[1] Neuroimaging tests such as magnetic resonance imaging (MRI) and positron emission tomography (PET) may identify individuals with hippocampal sclerosis.

[2] Hippocampal sclerosis occurs in 3 distinct settings: mesial temporal lobe epilepsy, adult neurodegenerative disease and acute brain injury.

[2][3]: 1503 In 1825, Bouchet and Cazauvieilh described palpable firmness and atrophy of the uncus and medial temporal lobe of brains from epileptic and non-epileptic individuals.

[6][3]: 1505  In 2006, researchers determined that amyotrophic lateral sclerosis and frontotemporal lobar degeneration are often TAR DNA-binding protein 43 (TDP-43) proteinopathies.

[7] In 1994, Dickson et al. described hippocampal sclerosis occurring in elderly demented individuals > 80 years old with disproportionately greater impaired memory.

HS ILAE type 3 is generally observed in cases of dual pathology, such as focal cortical dysplasia or brain tumors.

[3] The hippocampal neuronal cell loss and gliosis are disproportionate to the Alzheimer's disease "neuropathological change in the same section.

[3]: 1508  TDP-43 immunochemistry does not identify TDP-43 proteinopathy if hippocampal sclerosis arises from hypoxia or mesial temporal lobe epilepsy.

[13]: 9 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.

[2] This region of decreased glucose metabolism may extend beyond the hippocampus and involve the medial and lateral temporal lobe.

[14] The 18F-FDG PET scans of those with LATE show reduced glucose metabolism in the medial temporal lobe including the hippocampus.

[18] Electroencephalographic and surgical studies show that temporal lobe seizures arise from hippocampal regions with severe neuronal cell loss.

[19]: 9  Surgical removal of the hippocampus that spares neighboring structures leads to improved seizure control in many instances of mesial temporal lobe epilepsy.

[24][7] Hippocampal sclerosis occurs in about 60% of those with progressive supranuclear palsy TDP-43 proteinopathy (PSP-TDP) and in about 5% of those with Lewy body dementia.