闫兆芬 王静 周健 关宇光 翟锋 刘长青 韩一仙 栾国明 王梦阳

首都医科大学三博脑科医院

Abstract:

Purpose: The ictal semiology in posterior cingulate epilepsy is poorly described because the seizure onset zone(SOZ) is located in an anatomically deep region and the scalp electrodes are difficult to cover it for recordings. We can identify ictal onset zone by stereo-electroencephalography(SEEG) to better recognize the clinical features and epileptic network of PCE, consequently achieving better surgical outcomes.

Methods: We retrospectively evaluated six patients with drug-resistant posterior cingulate epilepsy who had been consecutively explored with SEEG, and followed by individually tailored resection including parts of the posterior cingulate gyrus.SEEG analysis confirmed that the posterior cingulate gyrus was included in the SOZ of the five patients.One patient’s SOZ was located in the hippocampus and ectosplenial portion of cingulate gyrus.

Results: The locations of the scalp EEG interictal discharges were varied, which included bilateral tempor-occipital, unilateral parieto-occipital and vertex region. Two patients had simple motor seizures, including bilateral asymmetric tonic seizures,versive seizures; four patients had dialeptic seizures and automatism. The epileptogenic zone often extended to hippocampus/parahippocampus predominance, and out of the range of posterior cingulate gyrus. The tailored resection included a lesion in five patients, and an EngeIclass IA outcomes as well as behavioral improvements were obtained in them.

Conclusion:We are aware that not all the patients show pure posterior cingulate epilepsy, but the posterior cingulate gyrus was always a part of the ictal onset zone. For identified cases of PCC plus hippocampus/parahippocampus epilepsy,a multilobar resection including the hippocampus/parahippocampus may lead to improved postoperative outcomes with minimal morbidity.

Keywords: PCC, SEEG, parahippocampus,hippocampus,PCE,epilepsy surgery

Introduction

Posterior cingulate gyrus(PCG) is located in the medial walls of the frontal and parietal lobe.The anatomical location of the posterior cingulate gyrus makes neurophysiological studies with scalp electrodes difficult. The posterior cingulate epilepsy(PCE) is controversial because of the types of seizures are relative complexity. In 2008, Garzon and Lüders described that the clinical manifestions of posterior cingulate epilepsies mainly showed dialeptic and automotor seizures. Enatsu et al(2014)descried six of seven patients who had posterior cingulate ictal onset identified by SEEG evaluations, and showed bilateral asymmetric tonic seizures, hypermotor seizures,dialeptic and automotor seizures .The role of SEEG has been widely demonstrated to be fundamental in defining PCG semiology through anatomo-electro-clinical correlations. The results of SEEG have improved our knowledge about functions of this deeply located lobe. In recent decades, epilepsy surgery in patients has demonstrated favourable outcomes in terms of seizure control and improved neuropsychological development. For those patients, the safety and utility of the SEEG technique has been well-established.

The aim of this retrospective study is to detailedly analyze the anatomo-electro-clinical correlations as well as the surgical results in patients with drug-refractory focal PCE which is identified by SEEG exploration.

MATERIALS AND METHODS

Patients

We enrolled six consecutive patients who had been diagnosed with focal PCE at the Epilepsy Center of Sanbo Brain Hospital between 2015 and 2016, and six patients fulfilled the following criterion: (i) SEEG recordings covering the posterior cingulate cortex. (ii) The PCG within the epileptogenic zone. (iii) The extent of surgical resection including the parts of the posterior cingulate cortex.

All patients underwent a rigorous evaluation performed in three steps as described previously: (i) Pre-surgical evaluation: detailed history, neurological examination,　scalp electroencephalography (EEG),long-term video-EEG monitoring (VEEG),stereo-electroencephalography (SEEG), high-resolution MRI. Neuropsychological testing was performed in three patients. PET-scan was performed in six patients. (ii) Tailored resection: pathological classification according to Blümcke I et al. (iii) Follow-up: seizure outcome was evaluated according to Engel’s classification ,Neurological examination, EEG, high-resolution MRI and neuropsychological testing.

For every patient, all types of seizures were recorded. SEEG exploration planning was performed according to noninvasive data， and including the hypothetical epileptogenic(s) zone(s) (Ez) and the lesion when it was present. The patient’s head was fixed in a standard stereotactic frame and depth electrode targeting and trajectory were determined using a robotic system (ROSA;Medtech,Montpellier,France). Theelectrodes consisted of 8, 10, 12 and 16 cylindrical 2.0mm-long platinum contacts with a diameter of 0.80mm, interval 1.5mm. SEEG electrodes were implanted into the sample targets of the fronto-parietal lobes in two patients(case 1and2), temporo-parieto-occipital-insular lobes in one patient ( case 5), and temporo-parieto-occipital lobes in three patients (case 3、4 and 6). We co-registered postoperative CT with preoperative MRI to confirm the final location of the SEEG contacts and electrodes.

The VEEG and SEEG data was reviewed independently by two epileptologists. We classified the seizure semiology at the ictal stage based on the semiological seizure classification proposed by Lüders and his colleaguese .The seizure onset zone and propagations were retrospectively analysed from SEEG data and monitor reports.We paid particular attention to electro-anatomy relationships between posterior cingulate cortex and adjacent structures.

Results

1. Participants and Descriptive Data

Clinical characteristics of the patients were shown in table 1. There were five males and 1 female, all of whom were right handed. Their age ranged from 10 to 28 years old (median=16.5years and their age at seizure onset ranged from 3-13 years old (median=8years). The study was approved by the Institutional Review Board Committee at Sanbo Brain Hospital.

None of them had a family history of epilepsy, history of foetal distress, febrile convulsions and head trauma. One child had tuberous sclerosis complex (case 2).Lesions could be found in 5 patients, which included focal cortical dysplasia (FCD) (case1and case 6) ,bilateral hippocampus sclerosis(case5),tuberous sclerosis on PCC and precuneus (case 2), and parieto-occipital lesion (case 4).one patient had a normal MRI (case 3). Three patients showed well-localized hypometabolism on FDG-PET,which was concordant with the localization of lesions on MRI, one showed multiregional hypometabolism (case 6), one showed normal metabolism (case 5) and one did notundergo a PET scan (case 4). Two of three patients had normal neuropsychological test results before operation (case 3 and 4) and the case 5 had decline of verbal logical memory and spatial memory, who had typical hippocampal tail sclerosis.n The VEEG recording data are given in table 1. Semiology analysis of the seizure by video-EEG examination. Interictal epileptiform abnormalities was recorded in six patients. The epileptiform discharges were exclusively ipsilateral to the side of lesion in two, independent bilateral in three but with a marked predominance also ipsilateral to the side of lesion, and on the vertex region in one. The form of epileptiform discharges is spike-slow waves.

Among the six patients with seizure recordings, the ictal EEG was regional in one (case1), lateralized in one(case6) and non-localizable in four.The four patients with non-localizable is a marked predominance to bilateral region temporo-occipital. The ictal rhythm consisted of varied patterns in both groups, with no predominance of any particular type. Low voltage fast activities of regular or irregular morphology were observed.

Table 1.Clinical Features of PCE Patients undergoing SEEG Evaluation

Rt,right;BATS:Bilateral asymmetry tonic seizure;Sz,seizure;Lt,left;GTC,genaral tonic clonic;Bil,bilatral;T-P,temporo-parie tal;TPO,temporo-parieto-occipital;C-P,centro-parietal;T-O,temporo-occipital;F-T:fronto-temporal;MCC,middle cingulate cortex;CG,cingulate gyrus;Pcu,precuneus;

2. SEEG findings and surgical outcomes

In patient 1, the initial bilateral asymmetric tonic seizures mainly involving the right upper limbs prominent with ictal from PCC spread to midcingulate and supplementary sensorimotor area (SSMA).She refused surgery treatment for she was afraid of functional deficit.(Figure1)

Figue 1

A Brain MRI of presurgery(She refused surgery treatment for she was afraid of functional deficit)B The schematic diagram of SEEG electrode placement-left view.black: seizure onset;grey: early propagation. S1-3:posterior cingulate gyrus;N1-2:ramus;M1-2:SMA; K1-2:posterior cingulate sulcus; C SEEG traces showing the firstspike-wave and high-freque- -ncy oscillations activities in theS1-3, in the ictal stage and subsequently in theN1–2, M1-2,K1-2.

In case 2, the patient had dialeptic, right deviation and left versive seizures , seizure onset zone was precuneus and PCC, then spread to parieto-occipital sulcus and intraparietal sulcus and precentral sulcus.

In three patients (patient 3，4 and 5), the seizure onset zone were isthmus and parahippocampus/hippocampus.

In patient 3 the seizure semiology evaluation who had a aura of picture flashed, then dialeptic seizures and bilateral hands automatisms. SEEG ictal activity originating from left isthmus,bilateral para-hippocampus and parieto-occipital sulcus.(Figure3)

Figue 3

A Brain MRI of presurgery.BThe schematic diagram of SEEG electrode placement-left view.black: seizure onset;grey: early propagation.G3-4:isthmus;D2-3:left parahippocampus;D'2-3： righthippocampus,T2-3:parieto-occipital sulcus , C SEEG traces showing the first unequivocal high-frequency oscillations activities in the G2-3,D'2-3,D2-3 in the ictal stage and subsequently in theB2–3, A1-2,B'11-12,C2-3. D Resection of the posterior cingulate gyrus.

The patient 4 had dialeptic seizure and tonic seizure, epileptic activity from isthmus and hippocampus to posterior cingulate gyrus (BA30), supramarginal gyrus, precuneus , middle temporal gyrus, intraparietal sulcus and superior temporal gyrus.

The patient 5 had oralimentary automatisms and complex motor seizure (bilateral hands fumbling,),the seizure onset zone was isthmus spread　to　hippocampus,　amygdala, parahippocampus,surperior temporal sulcus and inferior temporal gyrus.

The patient 6 had oralimentary and bilateral hands seizures,which was only one seizure onset zone was left hippocampus, left Isthmus, spread to right marginal isthmus , PCC, marginal ramus( the lesion zone)within 0-600 ms.(Figure 6)

Figue 6

A Brain MRI of presurgery.BThe schematic diagram of SEEG electrode placement-upper:left view,inferior:Right view.black: seizure onset;grey: early propagation.B2-3:left hippocampus head ,X2-3 isthmus;B'2-3 right hippocampus head;R':posterior cingulate gyrus;S'2-3:ramus C SEEG traces showing the first unequivocal polyspikes activities in the B2-3 in the ictal stage and subse- quently in theX2-3,B'2–3,R'2-3,S'2-3. D Resection of the posterior cingulate gyrus and precuneus

In summary, PCE patients has lateralizing sign, BATS and contralateral to versive seizure. Automotor seizures involved oralimentary and bilateral hands, Two of six patients showed motor manifestations including bilateral asymmetric tonic seizure and versive seizures. In these patients, ictal activities spread to frontal (SSMA, middle cingulate gyrus, precentral sulcus) and parietal (precuneus,PCG, intraparietal sulcus) areas. Four of six patients had dialeptic seizures and/or automotor seizures. The seizure onset zone was PCC and/or hippocampus/parahippocampus, then spread to medial temporal structures(hippocampus,para-hippocampus,amygdala),neocortical temporal lobe(MTL,ITL,STS),pareital,( intraparietal sulcus and parietooccipital sulcus).

The surgical data, histological results and seizure outcome are given in table 2. Five patients underwent surgical treatment. According to the SEEG results, a tailored surgery was performed, concerning the right hemisphere in three patients and the left in two patients. The respective surgery was: PCG in case 3, PCG lesion in case 6, PCG, medial temporal structures and surperior temporal gyrus in case 5, precuneus and PCG in case 2 and parieto-occipital lesion zone and PCG in case 4. The patient 3 can’t acquire seizure freedom after only PCG resection. The follow-up ranged from 12 to 19months (mean 13 months). According to Engel’s classification, seizure outcome resulted in: class Ia–four patients; III–one patients; One of four patients was submitted to neuropsychological evaluation after surgery. The neuropsychological evaluation was no change with one patient(patient five)

Table 2 Surgical planning and patient outcomes

Lt,left;PCG, posterior cingulate gyrus ;TSC, tuberous sclerosis complex;Rt,right;MTG,middle temporal gyrus;ITG,inferior temporal gyrus;MTC;middle temporal structures;SW,Spike-wave;

Discussion

This study aimed at determining the functional anatomy of the epileptogenic zone in the PCE. We present here a retrospective analysis of 6 patients with medically refractory PCE in whom SEEG was used to identify the Ez. It was difficult to localized the PCG as ictal onset areas based on the scalp EEG because of anatomically deep area. Previous reported that scalp interictal and ictal EEG lateralise or localize the seizures correctly in 50%-60% of cingulate epilepsy cases .We found that five patients showed interictal epileptiform discharges was regional on the temporo-parieto-occipital region and all of them was bilateral but with a marked predominance ipsilateral to the side of leison. Ictal scalp EEG often showed bilateral posterior temporo-occipital spike-wave or lower voltage fast.None of the patients had the typical organized or 2.4-10Hz rhythm associated with mesial temporal lobe epilepsy .So the anatomically deep location of this area might cause difficulties in localization in scalp EEG evaluations but often posterior tempor-occipital region. These findings are not all consistent with the previous literature.

Previous studies have reported that PCE tends to show predominantly alterations of consciousness, automatism and motor manifestations, including BATS and hypermotor seizure . Our study revealed that the semiology of PCE can include BATS and versive seizure. In these patients,ictal activities spread to frontal (midcingulate, SSMA, precentral sulcus) and parietal (precuneus, PCC,intreparietal sulcus and pariet-occipital suclus) area.Sugiura M et al(2005) showed PCC that comprised two different function areas: dPCC and vPCC .The dPCC had a broad swath on MCC, precuneus ,the SSMA and pre-SSMA, lateral swath inferior parietal lobe and superior parietal lobe BA7 .Therefore, this motor manifestation might reflect the activation of the fronto-parietal network .

The previous literature referred seizure types of PCE frequently present in patients with temporal lobe epilepsy .In our study, one patient who presented with complex seizure and ictal activities spread to medial temporal structure and neocortical temporal lobe . SEEG certify that the SOZ was PCG, bilateral para-hippocampus/hippocampus meanwhile in two patients (case 3and5). Interestingly , the patient 6 presented with dialeptic seizure and automotor seizure, the SOZ was left hippocampus ,and from left isthmus to right PCC lesion after one second. The symptomatogenic zone was PCC and neocortical temporal lobe. PCG adjacent to posterior hippocampus and para-hippocampus cortices and nearly connections . The posterior cingulate cortex is known to project to the hippocampus via the entorhinal and para-hippocampus cortex and to receive direct and indirect connections from the hippocampus .Differential activity is next demonstrated between the PHC and the retrosplenial complex (RSC) at 170–240 ms. It is suggested that this reflects activation of the relevant context frame .Alkawadri R et al highlights the importance of considering the posterior cingulate gyrus the group of pseudotemporal epilepsies. Koubeissi et al reported a case of lesion PCE with seizures characterized by staring and automatisms, with bilateral interictal mesial temporal discharges and a rapid propagation to the ipsilateral mesial structures on invasive studies . But case 6 who was right cingulate lesion and SEEG certified left hippocampcus, The pathology of surgery PCG lesions was FCD IIIB (FCD IC and Ganglion glioma).Indeed, the Ganglion glioma often associated with malformations of cortical development, in particular focal cortical dysplasia (FCD)which are most often the basis of lesion epilepsy . Invasive EEG investigations may provide useful information, although in GNT-associated focal epilepsy the main goal of intracerebral recordings is usually to map eloquent cortex in proximity of the neoplasm. The inferior cingulum bundle is a white matter tract projecting from the PCC to the hippocampus or parahippocampus and the entorhinal cortex .Ictal propagation to the cingulate gyrus is frequently observed among patients with temporal lobe epilepsy . YC Shih et al found in left mesial temporal lobe epilepsy with hippocampal sclerosis, the left inferior cingulum bundle undergoes degeneration in tandem with the left hippocampus volume, whereas intrinsic functional connectivity seems to react by compensating the loss of connectivity. Their results suggest that increased Intrinsic functional connectivity of the contra-lesion hippocampus is a compensatory response to decreased hippocampus connectivity on the lesion side .According to the hypothesis, we speculate that the PCG lesion and hippocampus functional connectivity decreased,but the contra-lesional PCG and hippocampus have heavy functional connection. Ictal symptoms are related to the abnormal activation or to the disruption of network mechanisms governing normal brain function .

The EZ in Talaraich and Bancaud definition as the site of the beginning of the epileptic seizures and of their primary organization .Lüders HO et al defined the epileptogenic zone as the “area of cortex that is necessary and sufficient for initiating seizures and whose removal (or disconnection) is necessary for complete abolition of seizures .For case 6, focal resection of the PCG lesion resulted in postoperative seizure freedom. Two patients(case 4 and 5) was seizure freedom after surgery whose resection was extended outside the cingulate and including hippocampus and middle temporal gyrus ,even in the absence of apparent lesion on neuroimaging. The patient 3 still had habitual seizure with only PCG reception. The epileptogenic zone is one of the key concepts of surgical treatment of epilepsy patients . It is defined as covering exactly those regions of the cortex that have the actual or potential capability of inducing seizures and that should ideally be removed completely in the surgical process. Currently, to our knowledge, there is no available biomarker of epileptogenicity to reliably identify relevant epileptogenic tissue. In this article, we used good surgical outcomes following resection as a surrogate gold standard of the epileptogenic zone. Consequently, for these pstients, multilobar resection including hippocampus/parahippocampus and superior temporal gyrus resulted in sustained freedom from disabling seizures.

This study has some limitations. First, this study was definitely limited by the location or number of implanted electrodes designed to treat epilepsy patients. This spatial limitation of recordings may cause difficulties in identifying the whole seizure pathway. Second, the sample size in this study was relatively small. Three of six patients underwent neuropsychological test. Neurological examination was not performed in all patients. Further studies employing a larger number of participants would be helpful to confirm these preliminary results. We should apply CCEP or others method to precisely track the seizure spread pathway.

Conclusion

From clinical and SEEG features,our findings support the notion that PCG play a role in primary seizure generation, often by extension to the temporal lobe( parahippocampus/hippocampus) .The latter patients often had dialeptic seizure, then involved to alimentary and bilateral hand automatism. For identified cases of PCC plus hippocampus/parahippocampus epilepsy,a multilobar resection including the hippocampus/parahippocampus may lead to improved postoperative outcomes with minimal morbidity. and that should ideally be removed completely in the surgical process. Currently, to our knowledge, there is no available biomarker of epileptogenicity to reliably identify relevant epileptogenic tissue. In this article, we used good surgical outcomes following resection as a surrogate gold standard of the epileptogenic zone. Consequently, for these pstients, multilobar resection including hippocampus/parahippocampus and superior temporal gyrus resulted in sustained freedom from disabling seizures.

This study has some limitations. First, this study was definitely limited by the location or number of implanted electrodes designed to treat epilepsy patients. This spatial limitation of recordings may cause difficulties in identifying the whole seizure pathway. Second, the sample size in this study was relatively small. Three of six patients underwent neuropsychological test. Neurological examination was not performed in all patients. Further studies employing a larger number of participants would be helpful to confirm these preliminary results. We should apply CCEP or others method to precisely track the seizure spread pathway.

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