- Email: [email protected]
Mammillary body changes and seizure outcome after laser interstitial thermal therapy of the mesial temporal lobe
Epilepsy Research 141 (2018) 19–22
Contents lists available at ScienceDirect
Epilepsy Research journal homepage: www.elsevier.com/locate/epilepsyres
Mammillary body changes and seizure outcome after laser interstitial thermal therapy of the mesial temporal lobe
T
⁎
Sanjeet S. Grewala, Vivek Guptab, , Prasanna Vibhuteb, Jerry J. Shihc,1, William O. Tatumc, Robert E. Wharena a
Department of Neurosurgery, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, United States Department of Radiology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, United States c Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, United States b
A R T I C L E I N F O
A B S T R A C T
Keywords: LiTT Mammillary body Mesial temporal lobe
Objective: The mammillary bodies have long been known as the primary relay center for the hippocampus. The fornix is the primary efferent pathway of the hippocampus, with its postcommissural fibers terminating in the mammillary bodies. In this study, we describe change in mammillary body volume after laser interstitial thermal therapy (LiTT) for mesial temporal lobe epilepsy and correlate it with seizure outcome. Methods: Pre- and post-LiTT ablation magnetic resonance imaging was reviewed in axial and coronal planes to determine mammillary body volume as calculated by the ellipsoid method. Patient demographics, clinical semiology, and seizure localization were analyzed. The primary end-point was seizure freedom at 1 year after LiTT. The change in the size of the mammillary body were correlated with the postoperative seizure freedom at 1 year using the Wilcoxon/Kruskal-Wallis test for statistical significance. Results: Between December 1, 2012 and June 1, 2015, 22 patients underwent LiTT for mesial temporal lobe epilepsy. Two patients were excluded due to lack of follow-up. Of the remaining 20 patients, 13 were seizure free at 1 year. In the seizure free group, there was an average 34.6% ( ± 13%) decline in ipsilateral mammillary body volume, as opposed to an average decline of 8.4% ( ± 10.9%) in patients with continued seizures (P = 0.0026). Conclusions: Our findings show a statistically significant correlation between postoperative volume reduction in ipsilateral mammillary body and seizure outcomes after LiTT. With further validation, this finding could be a useful marker of adequacy of ablation independent of ablation volumes and determinant of potential benefit of additional surgical intervention in patients with poor outcomes after LiTT.
1. Introduction
and mortality secondary to temporal lobectomy (Engel, 2013). Laser interstitial thermal therapy (LiTT) is a minimally invasive method of ablating the mesial temporal lobe structures and has been increasingly used in treatment of MTLE since the initial experience in 2011 (Curry et al., 2012). In patients with poor outcomes after undergoing either temporal lobectomy or LiTT, the value of further surgical intervention on the ipsilateral temporal lobe is often difficult to establish. The likelihood of seizure freedom after a repeat procedure is significantly lower than after the index operation (Jehi et al., 2010). This study is a blinded retrospective analysis correlating changes in ipsilateral mammillary body volume after amygdalo-hippocampal LiTT procedure to seizure outcomes. Atrophy of the mammillary body is well known in advanced hippocampal sclerosis (HS) (Wieser and ILAE
Refractory mesial temporal lobe epilepsy (MTLE) is the most common form of surgically treated epilepsy (Janszky et al., 2005). Despite advances in surgical techniques, neuroimaging, and patient selection, approximately one-third of patients undergoing temporal lobe surgery for epilepsy continue to have medically refractory seizures (Elsharkawy et al., 2009; Tellez-Zenteno et al., 2005; Wiebe et al., 2001). The extent of resection of the hippocampus has been associated with outcomes after temporal lobectomy (Wyler et al., 1995). While resective surgery is highly effective in medically refractory MTLE, only 2% of eligible patients undergo surgery annually (Engel, 2013). It is believed that this underutilization is likely related to fears of morbidity
Abbreviations: MTLE, mesial temporal lobe epilepsy; LiTT, laser interstitial thermal therapy; MRI, magnetic resonance imaging; HS, hippocampal sclerosis ⁎ Corresponding author at: Department of Radiology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, United States. E-mail address: [email protected] (V. Gupta). 1 Current affiliation: Department of Neurosciences, University of California, San Diego, United States. https://doi.org/10.1016/j.eplepsyres.2018.01.021 Received 28 October 2016; Received in revised form 17 January 2018; Accepted 24 January 2018 Available online 31 January 2018 0920-1211/ © 2018 Elsevier B.V. All rights reserved.
Epilepsy Research 141 (2018) 19–22
S.S. Grewal et al.
Commission on Neurosurgery of Epilepsy, 2004). We hypothesized that lack of ipsilateral mammillary body atrophy after LiTT would reflect persistence of hippocampal efferent activity and poor seizure outcome.
Table 1 Patient Demographics.
2. Material and methods The study was approved by our institutional review board. We retrospectively reviewed the medical records and high-resolution 3T brain magnetic resonance imaging (MRI) with an epilepsy protocol of 22 consecutive patients undergoing LiTT of the amygdala and hippocampus for medically intractable MTLE. Two patients were excluded due to lack of follow-up imaging. The medical records were reviewed for patient demographics including age, gender, age at seizure onset, seizure localization, length of follow-up, and prior epilepsy procedures. At our center, LiTT is performed with the patient in a prone position using intraoperative MR guided placement of the laser fiber. Using the ClearPoint platform system (MRI Interventions), a trajectory is planned through an occipital approach, avoiding cortical vessels and the ventricle, and targeting the body and head of the hippocampus along with as much of the amygdala as possible. The ablation is monitored in realtime using MR thermography. A gadolinium enhanced MR is performed to assess the technical adequacy of ablation i.e. inclusion of the amygdala, hippocampal head and anterior body before the patient is extubated. Mammillary body volume was calculated on both pre- and 1 year post-ablation high-resolution axial T1 (1 mm) and coronal T2 (2 mm) MRI. The MR images were reviewed by an experienced neuroradiologist who was blinded to preoperative data and postprocedure outcome. The ellipsoid method (a × b × c/2) was used to calculate the mammillary body volume (Fig. 1). To minimize the influence of manual error in measurement and avoid overestimation, the absolute net change in the contralateral mammillary body volume was subtracted from the net change in the mammillary body volume on the side of ablation. For analysis, the patients were classified into two groups based upon postoperative seizure freedom at 1-year follow-up. The statistical significance of the difference in the mammillary body volume change in the two groups was determined by the Wilcoxon/Kruskal-Wallis test. All statistical analyses were performed with JMP software (version 12.2; SAS Institute Inc., Cary, North Carolina).
Patient Number
Age (Y)
Sex
Seizure Type
Seizure Localization
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
22 29 44 58 17 39 52 34 63 31 57 48 38 56 49 46 54 26 46 66
M F M F F F M M M F M F M F M M F F M M
SPS CPS CPS SPS & GTC CPS CPS & GTC CPS CPS & GTC CPS CPS CPS CPS CPS & GTC CPS CPS CPS & GTC CPS & GTC CPS & GTC CPS & GTC CPS & GTC
Left Left Left Left Left Left Left Left Left Left Left Right Left Right Right Right Right Right Right Right
CPS: complex partial seizures; GTC: generalized tonic clonic seizures; SPS: simple partial seizures.
with or without generalized tonic clonic seizures. Two patients had focal seizures without impairment of consciousness, and one of which also had occasional generalized tonic clonic seizures (Table 1). Thirteen patients (65%) were seizure free at 1 year after LiTT. When comparing demographics between the two groups, there was no difference in age of seizure onset (21.0 ± 15.3 vs. 16.5 ± 20.0; P = 0.53), sex (8/13 male vs. 3/7 male; P = 0.64), and age at surgery (46.0 ± 14.3 vs. 39.6 ± 12.9; P = 0.34). Among the seizure free patient group, there was an average (34.6 ± 13%) decline in ipsilateral mammillary body volume, as opposed to a decline of (8.4 ± 10.9%) in patients with continued seizures (P = 0.0026, Table 2, Fig. 2). There were two patients in the seizure-free group that had a post LiTT MRI performed within 60 days of ablation. These patients had a reduction of 14% and 16% in their ipsilateral mammillary body volume. Our treatment protocol typically calls for attempting to decrease medications starting at one year post LiTT. Of the 13 patients who achieved seizure freedom, one patient was able to come completely off medications, 5 patients had a decrease in their medications, 6 patients had no change, and one had an increase in the dosage. Of the seven patients with continued seizures, 3 patients had an additional antiseizure medication added, one patient had medication dosage increased, and 3 patients did not have any changes to their medications. Of the patients with poor clinical outcome, one underwent repeat LiTT, and two underwent anteromedial temporal lobectomy; all repeat
3. Results Between December 1, 2012 and June 1, 2015, there were 20 patients (age, 43.8 ± 13.9 years; 11 males; 9 females) with both MRI and clinical follow-up after LiTT, all performed by a single operator. Twelve patients (60%) had seizure onset localized to the left mesial temporal lobe, and eight patients (40%) had right mesial temporal onset. Eighteen patients (90%) had focal seizures with impaired consciousness
Fig. 1. Measurement of Mammillary Body Volume. Coronal T2 (Fig. 1a) and axial T1 (Fig. 1b) MR images illustrating the (A × B × C)/2 technique to calculate the pre and post ablation mammillary body volumes.
20
Epilepsy Research 141 (2018) 19–22
S.S. Grewal et al.
knowledge, this is the first report of changes in mammillary body size after this procedure. These changes were visible as early as two months after the LiTT. In patients with poor outcomes after LiTT, there was an average decline of only 8.4% in the ipsilateral mammillary body volume. One patient with continued seizures and no volume reduction in the ipsilateral mammillary body after the first ablation became seizure free following repeat ipsilateral LiTT with subsequent 39% decline in the ipsilateral mammillary body volume. Our observations indicate that a 30% to 40% reduction in ipsilateral mammillary body volume is associated with favorable outcome after amygdalo-hippocampal LiTT, and can be used as an independent marker of adequacy of ablation in addition to the more commonly used metric of ablation volume. Minimal to no change in the mammillary body volume after LiTT likely reflects persistence of hippocampal efferent output and seizure network, and therefore, potential benefit of repeat ipsilateral surgical intervention in patients with unfavorable outcome. The purpose of this article is to report a potentially valuable preliminary observation which needs to be further validated in larger cohorts and experience of other centers. We found mammillary body shrinkage to be a straightforward anatomic marker of successful functional disconnection of the hippocampus after LiTT ablation. There is relatively little data regarding hippocampal ablation volumes and seizure outcomes. Kang et al. found no difference between seizure outcomes and ablation volumes, and the report by Jermajowicz et al. also failed to reveal a statistically significant difference between ablation volumes and outcomes, even though they did note a trend towards significance with a lateral trajectory leading to poorer outcomes (Jermakowicz et al., 2017; Kang et al., 2016). These results could be due to the small sample size of these studies, and we recognize that our study could suffer from similar limitation. We are currently undertaking a study of a larger multi-center cohort, which includes a detailed quantitative analysis of ablation volumes of the mesial temporal structures (hippocampal head, hippocampal body, and amygdala). While our results suggest mammillary body volume as a marker for surgical outcome, we recognize the retrospective study design and relatively small cohort size as limitations of our study. Nevertheless, our protocol included a blinded review of outcomes and mammillary body volume data, and attempted to control for errors in measurement by using the contralateral mammillary body as internal control for calculating the net change in mammillary body volume.
Table 2 Patient characteristics and post-laser interstitial thermal therapy mammillary body volume changes at 1 year in relation to seizure outcomes.
Age at Seizure Onset (y) Sex Age at Surgery (y) Mammillary Body Changes (%)
Seizure Free (N = 13)
Not Seizure Free (N = 7)
P-value
21.0 ± 15.3 8/13 Male 46.0 ± 14.3 34.6 ± 13.0
16.5 ± 20.0 3/7 Male 39.6 ± 12.9 8.4 ± 10.9
0.53 0.64 0.34 0.0026
y: years.
procedures were ipsilateral to the initial procedure. All three patients have remained seizure free after the repeat procedure. In the patient who underwent repeat LiTT, the decline in mammillary body volume after the first ablation was 3.8%. After repeat ablation, however, there was a 39% reduction in the ipsilateral mammillary body volume (Fig. 3). 4. Discussion In MTLE with HS, the most commonly observed MRI findings are hippocampal atrophy, loss of internal architecture, and increased T2 signal (Wieser and Epilepsy, 2004). Extrahippocampal findings of HS include atrophy of the mammillary body (Wieser and Epilepsy, 2004). The major efferent pathway of hippocampus is the alveus. The white matter fibers in the alveus converge to form the fimbria, which continues as the fornix. The fornix divides into anterior and posterior fibers. The dominant posterior bundle continues through the hypothalamus, terminating in the mammillary bodies. This anatomic relationship closely parallels the mammillary body’s principal role as the relay target of hippocampal output. Atrophy of the ipsilateral mammillary body would, therefore, be an expected anatomical consequence of successful hippocampal ablation. In our study, we obtained a 65% rate of seizure freedom after amygdalohippocampal LiTT. This result is similar to those reported by Willie et al. (67% seizure freedom) (Willie et al., 2014) and Kang et al. (60% seizure freedom) (Kang et al., 2016). Interestingly, the seizure outcomes did not demonstrate a discernible trend with increasing operator experience with LiTT (Fig. 2). We observed an average volume reduction of 34.6% in the ipsilateral mammillary body after successful (seizure freedom at 1 year) amygdalo-hippocampal LiTT. To our
Fig. 2. Net change in mammillary body volume for each patient numbered according to the date of LiTT in our series. The hollow bars reflect patients who did not attain seizure freedom, and the solid bars reflect patients who did become seizure-free.
21
Epilepsy Research 141 (2018) 19–22
S.S. Grewal et al.
Fig. 3. Mammillary Body Changes and Seizure Outcome after laser interstitial thermal therapy (LiTT). Arrows indicate left mammillary body: Coronal T1-weighted MRI. A) at presentation: mild volume loss in left mammillary body; B) no change in left mammillary body volume after first left mesial temporal LiTT with Engle class 4 outcome; C) distinct (39%) volume loss in the left mammillary body after repeat LiTT with Engel class 1 outcome.
5. Conclusions
laser ablation of epileptogenic foci in children. Epilepsy Behav. 24, 408–414. Elsharkawy, A.E., Alabbasi, A.H., Pannek, H., Oppel, F., Schulz, R., Hoppe, M., Hamad, A.P., Nayel, M., Issa, A., Ebner, A., 2009. Long-term outcome after temporal lobe epilepsy surgery in 434 consecutive adult patients. J. Neurosurg. 110, 1135–1146. Engel, J., 2013. Nonpharmacological Therapy of Seizures, 2nd ed. Oxford University Press, New York. Janszky, J., Janszky, I., Schulz, R., Hoppe, M., Behne, F., Pannek, H.W., Ebner, A., 2005. Temporal lobe epilepsy with hippocampal sclerosis: predictors for long-term surgical outcome. Brain 128, 395–404. Jehi, L.E., Silveira, D.C., Bingaman, W., Najm, I., 2010. Temporal lobe epilepsy surgery failures: predictors of seizure recurrence, yield of reevaluation, and outcome following reoperation. J. Neurosurg. 113, 1186–1194. Jermakowicz, W.J., Kanner, A.M., Sur, S., Bermudez, C., D’Haese, P.F., Kolcun, J.P.G., Cajigas, I., Li, R., Millan, C., Ribot, R., Serrano, E.A., Velez, N., Lowe, M.R., Rey, G.J., Jagid, J.R., 2017. Laser thermal ablation for mesiotemporal epilepsy: analysis of ablation volumes and trajectories. Epilepsia 58, 801–810. Kang, J.Y., Wu, C., Tracy, J., Lorenzo, M., Evans, J., Nei, M., Skidmore, C., Mintzer, S., Sharan, A.D., Sperling, M.R., 2016. Laser interstitial thermal therapy for medically intractable mesial temporal lobe epilepsy. Epilepsia 57, 325–334. Tellez-Zenteno, J.F., Dhar, R., Wiebe, S., 2005. Long-term seizure outcomes following epilepsy surgery: a systematic review and meta-analysis. Brain 128, 1188–1198. Wiebe, S., Blume, W.T., Girvin, J.P., Eliasziw, M., Effectiveness, Efficiency of Surgery for Temporal Lobe Epilepsy Study, G, 2001. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N. Engl. J. Med. 345, 311–318. Wieser, H.G., Epilepsy, I.C.o.N.o., 2004. ILAE Commission Report. Mesial temporal lobe epilepsy with hippocampal sclerosis. Epilepsia 45, 695–714. Wieser, H.G., ILAE Commission on Neurosurgery of Epilepsy, 2004. ILAE Commission Report. Mesial temporal lobe epilepsy with hippocampal sclerosis. Epilepsia 45, 695–714. Willie, J.T., Laxpati, N.G., Drane, D.L., Gowda, A., Appin, C., Hao, C., Brat, D.J., Helmers, S.L., Saindane, A., Nour, S.G., Gross, R.E., 2014. Real-time magnetic resonanceguided stereotactic laser amygdalohippocampotomy for mesial temporal lobe epilepsy. Neurosurgery 74, 569–584 discussion 584-565. Wyler, A.R., Hermann, B.P., Somes, G., 1995. Extent of medial temporal resection on outcome from anterior temporal lobectomy: a randomized prospective study. Neurosurgery 37, 982–990 discussion 990-981.
This retrospective analysis correlates a decline in ipsilateral mammillary body volume with postoperative seizure freedom after LiTT for MTLE. We believe that ipsilateral mammillary body atrophy may be a reliable marker of functional adequacy of LiTT hippocampal ablation and can be adjunct to ablation volumes when determining the role of further ipsilateral surgical interventions. For example, a patient who is not seizure free at 1 year with > 30% decline in mammillary body volume would likely not benefit from a repeat ipsilateral procedure. On the other hand, a patient with < 10% decline may benefit from repeat ablation or open hippocampactomy since a < 10% decline appears to indicate persistent functional output from the ipsilateral hippocampus. We propose further studies to validate our findings not only in patients undergoing LiTT but also in those treated with temporal lobectomy. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflicts of interest None. References Curry, D.J., Gowda, A., McNichols, R.J., Wilfong, A.A., 2012. MR-guided stereotactic
22
Contents lists available at ScienceDirect
Epilepsy Research journal homepage: www.elsevier.com/locate/epilepsyres
Mammillary body changes and seizure outcome after laser interstitial thermal therapy of the mesial temporal lobe
T
⁎
Sanjeet S. Grewala, Vivek Guptab, , Prasanna Vibhuteb, Jerry J. Shihc,1, William O. Tatumc, Robert E. Wharena a
Department of Neurosurgery, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, United States Department of Radiology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, United States c Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, United States b
A R T I C L E I N F O
A B S T R A C T
Keywords: LiTT Mammillary body Mesial temporal lobe
Objective: The mammillary bodies have long been known as the primary relay center for the hippocampus. The fornix is the primary efferent pathway of the hippocampus, with its postcommissural fibers terminating in the mammillary bodies. In this study, we describe change in mammillary body volume after laser interstitial thermal therapy (LiTT) for mesial temporal lobe epilepsy and correlate it with seizure outcome. Methods: Pre- and post-LiTT ablation magnetic resonance imaging was reviewed in axial and coronal planes to determine mammillary body volume as calculated by the ellipsoid method. Patient demographics, clinical semiology, and seizure localization were analyzed. The primary end-point was seizure freedom at 1 year after LiTT. The change in the size of the mammillary body were correlated with the postoperative seizure freedom at 1 year using the Wilcoxon/Kruskal-Wallis test for statistical significance. Results: Between December 1, 2012 and June 1, 2015, 22 patients underwent LiTT for mesial temporal lobe epilepsy. Two patients were excluded due to lack of follow-up. Of the remaining 20 patients, 13 were seizure free at 1 year. In the seizure free group, there was an average 34.6% ( ± 13%) decline in ipsilateral mammillary body volume, as opposed to an average decline of 8.4% ( ± 10.9%) in patients with continued seizures (P = 0.0026). Conclusions: Our findings show a statistically significant correlation between postoperative volume reduction in ipsilateral mammillary body and seizure outcomes after LiTT. With further validation, this finding could be a useful marker of adequacy of ablation independent of ablation volumes and determinant of potential benefit of additional surgical intervention in patients with poor outcomes after LiTT.
1. Introduction
and mortality secondary to temporal lobectomy (Engel, 2013). Laser interstitial thermal therapy (LiTT) is a minimally invasive method of ablating the mesial temporal lobe structures and has been increasingly used in treatment of MTLE since the initial experience in 2011 (Curry et al., 2012). In patients with poor outcomes after undergoing either temporal lobectomy or LiTT, the value of further surgical intervention on the ipsilateral temporal lobe is often difficult to establish. The likelihood of seizure freedom after a repeat procedure is significantly lower than after the index operation (Jehi et al., 2010). This study is a blinded retrospective analysis correlating changes in ipsilateral mammillary body volume after amygdalo-hippocampal LiTT procedure to seizure outcomes. Atrophy of the mammillary body is well known in advanced hippocampal sclerosis (HS) (Wieser and ILAE
Refractory mesial temporal lobe epilepsy (MTLE) is the most common form of surgically treated epilepsy (Janszky et al., 2005). Despite advances in surgical techniques, neuroimaging, and patient selection, approximately one-third of patients undergoing temporal lobe surgery for epilepsy continue to have medically refractory seizures (Elsharkawy et al., 2009; Tellez-Zenteno et al., 2005; Wiebe et al., 2001). The extent of resection of the hippocampus has been associated with outcomes after temporal lobectomy (Wyler et al., 1995). While resective surgery is highly effective in medically refractory MTLE, only 2% of eligible patients undergo surgery annually (Engel, 2013). It is believed that this underutilization is likely related to fears of morbidity
Abbreviations: MTLE, mesial temporal lobe epilepsy; LiTT, laser interstitial thermal therapy; MRI, magnetic resonance imaging; HS, hippocampal sclerosis ⁎ Corresponding author at: Department of Radiology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, United States. E-mail address: [email protected] (V. Gupta). 1 Current affiliation: Department of Neurosciences, University of California, San Diego, United States. https://doi.org/10.1016/j.eplepsyres.2018.01.021 Received 28 October 2016; Received in revised form 17 January 2018; Accepted 24 January 2018 Available online 31 January 2018 0920-1211/ © 2018 Elsevier B.V. All rights reserved.
Epilepsy Research 141 (2018) 19–22
S.S. Grewal et al.
Commission on Neurosurgery of Epilepsy, 2004). We hypothesized that lack of ipsilateral mammillary body atrophy after LiTT would reflect persistence of hippocampal efferent activity and poor seizure outcome.
Table 1 Patient Demographics.
2. Material and methods The study was approved by our institutional review board. We retrospectively reviewed the medical records and high-resolution 3T brain magnetic resonance imaging (MRI) with an epilepsy protocol of 22 consecutive patients undergoing LiTT of the amygdala and hippocampus for medically intractable MTLE. Two patients were excluded due to lack of follow-up imaging. The medical records were reviewed for patient demographics including age, gender, age at seizure onset, seizure localization, length of follow-up, and prior epilepsy procedures. At our center, LiTT is performed with the patient in a prone position using intraoperative MR guided placement of the laser fiber. Using the ClearPoint platform system (MRI Interventions), a trajectory is planned through an occipital approach, avoiding cortical vessels and the ventricle, and targeting the body and head of the hippocampus along with as much of the amygdala as possible. The ablation is monitored in realtime using MR thermography. A gadolinium enhanced MR is performed to assess the technical adequacy of ablation i.e. inclusion of the amygdala, hippocampal head and anterior body before the patient is extubated. Mammillary body volume was calculated on both pre- and 1 year post-ablation high-resolution axial T1 (1 mm) and coronal T2 (2 mm) MRI. The MR images were reviewed by an experienced neuroradiologist who was blinded to preoperative data and postprocedure outcome. The ellipsoid method (a × b × c/2) was used to calculate the mammillary body volume (Fig. 1). To minimize the influence of manual error in measurement and avoid overestimation, the absolute net change in the contralateral mammillary body volume was subtracted from the net change in the mammillary body volume on the side of ablation. For analysis, the patients were classified into two groups based upon postoperative seizure freedom at 1-year follow-up. The statistical significance of the difference in the mammillary body volume change in the two groups was determined by the Wilcoxon/Kruskal-Wallis test. All statistical analyses were performed with JMP software (version 12.2; SAS Institute Inc., Cary, North Carolina).
Patient Number
Age (Y)
Sex
Seizure Type
Seizure Localization
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
22 29 44 58 17 39 52 34 63 31 57 48 38 56 49 46 54 26 46 66
M F M F F F M M M F M F M F M M F F M M
SPS CPS CPS SPS & GTC CPS CPS & GTC CPS CPS & GTC CPS CPS CPS CPS CPS & GTC CPS CPS CPS & GTC CPS & GTC CPS & GTC CPS & GTC CPS & GTC
Left Left Left Left Left Left Left Left Left Left Left Right Left Right Right Right Right Right Right Right
CPS: complex partial seizures; GTC: generalized tonic clonic seizures; SPS: simple partial seizures.
with or without generalized tonic clonic seizures. Two patients had focal seizures without impairment of consciousness, and one of which also had occasional generalized tonic clonic seizures (Table 1). Thirteen patients (65%) were seizure free at 1 year after LiTT. When comparing demographics between the two groups, there was no difference in age of seizure onset (21.0 ± 15.3 vs. 16.5 ± 20.0; P = 0.53), sex (8/13 male vs. 3/7 male; P = 0.64), and age at surgery (46.0 ± 14.3 vs. 39.6 ± 12.9; P = 0.34). Among the seizure free patient group, there was an average (34.6 ± 13%) decline in ipsilateral mammillary body volume, as opposed to a decline of (8.4 ± 10.9%) in patients with continued seizures (P = 0.0026, Table 2, Fig. 2). There were two patients in the seizure-free group that had a post LiTT MRI performed within 60 days of ablation. These patients had a reduction of 14% and 16% in their ipsilateral mammillary body volume. Our treatment protocol typically calls for attempting to decrease medications starting at one year post LiTT. Of the 13 patients who achieved seizure freedom, one patient was able to come completely off medications, 5 patients had a decrease in their medications, 6 patients had no change, and one had an increase in the dosage. Of the seven patients with continued seizures, 3 patients had an additional antiseizure medication added, one patient had medication dosage increased, and 3 patients did not have any changes to their medications. Of the patients with poor clinical outcome, one underwent repeat LiTT, and two underwent anteromedial temporal lobectomy; all repeat
3. Results Between December 1, 2012 and June 1, 2015, there were 20 patients (age, 43.8 ± 13.9 years; 11 males; 9 females) with both MRI and clinical follow-up after LiTT, all performed by a single operator. Twelve patients (60%) had seizure onset localized to the left mesial temporal lobe, and eight patients (40%) had right mesial temporal onset. Eighteen patients (90%) had focal seizures with impaired consciousness
Fig. 1. Measurement of Mammillary Body Volume. Coronal T2 (Fig. 1a) and axial T1 (Fig. 1b) MR images illustrating the (A × B × C)/2 technique to calculate the pre and post ablation mammillary body volumes.
20
Epilepsy Research 141 (2018) 19–22
S.S. Grewal et al.
knowledge, this is the first report of changes in mammillary body size after this procedure. These changes were visible as early as two months after the LiTT. In patients with poor outcomes after LiTT, there was an average decline of only 8.4% in the ipsilateral mammillary body volume. One patient with continued seizures and no volume reduction in the ipsilateral mammillary body after the first ablation became seizure free following repeat ipsilateral LiTT with subsequent 39% decline in the ipsilateral mammillary body volume. Our observations indicate that a 30% to 40% reduction in ipsilateral mammillary body volume is associated with favorable outcome after amygdalo-hippocampal LiTT, and can be used as an independent marker of adequacy of ablation in addition to the more commonly used metric of ablation volume. Minimal to no change in the mammillary body volume after LiTT likely reflects persistence of hippocampal efferent output and seizure network, and therefore, potential benefit of repeat ipsilateral surgical intervention in patients with unfavorable outcome. The purpose of this article is to report a potentially valuable preliminary observation which needs to be further validated in larger cohorts and experience of other centers. We found mammillary body shrinkage to be a straightforward anatomic marker of successful functional disconnection of the hippocampus after LiTT ablation. There is relatively little data regarding hippocampal ablation volumes and seizure outcomes. Kang et al. found no difference between seizure outcomes and ablation volumes, and the report by Jermajowicz et al. also failed to reveal a statistically significant difference between ablation volumes and outcomes, even though they did note a trend towards significance with a lateral trajectory leading to poorer outcomes (Jermakowicz et al., 2017; Kang et al., 2016). These results could be due to the small sample size of these studies, and we recognize that our study could suffer from similar limitation. We are currently undertaking a study of a larger multi-center cohort, which includes a detailed quantitative analysis of ablation volumes of the mesial temporal structures (hippocampal head, hippocampal body, and amygdala). While our results suggest mammillary body volume as a marker for surgical outcome, we recognize the retrospective study design and relatively small cohort size as limitations of our study. Nevertheless, our protocol included a blinded review of outcomes and mammillary body volume data, and attempted to control for errors in measurement by using the contralateral mammillary body as internal control for calculating the net change in mammillary body volume.
Table 2 Patient characteristics and post-laser interstitial thermal therapy mammillary body volume changes at 1 year in relation to seizure outcomes.
Age at Seizure Onset (y) Sex Age at Surgery (y) Mammillary Body Changes (%)
Seizure Free (N = 13)
Not Seizure Free (N = 7)
P-value
21.0 ± 15.3 8/13 Male 46.0 ± 14.3 34.6 ± 13.0
16.5 ± 20.0 3/7 Male 39.6 ± 12.9 8.4 ± 10.9
0.53 0.64 0.34 0.0026
y: years.
procedures were ipsilateral to the initial procedure. All three patients have remained seizure free after the repeat procedure. In the patient who underwent repeat LiTT, the decline in mammillary body volume after the first ablation was 3.8%. After repeat ablation, however, there was a 39% reduction in the ipsilateral mammillary body volume (Fig. 3). 4. Discussion In MTLE with HS, the most commonly observed MRI findings are hippocampal atrophy, loss of internal architecture, and increased T2 signal (Wieser and Epilepsy, 2004). Extrahippocampal findings of HS include atrophy of the mammillary body (Wieser and Epilepsy, 2004). The major efferent pathway of hippocampus is the alveus. The white matter fibers in the alveus converge to form the fimbria, which continues as the fornix. The fornix divides into anterior and posterior fibers. The dominant posterior bundle continues through the hypothalamus, terminating in the mammillary bodies. This anatomic relationship closely parallels the mammillary body’s principal role as the relay target of hippocampal output. Atrophy of the ipsilateral mammillary body would, therefore, be an expected anatomical consequence of successful hippocampal ablation. In our study, we obtained a 65% rate of seizure freedom after amygdalohippocampal LiTT. This result is similar to those reported by Willie et al. (67% seizure freedom) (Willie et al., 2014) and Kang et al. (60% seizure freedom) (Kang et al., 2016). Interestingly, the seizure outcomes did not demonstrate a discernible trend with increasing operator experience with LiTT (Fig. 2). We observed an average volume reduction of 34.6% in the ipsilateral mammillary body after successful (seizure freedom at 1 year) amygdalo-hippocampal LiTT. To our
Fig. 2. Net change in mammillary body volume for each patient numbered according to the date of LiTT in our series. The hollow bars reflect patients who did not attain seizure freedom, and the solid bars reflect patients who did become seizure-free.
21
Epilepsy Research 141 (2018) 19–22
S.S. Grewal et al.
Fig. 3. Mammillary Body Changes and Seizure Outcome after laser interstitial thermal therapy (LiTT). Arrows indicate left mammillary body: Coronal T1-weighted MRI. A) at presentation: mild volume loss in left mammillary body; B) no change in left mammillary body volume after first left mesial temporal LiTT with Engle class 4 outcome; C) distinct (39%) volume loss in the left mammillary body after repeat LiTT with Engel class 1 outcome.
5. Conclusions
laser ablation of epileptogenic foci in children. Epilepsy Behav. 24, 408–414. Elsharkawy, A.E., Alabbasi, A.H., Pannek, H., Oppel, F., Schulz, R., Hoppe, M., Hamad, A.P., Nayel, M., Issa, A., Ebner, A., 2009. Long-term outcome after temporal lobe epilepsy surgery in 434 consecutive adult patients. J. Neurosurg. 110, 1135–1146. Engel, J., 2013. Nonpharmacological Therapy of Seizures, 2nd ed. Oxford University Press, New York. Janszky, J., Janszky, I., Schulz, R., Hoppe, M., Behne, F., Pannek, H.W., Ebner, A., 2005. Temporal lobe epilepsy with hippocampal sclerosis: predictors for long-term surgical outcome. Brain 128, 395–404. Jehi, L.E., Silveira, D.C., Bingaman, W., Najm, I., 2010. Temporal lobe epilepsy surgery failures: predictors of seizure recurrence, yield of reevaluation, and outcome following reoperation. J. Neurosurg. 113, 1186–1194. Jermakowicz, W.J., Kanner, A.M., Sur, S., Bermudez, C., D’Haese, P.F., Kolcun, J.P.G., Cajigas, I., Li, R., Millan, C., Ribot, R., Serrano, E.A., Velez, N., Lowe, M.R., Rey, G.J., Jagid, J.R., 2017. Laser thermal ablation for mesiotemporal epilepsy: analysis of ablation volumes and trajectories. Epilepsia 58, 801–810. Kang, J.Y., Wu, C., Tracy, J., Lorenzo, M., Evans, J., Nei, M., Skidmore, C., Mintzer, S., Sharan, A.D., Sperling, M.R., 2016. Laser interstitial thermal therapy for medically intractable mesial temporal lobe epilepsy. Epilepsia 57, 325–334. Tellez-Zenteno, J.F., Dhar, R., Wiebe, S., 2005. Long-term seizure outcomes following epilepsy surgery: a systematic review and meta-analysis. Brain 128, 1188–1198. Wiebe, S., Blume, W.T., Girvin, J.P., Eliasziw, M., Effectiveness, Efficiency of Surgery for Temporal Lobe Epilepsy Study, G, 2001. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N. Engl. J. Med. 345, 311–318. Wieser, H.G., Epilepsy, I.C.o.N.o., 2004. ILAE Commission Report. Mesial temporal lobe epilepsy with hippocampal sclerosis. Epilepsia 45, 695–714. Wieser, H.G., ILAE Commission on Neurosurgery of Epilepsy, 2004. ILAE Commission Report. Mesial temporal lobe epilepsy with hippocampal sclerosis. Epilepsia 45, 695–714. Willie, J.T., Laxpati, N.G., Drane, D.L., Gowda, A., Appin, C., Hao, C., Brat, D.J., Helmers, S.L., Saindane, A., Nour, S.G., Gross, R.E., 2014. Real-time magnetic resonanceguided stereotactic laser amygdalohippocampotomy for mesial temporal lobe epilepsy. Neurosurgery 74, 569–584 discussion 584-565. Wyler, A.R., Hermann, B.P., Somes, G., 1995. Extent of medial temporal resection on outcome from anterior temporal lobectomy: a randomized prospective study. Neurosurgery 37, 982–990 discussion 990-981.
This retrospective analysis correlates a decline in ipsilateral mammillary body volume with postoperative seizure freedom after LiTT for MTLE. We believe that ipsilateral mammillary body atrophy may be a reliable marker of functional adequacy of LiTT hippocampal ablation and can be adjunct to ablation volumes when determining the role of further ipsilateral surgical interventions. For example, a patient who is not seizure free at 1 year with > 30% decline in mammillary body volume would likely not benefit from a repeat ipsilateral procedure. On the other hand, a patient with < 10% decline may benefit from repeat ablation or open hippocampactomy since a < 10% decline appears to indicate persistent functional output from the ipsilateral hippocampus. We propose further studies to validate our findings not only in patients undergoing LiTT but also in those treated with temporal lobectomy. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflicts of interest None. References Curry, D.J., Gowda, A., McNichols, R.J., Wilfong, A.A., 2012. MR-guided stereotactic
22