The Malrotated Hippocampal Formation: How Often Must We Judge Function by Shape?

Commentary

Hippocampal Malrotation Is an Anatomic Variant and Has No Clinical Significance in MRI-Negative Temporal Lobe Epilepsy.

Tsai M-H, Vaughan DN, Perchyonok Y, Fitt GJ, Scheffer IE, Berkovic SF, Jackson GD. Epilepsia 2016;5710:1719–1728.

OBJECTIVE: There is considerable difficulty in diagnosing hippocampal malrotation (HIMAL), with different criteria of variable reliability. Here we assess qualitative and quantitative criteria in HIMAL diagnosis and explore the role of HIMAL in magnetic resonance imaging (MRI)–negative temporal lobe epilepsy (TLE). METHODS: We studied the MRI of 155 adult patients with MRI-negative TLE and 103 healthy volunteers, and we asked (1) what are the qualitative and quantitative features that allow a reliable diagnosis of HIMAL, (2) how common is HIMAL in a normal control population, and (3) is HIMAL congruent with the epileptogenic side in MRI-negative TLE. RESULTS: We found that the features that are most correlated with the expert diagnosis of HIMAL are hippocampal shape change with hippocampal diameter ratio > 0.8, lack of normal lateral convex margin, and a deep dominant inferior temporal sulcus (DITS) with DITS height ratio > 0.6. In a blinded analysis, a consensus diagnosis of unilateral or bilateral HIMAL was made in 25 of 103 controls (24.3% of people, 14.6% of hippocampi—14 left, six right, 10 bilateral) that did not differ from 155 lesion-negative TLE patients where 25 had HIMAL (16.1% of patients, 11.6% of hippocampi—12 left, two right, 11 bilateral). Of the 12 with left HIMAL only, 9 had seizures arising from the left temporal lobe, whereas 3 had right-sided seizures. Of the two with right HIMAL only, both had seizures arising from the left temporal lobe. SIGNIFICANCE: HIMAL is an anatomic variant commonly found in controls. HIMAL is also an incidental nonpathologic finding in adult MRI-negative TLE and should not influence surgical decision making.

Attempting to visualize normal hippocampal development to better understand function dates back to the early 20th century when the Golgi staining technique was pioneered by Cajal, and later his protégé Lorente de Nó. Tsai and coauthors explored the relationship of incomplete infolding or malrotation of the mesial temporal structures in adult patients with MRI-negative temporal lobe epilepsy compared with healthy control volunteers. The patient cohort included both intractable and medication-responsive temporal lobe epilepsy. The goal of this work was to understand whether such incomplete mesial temporal infolding increased the likelihood of an epileptogenic hippocampal network, or simply identified a normal developmental variant of the hippocampal formation. Such an objective is crucial for surgical decision making, particularly when considering MRI-negative intractable temporal lobe epilepsy.

The anatomy of the so-called malrotated human hippocampal formation resembles that of early fetal development seen at 14 to 20 weeks gestation. Hippocampal inversion may not be complete until up to 25 weeks gestation (1). In normal hippocampal development, the hippocampal formation inverts within the medial temporal lobe. That is, the disproportionately slower maturation of this region (also known as the allocortex), compared with that of the neocortex, results in medial displacement and internal inversion of the hippocampal formation into the medial temporal horn. Such a finding is seen on MRI as incomplete rotation of the hippocampus (2). The malrotated hippocampal formation predominantly has been reported in the literature as normal in size and signal intensity on MRI. However, such a hippocampus is characterized as atypically rounded in appearance with verticalization of the dominant inferior temporal sulcus. This deep verticalized sulcus, as seen on MRI, demonstrates significant individual variation. For example, the expected location of the collateral sulcus may be displaced by the typically more lateral occipitotemporal sulcus. The corpus callosum and the temporal lobe itself have been reported to appear normal in size, although the temporal horn may be enlarged. Therefore, hippocampal malrotation technically extends beyond the medial hippocampal structures.

Published reports attempting to relate such malrotation with ipsilateral intractable temporal lobe epilepsy have explored the possibility that such neuroanatomy is not only abnormal but predisposes to hippocampal epileptogenesis (3, 4). One example supporting this hypothesis has been described in children with 22q11.2 deletion syndrome associated with a marked increased risk of seizures (5). However, the relatively small sample size in this published study included other assorted structural abnormalities. Moreover, not all adult patients studied were diagnosed with epilepsy. To date, no clear connection has been identified between hippocampal malrotation and epilepsy. Of course, such a relationship, if considered pathological, is particularly of diagnostic value in otherwise MRI-negative, intractable temporal lobe epilepsy.

Unlike pathologically validated mesial temporal sclerosis associated with hippocampal atrophy and T2/FLAIR signal changes on MRI, hippocampal malrotation has no such validated pathological correlates. Atypical hippocampal rotation can be seen in 9 to 24% of healthy individuals on MRI (6–8). Furthermore, such findings on MRI are often discordant with complementary diagnostic findings. Furthermore, multimodality data, including scalp EEG recording and ictal SPECT, have captured only contralateral hemispheric signatures of the ictal onset in these patients. Although not definitive, such discordant information provides weight to the hypothesis that hippocampal malrotation is less likely a clinicopathological entity.

Hippocampal volumetric measurements were not reported by Tsai and colleagues in the present study. Previous work by Tsai and colleagues (9), however, found no changes in hippocampal volumes or signal intensity on MRI in the affected hippocampus compared with the nonmalrotated side. Obtaining volumetric measurements of malrotated medial hippocampal structures is often challenging, and usually not reliable when performing automated volumetry. Both decreased and normal volumes of malrotated hippocampi have been reported in the literature. For example, decreased hippocampal volumes were found in the malrotated hippocampal formation when compared interhemispherically in the multicenter Consequences of Prolonged Febrile Seizures in Childhood (FEBSTAT) study (8). This study found such an anatomic relationship in children with prolonged complex febrile status epilepticus compared with control subjects experiencing simple febrile seizures. These findings suggest that the presence of hippocampal malrotation in the large pediatric FEBSTAT cohort may be either a risk-factor, epiphenomenon, or “bystander” marker of another process associated with prolonged febrile seizures. The FEBSTAT study did not follow their subjects long term. Tsai and colleagues may have facilitated a better understanding of this relationship if they provided a febrile seizure history during childhood for their adult subject cohort.

A left-sided predominant hippocampal malrotation was also evident in most of the subjects included in the Tsai et al. cohort. Even when present bilaterally, a left-sided predominance was often seen. Such a finding, although of unclear clinical significance, is consistent with the previously published literature. One hypothesis states that the right hippocampus develops at a faster pace (10), and that if hippocampal inversion is halted, even bilaterally, then it is more likely to be incomplete in the left hemisphere compared with the right. Asymmetry of gene expression levels has been demonstrated in the human cortex, which may suggest a basis of structural and functional hemispheric asymmetries (11).

Also, not discussed by the authors are potential variations in hippocampal network connectivity. Further studies are necessary to better understand the cytoarchitecture of the hippocampal system in these patients. Specifically, visualizing any variations in the connectivity between the hippocampal pyramidal cell subfields, dentate gyrus, and parahippocampal region that includes the perforant pathway extending into the lateral temporal horn, is crucial for understanding whether a threshold of dysfunctional connectivity exists as it relates to epileptogenesis. To date, no clear cut hippocampal molecular biomarkers concordant with epileptogenesis have been associated with hippocampal malrotation.

The findings reported by Tsai and colleagues support the concept that hippocampal malrotation in temporal lobe epilepsy is a normal variant, unrelated to the epilepsy, and therefore not an indicator of focal pathology. However, these findings must be further reconciled with the literature. It is tempting to speculate that such a developmental variant is at the end of a phenotypic spectrum of normal hippocampal shape (4). As 7T MRI scanners become more available to better visualize cytoarchitecture in vivo, further quantitative studies including volumetry and morphometry will better assess for potentially more widespread morphologic changes throughout the brain. The authors make a compelling argument that this neuroanatomic variant must not influence surgical decision making in adults with intractable focal-onset epilepsy, particularly in those with MRI-negative temporal lobe epileptogenic networks.