Hippocampal Abnormalities in an MR Imaging Series of Patients with Tuberous Sclerosis

Discussion

The co-occurrence of MTS with another potentially epileptogenic extrahippocampal abnormality was observed in 15% of the patients. Cortical dysplasia was the most common association. Other extratemporal conditions have been described in the literature, including neuronal migration disorders, low-grade tumors, vascular malformations, porencephalic cysts, and gliotic lesions resulting from early-life cerebral insults.⁷ The combination with TS was only described in 1 recent report and was associated with polymicrogyria.¹² Another report also described the association of MTS with the forme fruste of TS in 2 patients.¹⁷

Abnormalities of the HF are not usually grouped with the typical structural lesions of TSC. The major lesions of this disease include cortical tubers, radial white matter bands, subependymal nodules, and subependymal giant cell astrocytomas. Other uncommon lesions have been shown, including parenchymal cysts and cortical calcifications.¹⁸ The association of TS with other cortical dysplasias (hemimegalencephaly and focal cortical dysplasia) is rare.¹⁹

The etiology of MTS remains controversial. Genetic and acquired factors are involved, but it likely results from a multifactorial process. MTS was found in association with prolonged febrile seizures, head trauma, infection, birth trauma, recurrent seizures, and suspected genetic predisposition.²⁰

In contrast, the etiology of TSC is well known. It is determined by mutations in tumor suppressor genes (TSC1 or TSC2) and results in abnormal differentiation, migration, and proliferation of germinal matrix cells.^21,22 Two-thirds of the known TSC cases were due to spontaneous mutations, and an autosomal dominant trait was found in a small group of patients.

In our study, we had 5 patients with TS with hippocampal abnormalities (16.2%), including MTS (4/31, 12.9%), and 1 patient with HIMAL (1/31, 3.3%). Moreover, we found a correlation between febrile seizures with an onset in the first year of life and MTS in patients with TS. Notably, 2 patients with MTS showed this relationship, indicating that multiple predisposing factors may cause MTS. We argue that MTS may be a secondary outcome of a multifactorial process, such as structural abnormalities of TS and recurrent epileptic activity. The occurrence of febrile seizures, particularly during the first year of life, represents an aggravating factor that could potentially damage the HF.

There are some theoretic mechanisms to explain the dual pathology identified in our study. First, the hippocampal injury may result from repeated seizures during the course of the TS syndrome. It can promote secondary damage to the hippocampus and anatomic connections within the temporal lobe. This phenomenon is called kindling.^17,23 The second possibility is related to a common pathogenetic mechanism during gestational development of the brain.²⁴ CNS alterations in patients with TS result from abnormal differentiation/proliferation of germinal matrix cells and migrational arrest of dysgenetic neurons. It is, therefore, possible that the HF abnormalities are markers of a more widespread expression of this disturbance or susceptibility. The cerebral cortex and the HF develop from the neocortex and archicortex, respectively. A disturbance occurring early in gestation could explain the involvement of structures derived from different germinal matrices. This is consistent with the presence of cortical tubers.²⁵ The association of mechanisms such as repeated stimuli in a vulnerable region may produce irreversible tissue damage, resulting in MTS. We argue that MTS is acquired and is not part of the inherited syndrome. MTS was observed in the older children in our series, and except for 1 patient (patient 17), none of our younger children presented with MTS.

It is possible that early febrile seizures damage the hippocampus and cause MTS.²⁶

It is interesting that patients with MTS presented with more cortical tubers in our study. It is possible that these patients have more epileptogenic foci, thus causing secondary damage to the hippocampus. Although higher numbers of tubers were not observed in the temporal lobes of patients with MTS, hippocampal abnormality was present in the temporal lobes of patients with more tubers, except for patient 31, who had the same number of tubers in both lobes. This indicated an increased probability of epileptogenic activity in the temporal lobe ipsilateral to the damaged hippocampus; however, this was only observed in 1 patient (patient 18) by interictal EEG. As expected for patients with TS, the cortical tubers predominated in the frontal and parietal lobes, likely because of their larger size.²⁷

Regarding the patient with HIMAL, a pathogenetic factor may be involved. Although this type of developmental abnormality is not a frequent cause of epilepsy, the demonstration of a multifocal EEG discharge could link it to a potentially epileptogenic focus.

Someone might argue that an anterior temporal cortical tuber may simulate a lesion in the hippocampus; however, the imaging pattern would be very different and the occurrence is low. The cortical tuber produces gyral expansion or distortion with subcortical signs of abnormality, while classic MTS presents with atrophy and hyperintensity on a T2-weighted image.²⁸

Autistic behavior was noted in 2 patients from our series, 1 of them with MTS. The occurrence of autism in TSC has been described in the literature and likely results from generalized epilepsy in early life and functional deficits in the temporal neocortices.²⁹ The 2 patients with autism presented with seizures before 1 year of age, which corroborates the hypothesis presented above. We did not, however, find other significant differences between these and the other patients with TS, including those with MTS. Moreover, 6 patients were identified with West syndrome. This association also occurs commonly in children with TSC and has a grave prognosis for cognitive and seizure outcomes.³⁰ None of these patients had MTS, despite the frequent seizures. This finding supports the hypothesis that epileptic activity is not solely responsible for the development of MTS.

Finally, interictal EEG was not useful for predicting the association of MTS and TS or detecting HF abnormalities in patients with TS. A relationship between the EEG focus and MTS was found in only 1 patient, and it was not possible to assess whether this abnormality was related to the hippocampal lesion or to a cortical tuber in the temporal lobe. Modern neuroimaging techniques, therefore, play an important role in this context. Interictal 2-deoxy-2 fluorine-[¹⁸F]fluorodeoxyglucose PET with MR imaging (PET/MR imaging fusion imaging) and α-¹¹C-labeled-methyl-L-tryptophan PET could identify the epileptogenic tuber, confirm the lateralization of the MTS, and predict an association between MTS and TSC, without invasive EEG or intraoperative electrocorticography.^31–34

The results of our study in a large series of patients confirm the occurrence of MTS in TSC and support previously published findings.¹² We failed to establish a clinical correlation showing seizures arising from the abnormal HF. This requires an appropriate clinical approach and needs further study. Nonetheless, we believe that use of an appropriate MR imaging protocol dedicated to the HF, including tilted coronal FLAIR and T2-weighted images of the temporal lobes in patients with TS, may help detect this abnormality. Our results also identified a minor relevance of the interictal EEG. The lack of a surgical correlation and intracranial electrocorticography limited our ability to interpret the involved mechanism of MTS development.