- Email: [email protected]
Pathology-Based Approach to Seizure Outcome After Surgery for Pharmacoresistant Medial Temporal Lobe Epilepsy
Accepted Manuscript Pathology based approach to seizure outcome after surgery for pharmacoresistant medial temporal lobe epilepsy Matteo Martinoni, MD, Pier Paolo Berti, MD, Gianluca Marucci, MD PhD, Guido Rubboli, MD, Lilia Volpi, MD, Patrizia Riguzzi, MD, Federica Marliani, MD, Francesco Toni, MD, Francesca Bisulli, MD, Paolo Tinuper, MD Prof, Roberto Michelucci, MD Prof, Agostino Baruzzi, MD Prof, Marco Giulioni, MD PII:
S1878-8750(16)00317-X
DOI:
10.1016/j.wneu.2016.02.072
Reference:
WNEU 3773
To appear in:
World Neurosurgery
Received Date: 20 December 2015 Revised Date:
14 February 2016
Accepted Date: 15 February 2016
Please cite this article as: Martinoni M, Berti PP, Marucci G, Rubboli G, Volpi L, Riguzzi P, Marliani F, Toni F, Bisulli F, Tinuper P, Michelucci R, Baruzzi A, Giulioni M, Pathology based approach to seizure outcome after surgery for pharmacoresistant medial temporal lobe epilepsy, World Neurosurgery (2016), doi: 10.1016/j.wneu.2016.02.072. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Pathology based approach to seizure outcome after surgery for pharmacoresistant medial temporal lobe epilepsy
Matteo Martinoni a, Pier Paolo Berti a, Gianluca Marucci b , Guido Rubboli cd , Lilia Volpi c, Roberto Michelucci c, Agostino Baruzzi
, Marco Giulioni a
IRCCS Institute of Neurological Science of Bologna, Division of Neurosurgery, Bellaria Hospital,
SC
a
fg
Bologna, Italy.
Section of Pathology “M. Malpighi”, Bellaria Hospital, Azienda USL - IRCCS Institute of Neuro-
logical Sciences, Bologna, Italy c
M AN U
b
RI PT
Patrizia Riguzzi c, Federica Marliani e, Francesco Toni e, Francesca Bisulli fg, Paolo Tinuper fg,
IRCCS Institute of Neurological Sciences of Bologna, Division of Neurology, Bellaria Hospital,
Bologna, Italy.
Danish Epilepsy Centre, Dianalund, Denmark.
e
IRCCS Institute of Neurological Sciences of Bologna . Section of Neuroradiology, Bellaria Hos-
TE D
d
pital, Bologna, Italy.
IRCCS Institute of Neurological Sciences of Bologna, Bologna Italy
g
Department of Biomedical and Neuromotor Sciences University of Bologna.
AC C
EP
f
Corresponding Author: Matteo Martinoni MD
IRCCS Institute of Neurological sciences of Bologna, Department of Neurosurgery, Bellaria Hospital 40100, Bologna, Via Altura 1/8 Tel. +39 051 6225111 Fax. +39 051 6225347 Email: [email protected]
ACCEPTED MANUSCRIPT Highest academic degrees for all authors Matteo Martinoni MD a, Pier Paolo Berti MD a, Gianluca Marucci MD PhD b, Guido Rubboli MD cd
, Lilia Volpi MD c, Patrizia Riguzzi MD c, Federica Marliani MD e, Francesco Toni MD e,
Baruzzi MD Prof fg, Marco Giulioni MD a Departmental and institutional affiliations for all authors.
IRCCS Institute of Neurological Science of Bologna, Division of Neurosurgery, Bellaria Hospital,
SC
a
Bologna, Italy.
Section of Pathology “M. Malpighi”, Bellaria Hospital, Azienda USL - IRCCS Institute of Neuro-
logical Sciences, Bologna, Italy c
M AN U
b
RI PT
Francesca Bisulli MD fg, Paolo Tinuper MD Prof fg, Roberto Michelucci MD Prof fg, Agostino
IRCCS Institute of Neurological Sciences of Bologna, Division of Neurology, Bellaria Hospital,
Bologna, Italy.
Danish Epilepsy Centre, Dianalund, Denmark.
e
IRCCS Institute of Neurological Sciences of Bologna . Section of Neuroradiology, Bellaria Hos-
TE D
d
pital, Bologna, Italy.
IRCCS Institute of Neurological Sciences of Bologna, Bologna Italy
g
Department of Biomedical and Neuromotor Sciences University of Bologna.
AC C
EP
f
Key Words : temporal lobe epilepsy; epilepsy surgery; hippocampal sclerosis; granule cell pathology; focal cortical dysplasia; seizure outcome
Abbreviations list: ATL (anterior temporal lobectomy), EEG (electroencephalography), FCD (focal cortical dysplasia), GCL (granular cell loss), GCP ( granular cell pathology), HS (hippocampal sclerosis), MTLE (mesial temporal lobe epilepsy)
ACCEPTED MANUSCRIPT Abstract
Backgrounds Hippocampal sclerosis (HS) is the most common cause of drug-resistant medial temporal lobe epilepsy (MTLE). Structural abnormalities such as HS, granule cell pathology (GCP) and
RI PT
focal cortical dysplasia (FCD), have been histopathologically classified possibly allowing more accurate prognostic seizure and neuropsychological outcome assessment. We correlated seizure outcome with comprehensive temporal lobe pathological findings, identified according to the most recent classification systems of HS, GCP and FCD.
Methods All the 83 patients submitted to anterior temporal lobectomy (ATL) for drug-resistant
SC
MTLE and with a proven diagnosis of HS between April 2001 and May 2014 were collected. Patients were divided in two main groups: 1) Isolated HS with/without GCP (HS +/- GCP) 2) HS as-
M AN U
sociated with FCD with/without GCP (HS+FCD +/- GCP). Patients were followed up at least 1 year and seizure outcome was reported in accordance with Engel classification. Results Group I: HS +/- GCP: Statistical analysis confirmed a better outcome in HS + GCP patients than in HS-noGCP (p < 0,05). Moreover, a better outcome for the patients affected by GCP type I was observed (p < 0,05). Group II: HS+FCD +/- GCP: Patients with HS variant type I pre-
II: 69% vs. 40%).
TE D
sented a better seizure outcome than the patients with HS type II (Engel class IA HS type I vs. type
Conclusions A pathology based approach to epilepsy surgery might improve the interpretation of the results, could predict which cases will enjoy a better seizure outcome and could help to the
AC C
EP
comprehension of the causes of failures.
Key Words : temporal lobe epilepsy ,epilepsy surgery , Hippocampal Sclerosis , Granule cell pathology , focal cortical dysplasia , seizure outcome
ACCEPTED MANUSCRIPT Introduction
Drug-resistant mesial temporal lobe epilepsy (MTLE) is the most common type of epilepsy requiring surgical treatment, with a favorable seizure outcome being achieved in about 60%–80% of pa-
RI PT
tients. Hippocampal sclerosis (HS) is the most common cause of drug-resistant MTLE1–3. Furthermore, in 50% of cases HS is associated with dentate gyrus pathology1,4,5) and in 60-70% of cases with focal cortical dysplasia (FCD) in temporopolar cortex3,6–12. Epileptogenic structural abnormalities, such as HS, granule cell pathology (GCP) and FCD, have been histopathologically subclassineuropsycological outcome assessment1,4,5,7,13,14.
SC
fied, possibly allowing more accurate clinico-pathological correlations and prognostic seizure and A pathology based approach15 might improve the interpretation of the results and the comprehen-
M AN U
sion of the causes of failures improving criteria for selection of patients for epilepsy surgery. In this study, we analyzed seizure outcome in a population of consecutive patients presenting with drug resistant MTLE, associated with HS, who underwent tailored anteromesial temporal lobe resection after extensive presurgical evaluation without invasive procedures. In particular, we correlated seizure outcome with comprehensive temporal lobe ( temporo mesial and temporo polar structures) pathological findings, identified according to the most recent
Material and Methods
TE D
classification systems of HS1, GCP4 and FCD7.
EP
We conducted a restrospective study at the Epilepsy Surgery Centre of the Institute of Neurological Sciences, Bellaria Hospital, Bologna. Data of all the patients who underwent tailored surgery for drug-resistant MTLE and with a proven diagnosis of HS between April 2001 and May 2014 were
AC C
collected, for a total of 83 patients. Following the most recent histopathological classification systems, patients were divided in two main groups: 1) Isolated HS with/without GCP (HS +/- GCP); 2) HS associated with FCD with/without GCP (HS+FCD +/- GCP). In all cases a detailed clinical history was taken and presurgical neurophysiological assessment was performed by means of EEG, inter-critial EEG and long-term video-EEG monitoring for seizure characterization. Electroencephalographic signals were collected by means of silver-silver chloride electrodes according to the international 10-20 system; only in selected cases were used additional electrodes (zygomatic or supraorbital). All the patients underwent MRI study (1,5T MRI until 2005 and 3-T MRI since 2006) using the following protocol: sagittal spoiled gradient-recalled acquisition
ACCEPTED MANUSCRIPT T1-weighted, axial T2-weighted, axial and coronal FLAIR T2-weighted, coronal gradient echo, coronal T2-weighted and coronal T1-weighted inversion recovery sequences and, when necessary, axial, sagittal, and coronal T1-weighted sequences obtained after injection of gadolinium were added. Proton Magnetic Resonance Spectroscopy (1H-MRS) was introduced in the presurgical examination since 2005. Moreover, all patients underwent a campimetric analysis of the visual field and a
RI PT
neuropsychological evaluation. The surgical planning and the surgical procedure were mainly defined according to the anatomoelectro-clinical correlations of the seizures, EEG and long term video EEG findings and MRI data. All patients were submitted to a preoperative neuropsychological evaluation. The Wada test was not
SC
performed in any case. Only in selected cases DTI, PET and functional MRI were performed for presurgical language mapping.
Patients were followed up at least 1 year and seizure outcome was reported in accordance with En-
M AN U
gel classification. In this study we did not analyze the neuropsychological outcome.
Surgical procedure
All operation were carried out by the same senior surgeon (M.G.), who performed tailored procedures of Anterior Temporal Lobectomy (ATL) aimed at removal of the epileptogenic zone (tailored
TE D
surgery) as identified by presurgical evaluation.
In all cases the tailored surgery mainly consisted of removing the temporal pole, the anterior necortical lateral cortex, the uncus-entorhinal area, the parahippocampal gyrus and the hippocampus. The main surgical specimens (hippocampus and temporal pole) were removed en bloc and spatially ori-
EP
ented. This procedure is essential to allow the best pathological examination and the identification
AC C
of an eventual FCD in the temporal pole cortex
Pathological examination
Hippocampal specimens were dissected along the anterior-posterior axis, and samples from the mid-hippocampal body were chosen for evaluation. The temporal pole was cut perpendicular to the pial surface and was analyzed in 3 to 5 mm sections. Tissue was fixed in 10% buffered formalin and embedded in paraffin. Paraffin sections of 4 µm were serially cut and underwent H&E, Nissl and Kluver staining. Serial, 4-lm-thick, paraffin sections mounted on precoated slides were processed using standardized automated procedures using prediluted antibodies (Ventana-Benchmark, Tucson, AZ, USA), with the exception of anti-NeuN (clone A60, dilution 1:500, Chemicon-Millipore Corp, Billerica, MA) antibody. Immunohistochemistry was performed using Polymer as detection system (Ultravision LP
ACCEPTED MANUSCRIPT Detection System HRP Polymer; LabVision, Freemont, CA, USA). The prediluted antibodies were anti-GFAP (polyclonal), anti-synaptophysin (polyclonal) and anti-CD34 (clone Qbend/10). Appropriate positive and negative controls were performed. All cases were histologically reviewed in accordance with the most recent pathological classifica-
RI PT
tion for HS1 , GCP4 and FCD7.
Statistical Analysis
Data are presented as mean and range. Statistical analysis was performed to investigate eventual differences between age at surgery, epilepsy duration or histopathological lesion pattern relative to
SC
seizure outcome.
Statistical significance for categorical comparison was determined by the Fisher exact test or Eta squared when more than 2 categories were considered. The Mann-Withney U-test and Kruskal-
M AN U
Wallis test were used for the comparison of continuous variables between 2 or more groups. A p value of less than 0.05 was considered statistically significant. Statistical analysis were performed using SPSS software version 16.0.
Results
TE D
We analyzed 83 consecutive patients (34 male and 49 female) submitted to anteromesial resection for drug-resistant MTLE between April 2001 and May 2014 with a proven diagnosis of HS. Mean age at epilepsy onset was 12 years (range 6 months – 46 years), mean age at surgery was 37 years (range 17 – 66 years) and mean duration of epilepsy was 25 years (range 2 – 53 years). Mean dura-
EP
tion of follow up was 8 years (range 1 – 14 years). In all cases the main surgical specimens (temporal pole and hippocampus) were adequate for an appropriate histopathological evaluation. Ac-
AC C
cording to the histological findings, the patients were divided into 2 main groups (table 1): Isolated HS with/without GCP: 36 cases HS associated with FCD with/without GCP: 47 cases. No statistically significant differences were found between any of the groups with respect to age at surgery, epilepsy duration and seizure outcome (fig. I). All the patients were submitted to postoperative CT scan immediately or within 6 hour and MRI study within 6 months after surgery. All patients performed an EEG study within 6 months after surgery. In 10 out of the 14 cases that did not achieve an Engel Class 1 the postoperative EEG showed omolateral temporal interictal epileptiform abnormalities however in 4 out of 14 cases no EEG abnormalities have been detected. Analysis of postoperative MRI in the group with a worse outcome showed in all cases a substantial agreement
ACCEPTED MANUSCRIPT with preoperative resection planning. Furthermore, in all cases EEG and clinical study did not ruled out clear suggestions helping to explain the causes of failures. We didn’t focused on the results of postoperative neuropsychological evaluation Group I: HS +/- GCP Isolated HS was observed in 36 patients (15 male, 21 female; 43,3% of the series). Mean age at sur-
RI PT
gery was 37 years (19 – 66 years); mean age at epilepsy onset was 11 years (range 6 months – 46 years) and mean duration of the epilepsy history was 23 years and 6 months (range 4 – 53 years). 30 patients (83,3%) presented HS type 1 while the remaining 6 patients (16,7%) had HS type 2. None of this group was affected by HS type 3. Concomitant abnormalities in the dentate gyrus was ob-
SC
served in 25 cases (69,4%): namely 10 patients (27,8%) presented GCP type I and the remaining 15 cases (41,6%) showed GCP type II.
In table IIa and IIb is illustrated seizure outcome related to each histological subgroups: only 1
M AN U
(16,7%) of 6 patients with an atypical pattern of HS (type 2) achieved Engel Class IA, while 20 of 30 patients (66,7%) affected by HS type 1 were seizure free (table. 2a). With respect to the presence of GCP only 2 out of 11 cases (18,2%) of HS-noGCP obtained complete seizure freedom while 19 of 25 patients (76%) with HS + GCP phenotype had Engel Class IA outcomes (table. 2B). None of the 4 patients with both of negative prognostic factors (HS type 2
TE D
and no GCP) reached seizure freedom (table. 2b).
Statistical analysis confirmed a better outcome in HS + GCP patients than in HS-noGCP (p < 0,05). Moreover, a better outcome for the patients affected by GCP type I was observed, comparing the different 3 subtypes of GCP (noGCP, GCP type I, GCP type II) (p < 0,05).
EP
Group II: HS+FCD +/- GCP
This group included 47 patients (19 male and 28 female; 56,6% of the series). Mean age at surgery was 38 years (range 17 – 60 years); mean age at epilepsy onset was 12 years (range 6 months – 32
AC C
years) with a particularly long pharmacoresistance history before surgery (from 2 to 44 years; mean age 26 years). The most common histological association observed in this group was HS + FCD type I (FCD type IIIa) with 37 cases (78,7%): 35 patients was affected by HS type 1 + FCD type I and only 2 patients by HS type 2 + FCD type I. In 10 cases (21,3%) was reported the association HS + FCD IIA (dual pathology): 7 patients were HS type 1 and the remaining 3 were HS type 2. Moreover, 30 of 47 patients (63,8%) had concomitant GCP: namely 11 patients (39,3%) had GCP type I and the remaining 19 were affected by GCP type II. In table 3 is reported seizure outcome with respect to histopathological background. Patients with HS type 1 presented a better seizure outcome than the patients with HS type 2 (Engel class IA HS type 1 vs. type 2: 69% vs. 40%).
ACCEPTED MANUSCRIPT However, no statistically significance was found between the different HS type, FCD type, or GCP type and seizure outcome. Complications No patients died during surgery or the postoperative course. Surgical complications occurred in 5 cases (6%): 1 patient with superficial wound infection needed antibiotic therapy, in 3 cases of post-
RI PT
operative deep venous thrombosis was necessary an anticoagulant treatment and 1 patients with sagging the bone flap required reoperation. 8 patients (9,6%) presented hyperpyrexia related to aseptic meningitis (no antibiotic therapy was required) and a considerable reduction of these cases after the introduction of intraoperative corticosteroids was observed.
SC
Major neurological complications were limited to 2 cases (2,4%) of hemianopia while, as minor complications, transitory dysphasia occurred in 1 patient (1,2%) and we didn’t observe any case of
M AN U
persistent postoperative language deficit.
Neuropsychological and psychiatric side effects were not addressed in this study.
Discussion
Mesial temporal lobe epilepsy associated to hippocampal sclerosis (MTLE-HS) is the most com-
TE D
mon cause of refractory epilepsy in adulthood and surgery is regarded as the treatment of choice16. The literature provides relatively consistent data that up to approximately two-thirds of patients will become seizure-free after surgery17–19. However approximately 20%–30% of patients continue to have seizures20–22.
EP
Five major causes are commonly identified in the literature as a cause of failures : (1) insufficient resection of mesial temporal structures, (2) insufficient or non resection of temporal neocortex, (3)
AC C
dual pathology, (4) relapse on the contralateral temporal lobe, (5) extratemporal and temporal plus epilepsy23.
The identification of reliable prognostic factors that could predict outcome following temporal lobe surgery for HS is therefore desirable. Studies to date have largely focused on clinical parameters, for example, preoperative seizure history and electroencephalography (EEG) findings18. Recently some impact on seizure outcome of type of auras or age at surgery has been postulated24 but never correlated with pathological type of HS. Temporal polar cortex is involved at the onset of seizures in about 35% of cases of temporal lobe epilepsy with HS3,8,9,11,25. The association of FCD with HS is very common3,6–9.
ACCEPTED MANUSCRIPT Over the past decades, various attempts have been made to classify specific patterns of hippocampal neuronal cell loss and correlate subtypes with postsurgical outcome1,26–28. Furthermore granule cell dispersion (GCD) is a common and as yet unexplained phenomenon of uncertain clinical significance4,5,29–31, occurring in 40-50% % of epilepsy HS specimens overall1,2,4,26. However, it is well known that some pathological changes in DG, such as GCD, granule cell loss (GCL), mossy fiber
RI PT
sprouting, and hilar basal dendrites formation, were closely associated with frequent seizures and status epilepticus (SE)32,33 . Prediction of outcome after temporal lobe surgery is nowadays known to be influenced both by underlying pathology and pre-operative clinical factors1,19,22,34.
Nowadays, the status of the dentate gyrus is no longer considered an accessory histological finding, but rather an additional parameter useful in the prediction of seizure and neuropsychological out-
SC
come4,5,30,35
Recently Na M. et al. demonstrated a significant correlation between HS ILAE types and long-term
M AN U
postoperative seizure outcome in patients with MTLE due to HS with the most favorable long-term seizure outcome noted in the HS type 1 group22.
The pathology driven postsurgical seizures outcome results support the conviction that histological findings represent a significant prognostic parameter and may explain some unexpected failures. Regarding the first Group with isolated HS only 16,7% of patients with an atypical pattern of HS
TE D
(type 2) achieved Engel Class IA, while 66,7% of patients affected by HS type 1 was seizure free. With respect to the presence of GCP only 18,2% of HS-noGCP cases obtained complete seizure freedom while 76% of patients with HS + GCP phenotype had Engel Class IA outcomes. None of the 4 patients with both of negative prognostic factors (HS type 2 and no GCP) reached seizure
EP
freedom.
Our results confirm, as already reported1,4,5,22, that the type of HS and GCP may influence seizure
AC C
outcome. About results of Group II Patients with HS variant type 1 showed a better seizure outcome than the patients with HS type 2 (Engel class IA HS type 1 vs. type 2: 69% vs. 40%). However, no statistically significance was found between the different HS type, FCD type, or GCP type and seizure outcome. In the present series 47 patients showed HS associated with FCD , namely FCD type I (i.e FCD type IIIa) in 78.7% of them and FCD type IIa (“Dual pathology”) in 21,3%( . Analyzing the subgroup of HS associated with FCD type IIa ( 10 cases ) 7 patients were HS type 1 with 85.7% Class I and the remaining 3 were HS type 2 with 66.7 % ClassI. Similar results were recently observed for cases of a glial/glioneuronal tumor associated with FCD type 1 ( FCD type IIIb ) and FCD type IIa ( Double pathology )8,9,36.
ACCEPTED MANUSCRIPT In our experience the patients harboring HS associated with FCD type I (i.e. FCD IIIa) show a seizure outcome similar to patients with isolated HS (81% Engel Class I versus 86%) and better than patients with isolated FCD type I (63% Class I)8,93. However we didn’t perform a multivariate analysis including all clinical features and distinguishing among different FCD types, MTS types
RI PT
and GCP types because of the little sample size.” Our finding, according with the recent literature1,3–5,8,9,26,37,38, suggest that different pathological subtypes are associated with different postsurgical seizure outcomes. This implies that surgical failure, that is seizure recurrence, may occur either because of incomplete resection of the epileptogen-
SC
ic zone or because of an underlying pathological condition predicting a worse outcome.
The relevance on seizure outcome of pathological temporal lobe substrate entail some effects. First of all the epilepsy surgeon should be aware of the relevance of the histopathological
M AN U
assessment and provide an adequate specimens for a proper pathological diagnosis. Moreover, neuropathological diagnosis must follow and strictly observe an adequate international pathological protocol, with demonstrated good interobserver and intraobserver reproducibility for histopathological categories39. Furthermore high-resolution MRI study will provide a valuable promising resource for presurgical identification of subtype of HS, status of DG and temporal pole (FCD) pathology10,33,40–44. Obviously the examination of postoperative imaging and electroclinical data con-
TE D
stitutes the first step of temporal lobe epilepsy surgery failures anyway, after this essential step, for a reliable comprehension of a worse outcome we should keep in mind the underliyng pathological substrate.
EP
Furthermore, considering that DG is a well known site of precursor cells and adult neurogenesis14,45,46 , the pattern of hippocampal and DG damage may influence neuropsycological ed behav-
AC C
ioural outcome14,27,30,35,47
. One limitation of our retrospective study is that it did not take into account the neuropsychological results. This important aspect of temporal lobe epilepsy surgery will be the issue of a further specific study.
Conclusion In our opinion, according to Blümcke et al.15, a pathology based approach to epilepsy surgery might improve the interpretation of the results and the comprehension of the causes of failures and possibly advance imaging pathology correlations. In addition, the recognition of the different subgroups of pathological features associated with different seizure outcomes may stimulate the investigation of the specific epileptogenic
ACCEPTED MANUSCRIPT mechanisms involved. This approach is also in agreement with the recent suggestions of the International League Against Epilepsy (ILAE) Commission on Classifications and Terminology48 to put more emphasis on the underlying pathological substrate in the assessment of postsurgical seizure outcome and in future epilepsy classifications. Correlation of clinical, EEG and neuroimaging aspects with pathological findings and seizure outcome may help to found presurgical markers pre-
RI PT
dictive of a better outcome.
AC C
EP
TE D
M AN U
SC
These information may be very useful to improve patients counseil and making surgical option .
ACCEPTED MANUSCRIPT References 1.
Blümcke I, Thom M, Aronica E, et al. International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: A Task Force report from the ILAE Commission on Diagnostic Methods. Epilepsia. 2013;54(7):1315-1329. doi:10.1111/epi.12220. Wieser H-G. ILAE Commission Report. Mesial temporal lobe epilepsy with hippocampal
RI PT
2.
sclerosis. Epilepsia. 2004;45(6):695-714. doi:10.1111/j.0013-9580.2004.09004.x. 3.
Tassi L, Meroni A, Deleo F, et al. Temporal lobe epilepsy: neuropathological and clinical correlations in 243 surgically treated patients. Epileptic Disord. 2009;11(4):281-292.
4.
SC
doi:10.1684/epd.2009.0279.
Blümcke I, Kistner I, Clusmann H, et al. Towards a clinico-pathological classification of granule cell dispersion in human mesial temporal lobe epilepsies. Acta Neuropathol.
5.
M AN U
2009;117(5):535-544. doi:10.1007/s00401-009-0512-5.
Marucci G, Rubboli G, Giulioni M. Role of dentate gyrus alterations in mesial temporal sclerosis. Clin Neuropathol. 2010;29(1):32-35. doi:10.5414/NPP29032.
6.
Marusic P, Tomásek M, Krsek P, et al. Clinical characteristics in patients with hippocampal sclerosis with or without cortical dysplasia. Epileptic Disord. 2007;9 Suppl 1(December):S75-S82.
Blümcke I, Thom M, Aronica E, et al. The clinicopathologic spectrum of focal cortical dys-
TE D
7.
plasias: A consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia. 2011;52(1):158-174. doi:10.1111/j.1528-
8.
EP
1167.2010.02777.x.
Giulioni M, Marucci G, Martinoni M, et al. Seizure outcome in surgically treated drugresistant mesial temporal lobe epilepsy based on the recent histopathological classifications.
9.
AC C
J Neurosurg. 2013;119(1):37-47. doi:10.3171/2013.3.JNS122132. Martinoni M, Marucci G, Rubboli G, et al. Focal cortical dysplasias in temporal lobe epilepsy surgery: Challenge in defining unusual variants according to the last ILAE classification. Epilepsy Behav. 2015;45:212-216. doi:10.1016/j.yebeh.2015.01.022. 10.
Naves PVF, Caboclo LOSF, Carrete H, et al. Temporopolar blurring in temporal lobe epilepsy with hippocampal sclerosis and long-term prognosis after epilepsy surgery. Epilepsy Res. 2015;112:76-83. doi:10.1016/j.eplepsyres.2015.02.013.
11.
Johnson AM, Sugo E, Barreto D, et al. Clinicopathological associations in temporal lobe epilepsy patients utilising the current ILAE focal cortical dysplasia classification. Epilepsy Res. 2014;108(8):1345-1351. doi:10.1016/j.eplepsyres.2014.06.013.
ACCEPTED MANUSCRIPT 12.
Di Gennaro G, D’Aniello A, De Risi M, et al. Temporal pole abnormalities in temporal lobe epilepsy with hippocampal sclerosis: Clinical significance and seizure outcome after surgery. Seizure. 2015;32:84-91. doi:10.1016/j.seizure.2015.09.016.
13.
Coras R, Siebzehnrubl FA, Pauli E, et al. Low proliferation and differentiation capacities of adult hippocampal stem cells correlate with memory dysfunction in humans. Brain.
14.
RI PT
2010;133(11):3359-3372. doi:10.1093/brain/awq215. Marucci G, Giulioni M, Rubboli G, et al. Neurogenesis in temporal lobe epilepsy: Relationship between histological findings and changes in dentate gyrus proliferative properties. Clin Neurol Neurosurg. 2013;115(2):187-191. doi:10.1016/j.clineuro.2012.05.012.
Blumcke I, Russo G Lo, Najm I, Palmini A. Pathology-based approach to epilepsy surgery.
SC
15.
Acta Neuropathol. 2014;128(1):1-3. doi:10.1007/s00401-014-1301-3. 16.
Wiebe S, Blume WT, Girvin JP, Eliasziw M. A Randomized, Controlled Trial of Surgery for
17.
M AN U
Temporal-Lobe Epilepsy. Vol 345. 2001. doi:10.1097/00132586-200206000-00024. Foldvary N, Nashold B, Mascha E, et al. Seizure outcome after temporal lobectomy for temporal lobe epilepsy: a Kaplan-Meier survival analysis. Neurology. 2000;54(3):630-634. doi:10.1212/WNL.54.3.630. 18.
Spencer S, Huh L. Outcomes of epilepsy surgery in adults and children. Lancet Neurol.
19.
TE D
2008;7(6):525-537. doi:10.1016/S1474-4422(08)70109-1.
McIntosh AM, Kalnins RM, Mitchell LA, Fabinyi GCA, Briellmann RS, Berkovic SF. Temporal lobectomy: Long-term seizure outcome, late recurrence and risks for seizure recurrence. Brain. 2004;127(9):2018-2030. doi:10.1093/brain/awh221. Aull-Watschinger S, Pataraia E, Czech T, Baumgartner C. Outcome predictors for surgical
EP
20.
treatment of temporal lobe epilepsy with hippocampal sclerosis. Epilepsia. 2008;49(8):13081316. doi:10.1111/j.1528-1167.2008.01732.x. Jehi LE, Silveira DC, Bingaman W, Najm I. Temporal lobe epilepsy surgery failures: predic-
AC C
21.
tors of seizure recurrence, yield of reevaluation, and outcome following reoperation. J Neurosurg. 2010;113(6):1186-1194. doi:10.3171/2010.8.JNS10180. 22.
Na M, Ge H, Shi C, et al. Long-term seizure outcome for international consensus classification of hippocampal sclerosis: A survival analysis. Seizure. 2014:1-6. doi:10.1016/j.seizure.2014.10.006.
23.
Harroud A, Bouthillier A, Weil AG, Nguyen DK. Temporal Lobe Epilepsy Surgery Failures: A Review. Epilepsy Res Treat. 2012;2012:1-10. doi:10.1155/2012/201651.
24.
Asadi-Pooya AA, Nei M, Sharan A, Sperling MR. Type of preoperative aura may predict postsurgical outcome in patients with temporal lobe epilepsy and mesial temporal sclerosis.
ACCEPTED MANUSCRIPT Epilepsy Behav. 2015;50:98-100. doi:10.1016/j.yebeh.2015.06.041. 25.
Chabardès S, Kahane P, Minotti L, et al. The temporopolar cortex plays a pivotal role in temporal lobe seizures. Brain. 2005;128(8):1818-1831. doi:10.1093/brain/awh512.
26.
Thom M, Liagkouras I, Elliot KJ, et al. Reliability of patterns of hippocampal sclerosis as predictors of postsurgical outcome. Epilepsia. 2010;51(9):1801-1808. doi:10.1111/j.1528-
27.
RI PT
1167.2010.02681.x. Thom M, Kensche M, Maynard J, et al. Interictal psychosis following temporal lobe surgery: dentate gyrus pathology. Psychol Med. 2014:1-13. doi:10.1017/S0033291714000452. 28.
Blümcke I, Pauli E, Clusmann H, et al. A new clinico-pathological classification system for
SC
mesial temporal sclerosis. Acta Neuropathol. 2007;113(3):235-244. doi:10.1007/s00401-0060187-0. 29.
Fahrner A, Kann G, Flubacher A, et al. Granule cell dispersion is not accompanied by en-
M AN U
hanced neurogenesis in temporal lobe epilepsy patients. Exp Neurol. 2007;203(2):320-332. doi:10.1016/j.expneurol.2006.08.023. 30.
D’Alessio L, Konopka H, Escobar E, et al. Dentate gyrus expression of nestinimmunoreactivity in patients with drug-resistant temporal lobe epilepsy and hippocampal sclerosis. Seizure. 2015;27:75-79. doi:10.1016/j.seizure.2015.02.008. Neves RSDC, De Souza Silva Tudesco I, Jardim AP, et al. Granule cell dispersion is associ-
TE D
31.
ated with memory impairment in right mesial temporal lobe epilepsy. Seizure. 2012;21(9):685-690. doi:10.1016/j.seizure.2012.07.008. 32.
Houser CR. Granule cell dispersion in the dentate gyrus of humans with temporal lobe epi-
33.
EP
lepsy. Brain Res. 1990;535(2):195-204. doi:10.1016/0006-8993(90)91601-C. Na M, Liu Y, Shi C, et al. Prognostic value of CA4/DG volumetry with 3T magnetic resonance imaging on postoperative outcome of epilepsy patients with dentate gyrus pathology.
34.
AC C
Epilepsy Res. 2014;108(8):1315-1325. doi:10.1016/j.eplepsyres.2014.06.005. Ozkara C, Uzan M, Benbir G, et al. Surgical outcome of patients with mesial temporal lobe epilepsy related to hippocampal sclerosis. Epilepsia. 2008;49(4):696-699. doi:10.1111/j.1528-1167.2007.01503.x. 35.
Coras R, Pauli E, Li J, et al. Differential influence of hippocampal subfields to memory formation: Insights from patients with temporal lobe epilepsy. Brain. 2014;137(7):1945-1957. doi:10.1093/brain/awu100.
36.
Cossu M, Fuschillo D, Bramerio M, et al. Epilepsy surgery of focal cortical dysplasiaassociated tumors. Epilepsia. 2013;54(SUPPL. 9):115-122. doi:10.1111/epi.12455.
37.
Tassi L, Garbelli R, Colombo N, et al. Type i focal cortical dysplasia: Surgical outcome is
ACCEPTED MANUSCRIPT related to histopathology. Epileptic Disord. 2010;12(3):181-191. doi:10.1684/epd.2010.0327. 38.
Thom M, Eriksson S, Martinian L, et al. Temporal lobe sclerosis associated with hippocampal sclerosis in temporal lobe epilepsy: neuropathological features. J Neuropathol Exp Neurol. 2009;68(8):928-938. doi:10.1097/NEN.0b013e3181b05d67.
39.
Coras R, De Boer OJ, Armstrong D, et al. Good interobserver and intraobserver agreement in
RI PT
the evaluation of the new ILAE classification of focal cortical dysplasias. Epilepsia. 2012;53(8):1341-1348. doi:10.1111/j.1528-1167.2012.03508.x. 40.
Garbelli R, Zucca I, Milesi G, et al. Combined 7-T MRI and histopathologic study of normal and dysplastic samples from patients with TLE. Neurology. 2011;76(13):1177-1185.
41.
SC
doi:10.1212/WNL.0b013e318212aae1.
Garbelli R, Milesi G, Medici V, et al. Blurring in patients with temporal lobe epilepsy: Clini-
doi:10.1093/brain/aws149. 42.
M AN U
cal, high-field imaging and ultrastructural study. Brain. 2012;135(8):2337-2349.
Colon-Perez LM, King M, Parekh M, et al. High-field magnetic resonance imaging of the human temporal lobe. NeuroImage Clin. 2015;9:58-68. doi:10.1016/j.nicl.2015.07.005.
43.
Zucca I, Milesi G, Medici V, et al. Type II FCD : ex vivo 7 Tesla MRI abnormalities and histopathological comparisons. Ann Neurol. 2015:1-37. doi:10.1002/ana.24541. Schoene-Bake JC, Keller SS, Niehusmann P, et al. In vivo mapping of hippocampal subfields
TE D
44.
in mesial temporal lobe epilepsy: Relation to histopathology. Hum Brain Mapp. 2014;35(9):4718-4728. doi:10.1002/hbm.22506. 45.
Siebzehnrubl F a., Blumcke I. Neurogenesis in the human hippocampus and its relevance to
EP
temporal lobe epilepsies. Epilepsia. 2008;49(SUPPL 5):55-65. doi:10.1111/j.15281167.2008.01638.x. 46.
Paradisi M, Fernández M, Del Vecchio G, et al. Ex vivo study of dentate gyrus neurogenesis
AC C
in human pharmacoresistant temporal lobe epilepsy. Neuropathol Appl Neurobiol. 2010;36(6):535-550. doi:10.1111/j.1365-2990.2010.01102.x. 47.
Winston GP, Stretton J, Sidhu MK, Symms MR, Thompson PJ, Duncan JS. Structural correlates of impaired working memory in hippocampal sclerosis. Epilepsia. 2013:1-11. doi:10.1111/epi.12193.
48.
Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia. 2010;51(4):676-685. doi:10.1111/j.1528-1167.2010.02522.x.
ACCEPTED MANUSCRIPT
TABLE 1: Seizure outcome analysis in group I (HS+/-GCP) and II (HS+FCD+/-GCP)
GROUP
LESION TYPE
NUMBER OF
OUTCOME
PATIENTS
HS* +/- GCP*
36
CLASS II
31 (86,1%)
5 (13,9%)
_
_
7 (14,9%)
2 (4,2%)
_
2 (2,4%)
_
IA:21(58,3%)
HS* + FCD* +/- GCP*
47
38 (80,9%)
TOTAL
83
M AN U
IA:31(66%)
69 (83,1%)
EP
TE D
IA:52(62,7%)
AC C
CLASS IV
SC
GROUP II
CLASS III
RI PT
GROUP I
CLASS I
12 (14,6%)
ACCEPTED MANUSCRIPT
TABLE 2a: Group I (Isolated HS +/- GCP): seizure outcome analysis stratified by HS subtypes
HS TYPE
NUMBER OF
OUTCOME
PATIENTS CLASS IA
OTHER CLASSES
HS TYPE 1
30
27 (90%)
20 (66,7%)
HS TYPE 2
6
4 (66,7%)
1 (16,7%)
RI PT
CLASS I
3 (10%) – 2 class IIB e 1 class IIA
AC C
EP
TE D
M AN U
SC
2 (33,3%) – 2 class IIB
ACCEPTED MANUSCRIPT
TABLE 2b: Group I (Isolated HS +/- GCP): seizure outcome analysis with respect to presence/absence of GCP
HS +/- GCP
NUMBER OF
OUTCOME
PATIENTSI CLASS IA
OTHER CLASSES
HS + GCP
25
24 (96%)
19 (76%)
GCP I
10
10 (100%)
9 (90%)
GCPII
15
14 (93,3%)
10 (66,7%)
HS - noGCP
11
7 (63,6%)
2 (18,2%)
RI PT
CLASS I
1 (4%) --
SC
M AN U TE D EP AC C
1 (6,7%) – class IIB
4 (36,3%) – 1 class IIA e 3 class IIB
ACCEPTED MANUSCRIPT
TABLE 3: Group II (HS + FCD +/- GCP):seizure outcome analysis stratified by FCD subtypes
FCD TYPE
No. OF
OUTCOME
PTS
8 (80%)
4 (40%)
HS 1
7
6 (85,7%)
3 (42,9%)
HS 2
3
2 (66,7%)
1 (33,3%)
37
30 (81,1%)
27 (72,9%)
HS 1
35
28 (80%)
26 (74,2%)
HS 2
2
2 (100%)
1 (50%)
AC C
EP
TE D
FCD IIIA
RI PT
10
FCD IIA + HS I/II
OTHER CLASSES
2 (20%)
1 (14,3%) – class IIB
1 (33,3%) – class IIA
SC
CLASS IA
M AN U
CLASS I
7 (18,9%)
7 (20%) – 4 class IIA, 1 class IIB, 2class IIIA --
ACCEPTED MANUSCRIPT
Highlights
We analyzed patients submitted to surgery for hippocampal sclerosis Associated granular cell pathology and focal cortical dysplasia were reported Relationship between pathology and postoperative seizure outcome is proposed
RI PT
A pathology based approach might improve the interpretation of surgical results
AC C
EP
TE D
M AN U
SC
Post operative failures could be better understood according to histopathology
ACCEPTED MANUSCRIPT
Pathology based approach to seizure outcome after surgery for pharmacoresistant medial temporal lobe epilepsy
The content of this manuscript, in part or in full, has not been published elsewhere in any form.
Financial disclosures: none
RI PT
The authors certify that there are not conflicts of interest.
Authors state they haven't any personal or institutional financial interest in drugs,
SC
materials, or devices described in this submission.
M AN U
Matteo Martinoni MD, Pier Paolo Berti MD, Gianluca Marucci MD, PhD, Guido Rubboli MD, Lilia Volpi MD, Patrizia Riguzzi MD, Federica Marliani MD, Francesco Toni MD, Francesca Bisulli MD, Paolo Tinuper MD, Roberto Michelucci MD, Agostino Baruzzi MD, Marco Giulioni
AC C
EP
TE D
MD
S1878-8750(16)00317-X
DOI:
10.1016/j.wneu.2016.02.072
Reference:
WNEU 3773
To appear in:
World Neurosurgery
Received Date: 20 December 2015 Revised Date:
14 February 2016
Accepted Date: 15 February 2016
Please cite this article as: Martinoni M, Berti PP, Marucci G, Rubboli G, Volpi L, Riguzzi P, Marliani F, Toni F, Bisulli F, Tinuper P, Michelucci R, Baruzzi A, Giulioni M, Pathology based approach to seizure outcome after surgery for pharmacoresistant medial temporal lobe epilepsy, World Neurosurgery (2016), doi: 10.1016/j.wneu.2016.02.072. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Pathology based approach to seizure outcome after surgery for pharmacoresistant medial temporal lobe epilepsy
Matteo Martinoni a, Pier Paolo Berti a, Gianluca Marucci b , Guido Rubboli cd , Lilia Volpi c, Roberto Michelucci c, Agostino Baruzzi
, Marco Giulioni a
IRCCS Institute of Neurological Science of Bologna, Division of Neurosurgery, Bellaria Hospital,
SC
a
fg
Bologna, Italy.
Section of Pathology “M. Malpighi”, Bellaria Hospital, Azienda USL - IRCCS Institute of Neuro-
logical Sciences, Bologna, Italy c
M AN U
b
RI PT
Patrizia Riguzzi c, Federica Marliani e, Francesco Toni e, Francesca Bisulli fg, Paolo Tinuper fg,
IRCCS Institute of Neurological Sciences of Bologna, Division of Neurology, Bellaria Hospital,
Bologna, Italy.
Danish Epilepsy Centre, Dianalund, Denmark.
e
IRCCS Institute of Neurological Sciences of Bologna . Section of Neuroradiology, Bellaria Hos-
TE D
d
pital, Bologna, Italy.
IRCCS Institute of Neurological Sciences of Bologna, Bologna Italy
g
Department of Biomedical and Neuromotor Sciences University of Bologna.
AC C
EP
f
Corresponding Author: Matteo Martinoni MD
IRCCS Institute of Neurological sciences of Bologna, Department of Neurosurgery, Bellaria Hospital 40100, Bologna, Via Altura 1/8 Tel. +39 051 6225111 Fax. +39 051 6225347 Email: [email protected]
ACCEPTED MANUSCRIPT Highest academic degrees for all authors Matteo Martinoni MD a, Pier Paolo Berti MD a, Gianluca Marucci MD PhD b, Guido Rubboli MD cd
, Lilia Volpi MD c, Patrizia Riguzzi MD c, Federica Marliani MD e, Francesco Toni MD e,
Baruzzi MD Prof fg, Marco Giulioni MD a Departmental and institutional affiliations for all authors.
IRCCS Institute of Neurological Science of Bologna, Division of Neurosurgery, Bellaria Hospital,
SC
a
Bologna, Italy.
Section of Pathology “M. Malpighi”, Bellaria Hospital, Azienda USL - IRCCS Institute of Neuro-
logical Sciences, Bologna, Italy c
M AN U
b
RI PT
Francesca Bisulli MD fg, Paolo Tinuper MD Prof fg, Roberto Michelucci MD Prof fg, Agostino
IRCCS Institute of Neurological Sciences of Bologna, Division of Neurology, Bellaria Hospital,
Bologna, Italy.
Danish Epilepsy Centre, Dianalund, Denmark.
e
IRCCS Institute of Neurological Sciences of Bologna . Section of Neuroradiology, Bellaria Hos-
TE D
d
pital, Bologna, Italy.
IRCCS Institute of Neurological Sciences of Bologna, Bologna Italy
g
Department of Biomedical and Neuromotor Sciences University of Bologna.
AC C
EP
f
Key Words : temporal lobe epilepsy; epilepsy surgery; hippocampal sclerosis; granule cell pathology; focal cortical dysplasia; seizure outcome
Abbreviations list: ATL (anterior temporal lobectomy), EEG (electroencephalography), FCD (focal cortical dysplasia), GCL (granular cell loss), GCP ( granular cell pathology), HS (hippocampal sclerosis), MTLE (mesial temporal lobe epilepsy)
ACCEPTED MANUSCRIPT Abstract
Backgrounds Hippocampal sclerosis (HS) is the most common cause of drug-resistant medial temporal lobe epilepsy (MTLE). Structural abnormalities such as HS, granule cell pathology (GCP) and
RI PT
focal cortical dysplasia (FCD), have been histopathologically classified possibly allowing more accurate prognostic seizure and neuropsychological outcome assessment. We correlated seizure outcome with comprehensive temporal lobe pathological findings, identified according to the most recent classification systems of HS, GCP and FCD.
Methods All the 83 patients submitted to anterior temporal lobectomy (ATL) for drug-resistant
SC
MTLE and with a proven diagnosis of HS between April 2001 and May 2014 were collected. Patients were divided in two main groups: 1) Isolated HS with/without GCP (HS +/- GCP) 2) HS as-
M AN U
sociated with FCD with/without GCP (HS+FCD +/- GCP). Patients were followed up at least 1 year and seizure outcome was reported in accordance with Engel classification. Results Group I: HS +/- GCP: Statistical analysis confirmed a better outcome in HS + GCP patients than in HS-noGCP (p < 0,05). Moreover, a better outcome for the patients affected by GCP type I was observed (p < 0,05). Group II: HS+FCD +/- GCP: Patients with HS variant type I pre-
II: 69% vs. 40%).
TE D
sented a better seizure outcome than the patients with HS type II (Engel class IA HS type I vs. type
Conclusions A pathology based approach to epilepsy surgery might improve the interpretation of the results, could predict which cases will enjoy a better seizure outcome and could help to the
AC C
EP
comprehension of the causes of failures.
Key Words : temporal lobe epilepsy ,epilepsy surgery , Hippocampal Sclerosis , Granule cell pathology , focal cortical dysplasia , seizure outcome
ACCEPTED MANUSCRIPT Introduction
Drug-resistant mesial temporal lobe epilepsy (MTLE) is the most common type of epilepsy requiring surgical treatment, with a favorable seizure outcome being achieved in about 60%–80% of pa-
RI PT
tients. Hippocampal sclerosis (HS) is the most common cause of drug-resistant MTLE1–3. Furthermore, in 50% of cases HS is associated with dentate gyrus pathology1,4,5) and in 60-70% of cases with focal cortical dysplasia (FCD) in temporopolar cortex3,6–12. Epileptogenic structural abnormalities, such as HS, granule cell pathology (GCP) and FCD, have been histopathologically subclassineuropsycological outcome assessment1,4,5,7,13,14.
SC
fied, possibly allowing more accurate clinico-pathological correlations and prognostic seizure and A pathology based approach15 might improve the interpretation of the results and the comprehen-
M AN U
sion of the causes of failures improving criteria for selection of patients for epilepsy surgery. In this study, we analyzed seizure outcome in a population of consecutive patients presenting with drug resistant MTLE, associated with HS, who underwent tailored anteromesial temporal lobe resection after extensive presurgical evaluation without invasive procedures. In particular, we correlated seizure outcome with comprehensive temporal lobe ( temporo mesial and temporo polar structures) pathological findings, identified according to the most recent
Material and Methods
TE D
classification systems of HS1, GCP4 and FCD7.
EP
We conducted a restrospective study at the Epilepsy Surgery Centre of the Institute of Neurological Sciences, Bellaria Hospital, Bologna. Data of all the patients who underwent tailored surgery for drug-resistant MTLE and with a proven diagnosis of HS between April 2001 and May 2014 were
AC C
collected, for a total of 83 patients. Following the most recent histopathological classification systems, patients were divided in two main groups: 1) Isolated HS with/without GCP (HS +/- GCP); 2) HS associated with FCD with/without GCP (HS+FCD +/- GCP). In all cases a detailed clinical history was taken and presurgical neurophysiological assessment was performed by means of EEG, inter-critial EEG and long-term video-EEG monitoring for seizure characterization. Electroencephalographic signals were collected by means of silver-silver chloride electrodes according to the international 10-20 system; only in selected cases were used additional electrodes (zygomatic or supraorbital). All the patients underwent MRI study (1,5T MRI until 2005 and 3-T MRI since 2006) using the following protocol: sagittal spoiled gradient-recalled acquisition
ACCEPTED MANUSCRIPT T1-weighted, axial T2-weighted, axial and coronal FLAIR T2-weighted, coronal gradient echo, coronal T2-weighted and coronal T1-weighted inversion recovery sequences and, when necessary, axial, sagittal, and coronal T1-weighted sequences obtained after injection of gadolinium were added. Proton Magnetic Resonance Spectroscopy (1H-MRS) was introduced in the presurgical examination since 2005. Moreover, all patients underwent a campimetric analysis of the visual field and a
RI PT
neuropsychological evaluation. The surgical planning and the surgical procedure were mainly defined according to the anatomoelectro-clinical correlations of the seizures, EEG and long term video EEG findings and MRI data. All patients were submitted to a preoperative neuropsychological evaluation. The Wada test was not
SC
performed in any case. Only in selected cases DTI, PET and functional MRI were performed for presurgical language mapping.
Patients were followed up at least 1 year and seizure outcome was reported in accordance with En-
M AN U
gel classification. In this study we did not analyze the neuropsychological outcome.
Surgical procedure
All operation were carried out by the same senior surgeon (M.G.), who performed tailored procedures of Anterior Temporal Lobectomy (ATL) aimed at removal of the epileptogenic zone (tailored
TE D
surgery) as identified by presurgical evaluation.
In all cases the tailored surgery mainly consisted of removing the temporal pole, the anterior necortical lateral cortex, the uncus-entorhinal area, the parahippocampal gyrus and the hippocampus. The main surgical specimens (hippocampus and temporal pole) were removed en bloc and spatially ori-
EP
ented. This procedure is essential to allow the best pathological examination and the identification
AC C
of an eventual FCD in the temporal pole cortex
Pathological examination
Hippocampal specimens were dissected along the anterior-posterior axis, and samples from the mid-hippocampal body were chosen for evaluation. The temporal pole was cut perpendicular to the pial surface and was analyzed in 3 to 5 mm sections. Tissue was fixed in 10% buffered formalin and embedded in paraffin. Paraffin sections of 4 µm were serially cut and underwent H&E, Nissl and Kluver staining. Serial, 4-lm-thick, paraffin sections mounted on precoated slides were processed using standardized automated procedures using prediluted antibodies (Ventana-Benchmark, Tucson, AZ, USA), with the exception of anti-NeuN (clone A60, dilution 1:500, Chemicon-Millipore Corp, Billerica, MA) antibody. Immunohistochemistry was performed using Polymer as detection system (Ultravision LP
ACCEPTED MANUSCRIPT Detection System HRP Polymer; LabVision, Freemont, CA, USA). The prediluted antibodies were anti-GFAP (polyclonal), anti-synaptophysin (polyclonal) and anti-CD34 (clone Qbend/10). Appropriate positive and negative controls were performed. All cases were histologically reviewed in accordance with the most recent pathological classifica-
RI PT
tion for HS1 , GCP4 and FCD7.
Statistical Analysis
Data are presented as mean and range. Statistical analysis was performed to investigate eventual differences between age at surgery, epilepsy duration or histopathological lesion pattern relative to
SC
seizure outcome.
Statistical significance for categorical comparison was determined by the Fisher exact test or Eta squared when more than 2 categories were considered. The Mann-Withney U-test and Kruskal-
M AN U
Wallis test were used for the comparison of continuous variables between 2 or more groups. A p value of less than 0.05 was considered statistically significant. Statistical analysis were performed using SPSS software version 16.0.
Results
TE D
We analyzed 83 consecutive patients (34 male and 49 female) submitted to anteromesial resection for drug-resistant MTLE between April 2001 and May 2014 with a proven diagnosis of HS. Mean age at epilepsy onset was 12 years (range 6 months – 46 years), mean age at surgery was 37 years (range 17 – 66 years) and mean duration of epilepsy was 25 years (range 2 – 53 years). Mean dura-
EP
tion of follow up was 8 years (range 1 – 14 years). In all cases the main surgical specimens (temporal pole and hippocampus) were adequate for an appropriate histopathological evaluation. Ac-
AC C
cording to the histological findings, the patients were divided into 2 main groups (table 1): Isolated HS with/without GCP: 36 cases HS associated with FCD with/without GCP: 47 cases. No statistically significant differences were found between any of the groups with respect to age at surgery, epilepsy duration and seizure outcome (fig. I). All the patients were submitted to postoperative CT scan immediately or within 6 hour and MRI study within 6 months after surgery. All patients performed an EEG study within 6 months after surgery. In 10 out of the 14 cases that did not achieve an Engel Class 1 the postoperative EEG showed omolateral temporal interictal epileptiform abnormalities however in 4 out of 14 cases no EEG abnormalities have been detected. Analysis of postoperative MRI in the group with a worse outcome showed in all cases a substantial agreement
ACCEPTED MANUSCRIPT with preoperative resection planning. Furthermore, in all cases EEG and clinical study did not ruled out clear suggestions helping to explain the causes of failures. We didn’t focused on the results of postoperative neuropsychological evaluation Group I: HS +/- GCP Isolated HS was observed in 36 patients (15 male, 21 female; 43,3% of the series). Mean age at sur-
RI PT
gery was 37 years (19 – 66 years); mean age at epilepsy onset was 11 years (range 6 months – 46 years) and mean duration of the epilepsy history was 23 years and 6 months (range 4 – 53 years). 30 patients (83,3%) presented HS type 1 while the remaining 6 patients (16,7%) had HS type 2. None of this group was affected by HS type 3. Concomitant abnormalities in the dentate gyrus was ob-
SC
served in 25 cases (69,4%): namely 10 patients (27,8%) presented GCP type I and the remaining 15 cases (41,6%) showed GCP type II.
In table IIa and IIb is illustrated seizure outcome related to each histological subgroups: only 1
M AN U
(16,7%) of 6 patients with an atypical pattern of HS (type 2) achieved Engel Class IA, while 20 of 30 patients (66,7%) affected by HS type 1 were seizure free (table. 2a). With respect to the presence of GCP only 2 out of 11 cases (18,2%) of HS-noGCP obtained complete seizure freedom while 19 of 25 patients (76%) with HS + GCP phenotype had Engel Class IA outcomes (table. 2B). None of the 4 patients with both of negative prognostic factors (HS type 2
TE D
and no GCP) reached seizure freedom (table. 2b).
Statistical analysis confirmed a better outcome in HS + GCP patients than in HS-noGCP (p < 0,05). Moreover, a better outcome for the patients affected by GCP type I was observed, comparing the different 3 subtypes of GCP (noGCP, GCP type I, GCP type II) (p < 0,05).
EP
Group II: HS+FCD +/- GCP
This group included 47 patients (19 male and 28 female; 56,6% of the series). Mean age at surgery was 38 years (range 17 – 60 years); mean age at epilepsy onset was 12 years (range 6 months – 32
AC C
years) with a particularly long pharmacoresistance history before surgery (from 2 to 44 years; mean age 26 years). The most common histological association observed in this group was HS + FCD type I (FCD type IIIa) with 37 cases (78,7%): 35 patients was affected by HS type 1 + FCD type I and only 2 patients by HS type 2 + FCD type I. In 10 cases (21,3%) was reported the association HS + FCD IIA (dual pathology): 7 patients were HS type 1 and the remaining 3 were HS type 2. Moreover, 30 of 47 patients (63,8%) had concomitant GCP: namely 11 patients (39,3%) had GCP type I and the remaining 19 were affected by GCP type II. In table 3 is reported seizure outcome with respect to histopathological background. Patients with HS type 1 presented a better seizure outcome than the patients with HS type 2 (Engel class IA HS type 1 vs. type 2: 69% vs. 40%).
ACCEPTED MANUSCRIPT However, no statistically significance was found between the different HS type, FCD type, or GCP type and seizure outcome. Complications No patients died during surgery or the postoperative course. Surgical complications occurred in 5 cases (6%): 1 patient with superficial wound infection needed antibiotic therapy, in 3 cases of post-
RI PT
operative deep venous thrombosis was necessary an anticoagulant treatment and 1 patients with sagging the bone flap required reoperation. 8 patients (9,6%) presented hyperpyrexia related to aseptic meningitis (no antibiotic therapy was required) and a considerable reduction of these cases after the introduction of intraoperative corticosteroids was observed.
SC
Major neurological complications were limited to 2 cases (2,4%) of hemianopia while, as minor complications, transitory dysphasia occurred in 1 patient (1,2%) and we didn’t observe any case of
M AN U
persistent postoperative language deficit.
Neuropsychological and psychiatric side effects were not addressed in this study.
Discussion
Mesial temporal lobe epilepsy associated to hippocampal sclerosis (MTLE-HS) is the most com-
TE D
mon cause of refractory epilepsy in adulthood and surgery is regarded as the treatment of choice16. The literature provides relatively consistent data that up to approximately two-thirds of patients will become seizure-free after surgery17–19. However approximately 20%–30% of patients continue to have seizures20–22.
EP
Five major causes are commonly identified in the literature as a cause of failures : (1) insufficient resection of mesial temporal structures, (2) insufficient or non resection of temporal neocortex, (3)
AC C
dual pathology, (4) relapse on the contralateral temporal lobe, (5) extratemporal and temporal plus epilepsy23.
The identification of reliable prognostic factors that could predict outcome following temporal lobe surgery for HS is therefore desirable. Studies to date have largely focused on clinical parameters, for example, preoperative seizure history and electroencephalography (EEG) findings18. Recently some impact on seizure outcome of type of auras or age at surgery has been postulated24 but never correlated with pathological type of HS. Temporal polar cortex is involved at the onset of seizures in about 35% of cases of temporal lobe epilepsy with HS3,8,9,11,25. The association of FCD with HS is very common3,6–9.
ACCEPTED MANUSCRIPT Over the past decades, various attempts have been made to classify specific patterns of hippocampal neuronal cell loss and correlate subtypes with postsurgical outcome1,26–28. Furthermore granule cell dispersion (GCD) is a common and as yet unexplained phenomenon of uncertain clinical significance4,5,29–31, occurring in 40-50% % of epilepsy HS specimens overall1,2,4,26. However, it is well known that some pathological changes in DG, such as GCD, granule cell loss (GCL), mossy fiber
RI PT
sprouting, and hilar basal dendrites formation, were closely associated with frequent seizures and status epilepticus (SE)32,33 . Prediction of outcome after temporal lobe surgery is nowadays known to be influenced both by underlying pathology and pre-operative clinical factors1,19,22,34.
Nowadays, the status of the dentate gyrus is no longer considered an accessory histological finding, but rather an additional parameter useful in the prediction of seizure and neuropsychological out-
SC
come4,5,30,35
Recently Na M. et al. demonstrated a significant correlation between HS ILAE types and long-term
M AN U
postoperative seizure outcome in patients with MTLE due to HS with the most favorable long-term seizure outcome noted in the HS type 1 group22.
The pathology driven postsurgical seizures outcome results support the conviction that histological findings represent a significant prognostic parameter and may explain some unexpected failures. Regarding the first Group with isolated HS only 16,7% of patients with an atypical pattern of HS
TE D
(type 2) achieved Engel Class IA, while 66,7% of patients affected by HS type 1 was seizure free. With respect to the presence of GCP only 18,2% of HS-noGCP cases obtained complete seizure freedom while 76% of patients with HS + GCP phenotype had Engel Class IA outcomes. None of the 4 patients with both of negative prognostic factors (HS type 2 and no GCP) reached seizure
EP
freedom.
Our results confirm, as already reported1,4,5,22, that the type of HS and GCP may influence seizure
AC C
outcome. About results of Group II Patients with HS variant type 1 showed a better seizure outcome than the patients with HS type 2 (Engel class IA HS type 1 vs. type 2: 69% vs. 40%). However, no statistically significance was found between the different HS type, FCD type, or GCP type and seizure outcome. In the present series 47 patients showed HS associated with FCD , namely FCD type I (i.e FCD type IIIa) in 78.7% of them and FCD type IIa (“Dual pathology”) in 21,3%( . Analyzing the subgroup of HS associated with FCD type IIa ( 10 cases ) 7 patients were HS type 1 with 85.7% Class I and the remaining 3 were HS type 2 with 66.7 % ClassI. Similar results were recently observed for cases of a glial/glioneuronal tumor associated with FCD type 1 ( FCD type IIIb ) and FCD type IIa ( Double pathology )8,9,36.
ACCEPTED MANUSCRIPT In our experience the patients harboring HS associated with FCD type I (i.e. FCD IIIa) show a seizure outcome similar to patients with isolated HS (81% Engel Class I versus 86%) and better than patients with isolated FCD type I (63% Class I)8,93. However we didn’t perform a multivariate analysis including all clinical features and distinguishing among different FCD types, MTS types
RI PT
and GCP types because of the little sample size.” Our finding, according with the recent literature1,3–5,8,9,26,37,38, suggest that different pathological subtypes are associated with different postsurgical seizure outcomes. This implies that surgical failure, that is seizure recurrence, may occur either because of incomplete resection of the epileptogen-
SC
ic zone or because of an underlying pathological condition predicting a worse outcome.
The relevance on seizure outcome of pathological temporal lobe substrate entail some effects. First of all the epilepsy surgeon should be aware of the relevance of the histopathological
M AN U
assessment and provide an adequate specimens for a proper pathological diagnosis. Moreover, neuropathological diagnosis must follow and strictly observe an adequate international pathological protocol, with demonstrated good interobserver and intraobserver reproducibility for histopathological categories39. Furthermore high-resolution MRI study will provide a valuable promising resource for presurgical identification of subtype of HS, status of DG and temporal pole (FCD) pathology10,33,40–44. Obviously the examination of postoperative imaging and electroclinical data con-
TE D
stitutes the first step of temporal lobe epilepsy surgery failures anyway, after this essential step, for a reliable comprehension of a worse outcome we should keep in mind the underliyng pathological substrate.
EP
Furthermore, considering that DG is a well known site of precursor cells and adult neurogenesis14,45,46 , the pattern of hippocampal and DG damage may influence neuropsycological ed behav-
AC C
ioural outcome14,27,30,35,47
. One limitation of our retrospective study is that it did not take into account the neuropsychological results. This important aspect of temporal lobe epilepsy surgery will be the issue of a further specific study.
Conclusion In our opinion, according to Blümcke et al.15, a pathology based approach to epilepsy surgery might improve the interpretation of the results and the comprehension of the causes of failures and possibly advance imaging pathology correlations. In addition, the recognition of the different subgroups of pathological features associated with different seizure outcomes may stimulate the investigation of the specific epileptogenic
ACCEPTED MANUSCRIPT mechanisms involved. This approach is also in agreement with the recent suggestions of the International League Against Epilepsy (ILAE) Commission on Classifications and Terminology48 to put more emphasis on the underlying pathological substrate in the assessment of postsurgical seizure outcome and in future epilepsy classifications. Correlation of clinical, EEG and neuroimaging aspects with pathological findings and seizure outcome may help to found presurgical markers pre-
RI PT
dictive of a better outcome.
AC C
EP
TE D
M AN U
SC
These information may be very useful to improve patients counseil and making surgical option .
ACCEPTED MANUSCRIPT References 1.
Blümcke I, Thom M, Aronica E, et al. International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: A Task Force report from the ILAE Commission on Diagnostic Methods. Epilepsia. 2013;54(7):1315-1329. doi:10.1111/epi.12220. Wieser H-G. ILAE Commission Report. Mesial temporal lobe epilepsy with hippocampal
RI PT
2.
sclerosis. Epilepsia. 2004;45(6):695-714. doi:10.1111/j.0013-9580.2004.09004.x. 3.
Tassi L, Meroni A, Deleo F, et al. Temporal lobe epilepsy: neuropathological and clinical correlations in 243 surgically treated patients. Epileptic Disord. 2009;11(4):281-292.
4.
SC
doi:10.1684/epd.2009.0279.
Blümcke I, Kistner I, Clusmann H, et al. Towards a clinico-pathological classification of granule cell dispersion in human mesial temporal lobe epilepsies. Acta Neuropathol.
5.
M AN U
2009;117(5):535-544. doi:10.1007/s00401-009-0512-5.
Marucci G, Rubboli G, Giulioni M. Role of dentate gyrus alterations in mesial temporal sclerosis. Clin Neuropathol. 2010;29(1):32-35. doi:10.5414/NPP29032.
6.
Marusic P, Tomásek M, Krsek P, et al. Clinical characteristics in patients with hippocampal sclerosis with or without cortical dysplasia. Epileptic Disord. 2007;9 Suppl 1(December):S75-S82.
Blümcke I, Thom M, Aronica E, et al. The clinicopathologic spectrum of focal cortical dys-
TE D
7.
plasias: A consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia. 2011;52(1):158-174. doi:10.1111/j.1528-
8.
EP
1167.2010.02777.x.
Giulioni M, Marucci G, Martinoni M, et al. Seizure outcome in surgically treated drugresistant mesial temporal lobe epilepsy based on the recent histopathological classifications.
9.
AC C
J Neurosurg. 2013;119(1):37-47. doi:10.3171/2013.3.JNS122132. Martinoni M, Marucci G, Rubboli G, et al. Focal cortical dysplasias in temporal lobe epilepsy surgery: Challenge in defining unusual variants according to the last ILAE classification. Epilepsy Behav. 2015;45:212-216. doi:10.1016/j.yebeh.2015.01.022. 10.
Naves PVF, Caboclo LOSF, Carrete H, et al. Temporopolar blurring in temporal lobe epilepsy with hippocampal sclerosis and long-term prognosis after epilepsy surgery. Epilepsy Res. 2015;112:76-83. doi:10.1016/j.eplepsyres.2015.02.013.
11.
Johnson AM, Sugo E, Barreto D, et al. Clinicopathological associations in temporal lobe epilepsy patients utilising the current ILAE focal cortical dysplasia classification. Epilepsy Res. 2014;108(8):1345-1351. doi:10.1016/j.eplepsyres.2014.06.013.
ACCEPTED MANUSCRIPT 12.
Di Gennaro G, D’Aniello A, De Risi M, et al. Temporal pole abnormalities in temporal lobe epilepsy with hippocampal sclerosis: Clinical significance and seizure outcome after surgery. Seizure. 2015;32:84-91. doi:10.1016/j.seizure.2015.09.016.
13.
Coras R, Siebzehnrubl FA, Pauli E, et al. Low proliferation and differentiation capacities of adult hippocampal stem cells correlate with memory dysfunction in humans. Brain.
14.
RI PT
2010;133(11):3359-3372. doi:10.1093/brain/awq215. Marucci G, Giulioni M, Rubboli G, et al. Neurogenesis in temporal lobe epilepsy: Relationship between histological findings and changes in dentate gyrus proliferative properties. Clin Neurol Neurosurg. 2013;115(2):187-191. doi:10.1016/j.clineuro.2012.05.012.
Blumcke I, Russo G Lo, Najm I, Palmini A. Pathology-based approach to epilepsy surgery.
SC
15.
Acta Neuropathol. 2014;128(1):1-3. doi:10.1007/s00401-014-1301-3. 16.
Wiebe S, Blume WT, Girvin JP, Eliasziw M. A Randomized, Controlled Trial of Surgery for
17.
M AN U
Temporal-Lobe Epilepsy. Vol 345. 2001. doi:10.1097/00132586-200206000-00024. Foldvary N, Nashold B, Mascha E, et al. Seizure outcome after temporal lobectomy for temporal lobe epilepsy: a Kaplan-Meier survival analysis. Neurology. 2000;54(3):630-634. doi:10.1212/WNL.54.3.630. 18.
Spencer S, Huh L. Outcomes of epilepsy surgery in adults and children. Lancet Neurol.
19.
TE D
2008;7(6):525-537. doi:10.1016/S1474-4422(08)70109-1.
McIntosh AM, Kalnins RM, Mitchell LA, Fabinyi GCA, Briellmann RS, Berkovic SF. Temporal lobectomy: Long-term seizure outcome, late recurrence and risks for seizure recurrence. Brain. 2004;127(9):2018-2030. doi:10.1093/brain/awh221. Aull-Watschinger S, Pataraia E, Czech T, Baumgartner C. Outcome predictors for surgical
EP
20.
treatment of temporal lobe epilepsy with hippocampal sclerosis. Epilepsia. 2008;49(8):13081316. doi:10.1111/j.1528-1167.2008.01732.x. Jehi LE, Silveira DC, Bingaman W, Najm I. Temporal lobe epilepsy surgery failures: predic-
AC C
21.
tors of seizure recurrence, yield of reevaluation, and outcome following reoperation. J Neurosurg. 2010;113(6):1186-1194. doi:10.3171/2010.8.JNS10180. 22.
Na M, Ge H, Shi C, et al. Long-term seizure outcome for international consensus classification of hippocampal sclerosis: A survival analysis. Seizure. 2014:1-6. doi:10.1016/j.seizure.2014.10.006.
23.
Harroud A, Bouthillier A, Weil AG, Nguyen DK. Temporal Lobe Epilepsy Surgery Failures: A Review. Epilepsy Res Treat. 2012;2012:1-10. doi:10.1155/2012/201651.
24.
Asadi-Pooya AA, Nei M, Sharan A, Sperling MR. Type of preoperative aura may predict postsurgical outcome in patients with temporal lobe epilepsy and mesial temporal sclerosis.
ACCEPTED MANUSCRIPT Epilepsy Behav. 2015;50:98-100. doi:10.1016/j.yebeh.2015.06.041. 25.
Chabardès S, Kahane P, Minotti L, et al. The temporopolar cortex plays a pivotal role in temporal lobe seizures. Brain. 2005;128(8):1818-1831. doi:10.1093/brain/awh512.
26.
Thom M, Liagkouras I, Elliot KJ, et al. Reliability of patterns of hippocampal sclerosis as predictors of postsurgical outcome. Epilepsia. 2010;51(9):1801-1808. doi:10.1111/j.1528-
27.
RI PT
1167.2010.02681.x. Thom M, Kensche M, Maynard J, et al. Interictal psychosis following temporal lobe surgery: dentate gyrus pathology. Psychol Med. 2014:1-13. doi:10.1017/S0033291714000452. 28.
Blümcke I, Pauli E, Clusmann H, et al. A new clinico-pathological classification system for
SC
mesial temporal sclerosis. Acta Neuropathol. 2007;113(3):235-244. doi:10.1007/s00401-0060187-0. 29.
Fahrner A, Kann G, Flubacher A, et al. Granule cell dispersion is not accompanied by en-
M AN U
hanced neurogenesis in temporal lobe epilepsy patients. Exp Neurol. 2007;203(2):320-332. doi:10.1016/j.expneurol.2006.08.023. 30.
D’Alessio L, Konopka H, Escobar E, et al. Dentate gyrus expression of nestinimmunoreactivity in patients with drug-resistant temporal lobe epilepsy and hippocampal sclerosis. Seizure. 2015;27:75-79. doi:10.1016/j.seizure.2015.02.008. Neves RSDC, De Souza Silva Tudesco I, Jardim AP, et al. Granule cell dispersion is associ-
TE D
31.
ated with memory impairment in right mesial temporal lobe epilepsy. Seizure. 2012;21(9):685-690. doi:10.1016/j.seizure.2012.07.008. 32.
Houser CR. Granule cell dispersion in the dentate gyrus of humans with temporal lobe epi-
33.
EP
lepsy. Brain Res. 1990;535(2):195-204. doi:10.1016/0006-8993(90)91601-C. Na M, Liu Y, Shi C, et al. Prognostic value of CA4/DG volumetry with 3T magnetic resonance imaging on postoperative outcome of epilepsy patients with dentate gyrus pathology.
34.
AC C
Epilepsy Res. 2014;108(8):1315-1325. doi:10.1016/j.eplepsyres.2014.06.005. Ozkara C, Uzan M, Benbir G, et al. Surgical outcome of patients with mesial temporal lobe epilepsy related to hippocampal sclerosis. Epilepsia. 2008;49(4):696-699. doi:10.1111/j.1528-1167.2007.01503.x. 35.
Coras R, Pauli E, Li J, et al. Differential influence of hippocampal subfields to memory formation: Insights from patients with temporal lobe epilepsy. Brain. 2014;137(7):1945-1957. doi:10.1093/brain/awu100.
36.
Cossu M, Fuschillo D, Bramerio M, et al. Epilepsy surgery of focal cortical dysplasiaassociated tumors. Epilepsia. 2013;54(SUPPL. 9):115-122. doi:10.1111/epi.12455.
37.
Tassi L, Garbelli R, Colombo N, et al. Type i focal cortical dysplasia: Surgical outcome is
ACCEPTED MANUSCRIPT related to histopathology. Epileptic Disord. 2010;12(3):181-191. doi:10.1684/epd.2010.0327. 38.
Thom M, Eriksson S, Martinian L, et al. Temporal lobe sclerosis associated with hippocampal sclerosis in temporal lobe epilepsy: neuropathological features. J Neuropathol Exp Neurol. 2009;68(8):928-938. doi:10.1097/NEN.0b013e3181b05d67.
39.
Coras R, De Boer OJ, Armstrong D, et al. Good interobserver and intraobserver agreement in
RI PT
the evaluation of the new ILAE classification of focal cortical dysplasias. Epilepsia. 2012;53(8):1341-1348. doi:10.1111/j.1528-1167.2012.03508.x. 40.
Garbelli R, Zucca I, Milesi G, et al. Combined 7-T MRI and histopathologic study of normal and dysplastic samples from patients with TLE. Neurology. 2011;76(13):1177-1185.
41.
SC
doi:10.1212/WNL.0b013e318212aae1.
Garbelli R, Milesi G, Medici V, et al. Blurring in patients with temporal lobe epilepsy: Clini-
doi:10.1093/brain/aws149. 42.
M AN U
cal, high-field imaging and ultrastructural study. Brain. 2012;135(8):2337-2349.
Colon-Perez LM, King M, Parekh M, et al. High-field magnetic resonance imaging of the human temporal lobe. NeuroImage Clin. 2015;9:58-68. doi:10.1016/j.nicl.2015.07.005.
43.
Zucca I, Milesi G, Medici V, et al. Type II FCD : ex vivo 7 Tesla MRI abnormalities and histopathological comparisons. Ann Neurol. 2015:1-37. doi:10.1002/ana.24541. Schoene-Bake JC, Keller SS, Niehusmann P, et al. In vivo mapping of hippocampal subfields
TE D
44.
in mesial temporal lobe epilepsy: Relation to histopathology. Hum Brain Mapp. 2014;35(9):4718-4728. doi:10.1002/hbm.22506. 45.
Siebzehnrubl F a., Blumcke I. Neurogenesis in the human hippocampus and its relevance to
EP
temporal lobe epilepsies. Epilepsia. 2008;49(SUPPL 5):55-65. doi:10.1111/j.15281167.2008.01638.x. 46.
Paradisi M, Fernández M, Del Vecchio G, et al. Ex vivo study of dentate gyrus neurogenesis
AC C
in human pharmacoresistant temporal lobe epilepsy. Neuropathol Appl Neurobiol. 2010;36(6):535-550. doi:10.1111/j.1365-2990.2010.01102.x. 47.
Winston GP, Stretton J, Sidhu MK, Symms MR, Thompson PJ, Duncan JS. Structural correlates of impaired working memory in hippocampal sclerosis. Epilepsia. 2013:1-11. doi:10.1111/epi.12193.
48.
Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia. 2010;51(4):676-685. doi:10.1111/j.1528-1167.2010.02522.x.
ACCEPTED MANUSCRIPT
TABLE 1: Seizure outcome analysis in group I (HS+/-GCP) and II (HS+FCD+/-GCP)
GROUP
LESION TYPE
NUMBER OF
OUTCOME
PATIENTS
HS* +/- GCP*
36
CLASS II
31 (86,1%)
5 (13,9%)
_
_
7 (14,9%)
2 (4,2%)
_
2 (2,4%)
_
IA:21(58,3%)
HS* + FCD* +/- GCP*
47
38 (80,9%)
TOTAL
83
M AN U
IA:31(66%)
69 (83,1%)
EP
TE D
IA:52(62,7%)
AC C
CLASS IV
SC
GROUP II
CLASS III
RI PT
GROUP I
CLASS I
12 (14,6%)
ACCEPTED MANUSCRIPT
TABLE 2a: Group I (Isolated HS +/- GCP): seizure outcome analysis stratified by HS subtypes
HS TYPE
NUMBER OF
OUTCOME
PATIENTS CLASS IA
OTHER CLASSES
HS TYPE 1
30
27 (90%)
20 (66,7%)
HS TYPE 2
6
4 (66,7%)
1 (16,7%)
RI PT
CLASS I
3 (10%) – 2 class IIB e 1 class IIA
AC C
EP
TE D
M AN U
SC
2 (33,3%) – 2 class IIB
ACCEPTED MANUSCRIPT
TABLE 2b: Group I (Isolated HS +/- GCP): seizure outcome analysis with respect to presence/absence of GCP
HS +/- GCP
NUMBER OF
OUTCOME
PATIENTSI CLASS IA
OTHER CLASSES
HS + GCP
25
24 (96%)
19 (76%)
GCP I
10
10 (100%)
9 (90%)
GCPII
15
14 (93,3%)
10 (66,7%)
HS - noGCP
11
7 (63,6%)
2 (18,2%)
RI PT
CLASS I
1 (4%) --
SC
M AN U TE D EP AC C
1 (6,7%) – class IIB
4 (36,3%) – 1 class IIA e 3 class IIB
ACCEPTED MANUSCRIPT
TABLE 3: Group II (HS + FCD +/- GCP):seizure outcome analysis stratified by FCD subtypes
FCD TYPE
No. OF
OUTCOME
PTS
8 (80%)
4 (40%)
HS 1
7
6 (85,7%)
3 (42,9%)
HS 2
3
2 (66,7%)
1 (33,3%)
37
30 (81,1%)
27 (72,9%)
HS 1
35
28 (80%)
26 (74,2%)
HS 2
2
2 (100%)
1 (50%)
AC C
EP
TE D
FCD IIIA
RI PT
10
FCD IIA + HS I/II
OTHER CLASSES
2 (20%)
1 (14,3%) – class IIB
1 (33,3%) – class IIA
SC
CLASS IA
M AN U
CLASS I
7 (18,9%)
7 (20%) – 4 class IIA, 1 class IIB, 2class IIIA --
ACCEPTED MANUSCRIPT
Highlights
We analyzed patients submitted to surgery for hippocampal sclerosis Associated granular cell pathology and focal cortical dysplasia were reported Relationship between pathology and postoperative seizure outcome is proposed
RI PT
A pathology based approach might improve the interpretation of surgical results
AC C
EP
TE D
M AN U
SC
Post operative failures could be better understood according to histopathology
ACCEPTED MANUSCRIPT
Pathology based approach to seizure outcome after surgery for pharmacoresistant medial temporal lobe epilepsy
The content of this manuscript, in part or in full, has not been published elsewhere in any form.
Financial disclosures: none
RI PT
The authors certify that there are not conflicts of interest.
Authors state they haven't any personal or institutional financial interest in drugs,
SC
materials, or devices described in this submission.
M AN U
Matteo Martinoni MD, Pier Paolo Berti MD, Gianluca Marucci MD, PhD, Guido Rubboli MD, Lilia Volpi MD, Patrizia Riguzzi MD, Federica Marliani MD, Francesco Toni MD, Francesca Bisulli MD, Paolo Tinuper MD, Roberto Michelucci MD, Agostino Baruzzi MD, Marco Giulioni
AC C
EP
TE D
MD