FG, Pohlmann-Eden B. (2007) The contribution of 18F-FDG PET in preoperative epilepsy surgery evaluation for patients with temporal lobe epilepsy A meta-analysis. Seizure 16:509520.
  • Woermann FG, Vollmar C. (2009) Clinical MRI in children and adults with focal epilepsy: a critical review. Epilepsy Behav 15:4049.
  • Woermann FG, Barker GJ, Birnie KD, Meencke HJ, Duncan JS. (1998) Regional changes in hippocampal T2 relaxation and volume: a quantitative magnetic resonance imaging study of hippocampal sclerosis. J Neurol Neurosurg Psychiatry 65:656664.
  • Woermann FG, Mclean MA, Bartlett PA, Parker GJ, Barker GJ, Duncan JS. (1999) Short echo time single-voxel 1H magnetic resonance spectroscopy in magnetic resonance imaging-negative temporal lobe epilepsy: different biochemical profile compared with hippocampal sclerosis. Ann Neurol 45:369376.
  • Wyler AR, Hermann BP, Somes G. (1995) Extent of medial temporal resection on outcome from anterior temporal lobectomy: a randomized prospective study. Neurosurgery 37:982990; discussion 990-1.
  • Yasargil MG, Teddy PJ, Roth P. (1985) Selective amygdalo-hippocampectomy. Operative anatomy and surgical technique. Adv Tech Stand Neurosurg 12:93123.
  • Yilmazer-Hanke DM, Wolf HK, Schramm J, Elger CE, Wiestler OD, Blumcke I. (2000) Subregional pathology of the amygdala complex and entorhinal region in surgical specimens from patients with pharmacoresistant temporal lobe epilepsy. J Neuropathol Exp Neurol 59:907920.