What Is Hippocampal Sclerosis? Signs & Treatment

Hippocampal sclerosis is a condition in which neurons in the hippocampus, a seahorse-shaped brain structure critical for memory, are lost and replaced by scar tissue. It is the most common pathological finding in people who undergo surgery for drug-resistant temporal lobe epilepsy, but it also appears in a separate context: as a feature of neurodegeneration in older adults whose primary symptom is dementia rather than seizures. The condition has been recognized for nearly two centuries, though it was only in the early 1990s that MRI became capable of detecting it in living patients.¹ Understanding what hippocampal sclerosis looks like, how it is diagnosed, and what treatments exist depends heavily on which of these two clinical settings you are dealing with.

What Happens Inside the Hippocampus

The hippocampus is divided into several subregions, labeled CA1 through CA4 (cornu ammonis, after its horn-like shape). In hippocampal sclerosis, specific populations of neurons in these subregions die off and are replaced by dense networks of glial cells, a process called gliosis. Which subregions are hit hardest varies, and the International League Against Epilepsy recognizes three subtypes based on the pattern of damage. Type 1 involves severe neuronal loss in both the CA1 and CA4 regions and is the most common form. Type 2 involves loss mainly in CA1, while Type 3 centers on CA4.² Some surgical specimens show no actual neuronal loss at all, just reactive gliosis, a pattern classified as “no-HS.” The subtype matters because it can influence cognitive profiles and, to some degree, how well a patient responds to surgery.

In children, the distribution of subtypes looks somewhat different from adults. One pediatric surgical series found Type 1 in about 54% of cases and Type 3 in 30%, a higher share of Type 3 than is typical in adult cohorts. Children under 12 were more likely to have Type 3 or no-HS, while a history of febrile seizures was more strongly linked to Type 1.³ This suggests that the underlying cause of the sclerosis shapes which hippocampal subregions are most vulnerable.

Causes and Risk Factors

The relationship between hippocampal sclerosis and epilepsy runs in both directions, and disentangling cause from consequence has occupied researchers for decades. A major suspected trigger is prolonged febrile seizures in childhood. The FEBSTAT study, a large prospective investigation tracking children after febrile status epilepticus, found evidence of acute injury to the hippocampus in the form of swelling and abnormal diffusion signals, concentrated in the CA1 region, the area known to be most vulnerable to seizure-related damage.⁴ This kind of acute cytotoxic edema may, over months or years, progress to the chronic scarring that defines hippocampal sclerosis. Animal research has shown that febrile seizures trigger rapid changes in the brain’s excitatory signaling system, which may serve as a compensatory brake against further neuronal death, though the protection is not always complete.⁵

Not everyone with hippocampal sclerosis has a history of childhood febrile seizures, of course. Other recognized precipitants include traumatic brain injury, central nervous system infections like encephalitis, and status epilepticus from any cause. Some patients have no identifiable initial insult at all, and in those cases a genetic predisposition likely plays a role.

The Genetics of Hippocampal Sclerosis in Aging

In older adults, hippocampal sclerosis often occurs alongside a protein abnormality called TDP-43 proteinopathy, a condition now formally named limbic-predominant age-related TDP-43 encephalopathy, or LATE.⁶ Genome-wide association studies have identified several genes linked to both hippocampal sclerosis and TDP-43 pathology in older people. The strongest signals come from APOE (the same gene famously associated with Alzheimer’s risk), TMEM106B, and GRN (the gene encoding progranulin). When researchers adjusted for TDP-43 pathology, the association between these genes and hippocampal sclerosis weakened, suggesting that the genetic risk may primarily drive the TDP-43 abnormality, which in turn leads to hippocampal damage.⁷⁸

The TMEM106B risk allele appears to exert its effect partly through disrupted lipid metabolism. Carriers of this allele show age-dependent increases in the TMEM106B protein in the hippocampus, along with lower levels of myelin-enriched lipids and higher levels of polyunsaturated phospholipids, changes that could destabilize nerve cell insulation over time.⁹ This genetic picture underscores that hippocampal sclerosis in the elderly is a distinct biological entity from the epilepsy-associated form, even though the end result under the microscope looks superficially similar.

Signs and Symptoms

What hippocampal sclerosis feels like to a patient depends on whether it presents as epilepsy or as cognitive decline. In the epilepsy setting, it is the hallmark of mesial temporal lobe epilepsy, the most common form of focal epilepsy in adults. Seizures typically begin with an aura, a brief subjective warning. One of the most characteristic auras is an abdominal sensation, often described as a rising feeling from the stomach toward the chest. In one study of over 200 patients with mesial temporal sclerosis, about 36% reported abdominal auras, and among those, about two-thirds described the rising sensation.¹⁰ Other aura types include déjà vu, fear, and an indescribable strange feeling. The aura may progress to loss of awareness, automatic behaviors like lip-smacking or hand-picking, and occasionally to a full tonic-clonic seizure.

Memory problems are the other cardinal feature. The left hippocampus is strongly tied to verbal memory, the ability to remember words, conversations, and stories, while the right hippocampus is more involved in spatial memory, such as remembering routes or locations.¹¹ Sclerosis on the left side therefore tends to impair word recall and narrative memory, while right-sided sclerosis is more likely to affect visual and spatial working memory. A recent study found that patients with right temporal lobe epilepsy and hippocampal sclerosis showed deficits in both the speed and accuracy of visual working memory, along with broader cognitive decline on screening tests.¹²

Psychiatric Burden

Depression is strikingly common. A meta-analysis found that temporal lobe epilepsy patients with hippocampal sclerosis are roughly twice as likely to develop depression as those without sclerosis.¹³ In one clinical cohort, 44% of patients had a history of major depression. Interestingly, the depression did not correlate with the degree of hippocampal shrinkage itself but rather with changes in the amygdala, the brain region that processes emotion. Patients with depression showed a relative preservation of the amygdala on the opposite side from their sclerosis, hinting at complex network-level disruptions rather than simple tissue loss.¹⁴

How It Is Diagnosed

MRI is the primary diagnostic tool. The two classic findings on MRI are a shrunken hippocampus (atrophy) and an abnormally bright signal on T2-weighted sequences, reflecting the water content of gliotic scar tissue. Hippocampal atrophy is visible in the vast majority of surgical cases, found in 96% in one study, while the high T2 signal shows up in a smaller proportion, roughly 60-70%, and tends to accompany more severe atrophy.¹⁵¹⁶ When MRI looks normal, the prognosis for surgery is worse: in one series, the only two patients with a “normal” hippocampus on MRI both had poor surgical outcomes.

PET scanning with a glucose tracer adds complementary information. In patients with hippocampal sclerosis, the affected temporal lobe shows reduced glucose metabolism between seizures. But the hypometabolism often extends well beyond the hippocampus. One study found that brain glucose metabolism in affected patients was reduced by 10-25% across the cortex compared with healthy controls, and the frontal lobes were actually hit harder than the temporal lobes.¹⁷ When this hypometabolism is widespread rather than localized, it correlates with more extensive microstructural brain changes on diffusion imaging.¹⁸

EEG, the recording of brain electrical activity, provides another diagnostic layer. During a seizure, specific patterns over the temporal region can help distinguish purely hippocampal epilepsy from cases where additional brain areas are involved. An initial delta wave followed by a delayed theta/alpha pattern had perfect specificity for identifying patients whose epilepsy originated solely from the hippocampus, though its sensitivity was lower.¹⁹ Newer techniques using high-density EEG to detect fast scalp oscillations during interictal spikes may help predict who will remain seizure-free after surgery. Patients who went on to have seizure recurrence showed higher-frequency oscillations across temporal and extratemporal areas, and a specific fast-oscillation pattern independently predicted recurrence with high sensitivity.²⁰

Why Medications Often Fall Short

Hippocampal sclerosis carries a reputation for drug resistance, and the data back this up. In one retrospective study of patients with mesial temporal lobe epilepsy and hippocampal sclerosis, only about 25% had achieved seizure freedom for more than one year on medications, including newer-generation drugs.²¹ That means roughly three out of four patients continued to have seizures despite multiple medication trials. This high rate of pharmacoresistance is one of the main reasons epilepsy surgery is considered early in the treatment of this condition rather than as a last resort. If two or three well-chosen medications have failed to control seizures, the likelihood of a fourth succeeding is low, and the cumulative toll of ongoing seizures on memory, mood, and daily function grows with each year.

Surgical Treatment Options

Surgery is the most effective treatment for drug-resistant epilepsy caused by hippocampal sclerosis. A comparison of surgical versus medical management found that seizure freedom rates at three years were about 82% in the surgery group versus 19% in those managed with medications alone, a gap that persisted at five and ten years.²² About 31% of surgical patients eventually met criteria for resolution of epilepsy, compared to less than 1% of those treated medically. Surgery also improves quality of life: operated patients scored higher on overall quality-of-life measures than those managed without surgery.²³

Open Surgery

The traditional approach is anterior temporal lobectomy, which removes the front portion of the temporal lobe along with the hippocampus and amygdala. A more targeted alternative is selective amygdalohippocampectomy, which spares the temporal neocortex and removes only the mesial structures. A meta-analysis comparing the two found that selective amygdalohippocampectomy actually had higher odds of achieving seizure freedom than the more extensive lobectomy.²⁴ This is somewhat counterintuitive, since removing more tissue might seem like it would catch more seizure-generating areas, but it suggests that in well-selected patients the seizure focus truly resides in the mesial structures, and removing extra cortex does not add benefit while potentially increasing the risk of cognitive side effects.

Laser Ablation

A less invasive option is laser interstitial thermal therapy (LITT), in which a thin laser fiber is threaded through a small skull opening and guided by MRI to heat and destroy the hippocampus and amygdala from within. In a series of 43 consecutive patients, about 68% were seizure-free at a median follow-up of roughly 20 months, and cognitive declines were modest, primarily affecting memory processes.²⁵ A larger series using a fully MRI-compatible laser platform reported that among 66 patients with mesial temporal sclerosis, 56% achieved the best seizure outcome category at 12 months.²⁶ These numbers are somewhat lower than those reported for open surgery, but the trade-off is a shorter hospital stay, a smaller incision, and less disruption to surrounding brain tissue.

Deep Brain Stimulation

Not everyone is a candidate for removing or ablating the hippocampus. The most common reason to avoid resection is when the sclerosis sits in the language-dominant hemisphere and the risk of serious memory loss is considered too high. For these patients, deep brain stimulation offers an alternative. Continuous electrical stimulation delivered to the hippocampus through implanted electrodes has been shown to reduce both focal and generalized seizures in refractory temporal lobe epilepsy.²⁷ Researchers have also explored stimulating the subiculum, a small relay region at the output end of the hippocampus. In one case of a woman with left hippocampal sclerosis who refused resective surgery over memory concerns, subiculum stimulation reduced seizure frequency by about 67% over 20 months.²⁸ A two-year follow-up study of subiculum stimulation in a small cohort found roughly 50% reduction in total seizures and a 68% reduction in the most severe seizure type, with better results emerging at longer follow-up times.²⁹

Memory After Surgery

The fear of losing memory after temporal lobe surgery is one of the biggest concerns patients raise. The risk is real but not universal. Verbal memory decline occurs in roughly a third of patients who undergo dominant-hemisphere surgery.³⁰ The strongest predictors of decline are good preoperative memory performance and a later age at the onset of epilepsy. In other words, people whose hippocampus was still doing a lot of memory work before surgery have more to lose. Functional MRI is increasingly used before surgery to measure how much the hippocampus on the affected side is still contributing to memory. Greater activity in the hippocampus slated for removal predicts a greater postoperative drop in verbal memory.³¹ This pre-surgical testing helps clinicians counsel patients about their individual risk and can influence the choice between open resection, laser ablation, or neuromodulation.

Aura type may also carry prognostic information. Patients with the classic abdominal aura had a seizure-freedom rate of about 65% after surgery, compared with about 43% for patients with other aura types.³² The abdominal aura may signal a more purely mesial temporal focus, which is exactly the tissue being targeted by surgery.

Dual Pathology

Hippocampal sclerosis does not always occur in isolation. In roughly 5-30% of temporal lobe epilepsy resections, the hippocampal sclerosis coexists with a second lesion.³³ These dual-pathology cases can involve focal cortical dysplasia, vascular malformations, low-grade tumors, or even old strokes in the neighboring temporal cortex.³⁴ In children, the most common dual pathology combination involves Type 3 hippocampal sclerosis alongside a low-grade brain tumor.³ Recognizing dual pathology before surgery is important because both the hippocampus and the additional lesion may need to be addressed to achieve seizure freedom.

Hippocampal Sclerosis in Older Adults Without Epilepsy

When hippocampal sclerosis occurs in older people, it typically presents not as seizures but as progressive memory loss that closely resembles Alzheimer’s disease. This entity, sometimes called hippocampal sclerosis of aging, is common in autopsy studies of elderly brains and has a clinical course similar enough to Alzheimer’s that the two are frequently confused during life.³⁵

Yet the two conditions are not identical. When researchers have compared the behavioral profiles, hippocampal sclerosis dementia more closely resembles frontotemporal dementia than Alzheimer’s disease. Behavioral changes like decreased grooming and socially inappropriate behavior show up earlier and more frequently, while the hallmark Alzheimer’s symptoms of disorientation, difficulty with calculations, and problems recognizing objects are less prominent.³⁶ The trajectory of decline also differs: hippocampal sclerosis dementia tends to progress more slowly across most cognitive domains, though by the final stages there is substantial overlap in test scores that makes the two nearly impossible to tell apart on cognitive testing alone.³⁷

Unlike the epilepsy-related form, hippocampal sclerosis of aging involves more severe neuronal and synaptic loss and more intense gliosis, and it occurs at older ages on average.³⁸ As noted earlier, genetic risk from the TMEM106B and GRN genes appears to operate largely through TDP-43 proteinopathy, making the aging form a fundamentally different disease process that happens to damage the same structure. There is currently no targeted treatment for hippocampal sclerosis of aging. Management follows the approach used for other neurodegenerative dementias: cognitive support, behavioral strategies, and management of co-occurring conditions.

When Multiple Treatments Interact

For patients with epilepsy-related hippocampal sclerosis who are not yet surgical candidates, or who choose to defer surgery, medication management continues to be refined. It is worth noting that polytherapy, the use of multiple antiepileptic drugs simultaneously, carries its own trade-offs. One study found that polytherapy had a negative effect on cognitive function but a somewhat positive effect on anxiety and depression levels, suggesting that the right combination of drugs may help mood even as it complicates thinking speed and memory.²³ Given the high rates of depression in this population, the psychiatric dimension of drug choice matters. For patients with active depression, choosing antiepileptic drugs that have mood-stabilizing properties or at least do not worsen mood is a practical consideration that should be part of the conversation with a neurologist.