Hippocampal Sclerosis in Younger Adults: Temporal Lobe Epilepsy (TLE)
In younger and middle-aged adults, hippocampal sclerosis (HS) is most commonly associated with mesial temporal lobe epilepsy (MTLE), often presenting with medically refractory seizures. This form of HS typically follows an "initial precipitating insult" (IPI), which most often occurs during early childhood. Potential causes include:
- Prolonged febrile seizures
- Traumatic brain injuries
- Central nervous system infections
After the initial insult, there is often a long "silent period" without seizures before the onset of chronic, medication-resistant epilepsy. Seizure symptoms typically involve focal seizures with impaired awareness, including auras, and oral automatisms. While MRI often shows characteristic hippocampal atrophy and signal changes, surgery to remove the affected area is often an effective treatment option for drug-resistant cases. Research indicates that younger patients undergoing surgery for TLE with HS tend to have better seizure-free outcomes compared to older patients.
Hippocampal Sclerosis in Older Adults: Hippocampal Sclerosis of Aging (HS-A)
For the "oldest-old," typically those over 85, hippocampal sclerosis presents as a distinct neurodegenerative disease, known as hippocampal sclerosis of aging (HS-A). Unlike the epilepsy-related form, HS-A is not typically associated with seizures. Instead, it manifests as a progressive dementia that can mimic Alzheimer's disease (AD), making clinical diagnosis challenging. Key characteristics of HS-A include:
Strong link to TDP-43 proteinopathy
A hallmark of HS-A is the presence of abnormal accumulations of the protein TDP-43. Studies have consistently found that a high percentage of elderly individuals with HS-A at autopsy also have extensive TDP-43 pathology in the hippocampus and surrounding brain regions. In fact, TDP-43 pathology is believed to be mechanistically upstream of the neuronal loss and gliosis seen in HS-A.
Comorbidities and diagnostic challenges
While HS-A can occur as a standalone pathology, it often coexists with other age-related brain diseases, such as AD neuropathologic change (ADNC) and vascular pathologies. The presence of mixed pathologies further complicates diagnosis. HS-A, with its associated TDP-43 pathology, appears to accelerate cognitive decline and brain atrophy beyond what is seen with ADNC alone. Imaging findings in HS-A can reveal disproportionate hippocampal atrophy relative to the level of cognitive impairment when compared to AD.
Clinical Presentation Differences
Patients with HS-A often present with a prominent amnestic (memory-based) cognitive impairment, similar to AD. However, careful neuropsychological testing might reveal differences. For instance, HS-A patients may have significantly impaired verbal recall but relatively preserved performance on tasks requiring other cognitive domains, in contrast to AD patients who show a broader pattern of cognitive deficits.
Comparison: Hippocampal Sclerosis by Age
| Feature | Younger Adults (TLE-related HS) | Older Adults (HS-A) |
|---|---|---|
| Typical Age | Childhood onset, seizures emerge later (adolescence, young adulthood) | Most prevalent in the "oldest-old" (≥ 85 years) |
| Primary Symptom | Medically refractory seizures, usually focal | Dementia, often misdiagnosed as Alzheimer's disease |
| Common Cause | Childhood brain insult (e.g., prolonged febrile seizure, trauma) | Neurodegenerative process linked to TDP-43 proteinopathy |
| Hippocampal Pathology | Neuronal loss and gliosis in specific regions, often bilateral | Severe neuronal loss and gliosis in CA1 and subiculum, frequently unilateral |
| TDP-43 Pathology | Typically absent | Highly prevalent, found in up to 90% of cases |
| Primary Treatment | Antiepileptic drugs (AEDs), followed by surgical resection if refractory | No specific treatment; medications used for AD symptoms often tried |
| Prognosis | Often good post-surgical outcome for seizure control | Prognosis is a progressive cognitive decline |
The Role of TDP-43 in Age-Related Hippocampal Sclerosis
The discovery of TDP-43 proteinopathy's strong association with HS-A was a major step forward in understanding the disease in the elderly. While TDP-43 accumulation is not exclusive to HS-A and can be found in other conditions like frontotemporal lobar degeneration (FTLD), its widespread presence in HS-A suggests it plays a critical role in the underlying pathophysiology. Research indicates that TDP-43 pathology in older adults is associated with accelerated rates of brain atrophy and a more aggressive cognitive decline. This discovery highlights that HS-A is a distinct neurodegenerative disease, not simply an outcome of AD or ischemic injury. Future research is focused on developing in-vivo biomarkers to aid in the diagnosis of TDP-43 related pathologies, which will be crucial for developing targeted therapies.
For more detailed information on TDP-43 and its role in neurodegeneration, the National Institute of Neurological Disorders and Stroke provides an excellent overview.
Conclusion
The link between age and hippocampal sclerosis is not a uniform relationship but one that bifurcates into two distinct disease entities: TLE-related HS in the young and HS-A in the elderly. In younger individuals, HS is an acquired condition often stemming from an early-life brain injury that leads to drug-resistant epilepsy. In contrast, older adults, particularly those over 85, are at risk for HS-A, a neurodegenerative disorder marked by TDP-43 proteinopathy and an amnestic dementia syndrome. The differing pathologies and clinical presentations underline the importance of considering a patient's age when diagnosing hippocampal sclerosis, which has implications for treatment strategies and predicting outcomes. Improved understanding of these age-specific manifestations is vital for advancing diagnostic tools and developing targeted therapies for both patient groups.
Potential Risk Factors Associated with Age-Related Hippocampal Sclerosis
- Genetics: Genetic risk factors have been identified, including common gene variants that appear to increase vulnerability to neurodegeneration outside the hippocampus.
- Autoimmune conditions: In some cohorts of the oldest-old, autoimmune diseases like rheumatoid arthritis and thyroid disease were found to be potential risk factors.
- Vascular disease: Brain arteriolosclerosis is a common comorbidity found with HS-A, indicating a possible pathogenic link, although the relationship is complex.
- Age itself: The risk of HS-A pathology increases dramatically after the age of 90, suggesting advanced age is a primary risk factor.
