Accepted Manuscript Awake Surgery for Brain Vascular Malformations and Moyamoya Disease Rami James N. Aoun, MD, MPH, Mithun G. Sattur, MBBS, Chandan Krishna, MD, Amen Gupta, MBBS, Matthew E. Welz, MS, Allan D. Nanney, III, MD, Antoun H. Koht, MD, Matthew C. Tate, MD, PHD, Katherine H. Noe, MD, PhD, Joseph I. Sirven, MD, Barrett J. Anderies, Patrick B. Bolton, MD, Terry L. Trentman, MD, Richard S. Zimmerman, MD, Kristin R. Swanson, PhD, Bernard R. Bendok, MD, MSCI, FACS PII: S1878-8750(17)30444-8 DOI: 10.1016/j.wneu.2017.03.121 Reference: WNEU 5490 To appear in: World Neurosurgery Received Date: 31 January 2017 Revised Date: 23 March 2017 Accepted Date: 25 March 2017 Please cite this article as: Aoun RJN, Sattur MG, Krishna C, Gupta A, Welz ME, Nanney III AD, Koht AH, Tate MC, Noe KH, Sirven JI, Anderies BJ, Bolton PB, Trentman TL, Zimmerman RS, Swanson KR, Bendok BR, Awake Surgery for Brain Vascular Malformations and Moyamoya Disease, World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.03.121. 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 Aoun et al. Awake Surgery for Brain Vascular Malformations and Moyamoya Disease 1 RI PT 2 3 4 8 9 10 11 12 13 14 15 16 17 18 19 20 21 SC 7 1. 2. 3. 4. 5. 6. 7. 8. 9. M AN U 6 Rami James N. Aoun, MD, MPH1,8,9; Mithun G. Sattur, MBBS1; Chandan Krishna, 1 1,8,9 1,8,9 MD ; Amen Gupta, MBBS ; Matthew E. Welz, MS ; Allan D. Nanney, III 2 3 2 MD ; Antoun H. Koht, MD ; Matthew C. Tate, MD, PHD ; Katherine H. Noe, MD, PhD5; Joseph I. Sirven, MD5; Barrett J. Anderies1,8,9; Patrick B. Bolton, MD6; 6 1 1 Terry L. Trentman, MD ; Richard S. Zimmerman, MD ; Kristin R. Swanson, PhD and Bernard R. Bendok, MD, MSCI, FACS1,4,7,8,9. Department of Neurological Surgery, Neurovascular and Skullbase Program, Mayo Clinic, Phoenix AZ Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago IL Department of Anesthesiology, Northwestern University Memorial Hospital, Chicago IL Department of Otolaryngology, Mayo Clinic, Phoenix AZ Department of Neurology, Mayo Clinic, Phoenix, AZ Department of Anesthesiology, Mayo Clinic, Phoenix AZ Department of Radiology, Mayo Clinic, Phoenix AZ Precision Neuro-therapeutics Innovation Lab, Mayo Clinic, Phoenix, AZ Neurosurgery Simulation and Innovation Lab, Mayo Clinic, Phoenix AZ TE D 5 Corresponding Author 24 25 26 27 28 29 30 31 32 33 34 Bernard R. Bendok, MD MSCI 35 36 Disclosures This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. EP 22 23 AC C William and Charles Mayo Professor, Chair, Department of Neurological Surgery, Mayo Clinic Mailing Address: 5777 East Mayo Boulevard Phoenix, AZ 85054 Email Address: Bendok.bernard@mayo.edu Telephone: 480-342-4889 Fax: 480-342-3699 1 ACCEPTED MANUSCRIPT Aoun et al. 37 AVM DCS DSA CTA ECog fMRI MRI MRA Arteriovenous Malformations Direct Cortical Stimulation Digital Subtraction Angiography Computed Tomographic Angiography Electrocorticography Function Magnetic Resonance Imaging Magnetic Resonance Imaging Magnetic Resonance Angiography 49 Keywords M AN U 50 51 52 53 Awake surgery, Arteriovenous Malformation, Direct Cortical Stimulation; Neurovascular surgery, Moyamoya, Cavernomas, fMRI 54 55 60 61 62 63 64 65 66 EP 59 AC C 58 TE D 56 57 RI PT Abbreviations SC 38 39 40 41 42 43 44 45 46 47 48 67 68 69 70 2 ACCEPTED MANUSCRIPT Aoun et al. Abstract 72 73 Objective While a significant amount of experience has accumulated for awake procedures for 74 brain tumor, epilepsy and carotid surgery, its utility for intracranial neurovascular indications 75 remains largely undefined. Awake surgery, for select neurovascular cases, offers the advantage 76 of precise brain mapping and robust neurological monitoring during surgery for lesions in 77 eloquent areas, avoidance of potential hemodynamic instability, and possible faster recovery. 78 Additionally, it opens the window for perilesional epileptogenic tissue resection with potentially 79 less risk for iatrogenic injury. 80 Methods IRB approval was obtained for a retrospective review of awake surgeries for 81 intracranial neurovascular indications over the past 36 months from a prospectively maintained 82 quality database. We reviewed patients’ clinical indications, clinical and imaging parameters, 83 and postoperative outcomes. 84 Results 8 consecutive patients underwent 9 intracranial neurovascular awake procedures 85 conducted by the senior author. A standardized “Sedated-Awake-Sedated” protocol was utilized 86 in all eight patients. For the two AVM patients and the three cavernoma patients, awake brain 87 surface and white matter mapping was performed before and during microsurgical resection. A 88 neurological exam was obtained periodically throughout all 5 procedures. There were no intra- 89 operative or peri-operative complications. Hypotension was avoided during the two Moyamoya 90 revascularization procedures in the patient with a history of labile blood pressure. Postoperative 91 imaging confirmed complete AVM and cavernoma resections. No new neurological deficits or 92 new onset seizures were noted on 3-month follow-up. 93 Conclusion Awake surgery appears to be safe for select patients with intracranial neurovascular 94 pathologies. Potential advantages include greater safety, shorter length of stay and reduced cost. AC C EP TE D M AN U SC RI PT 71 3 ACCEPTED MANUSCRIPT Aoun et al. 95 Introduction 96 The value of awake surgery has been effectively demonstrated in several surgical specialties 98 including plastic surgery, orthopedic surgery, cardiac surgery, and thoracic surgery, amongst others.1-5 99 The benefits of awake procedures in neurosurgery have also become apparent, especially for select brain 100 tumors in eloquent locations, epilepsy surgery and carotid disease.6-14 The utility of awake surgery for 101 intracranial neurovascular diseases, however, has not been well established. SC RI PT 97 The potential advantages of awake surgery for select intracranial arteriovenous malformations 103 and cavernomas include more reliable neurological monitoring, more accurate brain mapping and the 104 potential for confidently resecting perilesional epileptogenic tissue with lower risk for neurological 105 deficit. For Moyamoya disease, more robust neurological monitoring and avoidance of hypotension 106 induced ischemia are potential benefits of awake surgery. 9,13,15-19 The main concerns with awake 107 neurovascular procedures are patient movement, which might jeopardize delicate microsurgical 108 maneuvers, and patient discomfort during long procedures.20,21 TE D 109 M AN U 102 In this report we present our preliminary experience with awake surgery for highly selected patients with intracranial AVMs, cavernomas and Moyamoya disease. Our aim is to share our rationale 111 and establish the feasibility, and safety of awake surgery for these indications. EP 110 113 114 115 116 AC C 112 Methods Data Collection 117 IRB exemption was obtained for this retrospective case series analysis at Mayo Clinic and 118 Northwestern University. The prospectively maintained neurovascular databases at the Mayo Clinic 119 Hospital and Northwestern Memorial Hospital were queried for patients with intracranial neurovascular 4 ACCEPTED MANUSCRIPT Aoun et al. pathologies who had undergone an awake craniotomy by the senior author over the past 36 months. The 121 indications for awake surgery were: 1) identification of eloquent cortex (language, motor) in proximity to 122 the pathology or 2) avoidance of hypotension associated with general anesthesia in patients with 123 precarious cerebrovascular reserve. Patients were subsequently stratified into 2 subgroups: 124 • Group 1 included Cavernomas and AVMs and 125 • Group 2 included patients with Moyamoya disease. RI PT 120 The rationale for awake surgery differed between the two groups (see below). Data points 127 selected included clinical indications, clinical presentation, preoperative workup, intraoperative anesthetic 128 and mapping techniques, intraoperative hemodynamic parameters, preoperative and postoperative 129 imaging, intraoperative and postoperative complications, and clinical outcomes. The data points were 130 tabulated and subsequently analyzed. 131 133 Imaging studies All patients underwent standard MR imaging (contrast-enhanced T1, GRE, SWI, DWI), MR TE D 132 M AN U SC 126 angiography and digital subtraction angiography (DSA) when indicated. In addition, patients in group 1 135 underwent fMRI sequences and DTI studies for preliminary localization of the functional cortex (motor 136 and language areas) and the corresponding subcortical tracts. The location of the lesion in relation to the 137 fMRI generated functional areas and DTI generated tracts was noted. 139 140 AC C 138 EP 134 Preoperative patient preparation Preoperative evaluation of patients included specific attention to obstructive sleep apnea (OSA), 141 ischemic heart disease (IHD) and previous adverse events related to local anesthesia and sedation. All 142 patients were extensively counseled on the steps of the procedure. Special emphasis was placed on 143 educating them on the portions of surgery where their active co-operation would be required. We were 144 careful to obtain informed consent regarding the nature of awake surgery. 145 5 ACCEPTED MANUSCRIPT Aoun et al. 146 Technique for anesthetic management The asleep-awake-asleep technique, described previously, was used in all respective surgeries.22 148 Analgesia was achieved with a combination of a regional scalp block with local anesthetic mixture (6ml 149 of 1% tetracaine is mixed with 30 ml of 1% lidocaine and 1:200,000 epinephrine) and infusion of 150 intravenous remifentanil (2000 mcg in 50 ml). Sedation was achieved with an infusion of Propofol 151 titrated to clinical effect (10mg/ml). (Figure 1) Strategic discontinuation of sedation was employed to 152 ensure that patients were awake and cooperative for the mapping and assessment phases of the surgery. SC RI PT 147 153 Patient Positioning M AN U 154 All patients were positioned supine or lateral with close attention to comfort, optimization of 156 venous drainage, and pressure point padding. A Mayfield head fixation device (Integra LifeSciences, 157 Plainsboro, NJ) with pin site local anesthetic infiltration was used for patients in group 1 while a donut or 158 horseshoe device sufficed for those in group 2. Appropriate monitoring devices were placed. Care was 159 taken during draping to allow a direct line of sight between the patient’s face, and the anesthesiology and 160 neuro-monitoring teams. Constant periodic reassurance was quintessential for attending to patients’ 161 concerns and decreasing their anxiety. Another adopted strategy was playing their favorite music playlist 162 or movie during the operation. 165 EP 164 Awake phase monitoring AC C 163 TE D 155 Patients in group 1 underwent direct cortical stimulation and mapping using an Ojemann cortical 166 stimulator (Integra LifeSciences, Plainsboro, NJ) (1.5-10 ma is delivered by a constant current stimulator 167 in 4-second trains at 60 Hz across 1-mm bipolar electrodes separated by a 5-mm gap), or a grid electrode 168 array. Motor areas were identified with concomitant movement of the face/upper limb/lower limb 169 occurring after cortical stimulation. For language mapping, patients were asked to count numbers from 1 170 to 50, name objects presented as pictures and read words presented on a screen. Speech areas were 171 identified by stimulation-induced speech arrest, errors in naming or word reading for lesions near speech 6 ACCEPTED MANUSCRIPT Aoun et al. areas. Electrocorticography (ECoG) signals were recorded mainly for Group 1 patients to discern 173 epileptogenic foci from silent brain tissue. Additionally white matter stimulation was used where 174 relevant. Negative responses were seen as cautiously reassuring. Awake procedures for Group 2 were 175 carried out with the main aim of preventing blood pressure lability with general anesthesia. A secondary 176 benefit was the ability to monitor their general neurological status. Hence direct cortical stimulation and 177 mapping was not essential. Monitoring of somatosensory evoked potentials (SSEP) and 178 Electroencephalography (EEG) changes was standard in all patients. Clinical or electrocorticographic 179 seizure activity was suppressed with irrigation of ice-cold Ringer solution over the brain. SC RI PT 172 M AN U 180 181 182 Results A total of nine awake neurovascular surgeries were performed in eight patients. Demographics 184 and indications for surgery are summarized in Table 1. Two patients had arteriovenous malformations, 185 three had cavernous malformations and three patients had Moyamoya disease (bilateral surgeries in one 186 patient). Consequently, group 1 consisted of five awake procedures and group 2 consisted of four 187 procedures. Seven patients were female, and one was male. Age range was 21 to 64 years. All patients 188 were fluent with the English language. No interpreter was needed. All patients underwent postoperative 189 MRI; follow up angiography was performed in addition for patients with AVM or Moyamoya disease. 191 192 EP AC C 190 TE D 183 Group 1: A total of 2 AVM patients were included in group 1; Patient 1 had a grade 2 AVM located in the 193 posterior left temporal lobe and Patient 2 a grade 2 AVM in the right parietal lobe. A total of 3 cavernoma 194 patients were included in this group as well; Patient 3 had a cavernoma located in the right frontal lobe, 195 Patient 4 in the right parietal lobe and Patient 5 had multiple cavernomas. (Table 2) All lesions were 196 located in or adjacent to eloquent regions. Patient 2’s AVM and Patient 3 and 4’s cavernomas were 7 ACCEPTED MANUSCRIPT Aoun et al. 197 intimately related to the motor area, Patient 1’s AVM to the language area and Patient 5’s cavernoma to 198 both. Four cases (Patients 1, 2, 4 and 5) presented with seizures and Patient 3 presented with focal 199 neurological deficit. (Table 2) All patients underwent successful awake procedures. Smooth transition from asleep to awake RI PT 200 phases and back to asleep was achieved in all cases. Motor mapping and language mapping, in addition to 202 ECoG, were accomplished in all patients while in the awake phase. Correspondence between preoperative 203 fMRI and intraoperative awake direct cortical mapping was seen in patients 2, 3 and 4. These three 204 patients had functional cortex in close proximity to lesions. On the other hand, in patients 1 and 5, 205 intraoperative mapping revealed non-functional cortex from a motor and language standpoint surrounding 206 the target lesion. (Table 3) Subsequently, both positive and negative mappings allowed strategic 207 dissection around the targeted pathologies and complete resection in all cases. Patient 5 had a perilesional 208 epileptogenic focus detected on ECoG. (Table 3) The involved tissue was consequently removed with 209 non-obvious neurological sequelae. No cases were aborted due to issues with patient comfort or 210 cooperation. There were no adverse events such as noticeable brain swelling, desaturation or vomiting. 211 (Table 4) Patients 1, 3 and 4 had one episode of seizure each during the mapping process. All seizures 212 abated promptly with ice-cold Lactated Ringer irrigation. TE D M AN U SC 201 Postoperative courses were uneventful in all patients. No new or worsened deficit was observed. 214 All patients reported positive experiences with the awake procedures and were willing to undergo another 215 awake surgery should the need arise in the future. Follow up imaging consisted of postoperative MRI in 216 cases with cavernomas and follow up angiography in AVM patients. Total resection was achieved in all 217 cases. (Table 4) 219 220 AC C 218 EP 213 Group 2: Three patients with Moyamoya disease underwent four awake procedures. Patient 6 underwent 221 bilateral awake indirect bypass three months apart. Imaging demonstrated bilateral disease in all patients. 222 (Table 2) Patients were kept hypertensive during surgery, with SBP maintained between 160-190 mmHg. 8 ACCEPTED MANUSCRIPT Aoun et al. There were no episodes of significant blood pressure fluctuations during surgery in any of the patients. 224 There was no requirement of increasing blood pressure at any point during surgery since no motor nor 225 language deficits were noted during monitoring. Periodic evaluation of contralateral motor movements 226 was carried out during these procedures. No adverse events were noted during surgery. Postoperative 227 course was uneventful without new or worsening deficits. (Table 4) 228 RI PT 223 Case illustrations 230 Case 1 (Patient 1) 231 A 36-year-old female with a new onset seizure and normal exam was found to have an AVM in 232 the left superior temporal gyrus with evidence of prior hemorrhage on MRI (Figure 2A-B). Angiography 233 showed a Spetzler-Martin grade 2 AVM (Figure 2C). fMRI showed the lesion in close relation to 234 Wernicke’s area. Microsurgical resection was chosen after discussion of the options with the patient, as 235 we felt it had the added benefit of mapping and resecting epileptogenic tissue. During surgery, awake 236 language mapping revealed that the perinidal cortex was non eloquent and the AVM was resected along 237 with perilesional hemosiderin laden tissue with aid of ECoG (Figure 2D-E). An intraoperative seizure 238 occurred that was easily controlled with ice-cold Ringer solution. The patient remained intact 239 postoperatively. Postoperative angiography confirmed complete AVM resection. She remained seizure 240 free and without any deficits at one year follow up. 242 243 M AN U TE D EP AC C 241 SC 229 Case 2 (Patient 2) A 56-year-old female presented with left facial partial seizures and upper extremity paresis from 244 a right parietal hematoma within the post central gyrus.(Figure 3A) Angiography revealed a Spetzler- 245 Martin grade 2 AVM fed by a right middle cerebral artery branch with a single draining vein to the 246 sagittal sinus, just posterior to the hand knob.(Figure 3B) fMRI revealed right sided hand, lip, and tongue 247 sensorimotor activity abutting this area.(Figure 3C) Surgical resection was performed with awake 9 ACCEPTED MANUSCRIPT Aoun et al. cortical and subcortical motor mapping and complete AVM excision was achieved. Post operatively she 249 remained without motor deficits but had an episode of left faciobrachial focal motor seizure that resolved 250 promptly. Postoperative angiography showed no residual nidus and she remained seizure free at 6 month 251 follow up. RI PT 248 252 Case 3 (Patient 6) 254 A 64-year-old female presented with bilateral upper extremity sensory TIAs, left more than right 255 (Figure 4A). Digital subtraction angiography revealed bilateral moyamoya disease (Figure 4B-C). Right- 256 sided indirect bypass (encephaloduroarteriomyosynangiosis- EDAMS) was performed with the patient 257 awake to avoid hypotension related to general anesthesia. Adequate blood pressure was consistently 258 maintained during surgery and no adverse intra nor post operative neurological events were observed. She 259 was symptom free at 1-month follow up. 260 M AN U SC 253 Case 4 (Patient 5) 262 A 21-year-old male presented with intractable seizures and multiple cerebral cavernomas on 263 MRI. (Figure 5A) Video EEG determined possible ictal origin from a right frontal or a right temporal 264 lesion. fMRI revealed close proximity of the right posterior frontal cavernoma subcortical motor tracts on 265 DTI.(Figure 5B-C) Surgical resection of the right frontal and temporal cavernomas was undertaken with 266 awake cortical and subcortical motor mapping with electrocorticographic recording. (Figure 5D) 267 Perilesional hemosiderin stained tissue was resected at both locations safely without any intra- nor post- 268 operative deficits. He was seizure free on baseline dosage of anticonvulsants and was at neurological 269 baseline at 6-month follow up. Follow-up postoperative MRI showed complete resection. (Figure 5E) AC C EP TE D 261 270 271 272 Discussion 10 ACCEPTED MANUSCRIPT Aoun et al. 273 274 275 History of Awake Neurological Surgeries Initial descriptions of awake brain surgery date back to early 19 th century. G. Fritsh , E. Hitzig and D. Ferrier experimented with electrically stimulating the cerebrum of live animals and eliciting 277 specific contralateral movements 23,24 In 1874, R. Barthalow followed with the discovery of localized 278 brain functional maps by stimulating a human brain through a skull perforation secondary to an eroding 279 tumor.25 With the start of the 20th century, neurosurgeons recognized the potential of combined awake 280 surgery and brain mapping, especially in epilepsy surgery.26,27 O. Foerster was one of the first to map the 281 brain’s eloquent areas through direct electric stimulation allowing for functional delineation before the 282 epileptogenic foci were removed.27 Stimulation was noted to have the potential to elicit clinical seizures 283 and auras, thus aiding in the localization of epileptogenic focii. 27 In the 1980s, M. Berger and G. 284 Ojemann championed awake procedures and brain mapping for brain tumor surgery.17 This allowed the 285 meticulous removal of primary brain tumors while preserving eloquent areas and functional status.17 M AN U SC RI PT 276 287 288 TE D 286 Outcomes of Awake Surgery for Primary Brain Tumors and Epilepsy A meta-analysis conducted by Brown et al. demonstrated that awake tumor resection, as opposed to general anesthesia, led to a decrease in hospital stay, post-operative neurological deficit and surgical 290 time. Extent of resection was, additionally, notably enhanced.9 De Wit Hamer et al. in another meta- 291 analysis demonstrated the added value of intraoperative brain functional mapping for glioma resection. 292 They concluded that intraoperative mapping was associated with less severe neurological deficits and a 293 more extensive glioma resection.28 Millian et al. conducted a systematic review to study the psychological 294 sequela of awake surgery on patients. The majority of the patients stated that they were well prepared for 295 their surgeries and overall satisfaction after surgery was very high. The majority indicated they would 296 have the procedure performed again if it were indicated, even though up to 30% of them had reported 297 remembering moderate to severe pain during surgery and 14% reported anxiety during surgery.29 AC C EP 289 11 ACCEPTED MANUSCRIPT Aoun et al. 298 As for epilepsy surgery, an awake approach may be preferred over general anesthesia for two primary reasons; anesthetic interference with intracranial electrocorticography (ECoG) recordings and the 300 potential benefit of awake cortical functional mapping. 14,30,31 This in turn has led to possible improved 301 seizure outcomes.14 To our knowledge there has been no direct comparison of seizure outcomes with 302 awake resections versus non-awake procedures in epilepsy surgery. Though it has been suggested that 303 awake mapping enables more aggressive resection of lesional tissue.32 Moreover, greater extent of 304 resection in lesional epilepsy is known to correlate with improved seizure outcomes.33,34 SC RI PT 299 305 307 M AN U 306 Rational and Concerns of Neurovascular Awake Surgery The benefits of awake procedures for neurovascular indications may be extrapolated from other 309 neurosurgical disciplines, as outlined above, due to the scarcity of existing published data pertaining to 310 awake cranial neurovascular procedures and absence of any randomized trials. These benefits most 311 importantly include the potential for preservation of neurological function, delineating epileptogenic foci, 312 improving the sensitivity of neuromonitoring and mitigating the side effects of general anesthesia. As for 313 moyamoya disease, hemodynamic volatility, a potential sequela of general anesthesia, has been shown to 314 contribute to perioperative stroke in up to 3.8% to 16.9% of cases. There is increased incidence of 315 perioperative stroke in patients who are experiencing TIA preoperatively and may occur after 316 disconnecting collaterals from dura to the brain.35-37 The patients in our cohort were experiencing similar 317 preoperative hypotension associated TIAs and neurological deficits. Thus, application of awake 318 procedures in these patients mitigates the volatility of intraoperative blood pressure and may decrease risk 319 of perioperative stroke. 320 AC C EP TE D 308 The paucity of experience with awake surgery for neurovascular indications reflects several 321 commonly held concerns. The first is concern with patient motion given the delicate needs of vascular 322 micro-neurosurgery and the decreased ability to relax the brain when the patient is conscious. The second 323 is the potential need for burst suppression for temporary occlusion purposes. Awake surgeries do not 12 ACCEPTED MANUSCRIPT Aoun et al. permit the utilization of burst suppression essential to several neurovascular procedures. Hence, the 325 metabolic state of the brain cannot be altered in an attempt to protect the brain from ischemia during these 326 surgical procedures. A third is the potential for brain swelling particularly as one might expect with large 327 AVMs. Such barriers may not apply in cases involving small AVMs, cavernomas and moyamoya disease, 328 particularly with indirect bypass procedures. 329 RI PT 324 When functional mapping is required, awake direct cortical functional stimulation (DCS) remains the gold standard. Throughout the years, several modalities of non-invasive functional imaging, like 331 fMRIs, PET and DTI, have augmented but not yet supplanted this more invasive procedure. These 332 modalities remain limited by suboptimal sensitivity and specificity in localizing brain function when 333 compared to DCS functional mapping. 38-40 The hemodynamics of vascular lesions, moreover, add to the 334 uncertainty of fMRI imaging. The area of functional cortex may be overestimated secondary to an 335 increase in flow.41-43 M AN U SC 330 337 338 TE D 336 The Literature on Awake surgery for AVM, cavernoma and Moyamoya disease Pubmed was queried using the following terms: awake neurovascular, awake cavernoma, awake arteriovenous malformation, awake moyamoya, awake versus general anesthesia, functional mapping 340 cavernoma, functional mapping AVM, and functional mapping Moya Moya. Our search yielded 285 341 results of which, 19 publications were relevant to our literature review. The current published literature 342 pertaining to awake neurovascular procedures is limited to small case series and case reports 16,41,44-60. 343 Seven of these publications 41,44-48,51 encompassed a total of 33 patients who underwent awake AVM 344 surgery and eleven of these publications16,49,52-60 encompassed 32 patients who underwent awake 345 cavernoma surgery. (Table 5) To the best of our knowledge, there have been no reported cases on awake 346 Moyamoya disease revascularization surgery. One case report, however, has been reported on an awake 347 STA-MCA bypass for hemodynamic insufficiency related to vertebral and right ICA occlusion. The 348 indication for awake surgery in this case was to avoid any hypotension induced by general anesthesia 50. AC C EP 339 13 ACCEPTED MANUSCRIPT Aoun et al. Earlier attempts at awake AVM procedures, as outlined by Burchiel et al., involved awake 350 surgical functional mapping, followed by resection at a later date under general anesthesia.44 Gabarros et 351 al., on the other hand, kept their patients awake during language functional mapping while subjecting 352 them to general anesthesia for motor functional mapping and subsequent resection.41 In our cohort, both 353 language and motor functional mapping were performed in the awake phase with subsequent surgical 354 resection of the pathology. Cannestras et al. proposed a classification system of AVMs that relates preoperative language SC 355 RI PT 349 function fMRI findings to theoretic operative choice (between awake or asleep) and postoperative 357 outcome.45 They categorized AVM patients into 3 groups; Group 1, low risk, included AVMs which were 358 at least one gyrus removed from areas of language activation, Group 2, high risk, are the AVMs that are 359 intimately associated with language functional areas and Group 3, intermediate risk are the AVMs that are 360 adjacent to functional areas. Group 1 undergo asleep surgery, Group 2 undergo radiosurgery due to 361 proximity and Group 3 undergo awake surgery. M AN U 356 We found several reports which included one or two awake procedures for cavernomas. There 363 were two larger reports by Zhou (n=17), who used cortical mapping to locate the primary motor cortex, 364 and Matsuda (n=9), who performed sensory motor and language cortical mapping, as well as sub-cortical 365 mapping during the surgical approach.52,58 Matsuda reported two incidents of discovering language areas 366 using sub cortical mapping in the pericavernomatous gliosis. These incidents prevented the full removal 367 resection of gliosis and spared eloquent brain tissue. What is of note in both these studies is that all 368 patients were free of neurological deficits at long-term followup. 370 EP AC C 369 TE D 362 Patient Selection and Indications 371 Rigorous selection criteria and an experienced surgical team ensure optimal outcomes for awake 372 cranial neurovascular surgery. General contraindications for awake procedures are uncooperative patients, 373 patients with severe language disabilities (such as frank Wernicke's aphasia), very young patients or 374 patients with significant language barriers. Patient’s clinical presentation is also important. Patients 14 ACCEPTED MANUSCRIPT Aoun et al. presenting with hemorrhage associated with hemiplegia, aphasia or a comatosed state may not be good 376 candidates for awake mapping.41 Anesthetic contraindications include severe obstructive sleep apnea. 377 Specific relative neurovascular contraindications include large and deep AVMs, posterior fossa 378 cavernomas or AVMs and possibly patients undergoing direct bypasses for Moyamoya disease. (Table 6) RI PT 375 379 381 Our Cases in Perspective In Group 1, utilization of intraoperative functional mapping with direct cortical stimulation SC 380 (DCS) allowed functional delineation of tissue surrounding the AVMs and cavernomas. This permitted 383 the surgeon to more confidently remove the corresponding pathologies. Patients in this group had no 384 permanent neurological deficits postoperatively. Moreover, none of the cases exhibited any postoperative 385 residual pathology on post surgical or follow-up imaging. In Group 2, patients experienced preoperative 386 TIAs and neurological deficits induced by hypotensive episodes, which as mentioned previously, is 387 associated with increased incidence of perioperative stroke. Intraoperative hemodynamic instability also 388 increases perioperative stroke risk. The awake procedure prevented the lability in blood pressure, a 389 potential sequela of general anesthesia, thus averting any cerebral ischemia related events intra- 390 operatively and post-operatively. Moreover, it permitted better intraoperative neuromonitoring in this 391 group of patients by means of more robust serial neurological exams. The postoperative courses of these 392 patients were uneventful. Noted, however, are the intraoperative clinical and subclinical seizures with 393 Group 1 patients. This is a relatively common side effect of direct cortical stimulation. The involved 394 surgeons equated their experience in these 9 cases to other established awake procedures in terms of 395 difficulty and ease of operation. They also noted that the operative times of awake procedures in relation 396 to non-awake surgeries were comparable. 397 AC C EP TE D M AN U 382 Success with this approach requires multidisciplinary collaboration between anesthesia, the 398 neurosurgical and the neuromonitoring team. Operating room nurses play a critical role as well. 399 Seamless communication and a calm intraoperative environment are important for a successful outcome. 400 Music selection and a reassuring environment can make for a very smooth experience for the patient. 15 ACCEPTED MANUSCRIPT Aoun et al. 401 This is fundamental especially when transitioning from the sedated to the awake and back to the sedated 402 phase. 403 Conclusion RI PT 404 405 406 Our experience with this cohort adds to the body of literature on awake surgery for intracranial neurovascular diseases and may help clarify new indications and rationale. Awake surgery, including both 408 awake language and motor functional mapping, appears safe for microsurgical resection of select small 409 superficial AVMS, and superficial cavernomas. More robust neurological monitoring, cortical and white 410 matter mapping and aggressive resection of perilesional epileptogenic tissue appear to be important 411 advantages. 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Anesthesia and analgesia. 1997;85(5):1060-1065. EP 19. AC C 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 18 ACCEPTED MANUSCRIPT Aoun et al. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. RI PT 42. SC 41. M AN U 40. TE D 39. Roux FE, Boulanouar K, Lotterie JA, Mejdoubi M, LeSage JP, Berry I. Language functional magnetic resonance imaging in preoperative assessment of language areas: correlation with direct cortical stimulation. Neurosurgery. 2003;52(6):1335-1345; discussion 1345-1337. Giussani C, Roux FE, Ojemann J, Sganzerla EP, Pirillo D, Papagno C. Is preoperative functional magnetic resonance imaging reliable for language areas mapping in brain tumor surgery? Review of language functional magnetic resonance imaging and direct cortical stimulation correlation studies. Neurosurgery. 2010;66(1):113-120. Duffau H. 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AC C 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 19 ACCEPTED MANUSCRIPT Aoun et al. 612 613 614 615 616 617 618 619 620 621 58. 59. 60. RI PT 57. SC 56. M AN U 55. TE D 611 54. Joswig H, Bratelj D, Brunner T, Jacomet A, Hildebrandt G, Surbeck W. Awake Craniotomy: First-Year Experiences and Patient Perception. World neurosurgery. 2016;90:588-596.e582. Delion M, Terminassian A, Lehousse T, et al. Specificities of Awake Craniotomy and Brain Mapping in Children for Resection of Supratentorial Tumors in the Language Area. World neurosurgery. 2015;84(6):1645-1652. Duffau H, Fontaine D. Successful resection of a left insular cavernous angioma using neuronavigation and intraoperative language mapping. Acta neurochirurgica. 2005;147(2):205-208; discussion 208. Sakurada K, Sato S, Sonoda Y, Kokubo Y, Saito S, Kayama T. 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AC C 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 622 623 624 625 20 ACCEPTED MANUSCRIPT Aoun et al. Figure Legend Figure 1 Visual Schematic of Awake Anesthesia Protocol RI PT Figure 2A Axial view GRE MRI sequence demonstrating hemosiderin surrounding the AVM (red circle). Figure 2B Lateral view left carotid artery angiogram demonstrating posterior temporal AVM with venous stenosis (red arrow). Figure 2C Axial view fMRI demonstrating proximity of AVM to language centers (red arrow) SC Figure 2D Surgeons performing direct cortical stimulation utilizing an Ojemman bipolar M AN U Figure 2E Direct cortical stimulation mapping with corresponding legend. Figure 3A Axial T2 Magnetic Resonance imaging of a lateral right Post central gyrus hemorrhage. Figure 3B AP and lateral angiography delineating the right parietal AVM. TE D Figure 3C Axial fMRI demonstrating lip motor function in proximity to the AVM Figure 4A Axial FLAIR sequence Magnetic Resonance Imaging demonstrating areas of hypodensities concomitant with ischemia (String of Pearl sign). EP Figure 4B AP view angiography demonstrating Moymoya vessel stenosis. Figure 4C Lateral view angiography demonstrating Moymoya vessel stenosis. AC C 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 Figure 5A Axial T2 Magnetic Resonance imaging of the frontal cavernoma. Figure 5B Axial view T2 fMRI demonstrating proximity of cavernoma to motor area. Figure 5C Digital tractography imaging demonstrating proximity of the cavernoma to the subcortical tracts. Figure 5D Intraoperative grid array used in DCS functional mapping. 21 ACCEPTED MANUSCRIPT Aoun et al. EP TE D M AN U SC RI PT Figure 5E Sagittal view Post-operative Follow-up Magnetic resonance imaging demonstrating resolution of the frontal cavernoma. AC C 669 670 671 22 Group 1 CT/A MRI/A MRI Tractography ACCEPTED MANUSCRIPT f MRI Angiography Age Sex Presenting Sx Pathology Location Indication for Awake Surgery Patient 1 36 F New Onset Seizure No focal deficit Subjective Speech Impediment Partial seizure with speech arrest AVM Posterior left temporal lobe . Nearby eloquent language function . Evidence of prior hemorrhage, possible cause of intractable seizure . Superficial location Patient 2 56 F Partial Seizure; Left face and Left Upper extremity Left partial motor seizures AVM Right parietal post central gyrus behind hand knob . Nearby eloquent motor function Patient 3 23 F Several weeks of bilateral motor and sensory symptomatology. Cavernoma Right posterior frontal lobe . Cavernoma anterior to motor area Patient 4 38 F Intractable seizure secondary to residual/recurrence of cavernoma. (Prior cavernoma resected asleep) Cavernoma Right parietal lobe Patient 5 21 M Intractable seizures Multiple Cavernomas Right frontal . Right frontal cavernoma in proximity to lobe, Right subcortical motor fibers parietal lobe and . Intractable seizure Left occipital lobe Patient 6-1 64 F Right Upper Extremity Numbness Patient 6-2 64 F Previous right sided encephaloduroarteriomyosynangiosis Patient 7 43 F Patient 8 41 F SC M AN U TE D Group 2 RI PT Group 1 Diffuse . Avoidance of Hypotension . Better Neuromonitoring Moyamoya Diffuse . Avoidance of Hypotension . Better Neuromonitoring Intermittent left arm numbness, episodic aphasia and complicated headaches Moyamoya Diffuse . Avoidance of Hypotension . Better Neuromonitoring Multifocal ischemic strokes 14 months PTP associated with episodic aphasia and paresthesias Moyamoya Diffuse . Avoidance of Hypotension . Better Neuromonitoring AC C EP Moyamoya . Proximity to motor cortex Table 1 Patient Demographics and Indications for Surgery ACCEPTED MANUSCRIPT - . Small left temporal AVM with surrounding T2 signal change . Evidence of prior hemorrhage AVM and or associated hemosiderin possibly intersected the left temporal components of the arcuate fasciculus and the left interior longitudinal fasciculus Reading paradigm elicited strong activation in the left ventral temporal lobe in extremely close proximity to the AVM, with some areas of activation immediately posterior and others immediately ventral to the AVM 1x1.2 cm superficial left posterior temporal AVM with a single feeder off a temporal MCA branch. The draining vein into the sigmoid sinus was ectatic and stenotic Patient 2 CT Right posterior fronto-parietal intraparenchymal hematoma CTA Negative . Resolving hemorrhage in lateral right post central gyrus . Early AV shunting in the region of the previous hematoma with a prominent right frontoparietal cortical vein draining into the superior sagittal sinus - Chronic hemosiderin staining and mild volume loss of the right post central gyrus. Right sided hand, lip, and tongue sensorimotor activity abutting this area. Language function not in proximity. Right post central gyrus micro-AVM fed by middle cerebral artery branch with one superficial draining vein to the sagittal sinus Patient 3 CT: Right frontal hematoma . Right frontal cavernoma Frontal lesion in proximity to motor subcortical fibers Primary motor cortex posterior to cavernoma None Patient 4 - . Evolving residual or recurrent right parietal cavernoma in close proximity to the motor cortex - Activation in the hand region, just anterior to the lesion. No language function within proximity None Patient 5 - . Right frontal lobe 9 mm cavernoma Frontal lesion in close with adjacent parenchymal proximity to subcortical hemosiderin staining motor fibers . Right lateral temporal lobe approximately 8 mm cavernoma with a small amount of adjacent parenchymal hemosiderin. . Medial left occipital lobe 1.5 cm cavernoma with adjacent parenchymal hemosiderin staining SC M AN U TE D EP AC C Group 2 RI PT Patient 1 . Motor: The activation was None several gyri away from the area of signal change on T2 ACCEPTED MANUSCRIPT CTA bilateral ICA stenosis and prominent collateralization MRI bilateral small strokes N/A N/A Bilateral ICA stenosis with collateralization from ECA branches Patient 6-2 CTA bilateral ICA stenosis and prominent collateralization MRI bilateral small strokes N/A N/A Bilateral ICA stenosis with collateralization from ECA branches Patient 7 CTA bilateral M1 stenoses, greater on the left N/A N/A Patient 8 CTA small caliber bilateral internal carotid arteries, extending from the cervical segments to the supraclinoid segments. Nearly complete obliteration of the lumina at the supraclinoid segments. There are extensive lenticulostriate collateral vessels EP AC C Table 2 Preoperative Imaging SC N/A M AN U N/A TE D MRA Bilateral MCA territory cortical and white matter infarcts. Severe, preocclusive stenosis of the supraclinoid internal carotid artery bilaterally RI PT Patient 6-1 Progression of the disease with greater collateral and hypertrophy of the lenticulostriate Bilateral high-grade supraclinoid carotid artery stenosis. Leash of moyamoya vessels replacing the right supraclinoid carotid artery. Extracranial to intracranial collateral via the left middle meningeal artery supplying the right ACA distribution. Hypertrophy of the right lenticulostriate arterial system. ACCEPTED MANUSCRIPT Patient ECOG; Yes or No ECoG Findings Intraoperative Brain Functional Mapping (Y/N) Type of Cortical Mapping Language/Motor Intraoperative Direct Cortical Mapping Mapping Findings Patient 1 Yes No Epileptogenic foci Yes Direct Bipolar Stimulation Both Language and Motor Patient 2 Yes No epileptogenic foci Yes Direct Bipolar Stimulation Both Language and Motor Patient 3 Yes No epileptogenic foci Yes Direct Bipolar Stimulation Both language and motor Hand area is one gyrus away from cortical incision Patient 4 Yes No epileptogenic foci Yes Grid Array Both language and motor Left lower face, left mouth and left lower lip were within close proximity from cortical lesion Patient 5 Yes Singular frontal Yes epileptogenic focus detected Both language and motor Cortex around frontal cavernoma is quite from a motor and language perspective (negative mapping) RI PT SC M AN U TE D EP AC C Table 3 Intraoperative Mapping Parameters in Group 1 Grid Array Cortex around the AVM nidus appeared non functional from a language standpoint (negative mapping) In the post-central gyrus, the sensory cortex for left lip, left tongue, left thumb and index finger were mapped. In the precentral gyrus, the motor cortex for left face and left hand were mapped. Utilizing this information, dissection was initiated within the post central sulcus to address the underlying AVM. ACCEPTED MANUSCRIPT Postoperative Complications Clinical Outcome/Postop Neurological Deficits Imaging Outcome Patient 1 One brief episode of seizure during direct stimulation, treated with cold Ringer solution None No seizures. Normal neurological exam Postop angiogram: Total resection of AVM without residual No speech impediments nidus or AV shunting Patient 2 None Transient left facial droop and arm twitching No seizures Normal neurological exam No speech impediments Patient 3 One brief episode of seizure during direct stimulation. Managed with Cold Ringer solution None No seizures. Normal neurological exam Postop MRI: total resection of cavernoma No speech impediments Patient 4 Brief subclinical seizure episode managed by lactated ringer None No seizures. No speech impediments. No new neurological deficit. Postop MRI: total resection of residual cavernoma Patient 5 None None No seizures. No speech impediment. No new neurological deficit Postop MRI: total resection of both cavernomas Patient 6-1 None None Patient 6-2 None None Patient 7 None None Patient 8 None RI PT Intraoperative Complications M AN U SC Postop angiogram: Complete resection of the AVM without residual nidus or AV shunting AC C EP TE D Group 2 Multiple clinical episodes of ipsilateral hypoperfusion, resolved post HHH therapy Table 4 Intraoperative and Postoperative Clinical Course Normal neurological exam No speech impediments - Normal neurological exam No speech impediments Followup MRI and MRA show no evidence of new onset stroke Normal neurological exam No speech impediments Followup angiogram: good collateral to the underlying brain related to the superior left indirect bypass. Hypertrophied meningeal arteries are seen in relation to this area as well as a brain capillary stain with venous drainage Normal neurological exam No speech impediments Postoperative angiogram: excellent EC-IC collateralization through indirect bypass ACCEPTED MANUSCRIPT Year Awake Procedure Burchiel et al. 1989 AVM # of Patients 8 Gorecki et al. Zamorano et al. 1992 1998 AVM AVM 2 6 Cannestra et al. Yonekawa et al. Gabarros et al. Gamble et al Coppens et al. Zamorano et al. Daffau et al. Mikuni et al. Sakurada et al. Shinoura et al. Zhou et al. Leal et al. Chang et al. Matsuda et al. Delion et al. Joswig et al. 2004 2005 2012 2015 2008 1997 2005 2006 2007 2008 2009 2010 2011 2012 2015 2016 AVM AVM AVM AVM Bypass Cavernomas Cavernomas Cavernomas Cavernomas Cavernomas Cavernomas Cavernomas Cavernomas Cavernomas Cavernomas Cavernomas RI PT Study SC M AN U TE D AC C EP Table 5 Published awake neurovascular surgery cases 5 3 5 4 1 7 1 2 1 1 17 1 3 8 2 2 ACCEPTED MANUSCRIPT General Factors to Consider for Awake Neurovascular Surgery Most superficial cavernomas Experienced surgical and anesthesia team RI PT Specific Neurovascular Indications for Awake Surgery All Moyamoya disease except when direct bypass is needed Well equipped Center Adequate patient cognition AC C EP TE D Table 6 Specific and General Neurovascular Indications Patient willingness and psychological status M AN U Small unruptured MCA bifurcation aneurysms SC Superficial small AVMs AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT ACCEPTED MANUSCRIPT Highlights AC C EP TE D M AN U SC RI PT . Awake surgery is an established modality for select neurosurgical procedures, including neurooncology, epilepsy surgery and carotid surgery, but is still not well established for neurovascular indications. . Hindrances to adopt awake surgery for neurovascular indications include patient motion in a delicate microsurgical procedure, the need for burst suppression and the potential brain edema with large AVMs. . We present a cohort of awake neurovascular procedures; we are one of the first to implement both awake AVM motor and language functional mapping, and the first to publish an awake Moyamoya procedure. . With an experienced surgical team and stringent patient selection criteria, awake surgery for neurovascular indications is feasible, efficacious and safe with potentially lower intraoperative and postoperative squealae. ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC AVM Arteriovenous Malformations DCS Direct Cortical Stimulation DSA Digital Subtraction Angiography CTA Computed Tomographic Angiography ECog Electrocorticography fMRI Function Magnetic Resonance Imaging MRI Magnetic Resonance Imaging MRA Magnetic Resonance Angiography RI PT Abbreviations ACCEPTED MANUSCRIPT RI PT Bernard R. Bendok, MD Chair, Neurological Surgery in Arizona William J. And Charles H. Mayo Professor Professor of Neurosurgery 5777 East Mayo Boulevard Phoenix, AZ 85054 SC Edward C. Benzel World Neurosurgery Chairman Department of Neurological Surgery Cleveland Clinic 9500 Euclid Avenue / S-40, Cleveland OH 44195 M AN U Dear Dr. Benzel, This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. TE D Sincerely, AC C EP Bernard R. Bendok, MD Chair, Neurological Surgery in Arizona William J. and Charles H. Mayo Professor Professor of Neurosurgery 5777 East Mayo Boulevard Phoenix, Arizona 85054