193 Hippocampal Sclerosis: Causes and Prevention Matthew Charles Walker, FRCP, PhD1 1 Department of Clinical and Experimental Epilepsy, UCL Institute of Address for correspondence Matthew Charles Walker, FRCP, PhD, Neurology, University College London, London, United Kingdom Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, University College London, Queen Square, London WC1N Semin Neurol 2015;35:193–200. 3BG, United Kingdom (e-mail: [email protected]). Abstract Hippocampal sclerosis is the commonest cause of drug-resistant epilepsy in adults, and is associated with alterations to structures and networks beyond the hippocampus. In addition to being a cause of epilepsy, the hippocampus is vulnerable to damage from seizure activity. In particular, prolonged seizures (status epilepticus) can result in hippocampal sclerosis. The hippocampus is also vulnerable to other insults including traumatic brain injury, and inflammation. Hippocampal sclerosis can occur in associa- tion with other brain lesions; the prevailing view is that it is probably a secondary consequence. In such instances, successful surgical treatment usually involves the resection of both the lesion and the involved hippocampus. Experimental data have pointed to numerous neuroprotective strategies to prevent hippocampal sclerosis. Initial neuroprotective strategies aimed at glutamate receptors may be effective, but later, metabolic pathways, apoptosis, reactive oxygen species, and inflammation are involved, perhaps necessitating the use of interventions aimed at Keywords multiple targets. ► hippocampal sclerosis Some of the therapies that we use to treat status epilepticus may neuroprotect. ► status epileptics However, prevention of neuronal death does not necessarily prevent the later develop- ► epilepsy ment of epilepsy or cognitive deficits. Perhaps, the most important intervention is the ► neuroprotection early, aggressive treatment of seizure activity, and the prevention of prolonged seizures. The importance of the hippocampus as a cause of epilepsy However, the hippocampus has a twofold interest in was first recognized in 1825, when Bouchet and Cazauvielh epilepsy, as it also is an area of the brain that is particularly described the pathology of 18 autopsied patients in a thesis susceptible to damage by seizures (and other brain insults). that attempted to establish the relationship between epilep- This dichotomous role of hippocampal damage as the cause sy, “l’épilepsie,” and insanity, “l’aliénation mentale.”1 Later, and result of seizures stems possibly from its physiological Sommer (1880) described in detail the neuropathological role in memory formation and neuronal plasticity.5 finding of hippocampal sclerosis in the brains of patients with chronic epilepsy.2 He noted gliosis and pyramidal cell Hippocampal Sclerosis Is More than One This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. loss in predominantly the CA1 region of the hippocampus; he Condition proposed that these lesions were the cause of the epilepsy. Hippocampal sclerosis is now recognized as one of the Hippocampal sclerosis can have more than one cause, and main causes of focal epilepsy and is present in approximately often the cause is a complex interplay between genetic 10% of adults with new-onset focal epilepsy.3 Moreover, background and environmental insults (see below). However, hippocampal sclerosis often causes refractory epilepsy and hippocampal sclerosis is not even one neuropathological is the sole pathology in about a third of all surgical resections entity.6 Indeed, older systems of grading the severity of cell for epilepsy and is an associated pathology (so-called dual loss in hippocampal sclerosis7 have been superseded by a pathology) in approximately 5%.4 system that recognizes that it is not just the severity of cell Issue Theme Etiology of Epilepsy; Guest Copyright © 2015 by Thieme Medical DOI http://dx.doi.org/ Editors: Philip Smith, MD, FRCP, Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0035-1552618. FAcadMEd, and Rhys Thomas, BSc, MRCP, New York, NY 10001, USA. ISSN 0271-8235. MSc, PhD Tel: +1(212) 584-4662. 194 Hippocampal Sclerosis Walker Table 1 International League Against Epilepsy classification of hippocampal sclerosis Type 1 CA1: > 80% cell loss CA2: 30–50% cell loss CA3, 30–90% cell loss CA4 40–90% cell loss Dentate gyrus 50–60% granule cell loss Type 2 Predominant neuronal loss in CA1, affecting almost 80% of pyramidal cells. All other sectors show mild cell loss barely visible by qualitative microscopic inspection. Type 3 Predominant cell loss in CA4 (50% cell loss) and the dentate gyrus (35% cell loss), whereas CA3 (< 30%), CA2 (< 25%), and CA1 (< 20%) are only moderately affected Type 4 No hippocampal sclerosis and gliosis Source: After Blümcke I, Thom M, Aronica E, et al. International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: a Task Force report from the ILAE Commission on diagnostic methods. Epilepsia 2013;54(7):1315–1329. loss that is important, but also the pattern of that cell loss.6 resections; type 2, CA1 sclerosis, occurring in 5 to 10%; type 3, The new International League Against Epilepsy (ILAE) classi- also termed end-folium sclerosis (mainly involving CA4 and fication (►Table 1, ►Fig. 1) incorporates such concepts and dentate gyrus), occurring in 4 to 7% and gliosis without grades hippocampal sclerosis as type 1, previously termed hippocampal sclerosis, which may be seen in up to 20% of classical hippocampal sclerosis, occurring in 60 to 80% of temporal lobe resections.6 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Fig. 1 Histopathologic subtypes of hippocampal sclerosis. (A) International League Against Epilepsy (ILAE) hippocampal sclerosis type 1 shows pronounced preferential pyramidal cell loss in both CA4 and CA1 sectors. Damage to sectors CA3 and CA2 is more variable but frequently visible. (B) ILAE hippocampal sclerosis type 2 (CA1 predominant neuronal cell loss and gliosis): This is a rarer and atypical hippocampal sclerosis pattern characterized by neuronal loss primarily involving CA1 compared with other subfields where damage is often not detectable by visual inspection (C) ILAE hippocampal sclerosis type 3 (CA4 predominant neuronal cell loss and gliosis): This is characterized by restricted cell loss mostly in CA4. (D) No hippocampal sclerosis, gliosis only. All stainings represent NeuN immunohistochemistry with hematoxylin counterstaining using 4-μm-thin paraffin embedded sections. DGe/DGI, external/internal limbs of dentate gyrus; Sub, subiculum. Scale bar in A ¼ 1,000 μm (applies also to B–D). (Reprinted with permission from Blümcke I, Thom M, Aronica E, et al. International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: a task force report from the ILAE Commission on diagnostic methods. Epilepsia 2013;54(7):1315–1329.) Seminars in Neurology Vol. 35 No. 3/2015 Hippocampal Sclerosis Walker 195 The classification is important because it may relate to dence that the hippocampus is particularly vulnerable to surgical outcome–with the no hippocampal sclerosis but damage by seizures.20 Pfleger described hemorrhagic lesions gliosis and the type 2 hippocampal sclerosis having the in the mesial temporal lobe of a patient dying in status poorest outcomes (40% completely seizure free with 2- epilepticus, and concluded that neuronal necrosis was the year follow-up) compared with approximately 70% seizure result of impaired blood flow or metabolic disturbances that free with type 1 hippocampal sclerosis.8 occurred during the seizures. More recent postmortem stud- The other important question is whether the pattern of ies have also shown significant acute neuronal loss in the damage relates to the nature of the precipitating event, age at hippocampus of patients dying in convulsive status epilepti- the time of the precipitating event, and duration of epilepsy cus.21,22 DeGiorgio et al (1992) compared the hippocampi and seizure frequency. Interestingly, seizure frequency and from five patients dying in status epilepticus, five patients duration of epilepsy had minimal impact on the type of with epilepsy who had a similar degree of physiological hippocampal sclerosis. However, events before the age of compromise (e.g., hypoglycemia, hypotension and hypoxia), 3 years tended to be associated with type 1. Type 3 hippo- and five controls. The neuronal densities were least in those campal sclerosis and no hippocampal sclerosis were less dying with status epilepticus.21 Interestingly, a later unse- strongly associated with the occurrence of identifiable pre- lected postmortem series identified that there are patients ceding events, which tended to happen later, during who have had a long history of seizures and even episodes of adolescence.6 status epilepticus with no evidence of damage in the hippo- From a clinical perspective, it would be ideal to identify the campus, suggesting that status epilepticus alone may not be pattern of cell loss before resection. Although magnetic sufficient to cause neuronal damage.23 resonance imaging (MRI) studies can reliably determine the From the other perspective, a significant cerebral insult severity of hippocampal sclerosis (confirmed by histopathol- (or initial precipitating injury) occurring early in life, such as ogy),9 automated programs with conventional clinical MRI a febrile or prolonged seizure, is often reported (between