Accepted Manuscript Transradial Mechanical Thrombectomy For Proximal Mca Occlusion In A First Trimester Pregnancy: Case Report And Literature Review Sumedh S. Shah, B.S., Brian M. Snelling, M.D., Marie Christine Brunet, M.D., Samir Sur, M.D., David McCarthy, B.S., Alan Stein, M.D., Priyank Khandelwal, M.D., Robert M. Starke, M.D., Eric C. Peterson, M.D. PII: S1878-8750(18)32141-7 DOI: 10.1016/j.wneu.2018.09.095 Reference: WNEU 10300 To appear in: World Neurosurgery Received Date: 6 June 2018 Revised Date: 11 September 2018 Accepted Date: 12 September 2018 Please cite this article as: Shah SS, Snelling BM, Brunet MC, Sur S, McCarthy D, Stein A, Khandelwal P, Starke RM, Peterson EC, Transradial Mechanical Thrombectomy For Proximal Mca Occlusion In A First Trimester Pregnancy: Case Report And Literature Review, World Neurosurgery (2018), doi: https:// doi.org/10.1016/j.wneu.2018.09.095. 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 TRANSRADIAL MECHANICAL THROMBECTOMY FOR PROXIMAL MCA OCCLUSION IN A FIRST TRIMESTER PREGNANCY: CASE REPORT AND LITERATURE REVIEW RI PT Authors: Sumedh S. Shah, B.S.,1 Brian M. Snelling, M.D.,2 Marie Christine Brunet, M.D.,1 Samir Sur, M.D.,1 David McCarthy, B.S.,1 Alan Stein, M.D.,1 Priyank Khandelwal, M.D.,1 Robert M. Starke, M.D.,1,3 Eric SC C. Peterson, M.D.1 Author Affiliations: Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, FL. 2 Marcus Neuroscience Institute, Boca Raton Regional Hospital, Boca Raton, FL. 3 Department of Radiology, University of Miami Miller School of Medicine, Miami, FL. M AN U 1 Eric C. Peterson, M.D. Department of Neurosurgery TE D Corresponding Author: EP University of Miami Miller School of Medicine 1095 NW 14th Terrace, Miami, FL 33136 AC C Office: (305) 243-6946; FAX: (305) 355-1101; E-mail: ericpete@med.miami.edu Key Words: Mechanical Thrombectomy; Pregnancy; Transradial Access Running Title Transradial thrombectomy in first trimester pregnancy ACCEPTED MANUSCRIPT ABSTRACT Background. Acute ischemic stroke in pregnancy is a cause of maternal and fetal morbidity. Optimal treatment strategies for stroke in this population are undefined. Thrombolysis is recommended by RI PT guidelines should the benefit outweigh uterine bleeding risk. Alternately, data regarding mechanical thrombectomy (MT) is extremely limited. We present a 37-year-old female in the first trimester that developed recurrent proximal middle cerebral artery (MCA) occlusion after previous thrombolysis and SC underwent MT via transradial access. This report of transradial MT represents the first case performed through an extrafemoral route for large vessel occlusion in early pregnancy found in the literature. M AN U Clinical Presentation. A 37-year-old G8P7 at nine weeks’ gestation presented with left-sided hemiplegia and right gaze preference and underwent successful thrombolysis for a right MCA occlusion. Two days later, she exhibited the same symptoms, and a re-occluded right MCA was identified. As thrombolysis was unavailable given the recent stroke, the patient underwent emergent MT via radial access (to minimize fetal radiation exposure), and achieved TICI2b revascularization without complication to her or TE D her child. At 2-month follow-up, the patient is on anticoagulation and has a healthy pregnancy with only minor left-sided facial weakness. Conclusions. When thrombolysis is contraindicated, thrombectomy should be considered and weighed EP against risks of fetal radiation exposure and contrast load, especially in early pregnancy. Transradial MT is safe, feasible, and mitigates pelvic radiation. Multidisciplinary approach with obstetrics, stroke teams, AC C and neurointerventionalists is vital for successful therapy. 1 ACCEPTED MANUSCRIPT INTRODUCTION Ischemic stroke in pregnancy is a rare cause of maternal and fetal morbidity and mortality, with an incidence of 25-34 cases per 100,000 births.1-2 Treatment for stroke in this population remains RI PT controversial, though thrombolysis with tissue plasminogen activator (tPA) has been reported in the literature.3 Despite limited study, national guidelines recommend considering tPA use in pregnancy when its anticipated benefits for moderate and severe stroke outweigh bleeding risk.4 However, there is paucity SC in discussion of the role mechanical thrombectomy (MT) plays for stroke treatment in pregnancy. Several large trials have shown favorable safety and functional outcomes for MT in acute M AN U ischemic stroke.5-7 However, uncertainty exists whether these results can be applicable across high-risk populations, and there is reasonable apprehension over performing neurointervention in pregnancy given fetal exposure to radiation and contrast in utero. Nonetheless, in patients where tPA is contraindicated, MT could be vital in the therapeutic armament. Here, we present a 37-year-old woman at nine weeks gestation who was treated with MT for a recurrent right proximal middle cerebral artery (MCA) stroke TE D two days after successful thrombolysis of a clot in the same artery. To minimize pelvic and abdominal radiation, we opted to perform this case via transradial access (TRA). This report, to our knowledge, occlusion. AC C CASE REPORT EP represents the first documented MT safely performed via radial artery in early pregnancy for large vessel Case Presentation A 37-year-old G8P7 at nine weeks’ gestation with hypertension, hyperlipidemia, and dilated cardiomyopathy with reduced ejection fraction—diagnosed after her first pregnancy—presented to our institution complaining of acute left-sided hemiplegia and right gaze preference. Vital signs, blood glucose, and physical examination were otherwise unremarkable. Stroke alert was initiated, and initial NIH stroke score (NIHSS) was nine. Emergent non-contrast computerized tomography (CT) of the brain showed possible early ischemic changes with loss of gray-white differentiation along the right MCA 2 ACCEPTED MANUSCRIPT territory, and a right MCA vessel sign in the M1/M2 segments, suggestive of an acute thrombus (Figure 1a). CT angiogram of the head and neck confirmed a cut-off in the inferior division of the M2 segment (Figure 1b). RI PT Thrombolysis and Stroke Recurrence The decision to proceed with tPA was agreed upon by the stroke team and patient after discussion of risks and benefits. Intravenous (IV) tPA was administered with total dose of 0.9 mg/kg. Time from SC symptom onset to tPA was less than one hour. After tPA administration, her reevaluated NIHSS was four, and her left-sided hemiplegia and M AN U right gaze completely resolved. Post-tPA magnetic resonance imaging (MRI) showed right frontotemporal infarction (Figure 1c). Obstetrics was consulted for vaginal spotting and minor pelvic cramping, which also resolved. Ultrasound of the fetus confirmed an intact 9-week pregnancy. Two days after initial presentation, the patient acutely developed left upper extremity plegia, left lower extremity paresis, and right gaze preference. New NIHSS was 13, and repeat CT brain/CT TE D angiography revealed performed revealing a total right proximal M1 cutoff (Figure 1d). Due to her recent stroke, IV tPA was contraindicated, thus the decision was made for MT. TRA Mechanical Thrombectomy EP Two-physician emergency consent was obtained, and the patient was then placed in supine position. Right radial artery area was prepared, as previously described.8 Midazolam and fentanyl were AC C used to induce conscious sedation. The puncture area was located by palpation and ultrasound, and the radial artery was cannulated with a single wall technique. Time to puncture was three hours from lastknown well. A 6F vascular sheath was placed, and an antispasmolytic cocktail (verapamil 2.5mg and nitroglycerin 200µg) was administered to prevent radial artery spasm or occlusion. After a guidewire was introduced under roadmap guidance, the sheath was removed and exchanged for an Infinity sheath (Stryker Neurovascular, Fremont, CA). A Penumbra SIM catheter was then advanced and maneuvered into the right internal carotid artery (ICA) under roadmap, and angiography was performed. After 3 ACCEPTED MANUSCRIPT confirming the proximal right MCA syndrome, coaxial system of the ACE™ aspiration catheter (Penumbra, Inc., Alameda, CA) and Marksman™ microcatheter (Medtronic, Minneapolis, MN) was carried over first over the microwire. The microcatheter was placed across the clot and after satisfactory RI PT placement, a micro-run was done and air was seen into distal MCA branches. A 4x40mm stent-retriever was deployed, left for five minutes for better clot integration, and was pulled back under constant aspiration (CAPTIVE technique).9 Angiography of the right ICA was done post thrombectomy, which SC showed incomplete revascularization of MCA branches. Three more passes were completed until control angiogram demonstrated filling of both M2 segments; TICI 2b (Figure 2). M AN U Catheters were removed and a radial band was applied to establish patent hemostasis. The patient was hemodynamically stable and recovered uneventfully with no complication. Post-thrombectomy NIHSS was three. Follow-up The patient remained inpatient for an additional four days and was discharged without incident. TE D Follow-up non-contrast CT of the brain showed evolving infarct, but no other new findings. She was placed on anti-coagulation with enoxaparin for prophylaxis. Discharge modified Rankin Score (mRS) was one, and per Obstetrics documentation, the fetus was deemed viable despite acute stroke interventions. EP The patient is nearing end of her pregnancy. On most recent Obstetrics follow-up, she and the fetus were healthy. Recent fetal ultrasound was normal. During most recent stroke clinic follow-up, the AC C patient ambulates with a walker and exhibits mild left-sided facial droop, but is otherwise neurologically intact. Cause of her multiple strokes is currently under investigation; however, it is likely cardioembolic given history of cardiomyopathy with reduced ejection fraction, now in the context of hypercoagulability of pregnancy. Further coagulopathy work-up is planned after this current pregnancy. DISCUSSION Considerable controversy exists regarding the treatment of acute ischemic stroke in pregnancy, especially since the randomized-controlled trials supporting thrombolysis and thrombectomy for stroke 4 ACCEPTED MANUSCRIPT were conducted excluding pregnant patients altogether. However, considering tPA does not cross the placenta and taking into account that reported complications rates do not exceed those in large trials, many argue that thrombolytic therapy should not be withheld in pregnancy patients with life-threatening RI PT thromboembolic disease.10 The most current American Heart and American Stroke Associations stroke guidelines recommends consideration of tPA in patients with moderate to severe stroke if benefits outweigh the risk uterine bleeding.4 Leffert et al. found in their study that the hemorrhagic risk of tPA in pregnant women may be comparable to that of non-pregnant women when initial stroke severity is SC accounted for.11 This result was similar to that of Steinberg et al., who published in a review that complication rates of tPA in pregnant women treated for thromboembolic conditions and ischemic stroke M AN U were similar when compared to non-pregnant women.12 In our case however, the patient suffered an immediate recurrent stroke after initial successful tPA administration, and so repeat thrombolysis was contraindicated. The patient met the general indications for mechanical thrombectomy per the AHA Stroke Guidelines (i.e. prestroke mRS 0-1; causative occlusion of the proximal MCA; age ≥ 18; NIHSS ≥ TE D 6; ASPECT score ≥ 6; treatment can be initiated within six hours of symptom onset).4 However, there is unclear recommendation regarding thrombectomy in pregnancy, and this leads to difficult therapeutic decisions, particularly in situations as the one we encountered. EP In order to further understand endovascular treatment decisions and possible effects to the fetus in pregnancy, we turned to data of ischemic heart disease in this population, which can be extrapolated AC C cautiously to acute ischemic stroke. An important counseling point for patients regards radiation exposure to the fetus and expecting mother. Concerns regarding radiation are natural, but by performing procedures with lead shields, minimizing number of views obtained, and reducing high-dose acquisition times, fetal radiation doses can be limited to <1mGy.13 In addition, the attributable risk of radiation-related complications to the fetus, such as childhood cancer, from an angiogram has been calculated to be significantly lower than the background risk of childhood cancer (1 in 8000 versus 1 in 500, respectively).13 Medications are also of importance, particularly anticoagulation drug use, in these patients. 5 ACCEPTED MANUSCRIPT Heparins—both low molecular weight heparin and unfractionated heparin—are generally safe in pregnancy as they cannot cross the placenta. Unfractionated heparin is commonly used during coronary interventions, while low molecular weight heparins are utilized in the short-term as maintenance RI PT prophylaxis. Our patient was prescribed enoxaparin, which she will continue to take until her due date.13 Nonetheless, extrapolating data from cardiac disease to ischemic stroke in pregnancy is an imperfect comparison. Thus when looking at the endovascular literature for ischemic stroke, there are SC only four published cases where MT was used to treat acute stroke in pregnancy. Characteristics of these patients can be found in Table 1. Aaron et al. reported two cases of patients in their 20s who presented M AN U with acute stroke symptoms in the third trimester and NIHSS≥20. Both were treated successfully (NIHSS≤4; mRS≤2) with transfemoral aspiration thrombectomy and experienced no detrimental effects to their pregnancies as a result of therapy.14 Bhogal et al. similarly reported two cases of women in the third trimester who presented with severe stroke and high NIHSS; both of whom underwent successful transfemoral MT.15 Our case is unique in that the patient presented in the first trimester with a large MCA TE D occlusion, and we opted to approach the target vessel via TRA. These cases indicate that MT is feasible in this population despite the lack of randomizedcontrolled data, however, the question of radiation exposure to the fetus is a pertinent technical point with EP intervention. Low-dose fluoroscopy, pulsed fluoroscopy, radiation shields, and optimal collimator placement are suggested to reduce radiation exposure. In addition, TRA has been used in pregnant AC C patients when avoidance of femoral access and pelvic radiation was desired.16-17 We concluded that TRA could offer this benefit without increased contrast load, especially since the fetus is most vulnerable to radiation during organogenesis between eight and 15 weeks.18 We believe this report has important clinical implications as it represents the first documented instance of stroke in an early first trimester pregnancy treated with transradial MT. Thrombectomy should be considered a reasonable treatment option despite the lack of formal evidence, though the decision for treatment should be multidisciplinary, including obstetrics, stroke teams, and neurointerventionalists. It is necessary to account for and address factors such as abdominopelvic radiation exposure and contrast load. 6 ACCEPTED MANUSCRIPT In addition to using radiation shields and low-dose fluoroscopy to mitigate these risks, we advocate for the use of radial instead of femoral access, as it appears to be unlikely to increase fetal demise. RI PT CONCLUSIONS Acute ischemic stroke in pregnancy is associated with high maternal and fetal morbidity; however, there is controversy regarding adequate therapeutic options. While the evidence supporting SC thrombectomy is limited, it is safe and feasible when thrombolysis is unavailable or contraindicated. Care must be taken to avoid excess radiation exposure to the fetus, particularly in the first trimester when it is M AN U most vulnerable. Apart from low-dose fluoroscopy and radiation shields, transradial access instead of femoral approach may reduce radiation exposure, though formal study is necessary. Further research is warranted in determining the efficacy and safety of MT in pregnancy. REFERENCES TE D 1. Sells CM, Feske SK. Stroke in pregnancy. Semin Neurol 2017; 37(6):669-678. 2. James AH, Bushnell CD, Jamison MG, Myers ER. Incidence and risk factors for stroke in pregnancy and the puerperium. Obstet Gynecol 2005;106(3):509-16. EP 3. Terón I, Eng MS, Katz JM. Causes and Treatment of Acute Ischemic Stroke During Pregnancy. Curr Treat Options Neurol 2018;20(6):21. AC C 4. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2018;49(3):e46-e110. 5. Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 2015;372(11):1009-18. 6. Nogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva P, et al. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. N Engl J Med 2018;378(1):11-21. 7 ACCEPTED MANUSCRIPT 7. Jovin TG, Chamorro A, Cobo E, de Miquel MA, Molina CA, Rovira A, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med 2015;372(24):2296-306. 8. Snelling BM, Sur S, Shah SS, Khandelwal P, Caplan J, Haniff R, et al. Transradial cerebral RI PT angiography: techniques and outcomes. J Neurointerv Surg 2018 [Epub ahead of print]. 9. McTaggart RA, Tung EL, Yaghi S, Cutting SM, Hemendinger M, Gale HI, et al. Continuous aspiration prior to intracranial vascular embolectomy (CAPTIVE): a technique which improves SC outcomes. J Neurointerv Surg 2017;9(12):1154-1159. 10. Leonhardt G, Gaul C, Nietsch HH, Buerke M, Schleussner E. Thrombolytic therapy in pregnancy. J M AN U Thromb Thrombolysis 2006;21(3):271-6. 11. Leffert LR, Clancy CR, Bateman BT, Cox M, Schulte PJ, Smith EE, et al. Treatment patterns and short-term outcomes in ischemic stroke in pregnancy or postpartum period. Am J Obstet Gynecol 2016;214(6):723.e1-723.e11. 12. Steinberg A, Moreira TP. Neuroendocrinal, neurodevelopmental, and embryotoxic effects of TE D recombinant tissue plasminogen activator treatment for pregnant women with acute ischemic stroke. Front Neurosci 2016;10:51. 13. Fryearson J, Adamson DL. Heart disease in pregnancy: ischaemic heart disease. Best Pract Res Clin EP Obstet Gynaecol 2014;28(4):551-62. 14. Aaron S, Shyamkumar NK, Alexander S, Babu PS, Prabhakar AT, Moses V, et al. Mechanical AC C thrombectomy for acute ischemic stroke in pregnancy using the penumbra system. Ann Indian Acad Neurol 2016;19(2):261-3. 15. Bhogal P, Aguilar M, AlMatter M, Karck U, Bäzner H, Henkes H. Mechanical Thrombectomy in Pregnancy: Report of 2 Cases and Review of the Literature. Interv Neurol 2017;6(1-2):49-56. 16. Abrams J, Yee DC, Clark TW. Transradial embolization of a bleeding renal angiomyolipoma. Vasc Endovascular Surg 2011;45(5):470-3. 17. Sharma GL, Loubeyre C, Morice MC. Safety and feasibility of the radial approach for primary angioplasty in acute myocardial infarction during pregnancy. J Invasive Cardiol 2002;14(6);359-62. 8 ACCEPTED MANUSCRIPT 18. Singh S, Singh M, Grewal N, Khosla S. The fluoroscopy time, door to balloon time, contrast volume use and prevalence of vascular access site failure with transradial versus transfemoral approach in ST segment elevation myocardial infarction: A systematic review & meta-analysis. Cardiovasc Revasc RI PT Med 2015;16(8):491-7. FIGURE LEGEND SC Figure 1. Imaging of our patient prior to MT. A. CT brain without contrast revealed a hyperdense MCA vessel sign (arrow), indicative of acute thrombus. B. A cut-off (arrow) in the inferior division of the M2 M AN U segement was noted on CTA, after which IV tPA was administered. C. Frontotemporal lobe hyperintensity (asterisks) representing infarction on post-tPA T2-FLAIR MRI. D. The patient’s neurological status worsened on day two post-tPA, and repeat CTA showed re-occlusion of the proximal MCA (cut-off shown by arrow). Abbreviations: CT, computerized tomography; CTA, CT angiogram; FLAIR, fluid-attenuated inversion recovery; IV, intravenous; MCA, middle cerebral artery; MRI, TE D magnetic resonance imaging; MT, mechanical thrombectomy; tPA, tissue plasminogen activator. Figure 2. A. Cerebral angiography before MT shows proximal right MCA cut-off (arrow). B. Post-MT angiography shows revascularization (arrow), TICI2b. Abbreviations: MCA, middle cerebral artery; MT, AC C EP mechanical thrombectomy; TICI; Thrombolysis in Cerebral Infarction. 9 ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT Table 1. Characteristics of MT for pregnancy found in the literature Age Gestation Pre-MT Discharge TICI F/u mRS Patient (yr) (wk) NIHSS Vessel Access NIHSS Score (Time) Ob Comp Current Case #1 37 9 13 R MCA TRA 2 TICI2b mRS 1 (3mo) N/a* Aaron et al. (2016) #1 24 Third 20 R MCA TFA 1 NR mRS 0 (6mo) None Trimester #2 28 37 21 R MCA TFA 4 NR mRS 2 (6mo) None Bhogal et al. (2017) #1 38 24 15 L MCA TFA NR TICI2b mRS 1 (8yr) None #2 36 25 N/a+ BA TFA NR NR mRS 1 (POD 1) N/a* Abbreviations: BA, basilar artery; Comp, complications; L, left; MCA, middle cerebral artery; mRS, modified Rankin Score; N/a, not applicable; NIHSS, NIH Stroke Score; NR, not reported; Ob, obstetrics; R, right; TFA; transfemoral access; TICI, Thrombolysis in Cerebral Infarction; TRA, transradial access; wk, week; yr, year. * - Pregnancy ongoing at time of reporting. + - Not assessed due to patient intubation. 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 Treatment of ischemic stroke in pregnancy is not well-defined. • Interventionalists must address fetal radiation exposure and contrast load. • Low-dose fluoroscopy, radiation shield, and possible TRA vital for MT in pregnancy. • Transradial MT is safe and feasible for ischemic stroke during pregnancy. AC C EP TE D M AN U SC RI PT • ACCEPTED MANUSCRIPT ABBREVIATIONS CT, computerized tomography ICA, internal carotid artery MCA, middle cerebral artery MRI, magnetic resonance imaging mRS, modified Rankin Score MT, mechanical thrombectomy TICI, Thrombolysis in Cerebral Infarction tPA, tissue plasminogen activator AC C EP TE D TRA, transradial access M AN U NIHSS, National Institutes of Health Stroke Score SC RI PT IV, intravenous