2017 NPB-13

This case was originally published in 2017. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

A 35-year-old woman presented to her neurologist with a 16-year history of complex partial seizures, manifesting mainly with an aura of déjà vu, epigastric sensation, and stereotyped oral automatisms. She has a history of head injury as a child with unclear details. She has been treated with antiepileptic medications that offered control for the first 13 years of her condition, at which point she started having breakthrough seizures with secondary generalization. There is no family history of epilepsy. She was able to work before her breakthrough seizures occurred, but is now being cared for by her family. Her brain MRI demonstrated increased T2 signal with volume loss in both hippocampi, more pronounced in the right than the left. The hippocampal interdigitations were not clearly visualized. No focal parenchymal loss or lesions were seen elsewhere. She underwent a right temporal lobectomy with hippocampectomy and amygdalectomy.

Tissue Site
Right hippocampal formation

The whole slide image provided is an H&E stained slide of hippocampus from hippocampectomy.

Virtual image used with permission from Dr. Matthew Schniederjan. Emory University.

The diagnosis is hippocampal sclerosis (HS) related to temporal lobe epilepsy (TLE). HS, also known as Ammon's Horn sclerosis, is defined as selective neuronal loss and gliosis of Ammon's Horn (Cornu Ammonis or CA) and sometimes extends to the subiculum in the hippocampal formation. Mesial temporal sclerosis (MTS) comprises HS with additional similar degeneration in the amygdala and/or entorhinal cortex. It is important for anatomic pathologists to be familiar with basic neuroanatomy of the hippocampus, especially in the coronal plane (Image A). The 2013 International League Against Epilepsy (ILAE) classification of HS associated with TLE distinguishes three types of HS (see table). This classification may not be applicable to fragmented or poorly oriented specimens, which is often the case in surgical specimens.

CA2 is known to be the subfield most resistant to degeneration. Of the three types of TLE-associated HS classified by ILAE, type 1 is the most classic. ILAE types 2 and 3 (“atypical”) HS have been associated with poor outcomes relative to seizures, following hippocampectomy. There is no evidence supporting the hypothesis that types 2 and 3 evolve to type 1 HS over time.

Grossly, HS is characterized by a firm, shrunken hippocampus with corresponding dilatation of the temporal horn of the lateral ventricle. An en bloc hippocampectomy specimen is slightly curved and shows a recognizable smooth and convex ependymal surface (medial wall of temporal horn). This dorsolateral surface of hippocampus provides adequate orientation for specimen sectioning in the coronal plane. The entire specimen (particularly its mid body) should be so sectioned and submitted for histologic examination. Identification of HS in incomplete and/or fragmented specimens can be very challenging. As illustrated in this case (Image B), the classic TLE-associated HS (ILAE type 1) shows loss of pyramidal neurons and gliosis in CA1 (Sommer sector) (Image C), CA4 (hilus or end folium) (Image B and Image D), and minimally, in CA3 subfield, with sparing of neurons in CA2 subfield and small granule cells in the dentate gyrus (Image B and Image D). Segmental loss of neurons is easily appreciated by stains that highlight neurons, such as Neu-N IHC (Image B, Image D and Image F), whereas reactive gliosis is demonstrated by GFAP IHC (Image E). Prominent gliosis is responsible for the firmer tissue consistency recognized grossly, hence the term “sclerosis.” Focal granule cell dispersion of the dentate gyrus (thickness >10 cells or >120 μm; Image D) is present. The subiculum (Image F), amygdala and temporal isocortex are unremarkable in this case. Studies have shown that the pattern of HS tends to stay uniform along the longitudinal axis of a single specimen, but variations in distribution and extent of subfield neuronal loss may be seen occasionally. Other microscopic abnormalities that may be associated with HS include neuronal loss with astrogliosis in adjacent medial temporal cortex and amygdala (MTS). Perivascular lymphocytic cuffing is rarely seen, and significant inflammatory infiltration in the parenchyma raises the possibilities of limbic encephalitis or inflammation resulting from recent invasive depth electrode recording. Remote microinfarcts manifest as small gliotic scars with associated macrophages between preserved areas is more consistent with vascular dementia and should not be mistaken as HS.

A seizure is a paroxysmal behavioral spell caused by an excessive disorderly discharge of cortical neurons, whereas epilepsy is a syndrome of two or more unprovoked or recurrent seizures on more than one occasion. Pediatric epilepsy affects 1 of every 100 children, and about one-third of these patients develop drug-resistant epilepsy (DRE; defined by ILAE as “failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules to achieve sustained seizure freedom”). Young patients with DRE may develop significant comorbidities, such as developmental delay, depression, anxiety, cognitive impairment, and impaired daily living. In many such patients (especially those with TLE), HS is a common underlying neuropathology amenable to surgical treatment (ie, hippocampectomy or anterior temporal lobectomy), with a long-term seizure control rate of 50% to 70%. MRI has been instrumental in detecting HS and is an essential part of epilepsy workup, particularly in selecting surgical candidates among patients with DRE. In larger series, HS has been found in up to 66% of epilepsy surgical specimens and up to 45% of all epilepsy syndromes at autopsy. In recent years, less invasive ablative procedures have been tried with reasonable success, such as image-guided radiosurgery (gamma knife), MRI-guided laser interstitial thermal therapy (LITT), radiofrequency thermocoagulation, ultrasound ablation, etc.

The etiology of HS is controversial and is likely multifactorial. It is widely accepted as an acquired condition, probably from neuronal injury caused by calcium influx from glutamatergic excitotoxicity. Prolonged febrile convulsions/seizures and status epilepticus are known to damage hippocampal neurons, but only a minority of these patients have been found to develop HS. The fact that HS (often of ILAE type 3) has been associated with other known epileptogenic conditions (eg, focal cortical dysplasia, tumors, and vascular malformations), so-called “dual pathologies,” suggests that epilepsy may cause HS. However, a genetic or a developmental predisposition for developing HS has not been ruled out.

• HS is found commonly in resected hippocampi from patients with DRE, characterized by segmental neuronal loss and gliosis primarily in CA1 and CA4 subfields.
• Adequate examination of hippocampi resected from epilepsy patients requires proper orientation of intact specimens for sectioning, and is facilitated by IHC for NeuN and GFAP.
• Epilepsy is not the only condition associated with HS; others include advanced age, neurodegenerative disorders, hypoxic-ischemic injuries, and limbic encephalitis.
• Based on the pattern of neuronal loss in various CA subfields of hippocampus, epilepsy-associated HS is classified by ILAE into three types, with CA2 as the most resistant subfield.
• The pathogenesis of HS associated with epilepsy is complex and its exact role in epileptogenesis remains unclear.
• In epilepsy patients HS can be an isolated finding, be accompanied by granule cell dispersion of dentate gyrus, or be a part of “dual pathologies” associated with focal cortical dysplasia, tumors, or vascular malformations.

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