Hippocampal sclerosis (HS) or mesial temporal sclerosis (MTS) is a neuropathological condition with severe neuronal cell loss and gliosis in the hippocampus. Neuroimaging tests such as magnetic resonance imaging (MRI) and positron emission tomography (PET) may identify individuals with hippocampal sclerosis. Hippocampal sclerosis occurs in three distinct settings: mesial temporal lobe epilepsy, adult neurodegenerative disease and acute brain injury.
History In 1825, Camille Bouchet and Jean-Baptiste Cazauvieilh described palpable firmness and atrophy of the uncus and medial temporal lobe of brains from epileptic and non-epileptic individuals. In 1880, Wilhelm Sommer investigated 90 brains and described the classical Ammon's horn sclerosis pattern, severe neuronal cell loss in hippocampal subfield cornum Ammonis 1 (CA1) and some neuronal cell loss in hippocampal subfield CA4. a finding later confirmed by Emil Bratz. In 1927, Walther Spielmeyer described cell loss of all hippocampal subfields, the total Ammon's horn sclerosis pattern, and in 1966, James H. Margerison and John Arthur Nicholas Corsellis described cell loss primarily involving the CA4 subfield, the end folium sclerosis pattern. In 1935. Karl Heinz Stauder linked mesial temporal lobe seizures to hippocampal sclerosis. Hippocampal sclerosis was later found to occur in older adults with neurodegenerative diseases such as frontotemporal lobar degeneration and amyotrophic lateral sclerosis. In 2006, researchers determined that amyotrophic lateral sclerosis and frontotemporal lobar degeneration are often TAR DNA-binding protein 43 (TDP-43) proteinopathies. In 2009, researchers recognized that about 10-20% of individuals with frontotemporal lobar degeneration not caused by tau proteinopathy occurred because of a RNA-binding protein FUS (FUS) proteinopathy; hippocampal sclerosis often accompanied the FUS proteinopathy. In 1994, Dickson et al. described hippocampal sclerosis occurring in elderly demented individuals > 80 years old with disproportionately greater impaired memory. In 2007, researchers determined that this neurodegenerative disease, Limbic-predominant age-related TDP-43 encephalopathy (LATE), is a TDP-43 proteinopathy.
Pathology
Mesial temporal lobe epilepsy The typical brain sample is a surgical specimen, a brain sample obtained during epilepsy surgery. The International League Against Epilepsy (ILAE) defines three hippocampal sclerosis (HS) types: predominant neuronal cell loss in subfields CA1 and CA4 (HS ILAE type 1); subfield CA1 (HS ILAE type 2); subfield CA4 (HS ILAE type 3). The classic and total Ammon's horn sclerosis pattern correspond to HS ILAE type 1. Among brain samples with hippocampal sclerosis, HS ILAE type 1 is the most prevalent, HS ILAE type 2 has a 5-10% prevalence, and HS ILAE type 3 has a 4-7.4% prevalence. HS ILAE type 3 is generally observed in cases of dual pathology, such as focal cortical dysplasia or brain tumors. Mossy fiber sprouting is common. Dentate gyrus granule cell dispersion refers to a granule cell layer that is widened, poorly demarcated, or accompanied by granule cells outside the layer (ectopic granule cells). Although this pattern was thought to be linked to hippocampal sclerosis, a comparative study has shown this association is not correct as the same pattern occurs in brains without hippocampal sclerosis. A dual pathology is a temporal lobe abnormality that accompanying hippocampal sclerosis. This occurs in about 15% of those with hippocampal sclerosis who completed epilepsy surgery. The dual pathologies include cavernous hemangioma, heterotopia, cortical dysplasia, arteriovenous malformation, dysembryoplastic neuroepithelial tumor, cerebral infarction and cerebral contusion. The common association is dual pathology with HS ILAE type 3.
Adult neurodegenerative disease The typical brain sample is an autopsy specimen, a brain sample obtained during an autopsy. For elderly adults with suspected LATE, TDP-43 immunochemistry will determine if TDP-43 proteinopathy caused hippocampal sclerosis. Pyramidal cell loss and gliosis occurs in the CA1 sector, subiculum, entorhinal cortex, and the amygdala. The hippocampal neuronal cell loss and gliosis are disproportionate to the Alzheimer's disease "neuropathological change in the same section." One sided hippocampal sclerosis has a 40-50% prevalence even when the TDP-43 inclusions involve both sides of the brain. TDP-43 immunochemistry does not identify TDP-43 proteinopathy if hippocampal sclerosis arises from hypoxia or mesial temporal lobe epilepsy. Mossy fiber sprouting is uncommon. The LATE consensus working group report proposed a LATE staging system based on the anatomic location of TPD-43 proteinopathy: amygdala alone (stage1), amygdala and hippocampus (stage 2), and amygdala, hippocampus, and middle frontal gyrus (stage 3); hippocampal sclerosis is not sufficient or necessary for staging. Immunochemistry may identify RNA-binding protein FUS, phosphorylated tau protein or ubiquitin if frontotemporal lobar degeneration is not caused by TGP-43 proteinopathy.
Neuroimaging
Mesial temporal lobe epilepsy On an MRI T2-weighted or T2–fluid‐attenuated inversion recovery (FLAIR) scan, hippocampal sclerosis appears as an increased signal, smaller sized (atrophic) hippocampus with a less well-defined internal structure. Increased signal means that hippocampal sclerosis will appear brighter on the MRI image. Less well-defined internal structure means the expected sharp boundaries between hippocampal gray and white matter structures are absent. The total volume of the hippocampus is also reduced. The reduced volume arises from neuronal cell loss, and increased signal arises from gliosis. The 18F-fluorodeoxyglucose PET (18F-FDG) scan may show decreased glucose metabolism in the temporal lobe with hippocampal atrophy. This region of decreased glucose metabolism may extend beyond the hippocampus and involve the medial and lateral temporal lobe.
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