A teenage girl with drug-resistant epilepsy and a hippocampal angiocentric neuroepithelial tumor (ANET) – illustrative case of 7T MRI in clinical practice

In patients with drug-resistant epilepsy, especially those in the trajectory for epilepsy surgery, neuroimaging is crucial: identifying and delineating a lesion improves postoperative seizure outcome. MRI with higher field strength has an increased signal and contrast to noise ratio (SNR/CNR) leading to an increased spatial resolution. Since over a decade, research related to the application of ultra-high field MRI is increasing. Studies in patients with focal drug-resistant epilepsy, both with and without a lesion on “ standard ” 3T MRI images, show promising results on high field MRI.

In patients with drug-resistant epilepsy, especially those in the trajectory for epilepsy surgery, neuroimaging is crucial: identifying and delineating a lesion improves postoperative seizure outcome.MRI with higher field strength has an increased signal and contrast to noise ratio (SNR/CNR) leading to an increased spatial resolution.Since over a decade, research related to the application of ultra-high field MRI is increasing.Studies in patients with focal drug-resistant epilepsy, both with and without a lesion on "standard" 3T MRI images, show promising results on high field MRI.
The translation of 7T to clinical practice has been challenging and guidelines have been provided [3].The academic center for epileptology Maastricht applies UHF-MRI as an adjunct in the work-up for epilepsy surgery in selected patients with drug-resistant focal epilepsy.

Case report
We illustrate a case of a 15 year old girl with drug-resistant temporal lobe epilepsy (TLE) and a questionable intrahippocampal lesion on 3 Tesla MRI.She had her debut of epilepsy at the age of nine years old and had been referred to our tertiary epilepsy center because of drugresistancy.The seizure semiology was suspect for TLE with preference for lateralisation to the right side.She had a high burden of suffering with daily several seizures.Initial 3T MRI revealed no cortical abnormalities, but a subtle increase in signal intensity of the right hippocampus was noted on coronal FLAIR images (Fig. 1a).
Follow-up MRI at the age of 12 years, still demonstrated the increased right hippocampal signal intensity without volume loss (Fig. 1b).The hippocampal abnormality lacked features of hippocampal sclerosis, i.e. reduced hippocampal volume and disturbed internal architecture.The amount of hippocampal edema exceeded expected seizure-induced changes.Ictal SPECT showed hyperperfusion in the mesiotemporal region of the right temporal lobe.
The multidisciplinary epilepsy surgery patient conference agreed on the right-sided lateralisation of the epileptogenic zone (EZ) in the temporal lobe, but because of uncertainty of the exact focus localization and how to classify the right-sided hippocampal abnormality, a stereo-EEG (SEEG) and a 7T MRI were indicated.
The 7T MRI protocol consisted of 4 sequences: (1) 3D T1-MP2rage with voxel size 0.7 × 0.7 × 0.7 mm, (2) 3D SPACE FLAIR 0.8 × 0.8 × 0.8 mm, (3) 2D T2 SPACE 0.6 × 0.6 × 2 mm and (4) 2D dual echo gradient images 0.3 × 0.3 × 2.0 mm.7T MRI not only showed the increased volume of the right hippocampus, but also raised the possibility of an underlying small and ill-defined mass in the hippocampal head (Fig. 1c and 2d).Because there was no enhancement nor visible growth in 5 years, this suspected hippocampal neoplasm was thought to be low-grade.There were no imaging features allowing further radiological specification.A dysplasia or hamartoma of the hippocampus was considered less likely, because the lesion was not isointense to normal hippocampus.
For the SEEG registration 11 oblique and orthogonal electrodes were implanted in the right hemisphere (Supplementary data).During the registration phase, patient had five habitual seizures, all originating from the hippocampus with extensive spreading pattern.
As the epilepsy was drug-resistant with consistent semiology, EEG and additional investigations all pointing to the right temporomesial structures, patient was scheduled for a right-sided selective amygdalohippocampectomy.The 7T findings gave no reasons to deviate from this decision.Normal neuropsychological examination argued against an anterior temporal lobectomy.
Histology revealed a small angiocentric neuroepithelial tumor surrounded by edema in the right hippocampus (Fig. 2e-h).Currently we have six months postoperative follow up.Patient reports a significant decrease in seizure frequency, with potential seizures 6 weeks, 10 weeks and 4.5 months after surgery, but none of these have been confirmed on

Discussion
A low-grade epilepsy associated brain tumors (LEAT) is the second most frequent encountered etiology after surgery in pediatric patients with drug-resistant, focal epilepsy [4].Traditionally, ganglioglioma and dysembryoplastic neuroepithelial tumors (DNET) were considered typical LEAT, but the spectrum has expanded in the last decades and several newly classified tumors have been added: angiocentric neuroepithelial tumor (ANET), isomorphic astrocytoma, multinodular and vacuolating neuronal tumor (MVNT) and polymorphous low-grade neuroepithelial tumor of the young (PLNTY).
All types of LEATs are mainly located in the neocortex, predominantly in the temporal lobe [4].Hippocampal tumors are rare with sporadic case reports of both MVNT and ANET in the hippocampus [2].
An angiocentric neuroepithelial tumor is one of the most uncommon WHO grade I tumors, occurring mainly in children and young adults with chronic, drug-resistant epilepsy.The exact origin of ANETs is not clear.ANETs are usually located at the base of the brain and have a very typical histological pattern with isomorphic bipolar cells arranged around blood vessels, hence the name angiocentric.These uniform bipolar tumor cells resemble tanycytes and radial glial cells, whereas other authors have linked them to ependymal cells.The bipolar tumor cells in ANET exhibit astroglial markers and stain immunohistochemically positive for GFAP (Fig. 2f) and EMA.The neurons in ANET have normal morphology.In the first descriptions of ANET as a distinct entity, a white matter abnormality extending from the center of the tumor going perpendicular towards the nearest ventricle was shown [1], supporting a (partly) dysplastic origin, but this was not consistently present in later cases.
Neocortical ANETs are located cortical-subcortical transition zones with ill-defined margins and do not enhance, thus resembling a lowgrade glioma.ANETs can have a characteristic imaging pattern with a T1 hyperintense rim or a T2 hyperintense stalk-like extension toward to ventricle, which can help to discriminate it from other LEATs [1].In our case, no T1 hyperintense rim or stalk-like extension was present.
In our patient the ANET was located in the hippocampus, a structure at the base of the brain consisting of two interlocking gyri -the dentate gyrus and Ammon's horn -and with a close relationship to the temporal horn of the lateral ventricle.The most cellular part of the tumor was located in Ammon's horn (Fig. 2e).
This case illustrates how the histological findings in detail corrrespond to the 7T MRI images.Retrospective radio-pathological correlation can improve our interpretation of high field images and teach us imaging features to look for.This knowledge can facilitate the follow up in an individual patient and increase the value of 7T MRIs in future patients.Therefore, we encourage adding UHF MRI in patients with drug-Fig.2. A-C Left column detail showing the abnormal right hippocampus on T2* (same as Fig. 1c), FLAIR and MP2RAGE images from 7T.D-F MP2rage, hematoxylin and eosin staining and GFAP immunohistochemistry staining of the right hippocampus: Ammon's horn outlined in red, dentate gyrus in purple and tumor indicated in black with mass effect with indentation of the dentate gyrus.(E) The overview HE staining shows an infiltrative glial tumor (GFAP+) in Ammon's horn.On higher magnification (G) elongated atypical glial cell are visible with partly diffuse infiltration patten.The highest magnification (H) illustrates the perivascular (angiocentric) orientation of the abnormal, similar looking (isomorphous) glia cells (purple arrow).

Fig. 1 .
Fig. 1.Detail from consecutive coronal FLAIR (3T) and T2* (7T) images showing both hippocampi.On the right side the signal is increased compared to the normal left side, with swelling and mass effect.