Accepted Manuscript Pattern of corticospinal projections defined by brain mapping during resective epilepsy surgery in a patient with congenital hemiparesis and intractable epilepsy Chen-Ya Yang, MD, Hsin-Hung Chen, MD, Chien Chen, MD, Jan-Wei Chiu, MD, Chen-Liang Chou, MD, Tsui-Fen Yang, MD PII: S1878-8750(17)31372-4 DOI: 10.1016/j.wneu.2017.08.071 Reference: WNEU 6321 To appear in: World Neurosurgery Received Date: 7 May 2017 Revised Date: 8 August 2017 Accepted Date: 10 August 2017 Please cite this article as: Yang C-Y, Chen H-H, Chen C, Chiu J-W, Chou C-L, Yang T-F, Pattern of corticospinal projections defined by brain mapping during resective epilepsy surgery in a patient with congenital hemiparesis and intractable epilepsy, World Neurosurgery (2017), doi: 10.1016/ j.wneu.2017.08.071. 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. 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An innovative IONM technique in resective epilepsy surgery ACCEPTED MANUSCRIPT 1 Pattern of corticospinal projections defined by brain mapping during 2 resective epilepsy surgery in a patient with congenital hemiparesis 3 and intractable epilepsy RI PT 4 5 Chen-Ya Yang, MD,1 Hsin-Hung Chen, MD,2,4 Chien Chen, MD,3,4 Jan-Wei Chiu, 6 MD,1 Chen-Liang Chou, MD,1,4 *Tsui-Fen Yang, MD,1,5 1 M AN U SC Department of Physical Medicine & Rehabilitation, Taipei Veterans General Hospital, Taipei, Taiwan 2 Department of Neurosurgery, The Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan 3 Department of Neurology, The Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan 4 School of Medicine, National Yang-Ming University, Taipei, Taiwan 5 Departments of Physical Therapy and Assistive Technology, National Yang-Ming University, Taipei, Taiwan Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. TE D 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Correspondence and reprint requests: 23 Dr. Tsui-Fen Yang 24 Department of Physical Medicine and Rehabilitation 25 Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Road, Beitou District, 26 Taipei City, Taiwan 11217, R.O.C. 27 E-mail: tfyang@vghtpe.gov.tw 28 TEL: +886-2-2875-7360 29 FAX: +886-2-2875-7359 AC C EP 22 30 31 32 1 An innovative IONM technique in resective epilepsy surgery ACCEPTED MANUSCRIPT Abbreviations: AEDs, Antiepileptic Drugs; APB, abductor pollicis brevis; AH, CMAP, compound 3 4 5 6 7 muscle action potentials; DCS, direct cortical stimulation; EEG, Electroencephalography; fMRI, functional magnetic resonance imaging; IONM, intraoperative neurophysiologic monitoring; TCS, transcranial stimulation; TMS, transcranial magnetic stimulation. 8 9 10 11 Key words: congenital hemiparesis; corticospinal projection; intraoperative neurophysiological monitoring; resective epilepsy surgery; SC RI PT 1 2 12 M AN U 13 14 15 16 20 21 22 23 24 EP 19 AC C 18 TE D 17 25 26 27 28 2 An innovative IONM technique in resective epilepsy surgery ACCEPTED MANUSCRIPT Abstract Background: Congenital or early acquired brain structural lesions often cause 3 4 5 6 contralateral hemiparesis as well as cognitive deficits, developmental delays, and seizures. Among them, seizure is the most debilitating condition, as it greatly impairs the quality of life in both the affected individuals and their caregivers and prevents them from active social participation. 7 8 9 10 Case Description: Here, we present a 34-year-old man with hemiparesis and early-onset seizures since childhood owing to a congenital brain lesion. He developed intractable seizures in the last two years, and was subsequently admitted for resective epileptic surgery. During the operation, we employed an innovative intraoperative 11 12 13 14 neurophysiological monitoring technique. Unlike routine application for transcranial stimulation (TCS), we recorded compound muscle action potentials (CMAPs) over the bilateral limb muscles simultaneously instead of over the contralateral muscles only, to determine the patterns of the corticospinal projections. TCS over the bilateral 15 16 17 hemispheres was applied before craniotomy and direct cortical stimulation over the lesioned hemisphere was applied after craniotomy. By integrating both approaches, we could first identify the pattern of corticospinal projections before craniotomy and 18 19 20 21 then accurately define the non-eloquent area, which in turn guided the resection to successfully accomplish the surgical goal. Conclusions: The technique is simple because no patient participation is required. Moreover, we believe that it has the potential to replace conventional preoperative 22 23 24 25 functional magnetic resonance imaging and transcranial magnetic stimulation in resective epilepsy surgery, particularly for young patients. Not only can it improve the safety of surgical procedures, it can help predict the functional outcome as well. SC M AN U TE D EP AC C 26 27 28 RI PT 1 2 3 An innovative IONM technique in resective epilepsy surgery ACCEPTED MANUSCRIPT Introduction 3 4 5 6 Many forms of prenatal and perinatal brain injury can lead to congenital hemiparesis. Periventricular white matter injury is the most common lesion type, 1 whereas other causes include perinatal arterial stroke, brain malformations, and intracranial haemorrhage. Patients with congenital or early-acquired brain structural 7 8 9 10 lesions present not only with contralateral hemiparesis but also cognitive deficits, developmental delays, and seizures. Among them, seizure is the most debilitating manifestation, which greatly impairs the quality of life in both the affected individuals and their caregivers as well as prevents them from active social participation.2-4 11 12 13 14 Children with epilepsy may also have cognitive and learning difficulties, leading to low academic performance in school and poor interpersonal relationships with their peers.5 Antiepileptic drugs (AEDs), a ketogenic diet, nonspecific interventions, and surgery are the mainstay of the treatment for seizures in childhood. Among them, 15 16 17 18 19 medication is usually the first-line treatment for confirmed and persistent seizures. Seventy to 80% of epileptic children achieve seizure control with the first or second AED, and about two-thirds of those that take AEDs can be weaned off after two years of being seizure-free.6 However, the short-term and long-term adverse effects of AEDs often limit their use. AEDs can cause dose-dependent adverse effects such as 20 21 22 23 cognitive decline, persistent somnolence, and ataxia as well as idiosyncratic responses such as Steven-Johnson disease, or chronic adverse effects including altered hormonal regulation, weight gain, hair loss, and loss of bone density.7 Among all the known adverse effects, cognitive decline probably poses the greatest risk on children because 24 25 they cause long-term developmental impairment.8 Thus, early-onset epilepsy disorder as well as its pharmacological management intertwine to create a sub-optimal 26 27 situation for affected children. If the seizures cannot be managed by AEDs or the adverse effects of the 28 29 30 31 32 anticonvulsants are intolerable, surgical resection of the epileptogenic focus is the next option to achieve better seizure management. According to a meta-analysis conducted by Cao et al., 71% of epileptic children receiving hemispheric surgery could maintain a seizure-free status in five years, an outstanding long-term prognosis.9 Nevertheless, surgical resection of the epileptogenic focus poses the risk 33 34 35 of creating new functional deficits. However, it is possible that corticospinal projections of the lesioned hemisphere might migrate to the opposite hemisphere in younger individuals, owing to early onset of the lesions and children’s pronounced 36 37 neuroplasticity.10 This consideration should affect surgical decision-making and the prognosis of functional outcomes. AC C EP TE D M AN U SC RI PT 1 2 4 An innovative IONM technique in resective epilepsy surgery ACCEPTED MANUSCRIPT In the present study, we employed an innovative intraoperative neurophysiologic monitoring (IONM) approach to determine the pattern of corticospinal projections 3 4 5 6 during resective surgery of an adult patient with congenital hemiparesis and refractory epilepsy. We believe that a thorough understanding of the anatomy is essential not only for surgical decision-making but also for predicting functional outcomes following surgery. 7 8 9 Case report History and Examination 10 A 34-year-old man was born full-term via normal spontaneous delivery. His mother 11 12 denied any abnormality or events during perinatal follow-ups or postpartum. The patient had a history of developmental delay, right hemiparesis since infancy, and 13 seizures starting at the age of six years. He developed dystonia of the right upper 14 15 16 17 extremity in flexor posturing since his adolescence, yet he could still walk a long distance with a hemiparetic gait and was partially independent in activities of daily living. At the time of writing, he was employed at a full-time sheltered job in the housing intermediary industry. In the last two years, the patient developed 18 19 20 21 drug-resistant seizures that significantly impaired his quality of life and prevented him from engaging in active social and vocational activities. The seizures occurred without prodromes or an aura 4–5 times each day, but improved to 1–2 times every 3 months under treatment with anticonvulsants. Electroencephalography (EEG) showed 22 23 24 25 a general spike-and-wave complex, 1.5–2.0 Hz over F-C max. A preoperative intelligence test, using the Wechsler Adult Intelligence Scale, indicated borderline mental deficit with a total intelligence quotient of 72. He was admitted to the neurosurgery ward in a tertiary medical centre to undergo resective epileptic surgery. 26 Imaging 27 28 29 Preoperative brain magnetic resonance imaging (MRI) revealed tissue loss and cystic encephalomalacia in the left parietal and temporal lobes and insular regions, which suggested an old cerebrovascular insult (Fig 1). 30 Operation and intraoperative neurophysiological monitoring technique AC C EP TE D M AN U SC RI PT 1 2 31 After anaesthesia, a pair of needle electrodes was inserted at the bilateral 32 33 34 abductor pollicis brevis (APB) and abductor hallucis (AH) to record compound muscle action potentials (CMAPs). Stimulating electrodes were placed at Cz, C3, and C4 according to the international 10–20 system for transcranial stimulation (TCS). 35 Responses from bilateral APB and AH to multipulse train TCS with either C3/Cz or 5 An innovative IONM technique in resective epilepsy surgery ACCEPTED MANUSCRIPT C4/Cz montages were recorded before incision to define the pattern of corticospinal projections. In this patient, when stimulating with C3/Cz montage (254 V, train of 5, 3 4 5 6 pulse-width 50 µs), we obtained a motor response from only the right-hand muscle. However, when stimulating with C4/Cz montage (226 V, train of 5, pulse width 50 µs), we obtained compound muscle action potentials (CMAP) over the bilateral hand muscles and AH, which indicated that corticospinal projections from both 7 8 9 10 hemispheres innervated muscles in the paretic limbs (Fig 2). After craniotomy, the central sulcus could not be defined by phase reversal probably owing to severely destructive brain lesions of the left hemisphere. Thus, we used multipulse train direct cortical stimulation (DCS) with a monopolar electrode to help the surgeon confine the 11 12 13 14 resection to the non-eloquent cortex (stimulus parameters--train of 5, 2–4 inter-stimulus interval, 0.5 ms pulse width, 0.5–20 mA). The region underneath disc 16 was the only area with a motor response from the hand muscle when performing DCS with multipulse train stimulation and stimulus intensity 20 mA, and needed to be 15 16 17 preserved (Fig 3). The surgeon then performed a left frontal corticectomy and the extent of resection was defined by pre-operative epilepsy survey (semiology, video-EEG, positron-emission tomography, and MRI) and tailored by 18 19 20 21 electrocorticography. The postoperative course was uneventful and there was no postoperative motor functional deterioration. Moreover, pre- and post-operative linguistic tests, both graded as with mild degree of deficits, did not reveal any significant interval change, although no linguistic mapping was performed during the 22 23 24 surgical procedure. The patient had remained seizure-free six months after the operation. 25 26 27 28 29 30 31 32 Discussion Children with congenital or early onset brain lesions frequently experience contralateral hemiparesis, mental deficits, and seizures, which have a tremendous impact on their development. Among those effects, seizures increase caregivers’ burden and unsurprisingly negatively affect their quality of life as well.11,12 Surgical resection of the epileptogenic focus is an alternative option if medical treatment fails to offer a satisfactory control of seizure attacks.13,14 However, resective surgery of the 33 34 35 cortex does carry the risk of postoperative deficits, particularly if the focus lies in proximity to the eloquent cortex. Thus, a thorough understanding of the pattern of corticospinal projections before resection of the epileptogenic focus is mandatory to 36 37 38 maximally reduce any possible postoperative deficits. A congenital or early-acquired insult of the brain might result in reorganization of the corticospinal projections because of the greater neuroplasticity in AC C EP TE D M AN U SC RI PT 1 2 6 An innovative IONM technique in resective epilepsy surgery ACCEPTED MANUSCRIPT childhood.10,15 Therefore, there is the possibility that the eloquent cortex shifts to the unaffected hemisphere or to another part of the affected hemisphere, which will 3 4 5 6 certainly influence the surgeon’s decision-making when performing resective epilepsy surgery. This is because the possibility and severity of postoperative deficits will differ according to the kind of functional reorganization of the brain. In a previous study, three out of 10 epileptic children possessed ipsilateral corticospinal projections 7 8 9 10 from the contralesional hemisphere, three patients presented with corticospinal projections from both hemispheres, and four patients had preserved corticospinal projections from the affected hemisphere.16 Currently, neuroimaging and brain stimulation either intraoperatively or 11 12 13 14 extraoperatively as well as intraoperative neuromonitoring all could be utilized solely or collaboratively to determine the pattern of corticospinal projections, the extent of the lesion, and the relationship with its contiguous tissue. These are crucial for surgical decision-making and the prediction of functional outcomes. 10,17 Hooi et al. 15 16 17 18 19 even proposed that when combining quantitative diffusion tensor imaging fibre tracking and fractional anisotropy values, one can predict the post-operative high cognitive and neuropsychological outcomes such as in language, memory, and attention. 18 However, some of these procedures require active patient participation and cooperation, which is frequently very challenging in patients with congenital 20 21 22 23 hemiparesis due to their younger age and/or associated mental deficits. This case report shows how intraoperative brain mapping helps to define the pattern of corticospinal projections and how it can contribute to surgical decision-making during resective epilepsy surgery and in turn lessen the possibility of new postoperative 24 25 motor functional deficits. However, this technique cannot replace the role of pre-operative functional MRI and awake surgery regarding mapping of the linguistic 26 27 centres. Chandra et al. published a retrospective study in 2008, reviewing 462 cases aged 28 29 30 31 between 4 to 23, undergoing hemispherotomy for intractable seizures. Of all cases, four experienced immediate post-operative weakness, which improved to preoperative level in 5 to 8 weeks. The study illustrated that even though hemispherotomy is considered safe for functional maintenance, worsening motor function is still likely to 32 33 34 35 occur. 19 We exerted every effort to preserve this young man’s functionality because although he had borderline intellectual disability, he was holding a full-time sheltered job and was financially independent. Thus, when the intraoperative brain mapping revealed bilateral corticospinal projections, given his high functionality and personal 36 37 expectation, the surgeon decided to perform frontal corticectomy and under guidance of DCS, spared the eloquent cortical region (underneath disc 16) to avoid causing any, AC C EP TE D M AN U SC RI PT 1 2 7 An innovative IONM technique in resective epilepsy surgery ACCEPTED MANUSCRIPT albeit trivial according to previous research, but possible new deficit, which may have impeded his current daily performance. 3 4 5 6 TCS over the bilateral hemispheres (using either C3/Cz or C4/Cz montages) is applied before craniotomy and DCS over the lesioned hemisphere is applied after craniotomy. Conventional C3/C4 montage is not recommended during TCS in order 7 8 9 10 to avoid deeper penetration of the stimulus current with simultaneous activation of the bilateral corticospinal tracts, which certainly will confound the results. Based on the information gathered from the aforementioned approaches, we could first identify the pattern of corticospinal projections before craniotomy and then accurately define the 11 12 13 14 non-eloquent area using DCS, which in turn guided surgical resection and successfully accomplished the surgical goal. In this patient, corticospinal projections from both hemispheres to target muscles in the paretic limb rendered the resection less risky. Furthermore, the technique is simple because no cooperation or 15 16 17 participation is required from the patient, who remained under anaesthesia. This patient sustained no new functional deficits after operation and had stayed seizure free six months after the operation. 18 19 20 21 The main difference of this approach, unlike previous routine applications, is that we recorded CMAPs over the bilateral limb muscles simultaneously instead of only over the contralateral muscles to determine the corticospinal projection pattern. We believe that it has the potential to replace preoperative fMRI and TMS in resective 22 23 epilepsy surgery, particularly for young patients. Not only can it improve the safety of surgical procedures, it helps to predict the functional outcome as well. 24 25 Disclosure 26 27 The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. SC M AN U TE D EP AC C 28 RI PT 1 2 29 Funding sources 30 31 This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. 32 33 34 35 8 An innovative IONM technique in resective epilepsy surgery ACCEPTED MANUSCRIPT 1 2 Figure 1. Brain magnetic resonance imaging showing tissue loss and cystic encephalomalacia in the left parietal and temporal lobes and insular regions (left, axial 3 4 5 6 view on T1-weighted imaging; right, frontal view on T2-weighted imaging). RI PT 7 8 9 10 M AN U SC 11 12 13 14 26 27 28 29 30 31 32 33 EP 22 23 24 25 AC C 18 19 20 21 TE D 15 16 17 34 35 36 37 9 An innovative IONM technique in resective epilepsy surgery ACCEPTED MANUSCRIPT 1 2 Figure 2a. While stimulating with C3/Cz montage, we obtained a motor response from only the right hand muscle (left). However, when stimulating with C4/Cz 3 4 5 6 montage, there were compound muscle action potentials in the hand muscles and the abductor hallucis bilaterally (right). RI PT 7 8 9 10 M AN U SC 11 12 13 14 26 27 28 29 30 31 32 33 EP 22 23 24 25 AC C 18 19 20 21 TE D 15 16 17 34 35 36 37 38 10 An innovative IONM technique in resective epilepsy surgery ACCEPTED MANUSCRIPT 1 2 Figure 2b. Corticospinal projections from both hemispheres to target muscles in the right paretic limbs made the resection of the left epileptogenic focus less risky in this 3 4 5 6 patient. 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