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Journal of Neurointensive Care Vol.1 · No.1 · October 2018 eISSN 2635-5280 http://www.e-jnic.org

Vol. 1 · No. 1 · October 2018

Aims and Scope Journal of Neurointensive Care (J Neurointensive Care, JNIC) is the official journal of the Korean Neurointensive Care Society and is published biannually (the last day of April and October). It is a peer reviewed, open access journal aimed at publishing all aspects of neurointensive care medicine, such as stroke, brain and spine trauma, perioperative neurosurgical intensive care, neuro-pediatric severe anormaly, CNS infection, seizure, myelitis and etc. It is intended for all neurointensive care providers as neurosurgeons, neurologists, anesthesiologists, emergency physicians, and critical care nurses treating patients with urgent neurologic disorders.

Open Access This is an open-access article distributed under the terms of the Creative Commons Attribution Non- Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Subscription information The Korean Neurointensive Care Society will send J Neurointensive Care for free to some important individuals and institutions. Full text PDF files are also available at the official website (http://www.e-jnic. org). To order a subscription to J Neurointensive Care, please contact out editorial office.

Publisher: Yong Ko

Editors-in-Chief: Dong-Hyuk Park, Sang Gu Lee

Editorial Office Department of Neurosurgery, Korea University College of Medicine 73, Inchon-ro, Seongbuk-gu, Seoul 02841, Korea Tel: +82-2-920-6833 Fax: +82-2-929-0629 E-mail: [email protected]

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Copyright © 2018 by Korean Neurointensive Care Society ∞This paper meets the requirements of KS X ISO 9706, ISO 9706-1994 and ANSI/NISO Z39.48-1992 (Permanence of Paper) eISSN 2635-5280 http://www.e-jnic.org

Editorial Board Editors-in-Chief Dong-Hyuk Park Korea University, Korea Sang Gu Lee Gachon University, Korea

Editorial Board Jin Hwan Cheong Hanyang University, Korea Won-Sang Cho Seoul National University, Korea Kyu-Sun Choi Hanyang University, Korea Joon ho Chung Yonsei University, Korea Eun Jin Ha Seoul National University, Korea Kyung Sool Jang The Catholic University of Korea, Korea Ju Ho Jeong Dongguk University, Korea Kwang Wook Jo The Catholic University of Korea, Korea Sung Pil Joo Chonnam National University, Korea Chang-Hyun Kim Keimyung University, Korea Tae Gon Kim CHA University, Korea Young Jin Kim Dankook University, Korea Young Woo Kim The Catholic University of Korea, Korea Young Zoon Kim Sungkyunkwan University, Korea Doo-Sik Kong Sungkyunkwan University, Korea Hyon-Jo Kwon Chungnam National University, Korea Soon Chan Kwon Ulsan University, Korea Jong-Young Lee Hallym University, Korea Sang Weon Lee Pusan National University, Korea Sung Ho Lee Kyung-Hee University, Korea Taek Kyun Nam Chung-Ang University, Korea Cheol Wan Park Gachon University, Korea Jun Bum Park Ulsan University, Korea Keun Young Park Yonsei University, Korea Young Seok Park Chonbuk National University, Korea Jeong-Am Ryu Sungkyunkwan University, Korea Sang Woo Song Konkuk University, Korea Chan Jong Yoo Gachon University, Korea

Editorial Staff Jun Seok W. Hur Korea University, Korea Vol. 1 · No. 1 · October 2018 CONTENTS

Presidential Message 1 Presidential Message Yong Ko

Editorial 2 We Have a Historical Inaugural Issue of JNIC ahead Dong-Hyuk Park, Sang Gu Lee

Review Articles 3 Postoperative Cerebrospinal Fluid Hypovolemia in Neurosurgery Cheol Wan Park

7 New Parameters for Evaluating Cerebral Autoregulation and Pressure-Volume Compensatory Reserve in Neurocritial Patients Won-Sang Cho, Eun Jin Ha, Sang Bae Ko, Seungman Yang, Hee Chan Kim, Jeong Eun Kim

12 Neurological Intensive Care for Acute Spinal Cord Injury Patients Junseok W Hur, Dong-Hyuk Park, Jang-Bo Lee, Tai-Hyoung Cho, Jung-Yul Park

15 Surgical Treatment in Neurocritical Care for Acute Spinal Cord Injuries Woo-Keun Kwon, Dong-Hyuk Park, Han Kim, Woong-Bae Park, Jong-Keon Oh, Hong Joo Moon, Joo Han Kim, Youn-Kwan Park

20 Deep Vein Thrombosis and Pulmonary Embolism following Hemorrhagic Stroke Sung Ho Lee, Won Joo Chung, Seok Keun Choi, Byung Duk Kwun

Original Articles 25 The Prognostic Value of Optic Nerve Sheath Diameter in Patients with Poor-Grade Subarachnoid Hemorrhages Dong Gyun Ju, Jeong-Am Ryu, Yong Oh Kim, Sangkil Lee, Ji Sun Baek

32 Clinical Advantage of Propofol Compared with Barbiturate for the Coma Therapy in the Patients with Severe Traumatic Brain Injury Hye Jin Shin, Geun Young Yang, Young Zoon Kim

40 Analysis of Predisposing Factors of the Treatment of Patients with Unruptured Intracranial Aneurysm Seong-woo Lee, Jin-Woo Park, Kyung-Jae Park, Shin-Hyuk Kang, Yong-Gu Jung, Jung-Yul Park, Dong-Hyuk Park

Case Reports 47 Posterior Reversible Encephalopathy Syndrome in a Patient with Spinal Metastasis Jin Wook Kim, Ju Ho Jeong

51 Concurrent Isolated Cortical Vein Thrombosis and Pulmonary Thromboembolism as an Initial Presentation of Protein S Deficiency Kun-Hee Han, Kyu-Sun Choi, Yong Ko, Hyeong-Joong Yi, Dae Hyo Song eISSN 2635-5280 Presidential Message J Neurointensive Care 2018;1(1):1. https://doi.org/10.32587/jnic.2018.00008

Presidential Message

I am very happy to congratulate you on making the Journal of Neurointensive Care (JNIC), the official journal of the Korean Neurointensive Care Society. The creation of the journal was a long-awaited wish of the Korean Neurointensive Care Society. In the meantime, many excellent papers have been published in the society for more than 8 years, but I was very disappointed because there was no space to link to the journal. In this journal we hope to present more active and advanced treatment and research methods by addressing various problems encountered in the treatment of central nervous system. The life of a journal is for the participation of its members and for securing readers. It is based on active involvement of members and contribution of articles in order to place the position as Yong Ko representative of the society which focuses on the central nervous system in the world. Department of Neurosurgery, I believe that you will be able to submit various papers and opinions to the journal as if they are College of Medicine, Hanyang loving the Korean Neurointensive Care Society and to raise them as a global journal. University, Seoul, Korea I appreciate to the editors of the Publication Committee for preparing the journal, and to the Korean Neurosurgical Society and Foundation for support to make the JNIC.

Yong Ko, M.D., Ph.D. President, Korean Neurointensive Care Society

We Have a Historical Inaugural Issue of JNIC ahead

We are very pleased to announce that the official English journal of the Korean Neurointensive Care Society, Journal of Neurointensive Care (JNIC), have launched in October 2018. Since the Korean Neurointensive Care Society was founded as a division of the Korean Neurosurgical Society, we have deeply felt the need for official journals. In the meantime, the former presidents and the executives have been making efforts for the publication of the journal. Finally, in December of 2017, we started to prepare the launching of the English Journal by the resolutions of the executives including the present president, professor Yong Ko. We have repeatedly held meetings with editorial committee members and related persons and finally published an inaugural issue Dong-Hyuk Park with the dedication of all authors, editors, and reviewers for the first issue. Department of Neurosurgery, The JNIC is the official English journal of the Korean Neurointensive Care Society and will College of Medicine, Korea be published twice a year. The JNIC publishes important papers covering the whole field of University, Seoul, Korea neurosurgical intensive care unit, including studies in neuroscience, neurology, neurocritical care and basic researches. Studies on rare cases and technical notes of special instruments or equipment that might be useful to the field of neurosurgical intensive care are also acceptable. Drawing upon the expertise of an interdisciplinary team of physicians from neurosurgery, neurology, anesthesiology, critical care, and nursing backgrounds, JNIC covers all aspects neurosurgical intensivists need to be aware of in order to provide optimal patient care. In the future, the editorial committee of JNIC will do its best for the continuous development and become an international journal without being satisfied with the domestic journal. On the basis of JNIC, we will make an effort for the Korean Neurointensive Care Society to become a member of the Korean Medical Association. To do this, We would like to ask all members of Sang Gu Lee Korean Neurosurgical Society and readers to be enthusiastic supporters and contributors to the JNIC. Department of Neursurgery, Lastly, we would like to express special appreciation to professor Yong Ko, the present president Gil Medical Center, Gachon University, Incheon, Korea of the Korean Neurointensive Care Society, professor Jun Seok W. Hur, an editorial staff, and the other editorial committee members for the publication of this journal.

Dong-Hyuk Park, M.D., Ph.D., Sang Gu Lee, M.D., Ph.D. Editors-in-chief

2 www.e-jnic.org eISSN 2635-5280 Review Article J Neurointensive Care 2018;1(1):3-6. https://doi.org/10.32587/jnic.2018.00017

Postoperative Cerebrospinal Fluid Hypovolemia in Neurosurgery Cheol Wan Park Department of Neurosurgery and Emergency Medicine, Section of Critical Care Medicine, Gil Medical Center, Gachon University, Incheon, Korea

Received: August 17, 2018 Accepted: September 19, 2018 Almost all neurosurgeons have concerned with postoperative uneventful recovery of their pa- Published: October 10, 2018 tients. However, although rare but endlessly, unexpected postoperative adverse events have occurred. Neurosurgeons, then are embarrassed and they search the causes and/or pathogenesis of Corresponding Author: such problems. Also rare, a few neurosurgeons may have been forced to litigate because of such Cheol Wan Park, M.D., Ph.D. unexpected and thus uninformed postoperative events. Department of Neurosurgery and Emergency Medicine, Section of As many postoperative complications, postoperative adverse events from cerebrospinal fluid Critical Care Medicine, Cancer (CSF) hypovolemia may have led to tough circumstances. Although the exact pathomechanisms Center, Gil Medical Center, have not been fully cleared, a CSF hypovolemia can be spontaneous or postoperative, clinically. Gachon University, 1141-8 And both the cranial and spinal surgeries can cause CSF hypovolemia. It usually have taken be- Guweol-Dong, Namdong-Gu, nign courses, and some cases may have exhibited serious outcomes. We, neurosurgeons, then Incheon 21556, Korea have considered the possibility of CSF hypovolemia in differential diagnosis for unanticipated Tel: +82-32-460-3304 Fax: +82-32-460-3899 postoperative neurologic deterioration. E-mail: [email protected] Since only the early recognition and prompt treatment may reverse those situations, the author try to settle and summarize comprehensively the postoperative adverse events due to CSF hypovolemia through the review of recently published or frequently cited reports on the postoperative CSF hypovolemia. Keywords: Postoperative complications; Intracranial hypotension; Brain sag; Pseudohypoxic brain swelling; Remote site intracranial hemorrhage; Cerebrospinal fluid

Cerebrospinal fluid (CSF) hypovolemia may occur spontaneously clearly demonstrated, of these acute deteriorations which or after neurosurgical procedures. A spontaneous form of CSF the most close pathomechanism have been seemed to have a hypovolemia have also known as spontaneous intracranial considerable consensus among many interested neurosurgeons, hypotension and usually take chronic and/or benign clinical have been described separately in a number of case reports and course8). The other form of CSF hypovolemia is postoperative case series1-13,15-17,19,21). and often show problematic acute exacerbations during A comprehensive description, however, for clinical entities recovery from anesthesia or critical care except intraoperative of postoperative CSF hypovolemia is almost rare until therapeutic extensive CSF removal18) in some particular lately. Also, the terminologies related to postoperative CSF conditions. The pathophysiologic mechanisms, though not hypovolemia have not been uniformly standardized yet. The

Copyright © 2018 The Korean Neurointensive Care Society License: This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by- nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. www.e-jnic.org 3 Review of postoperative CSF hypovolemia Cheol Wan Park et al. aim of this brief review of literatures is attempt to settle and the general principles are fundamentally same. That is, flat or analyze postoperative CSF hypovolemia comprehensively. As Trendelenberg positioning of the patient and prevention of a postoperative complication, both the cranial and spinal16) further CSF loss. Of course, detailed methods of treatment for surgeries, CSF hypovolemias might have been expressed in each type of this clinical condition by the postoperative CSF three different clinical types of phenomena; 1) brain sag, hypovolemia can be exceedingly different. 2) pseudohypoxic brain swelling (PHBS), 3) remote site The brain sagging, also called 'sinking brain syndrome5) is hemorrhage. Basically, these three clinical phenomena do typically mild, and an upright positional headache is the most not have any new theoretical concept. The author’s proposed common presenting symptom. Other complaints such as classification and pathomechanism for these phenomena is nausea, vomiting, vertigo and visual disturbance may be subtle. shown in Fig. 1. Mild symptomatic brain sagging tends to recover spontaneously without any intervention except a few cases that may need the patients flat position for some time with or without epidural blood patches. Some brain saggings, especially immediate postoperative, may develop serious symptoms and signs such as coma with abnormal pupillary reflexes1,5-7,15). Diagnostic criteria for severe brain sagging by Komotar et al.10) are as followings; 1) clinical signs of transtentorial herniation, 2) head computed tomography (CT) scans revealing effacement of the basal cisterns with an oblong brainstem, 3) improvement of symptoms and/or signs upon placing the patient in the Trendelenberg position. In those circumstances, early detection and identification of brain sagging then Trendelenberg positioning, with primary cause management to prevent further CSF loss is mandatory. This management policy is extremely significant to arrest progression to irreversible neurologic deficits or death and to promote whole recovery. PHBS, relatively newly coined and defined term, may be also caused by excessive CSF loss, especially through the subgaleal or epidural negative pressure suction drain19). And intraoperative CSF drainage may contribute to this complication. Variable degree of severity for PHBS can occur, although majority of PHBS cases are found to be grave neurologic deficits including not awakening from anesthesia, unreactive mydriasis, Fig. 1. A proposed pathomechanism of three clinical phenomena 19,20) due to postoperative cerebrospinal fluid hypovolemia. generalized seizure in uneventful elective neurosurgery . This prevalence of critical severity especially, before the report by Van Roost et al.19), may be insufficient understanding of this Above three types of clinical entities may have, essentially phenomenon. Mild to moderate degree of PHBS may occur identical pathophysiologic mechanisms such as venous presenting abnormal mental status, signs of abnormal brainstem stretching, angulation, occlusion, or disturbed intracranial function, and etc, Typical imaging characteristics are diffuse venous return to heart then venous hypertension, and may brain swelling particularly involving bilateral basal ganglia and arise from the intra-or post-operative excessive loss of CSF thalami on head CT or magnetic resonance images (MRI). via diverse routes including subarachnoid cisternal spaces, Angiographic findings are commonly non-specific and may lamina terminalis, extraventricular drain, lumbar drain or demonstrate only a slow circulation time by microcirculatory puncture, subgaleal or epidural negative vacuum drain, or disturbance from diffuse brain swelling19,20). Principles of traumatic fractures of the skull base. And they also may have management are almost conclusive i.e., prevention of further similar symptoms and signs whether benign or malignant form CSF loss, Trendelenberg positioning, reduction of increased although their radiologic characteristics are quite distinct one intracranial pressure. The prognosis of PHBS is variable, and another. In the management for these three clinical phenomena, usually depends on the time of correct diagnosis and treatment,

4 www.e-jnic.org Cheol Wan Park et al. Review of postoperative CSF hypovolemia then may be fatal or may show complete recovery19). hemorrhage after surgery for an unruptured aneurysm. Remote site hemorrhage is the most repeatedly reported Korean J Cerebrovasc Surg 2008;10:454–458. postoperative complication among three clinical phenomena 3. Borkar SA, Lakshmiprasad G, Sharma BS, Mahapatra AK. due to postoperative CSF hypovolemia as mentioned Remote site intracranial haemorrhage: a clinical series earlier2,4,8,12,21). By definition, remote site hemorrhage is bleeding of five patients with review of literature. Br J Neurosurg at a location or locations distant from the site of original 2013;27:735–738. surgery21). Although the first report was after supratentorial 4. Chang SH, Yang SH, Son BC, Lee SW. Cerebellar hemorrhage craniotomy it can occur after supra- or infra-tentorial surgery after burr hole drainage of supratentorial chronic subdural especially in sitting position3), burr hole trephination4), or spinal hematoma. J Korean Neurosurg Soc 2009;46:592–595. surgery20) i.e., neurosurgery of almost all kinds. Its prevalence 5. Francel PC, Persing JA, Cantrell RW, Levine PA, Newman is rather wide-ranging, from 0.2 to 4.9% after different kinds of SA. Neurological deterioration after lumbar cerebrospinal neurosurgery2-4,8,12,21). Many hypotheses have been advocated fluid drainage. J Craniofac Surg 1992;3:145–148. and published for decades though the exact pathophysiologic 6. Guido LJ, Patterson RH Jr. Focal neurological deficits cause has not been fully revealed yet. Radiologic findings are secondary to intraoperative CSF drainage: successful often non-specific except remote site intracranial hemorrhage in resolution with an epidural blood patch. Report of two cases. epidural, intracerebral, or cerebellar, which may appear solitary J Neurosurg 1976;45:348–351. or multiple on head CT and/or MRI. Once such a adverse event 7. Kelley GR, Johnson PL. Sinking brain syndrome: craniotomy develop it can become fatal. Surely, perfect restoration from can precipitate brainstem herniation in CSF hypovolemia. neurologic deterioration after conservative management or Neurology 2004;62:157. asymptomatic cases are also possible2-4,8,12,16,17,21). 8. Kim SH, Lee HK, Moon JG, Kim CH, Choi JH. Remote More recently, remote site hemorrhages have been published cerebellar hemorrhage after supratentorial aneurysm surgery: after successful endovascular treatment of cerebral aneurysms14). report of 2 cases. Korean J Cerebrovasc Surg 2008;10:570–574. The suggested mechanisms of this complication have been far 9. Komotar RJ, Mocco J, Ransom ER, et al. Herniation from the CSF hypovolemia, and are beyond the scope of the secondary to critical postcraniotomy cerebrospinal fluid author’s discussion. hypovolemia. Neurosurgery 2005;57:286–292. In summary, it is very crucial for neurosurgeons to remember 10. Komotar RJ, Ransom ER, Mocco J, et al. Critical that 1) most CSF hypovolemias after neurosurgery are postcraniotomy cerebrospinal fluid hypovolemia: risk factors probably unnoticed, and thus much underrated. 2) we, and outcome analysis. Neurosurgery 2006;59:284–290. neurosurgeons always consider the possibility of above 11.Liu JKC. Neurologic deterioration due to brain sag after three clinical phenomena for differential diagnosis in case bilateral craniotomy for subdural hematoma evacuation. of neurologic deterioration after uneventful neurosurgical World Neurosurg 2018;114:90–93. procedure. 3) prevention, although limited, of excessive loss of 12. Mandonnet E, Faivre B, Bresson D, et al. Supratentorial CSF perioperatively may be the best way to treat complications craniotomy complicated by an homolateral remote cerebellar from postoperative CSF hypovolemia. Clear verification of hemorrhage and a controlateralperisylvian infarction: case the root pathomechanisms for these unanticipated and tough report. Acta Neurochir 2010;152:169– 172. complications would create further investigations. 13. Roth J, Galeano E, Milla S, Hartmannsgruber MW, Weiner HL. Multiple Epidural hematomas and hemodynamic CONFLICT OF INTEREST collapse caused by a subgaleal drain and suction-induced intracranial hypotension: case report. Neurosurgery No potential conflict of interest relevant to this article was 2011;68:E271–E276. reported. 14. Sim SY, Song J, Oh SY, et al. Incidence and characteristics of remote intracerebral hemorrhage after endovascular REFERENCES treatment of unruptured intracranial aneurysms. World Neurosurg 2016;95:335–340. 1. Alaraj A, Munson T, Herrera SR, Aletich V, Charbel FT, 15. Snow RB, Kuhel W, Martin SB. Prolonged lumbar spinal Amin-Hanjani S. Angiographic features of “brain sag”. J drainage after the resection of tumors of the skull base: a Neurosurg 2011;115:586–591. cautionary note. Neurosurgery 1991;28:880–883. 2. Baek IH, Park KY, Lee JW, Huh SK. Remote cerebellar 16. Sturiale CL, Marta Rossetto M, Ermani M, et al. Remote www.e-jnic.org 5 Review of postoperative CSF hypovolemia Cheol Wan Park et al.

cerebellar hemorrhage after supratentorial procedures (part Schramm J. Pseudohypoxic brain swelling: a newly defined 1): a systematic review. Neurosurg Rev 2016;39:565–573. complication after uneventful brain surgery, probably related 17. Sturiale CL, Rossetto M, Ermani M, et al. Remote cerebellar to suction drainage. Neurosurgery 2003;53:1315–1327. hemorrhage after spinal procedures (part 2): a systematic 20. Yokota H, Yokoyama K, Miyamoto K, Nishioka T. review. Neurosurg Rev 2016;39:369–376. Pseudohypoxic brain swelling after elective clipping of an 18. Tartara F, Bongetta D, Colombo EV, et al. Strokectomy and unruptured anterior communicating artery aneurysm. case extensive cerebrospinal fluid drainage for the treatment report. Clin Neurol Neurosurg 2009;111:900–903. of space-occupying cerebellar ischemic stroke. World 21. You SH, Son KR, Lee NJ, Suh JK. Remote cerebral and Neurosurg 2018;115:e80–e84. cerebellar hemorrhage after massive cerebrospinal fluid 19. Van Roost D, Thees C, Brenke C, Oppel F, Winkler PA, leakage. J Korean Neurosurg Soc 2012;51:240–243.

6 www.e-jnic.org eISSN 2635-5280 Review Article J Neurointensive Care 2018;1(1):7-11. https://doi.org/10.32587/jnic.2018.00038

New Parameters for Evaluating Cerebral Autoregulation and Pressure-Volume Compensatory Reserve in Neurocritial Patients Won-Sang Cho1, Eun Jin Ha1, 4, Sang Bae Ko2, 4, Seungman Yang3, 5, Hee Chan Kim3,5, Jeong Eun Kim1 1 Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea 2 Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea 3 Department of Biomedical Engineering, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea 4 Critical Care Center, Seoul National University Hospital, Seoul, Korea 5 Interdisciplinary Program in Bioengineering, Seoul National University, Seoul, Korea

Received: September 11, 2018 Accepted: September 19, 2018 The goals of neurocritical care are to resolve primary causes, minimize secondary insults and Published: October 10, 2018 maximize patient recovery. Concepts such as intracranial pressure (ICP), cerebral perfusion pressure (CPP) and cerebral blood flow have been long applied in neurocritical care; however, Corresponding Author: patient care involving these concepts alone is not satisfactory. Recently, new developments have Won-Sang Cho, M.D., Ph.D. allowed integrative physiological and biochemical data to be acquired and analyzed using multi- Associate Professor Department of modality monitoring with invasive devices. In addition, newly developed parameters have con- Neurosurgery, Seoul National tributed to improvement in clinical outcomes in neurocritical patients. Beyond the indiscrimi- University Hospital, 101 Daehak- ro, Seoul 03080, Korea nate application of threshold values for ICP and CPP in all patients, precision care can be provid- Tel: +82-2-2072-2824 ed by finding the optimal values of parameters and adjusting treatment for each patient in a par- Fax: +82-2-744-8459 ticular time period. Here, we introduce representative parameters including the pressure reactivi-

E-mail: [email protected] ty index (PRx) for evaluating the status of cerebral autoregulation and optimal CPP (CPPopt) and the correlation between the amplitude of ICP and the mean ICP (RAP) for assessing the pressure-volume compensatory reserve. Additionally, we present a bedside software and monitoring system that we recently developed for analyzing these parameters.

Keywords: Neurocritical care; PRx; CPPopt; RAP

INTRODUCTION higher level of evidence, new devices and parameters and by determining optimal values of physiological and biochemical Practice and knowledge in the field of neurocritical care have parameters in each individual patient. We tried to introduce rapidly progressed. Physicians have managed neurocritical significant parameters for the pressure reactivity index (PRx) patients for a long time based on methods with a low level of and the correlation between the pulse amplitude of intracranial evidence and their experience. However, neurointensivists pressure (ICP) and the mean ICP (RAP) with a new bedside currently care for patients by integrating methods with a monitoring system that they developed recently.

HISTORICAL PERSPECTIVE clinical outcomes. Recently, in 2012, a randomized controlled trial was conducted in South America that compared the survival Neurocritical care seems to have begun from the time point rates of patients with traumatic brain injury between an ICP when the concept of ICP was formed. The existence of ICP was monitoring group (maintaining ICP below 20 mmHg) and first recognized by Alexander Monro approximately 200 years ago. another group of patients who were monitored with imaging and The Monro-Kellie hypothesis or doctrine suggests that the brain, clinical examinations7). The study failed to show the superiority of cerebrospinal fluid (CSF) and blood maintain the balance of ICP ICP monitoring compared with the other group. Some questions within a nonexpandable skull1). When a space-occupying lesion still exist including the followings: (1) Are ICP and CPP sufficient develops, CSF and venous blood decrease, and ICP is controlled for saving the brain? (2) Are the thresholds for ICP and CPP truly within the normal range of pressure. However, when the volume absolute for all patients? (3) Are ICP values that are measured of a new lesion is beyond the compensatory capacity, ICP truly exact measurements? abruptly increases followed by a decrease in cerebral perfusion From these questions regarding the usefulness of ICP and CPP pressure (CPP) and cerebral blood flow (CBF) and ultimately values, new physiological and biochemical parameters have been brain herniation. Harvey Cushing developed the modern field of developed. In addition to ICP, CPP and CBF, data regarding brain neurocritical care. He reported a research paper on the association oxygenation, glucose metabolism, neuronal electrical activity, among ICP, systemic arterial pressure and respiration in 19012). brain water content, etc., are simultaneously collected and used Saline-induced increases in ICP corresponds to increases in for evaluating brain conditions and modulating appropriate systemic arterial blood pressure and respiratory depression. Based treatment in each patient in a technique called ‘multimodality on the previous research, the ‘Cushing reflex’ was defined. In the monitoring’8). Multimodality monitoring is applied in limited 1960s, Nil Lundberg began directly measuring ICP by inserting medical institutions all over the world; however, this technique is a ventricular catheter and reported normal and pathologic expected to become popular in Korea in the near future. waveforms of ICP3). Thereafter, ICP measurement was applied in the clinical setting for treating neurocritical patients. ICP control CEREBRAL AUTOREGULATION is most important goal of neurocritical care, especially in patients AND ITS MEASUREMENT with traumatic brain injury. There are many guidelines for the care of neurocritical patients, among which the guidelines from the The existence of cerebral autoregulation was established by Brain Trauma Foundation are the most well described in detail4). Danish physicians in the 1970s9). Cerebral autoregulation works The Brain Trauma Foundation published the first edition of between a mean arterial blood pressure (MAP) of 50 and 150 “Guidelines for the management of severe traumatic brain injury” mmHg, and CBF is steadily maintained within the range of 45- in 1995, and successive editions have been updated in 1999, 2007 50 mL/100 g/min by automatic regulation of vessel diameters. and 2016. Among them, a detailed description of each topic Thereafter, in 1997, a Cambridge group of physicians reported a was reported in the 3rd version of the guidelines in 2007. The 3rd new parameter that was able to indirectly measure the functional version dealt with blood pressure and oxygenation, hyperosmolar status of cerebral autoregulation, namely, the “pressure reactivity therapy, prophylactic hypothermia, infection prophylaxis, deep index (PRx)”10). The PRx is the correlation coefficient between vein thrombosis prophylaxis, indications for ICP monitoring, MAP and ICP. When cerebral autoregulation is impaired, ICP monitoring technology, ICP thresholds, CPP thresholds, increases in ICP lead to subsequent increases in MAP and brain oxygen monitoring and thresholds, anesthetics, analgesics cerebral blood volume in order to maintain CBF, and a vicious and sedatives, nutrition, antiseizure prophylaxis, hyperventilation cycle without any regulations can form. In this situation, MAP and steroids. In the chapters about ICP and CPP thresholds, and ICP are positively proportional, and the PRx increases. treatment with a low level of evidence is recommended to When cerebral autoregulation is preserved, increases in ICP maintain ICP below 20 mmHg and CPP between 50 and 70 are buffered by vasoconstriction and outflow of CSF and mmHg. These thresholds were not updated even in the 4th venous blood, resulting in limited increases in MAP. Thus, the edition of the guidelines published in 2016. In addition, those are slope between MAP and ICP becomes smoother, and the PRx recommended in patients with intracerebral hemorrhage5) and decreases (Fig. 1). In real clinical situations, a group with lower acute ischemic stroke6) as they are. The fixed thresholds for ICP PRx values showed more favorable outcomes than a group with and CPP are currently applied like a central dogma in the genetics. higher values10). Although there are some differences in standard However, physicians have felt that these thresholds are PRx values among reports, PRx values higher than 0.2 - 0.3 are inappropriate in some patients and insufficient in improving generally considered to indicate impaired cerebral autoregulation.

8 www.e-jnic.org Won-Sang Cho et al. PRx, CPPopt and RAP

A B

Fig. 1. Concept and definition of the pressure reactivity index (PRx). A: In patients with impaired cerebral autoregulation, a vicious cycle occurs (upper), and the correlation coefficient (PRx) between MAP and ICP is positively increased (lower). B: In patients with preserved cerebral autoregulation, a positive cycle is formed by cerebral autoregulation (upper), and the PRx decreases and sometimes becomes negative (lower) (This is modified from reference 10). CBV, cerebral blood volume; MAP, mean arterial pressure; CPP, cerebral perfusion pressure; ICP, intracranial pressure.

In contrast, PRx values lower than 0.2 - 0.3 are thought to indicate preserved autoregulation. The same group subsequently proposed the concept of optimal 11) CPP (CPPopt) in 2002 . When the PRx is at the lowest value, cerebral autoregulation is considered to be at its best, and CPP at this PRx value is also the best. Actually, when CPP is controlled as close to CPPopt as possible, clinical outcomes are better. Thus, the most appropriate CPP is not within the absolute range of CPP = 50 – 70 mmHg, as recommended in some guidelines, and the best CPP can be different under different conditions in each patient (Fig. 2). Some institutions have developed bedside software and monitoring systems for acquiring real time PRx Fig. 2. Concept of CPPopt. When the PRx is the lowest, cerebral autoregulatory function is considered to be the best, and CPP and CPPopt measurements. Among them, the ICM+ software® at the lowest PRx is defined as CPP (This is modified from (Cambridge, UK) and monitoring system from the Cambridge opt reference 11). CPP, cerebral perfusion pressure; CPPopt, optimal group is the most popular. Recently, we also developed a CPP; PRx, pressure reactivity index. prototype of a Korean version of a software monitoring system.

PRESSURE-VOLUME for evaluating the pressure-volume compensatory reserve in COMPENSATORY RESERVE AND RAP 200412). After gathering ICP data for a fixed time interval and distributing the ICP waveforms according to the frequency, The Cambridge group also demonstrated a new parameter waveforms are divided into 3 components: slow waves less than www.e-jnic.org 9 PRx, CPPopt and RAP Won-Sang Cho et al.

0.1 Hz, respiratory waves between 0.2 and 0.3 Hz, and pulse CONCLUSION waves higher than 1 Hz generated by heart rate. Among them, the first pulse wave with the highest amplitude is detected at The era is declining in which neurocritical patients are approximately 1 Hz, and the pulse amplitude of ICP (AMP) is managed based on methods with a low level of evidence and defined as the amplitude of the first pulse wave. the uniform criteria of conventional parameters. Recently, Then, the correlation coefficient between AMP and mean neurocritical care is performed based on personalized data and ICP is defined as RAP. When the value of RAP is closer to 0, new parameters obtained from multimodality monitoring. the pressure-volume compensatory reserve is considered to be Representative parameters include the PRx, CPPopt, and RAP. good; when the value of RAP becomes closer to 1, the pressure- As newly developed devices and data are applied to manage volume compensatory reserve is considered to be poor; and these patients, their final outcomes are expected to improve, and when the value of RAP becomes negative, brain function is we can save more patients. thought to have shut down (Fig. 3). As intracranial volume increases and ICP begins to increase beyond the reserve capacity, CONFLICT OF INTEREST AMP subsequently increases, and RAP ultimately increases; however, when ICP is constantly maintained with the aid of the No potential conflict of interest relevant to this article was compensatory reserve, AMP decreases and the value of RAP reported. becomes closer to 0. RAP and the PRx are thought to be useful parameters for evaluating brain condition and modulating the ACKNOWLEDGEMENTS types and intensity of treatment. As mentioned above, a bedside monitoring system developed by our group can display both of This research was supported grant (03-2017-0430) from the these features (Fig. 4). Seoul National University Hospital Research Fund.

A C

B D

Fig. 3. Concept of RAP. A: ICP waveforms in a timeline. B: After unfolding the ICP waves within a fixed time interval, some wave peaks are grouped in different frequency sections. The amplitude of the first pulse wave at approximately 1 Hz is defined as AMP. C and D: RAP is the correlation coefficient between AMP and the mean ICP. As the pressure-volume compensatory reserve decreases, AMP increases, and the value of RAP consequently becomes closer to 1. When the brain is completely damaged, AMP abruptly decreases, and the value of RAP can become negative (This is modified from reference 12). ICP, intracranial pressure; AMP, amplitude of ICP; RAP, correlation coefficient between AMP and mean ICP.

10 www.e-jnic.org Won-Sang Cho et al. PRx, CPPopt and RAP

Fig. 4. New bedside software and monitoring system that we developed. This system displays ICP, MAP, CPP, PRx, CPPopt, RAP, and other graphs and histograms. ICP, intracranial pressure; MAP, mean arterial pressure; CPP, cerebral perfusion pressure; PRx, pressure reactivity index; CPPopt, optimal CPP; RAP, correlation coefficient between AMP and mean ICP.

REFERENCES a guideline for healthcare professionals from the american heart association/american stroke association. Stroke 1. Andrews PJ, Citerio G. Intracranial pressure. Part one: 2018;49:e46–e110. historical overview and basic concepts. Intensive Care Med 7. Chesnut RM, Temkin N, Carney N, Dikmen S, Rondina C, 2004;30:1730–1733. Videtta W, et al. A trial of intracranial-pressure monitoring in 2. Cushing H. Concerning a definite regulatory mechanism traumatic brain injury. N Engl J Med 2012;367:2471–2481. of the vasomotor center which controls blood pressure 8. Ko SB. Multimodality monitoring in the neurointensive care during cerebral compression. Bull Johns Hopkins Hosp unit: a special perspective for patients with stroke. J Stroke 1901;12:290. 2013;15:99–108. 3. Lundberg N. Continuous recording and control of ventricular 9. Strandgaard S, Olesen J, Skinhoj E, Lassen NA. fluid pressure in neurosurgical practice. Acta Psychiatr Scand Autoregulation of brain circulation in severe arterial Suppl 1960;36:1–193. hypertension. Br Med J 1973;1:507–510. 4. Brain Trauma Foundation. The 4th edition of guidelines 10. Czosnyka M, Smielewski P, Kirkpatrick P, Laing RJ, Menon D, for management of severe traumatic brain injury [Internet]. Pickard JD. Continuous assessment of the cerebral vasomotor Brain trauma foundation; 2016 [cited 2018 July 16]. reactivity in head injury. Neurosurgery 1997;41:11–17. Available from: https://www.braintrauma.org. 11. Steiner LA, Czosnyka M, Piechnik SK, Smielewski P, 5. Hemphill JC 3rd, Greenberg SM, Anderson CS, Becker Chatfield D, Menon DK, et al. Continuous monitoring of K, Bendok BR, Cushman M, et al. Guidelines for the cerebrovascular pressure reactivity allows determination of management of spontaneous intracerebral hemorrhage: a optimal cerebral perfusion pressure in patients with traumatic guideline for healthcare professionals from the american brain injury. Crit Care Med 2002;30:733–738. heart association/american stroke association. Stroke 12. Balestreri M, Czosnyka M, Steiner LA, Schmidt E, 2015;46:2032–2060. Smielewski P, Matta B, et al. Intracranial hypertension: what 6. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, additional information can be derived from ICP waveform Bambakidis NC, Becker K, et al. 2018 guidelines for the after head injury? Acta Neurochir (Wien) 2004;146:131– early management of patients with acute ischemic stroke: 141. www.e-jnic.org 11 eISSN 2635-5280 Review Article J Neurointensive Care 2018;1(1):12-14. https://doi.org/10.32587/jnic.2018.00045

Neurological Intensive Care for Acute Spinal Cord Injury Patients Junseok W Hur, Dong-Hyuk Park, Jang-Bo Lee, Tai-Hyoung Cho, Jung-Yul Park Department of Neurosurgery, College of Medicine, Korea University, Seoul, Korea

Received: September 13, 2018 Accepted: September 19, 2018 The spinal cord injury (SCI) patients suffer various medical conditions at early period after inju- Published: October 10, 2018 ry. Methylprednisolone could be administrated for neurologic recovery but the potential side effects could be carefully considered. Besides limb motor and sensory deficits, SCI could affect Corresponding Author: various respiratory muscles as diaphragm, chest wall, and abdomen which leads to respiratory Junseok W Hur, M.D., Ph.D. failure and mechanical ventilation. Sympathetic nerve denervation could lead hypotension and Department of Neurosurgery, bradycardia. Volume supplement and cardiovascular constrictor could be considered. Preven- College of Medicine, Korea tion and treatment of pressure sore are essential and active pain control should be started from University, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Korea the intensive care unit. Tel: +82-2-920-5729 Keywords: Spinal cord injury; Neurology; Intensive care; Shock; Methylprednisolone Fax: +82-2-929-0629 E-mail: [email protected]

INTRODUCTION example, fracture and spinal cord compression at T5 level could induce neurologic symptom below T10. Therefore, In the 21st century, remarkable advances in medicine have led accurate manifestation of neurologic disorders should be held. to the development of treatments for many diseases. However, Depending on the level of nerve damage, the sensory and motor in the case of spinal cord injury (SCI), no clear solution has been nerve damage ranges are determined. Furthermore, there are found to restore neural damage even after pouring astronomical also other important points to consider due to injured level research costs into the development of new therapeutic drugs. as respiratory function failure, reduced sympathetic nervous However, it is encouraging that many empirical knowledge function, immunodeficiency and etc. about acute critical care has accumulated. We will review the problems that may appear in patients immediately after injury 2. Respiratory dysfunction of the spinal cord and summarize the latest knowledge for the Phrenic motor neurons are located at C3-5. Therefore, treatment of patients in the neurological intensive care unit. damage above the C5 may affect diaphragm function, resulting in hypercapnia, hypoxemia, and poor secretion clearance10, CLINICAL MANIFESTATIONS 17). Injuries above T11 destroy innervation to the intercostal muscles leading to reduced chest wall motion, and injuries above 1. Motor and sensory deficit associated to injury level L1 may interfere the innervation to the abdominal muscle1). Spinal cord injury levels due to vertebral fractures may differ These neurological deficits can cause serious respiratory from spinal cord injury levels in actual clinical symptoms. For problems as dyspnea, apnea, and pneumonia.

12 www.e-jnic.org Junseok W Hur et al. Neuro-intensive care for SCI

3. Neurogenic shock for the first 7days post injury. Oxygen saturation should be Injury above T6 may affect sympathetic nerve and induce maintained over 90%9, 16). To prevent hypotension, lower hypotension and bradycardia due to vasodilatation14). For extremity compression stockings, abdominal binding, volume cervical lesion injury, 20% of patients show neurogenic shock augmentation (hydration, salt tablets or fludrocortisone), and almost all patients show bradycardia8). If there is no peripheral vasoconstriction (midodrine, ephedrine or evidence of severe blood loss after trauma, neurogenic shock droxidopa) should be considered12). should be considered. 3. Respiration NEUROGENIC INTENSIVE CARE Depending on the level and degree of SCI, spontaneous breathing may not be smooth due to paralysis of the diaphragm, 1. Methylprednisolone chest wall, and abdomen muscle. Therefore, if the patient's Three large randomized clinical trials named National Acute respiration pattern is paradoxical or if the saturation is Spinal Cord Injury Studies (NASCIS) were performed. continuously lowered to 90% or less, intubation and mechanical First trial published at 1984 concluded there is on significant ventilation should be considered. Even if the breathing seems difference between high dose methylprednisolone group not so bad at early period, the oral secretions cannot be spit out (1,000-mg bolus and daily thereafter for ten days) and standard well, so the airway obstruction often occurs. Theophylline could dose methylprednisolone group (100-mg bolus and daily be helpful for respiratory function improvement5). There are thereafter for ten days)2). However, second trial adapted studies that muscle spasticity could affect respiration function, different infusion amount and type of methylprednisolone for and in this case, baclofen could be helpful4, 13). the treatment group (a bolus of 30 mg per kilogram of body weight, followed by infusion at 5.4 mg per kilogram per hour 4. Pressure sores for 23 hours) compared with naloxone administrated and With sensory loss and immobilization due to motor deficit, placebo groups. This study concluded methylprednisolone pressure sores develop rapidly. Sore starts with focal infection have positive effect for the neurology recovery at 6 months and if not controlled well, immunodeficiency and systemic period after injury3). The third NASCIS reported that patients infection could occur and life threatening condition could be recieving methylprednisolone within 3 hours of injury should caused. Prevention is the most important treatment. Frequent be maintained on the treatment regimen for 24 hours and 48 position change, using anti-sore mattress are helpful. Once a hours when initiated 3 to 8 hours after injury. After this studies, sore develops, daily dressing, surgical debridement, vacuum high dose methylprednisolone has emerged as golden standard suction could be considered7). therapy for SCI. However, numerous comments against those have been poured out. Many scientist and physicians 5. Pain control pointed out the statistical bias. Numerous retrospective and Active control of pain is essential from the beginning of prospective studies refute the second and third NASCIS SCI treatment. If the pain is not controlled, the prognosis of conclusion. They claimed there was no neurologic difference the patient is adversely affected. Additionally to nociceptive between high methylprednisolone group and placebo group, pain, neuropathic pain as allodynia and hyperalgesia occur however, complications as gastrointestinal bleedings, wound almost 40% of SCI patients1). NSAIDs, anticonvulsants, infection, sudden death, pulmonary embolism seemed to be antidepressants, and opioids should be considered. higher incidence for high dose methylprednisolone group6, 11, 15). The two arguments are still conflicting and have been CONCLUSION subject to contradictions that have been reversed according to the guidelines. Therefore, the authors recommends to use it SCI patients suffer various medical conditions from the according to the judgment of the clinician. early period of injury. Meticulous clinical manifestations and appropriate intensive treatments are mandatory. 2. Hemodynamics Maintenance of adequate blood supply to spinal cord is CONFLICTS OF INTEREST essential. Systemic hypotension should be avoided. Mean arterial pressure (MAP) between 85~90mmHg is recommended and No potential conflict of interest relevant to this article was systolic blood pressure under 90mmHg should be avoided reported. www.e-jnic.org 13 Neuro-intensive care for SCI Junseok W Hur et al.

ACKNOWLEDGEMENTS shock in patients with isolated spinal cord injury in the emergency department. Resuscitation 2008;76:57–62. This study was supported in part by a grants of Korea University 9. Hadley M, Walters B, Grabb P, Oyesiku N, Przybylski G, (K1809751, K1808641, K1722461), the Basic Science Research Resnick D, et al. Guidelines for the management of acute Program through the National Research Foundation of Korea cervical spine and spinal cord injuries. Neurosurgery (NRF) funded by the Ministry of Education, Science and 2002;49:407–498. Technology (NRF-2017R1D1A1B03035760) to Junseok W Hur. 10. Autho . Physiology and pathophysiology of glottic reflexes and pulmonary aspiration: from neonates to adults: Seminars REFERENCES in respiratory and critical care medicine NIH Public Access, 2010, p554. 1. Ahuja CS, Wilson JR, Nori S, Kotter MR, Druschel C, Curt 11. Kiwerski J . Application of dexamethasone in the treatment of A, et al. Traumatic spinal cord injury. Nat Rev Dis Primers acute spinal cord injury. Injury 1993;24:457–460. 2017;3:17018. 12. Krassioukov A, Eng JJ, Warburton DE, Teasell R, Team 2. Bracken MB, Collins WF, Freeman DF, Shepard MJ, Wagner SCIRER . A systematic review of the management of FW, Silten RM, et al. Efficacy of methylprednisolone in acute orthostatic hypotension after spinal cord injury. Arch Phys spinal cord injury. JAMA 1984;251:45–52. Med Rehabil 2009;90:876–885. 3. Bracken MB, Shepard MJ, Collins WF, Holford TR, Young 13. Laffont I, Durand M-C, Rech C, De La Sotta AP, Hart N, W, Baskin DS, et al. A randomized, controlled trial of Dizien O, et al. Breathlessness associated with abdominal methylprednisolone or naloxone in the treatment of acute spastic contraction in a patient with C4 tetraplegia: a case spinal-cord injury: results of the Second National Acute Spinal report 1. Arch Phys Med Rehabil 2003;84:906–908. Cord Injury Study. N Engl J Med 1990;322:1405–1411. 14. Ploumis A, Yadlapalli N, Fehlings M, Kwon B, Vaccaro A . 4. Britton DB, Goldstein BG, Jones-Redmond J, Esselman A systematic review of the evidence supporting a role for P . Baclofen pump intervention for spasticity affecting vasopressor support in acute SCI. Spinal Cord 2010;48:356. pulmonary function. J Spinal Cord Med 2005;28:343–347. 15. Prendergast MR, Saxe JM, Ledgerwood AM, Lucas CE, 5. Ferguson GT, Khanchandani N, Lattin CD, Goshgarian HG . Lucas WF . Massive steroids do not reduce the zone of injury Clinical effects of theophylline on inspiratory muscle drive in after penetrating spinal cord injury. J Trauma 1994;37:576– tetraplegia. Neurorehabil Neural Repair 1999;13:191–197. 579; discussion 579-580. 6. Galandiuk S, Raque G, Appel S, Polk HC Jr . The two-edged 16. Walters BC, Hadley MN, Hurlbert RJ, Aarabi B, Dhall sword of large-dose steroids for spinal cord trauma. Ann Surg SS, Gelb DE, et al. Guidelines for the management of 1993;218:419. acute cervical spine and spinal cord injuries: 2013 update. 7. Consortium for Spinal Cord Medicine Clinical Practice Neurosurgery 2013;60:82–91. Guidelines . Pressure ulcer prevention and treatment 17. Autho . Effect of spinal cord injury on the respiratory system: following spinal cord injury: a clinical practice guideline for basic research and current clinical treatment options 2007. health-care professionals. J Spinal Cord Med 2001;24:S40. Taylor & Francis. 8. Guly H, Bouamra O, Lecky F . The incidence of neurogenic

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Surgical Treatment in Neurocritical Care for Acute Spinal Cord Injuries Woo-Keun Kwon1, 3, Dong-Hyuk Park2, Han Kim1, Woong-Bae Park1, Jong- Keon Oh, MD, PhD3, 4, Hong Joo Moon1, Joo Han Kim1, Youn-Kwan Park1 1 Department of Neurosurgery, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea 2 Department of Neurosurgery, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea 3 Focused Training Center for Trauma, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea 4 Department of Orthopedic Surgery, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea

Received: September 13, 2018 Accepted: September 19, 2018 Traumatic spinal cord injury (SCI) is common devastating injury which results in enormous so- Published: October 10, 2018 cioeconomic burden. Multimodal approach to the patient is essential in neurocritical care for SCI patients. Among various treatment modalities, surgical decompression and stabilization Corresponding Author: plays an important role. This article highlights the issues regarding surgical management of neur- Woo-Keun Kwon, M.D., Ph.D. ocritical and neurointensive care for SCI. Although there are still some debate regarding the opti- Department of Neurosurgery, mal timing for surgery in SCI patients, it is clear by previous literature that surgery has a specific Korea University Guro Hospital, benefit for neurocritical care in SCI patients and early surgery benefits specific SCI patients. The Korea University College of Medicine, 148 Gurodongro, goals of surgery in SCI are correcting and reducing the broken biomechanical alignment and sta- Gurogu, Seoul 08308, Korea bilizing it by instrumentation while decompressing the neural structures. By understanding the Tel: +82-2-2626-3100 role of surgery in SCI neurociritcal care, we believe we can better access and treat these patients. Fax: +82-2-863-1684 Keywords: Spinal cord injury; Neurointensive care; Neurocritical care; Spine Email: [email protected]

INTRODUCTION finally remain with residual neurologic deficits. Considering this impact of SCI on each patients personally, and also the social Acute traumatic spinal cord injury (SCI) is a devastating impact, proper approach to the individual patients and adequate condition which follows after high energy traumatic insult to selection of treatment modalities are of great interest. the spinal cord, and the prevalence worldwide is more than When high energy insult occurs on the spinal cord, it gets 750 per million with annual increase5). As this type of injury damaged by two steps, which are primary and secondary usually leads to irreversible neurologic deficits, it finally results injuries. It is a widely accepted concept that these two injury in huge social costs as well as great personal loss. The functional pathomechanisms lead to neurologic deficits2,5,12). Primary injury impairment following SCI and the socioeconomic burden is happens due to the initial impact on the spinal cord, and sudden already well documented1,9). Although numerous previous spinal cord compression, and contusion while the secondary studies have been introduced regarding the treatment for spinal injury is rather a resultant cascade following the primary injury. cord injury and many new treatment modalities have been The primary injury itself is irreversible, but there are some taken to the field, majority of hospitalized SCI patients still opportunity for neural salvation by minimizing the secondary

SCI and this is the point that most treatment modalities target. SURGICAL TREATMENT IN In a spinal surgeons perspective focused on neurocritical care, NEUROCRITICAL CARE FOR SCI surgical intervention is also one of the therapeutic attempts targeting this point. It is important to optimize treatment and care for SCI patients, In this article, the focus is on the role of surgical intervention in order to minimize the risk of any possible loss of neurologic in neurocritical care for SCI patients with a brief review on the function. The therapeutic approach to SCI is rather a complex pathophysiology of SCI. of multimodal neurocritical care and treatments. Neurocritical care for SCI includes various treatment steps including early PATHOPHYSIOLOGY OF SCI pre-hospital immobilization, acute phase medical treatment, administration of neuroprotective agents, and of course surgical As briefly mentioned in the introduction, SCI following high decompression and stabilization. In this article, the focus is on energy trauma to the spinal cord is a result of initial primary the role of surgical treatment in SCI neurocritical care. injury accompanied with a subsequent secondary injury. Early surgical intervention has a significant role in controlling Thorough understanding of this pathomechanism is a key step the secondary injury by getting rid of the compressive force to understanding SCI itself, and it also provides a basis for SCI made by SCI. If left untreated, ongoing dynamic damage of management not only medical but also surgical treatments. spinal cord cannot be stopped, and this secondary injury leads Primary injury of the spinal cord occurs as a result of direct to progressive worsening neurologic deficits12). Although traumatic insult to the spine. It is commonly accompanied with surgical decompression and stabilization is a widely accepted breakage of the normal structural integrity of the spinal column, therapeutic tool for SCI, there is still some points in debate which results in compressive impact to the spinal cord. By this regarding the timing of surgery or selecting right indications for impact, direct trauma and description occurs to the neural surgery. In this section, we would like to discuss on these issues. tissues. At the same time, neuronal axons get damaged as well as blood vessels and cell structures of the spinal cord10,16). By this Rationale for surgical treatment primary insult the cascade of SCI is started leading to secondary Surgical treatment for SCI cannot be defined in a uniform injuries. way. Each part of the spine ; cervical, thoracic, lumbar and The secondary injury of spinal cord which is triggered by the sacral spines have each documented treatment principals, primary injury, is a cascade of pathologic changes and it evolves and they usually depend on both clinical and radiological over days or weeks. Shortly after the microvascular breakage classifications. In general, when considering the role of surgery by primary injury, a focal development of intramedullary in SCI, two gross points should be taken in to discussion. If the hemorrhage occurs and edematous change follows10). neural structure is mechanically compromised after trauma Hemorrhage and edema of the spinal cord does not only injure and SCI has occurred, proper decompression of the neural the neural axons of spinal cord, but also leads to impairment of tissue is required. Another point is that if the primary insult proper blood perfusion within the cord. Impaired circulation has resulted in any displacement or instability of the spinal then results in formation of microthrombus and vasospasm of alignment, it should be reduced and then stabilized by proper microvasculature, which leads to more impaired circulation, instrumentations with or without instrumentation. Proper finally a vicious cycle12). Another phenomenon of secondary surgery can restore the mechanical stability and optimize clinical injury after SCI includes necrotic change of the injured cord. outcomes by giving the neural elements a chance to recover15). By exacerbated ischemia of the spinal cord, breakage of cellular So, the need of decompression and stabilization with proper membranes and dysregulation of ions occur, and the cord gets fusion is a key factor and should be always taken into account necrotic within a short time10,16). when making decisions whether to operate the patient or not in Considering the pathophysiology of SCI, there is no possible SCI neurocritical care. treatment for the initial impact of primary injury. However, the As mentioned in the prior section, the primary insult and pathomechanism of secondary injury following SCI should be injury itself is irreversible, and the initiation of secondary insult considered as the target for treatment. In order to maximize the is inevitable. However, we can minimize the damage of the effect of treatment, breaking into the early steps of secondary spinal cord my properly managing the secondary insult, and this injury should be done, both medically and surgically. is why mitigating secondary cord injury is the main target of neurocritical care in SCI. Both restoration of spinal stability and decompression of neural tissues can break through the vicious

16 www.e-jnic.org Woo-Keun Kwon et al. Surgery for SCI neurocritical care cycle of SCI by minimizing secondary injury9,15). Table 2. The subaxial cervical spine injury classification system (SLIC) Classification of Spinal Injuries and Surgical Contents Points indications for SCI Injury morphology Several points should be thoroughly taken into discussion No abnormality 0 when considering a SCI patient as a candidate for surgery. Bony Compression/Burst 2 fracture morphology, integrity of the posterior ligamentous Distraction 3 Rotation/translation 4 complex, the trauma mechanism and of course the neurologic Neurologic status status of the patient should all be considered5,15). Prior to Intact 0 discussing about the surgical indications, the spinal injuries need Nerve root injury 2 to be well classified, both in order to well access the patients Complete cord injury 2 and also to decide proper treatment modalities according to Incomplete cord injury 3 the classifications. In this aspect, various classification systems Continuous cord compression +1 have been introduced to support the physicians practice. Discoligamentous complex integrity Recently the Thoracolumbar Injury Classification and Severity Intact 0 Score (TLICS)14) and the Subaxial Injury Classification Suspected/Intermediate injury 1 (SLIC)13) system are widely used as a classification tool for the Definite injury 2 thoracolumbar spine and cervical spine, respectively. (Tables 1 Non-surgical management for total score ≤ 3, surgeons decision for and 2) TLICS and SLIC have been developed as an alternative total score = 4 and surgical intervention for total score≥ 5 classification, as the formerly used systems were limited to classifying the injuries. TLICS and SLIC have advantage but significant indications. 1) Clinically and radiologically compared to those former classifications, not only regarding the confirmed spinal cord compressive lesions with or without simplicity and easy applicability but also by giving the physician fractures, 2) SCI patient presenting with progressive neurologic a clue for surgical decisions. deterioration and 3) significant instability proven by imaging Although there is an widely agreed consensus that surgical studies9,15). decompression and stabilization has a significant beneficial role for SCI patients5,15), there is still debate regarding the Optimal timing for surgical treatment documented indications for surgical intervention. In terms The optimal timing of surgery that may maximize the clinical of “indications” for surgical treatment, there are only few, prognosis of SCI patients are still controversial. For those whom come into the indications for surgical decompression, there are recent strong evidences that early decompression Table 1. Thoracolumbar Injury Classification and Severity within 24 hours show better improvement than later surgeries. (TLICS) score system In a recent meta-analysis by Liu et al., the early decompression Contents Points group presented significantly better neurologic outcome, earlier Injury morphology discharge and even a lower complication rate compared to Compression 1 later surgery group8). In 2012 Fehlings et al. reported a study Burst 2 Translation/rotation 3 called the Surgical Timing in Acute Spinal Cord Injury Study Distraction 4 (STASCIS), which was a large multicenter prospective cohort 5) Neurologic status study on the timing of surgery after SCI . 313 patients were Intact 0 involved and the clinical outcome were compared among Nerve root injury 2 groups; surgery within 24 hours after trauma and later than Complete cord injury 2 24 hours after trauma. At 6 months post-operatively, early Incomplete cord injury 3 decompression group revealed 2.8-fold larger odds of 2 or Posterior ligamentous complex integrity more grades improvement in (ASIA) impairment scores. After Intact 0 the introduction of STASCIS study, early decompression Suspected/Intermediate injury 2 surgery have become an feasible standard for making decisions Definite injury 3 regarding surgical timing, and many other studies have reported Non-surgical management for total score ≤ 3, surgeons decision for 3,6-8,11) total score = 4 and surgical intervention for total score≥ 5 compatible results with this study . Not only proven by www.e-jnic.org 17 Surgery for SCI neurocritical care Woo-Keun Kwon et al. these evidence based clinical studies, it is already a widely agreed strategies for mitigating secondary damage in acute spinal consensus by spinal surgeons. In 2010, Fehlings et al conducted cord injury. Neurosurgery 1999;44:1027–1039; discussion a survey study asking for the preferred surgical timing to more 1039-1040. than 900 active spinal surgeons4). More than 80% answered 3. Anderson KK, Tetreault L, Shamji MF, Singh A, Vukas RR, that they would operate a ASIA B or C patient within 24 Harrop JS, et al. Optimal timing of surgical decompression for hours, indicating that this timing is widely agreed by spinal acute traumatic central cord syndrome: a systematic review surgeons. Therefore, medically stable patients without any other of the literature. Neurosurgery 77 Suppl 2015;4:S15–32. significant risk factors should be considered to be candidates for 4. Fehlings MG, Rabin D, Sears W, Cadotte DW, Aarabi B. early surgery. Current practice in the timing of surgical intervention in Recently, there are even some groups that insist that ultra-early spinal cord injury. Spine 2010;35:S166–173. surgery ; decompression within 6 to 8 hours after SCI, should be 5. Fehlings MG, Vaccaro A, Wilson JR, Singh A, D WC, Harrop done for even better surgical outcomes. However, more clinical JS, et al. Early versus delayed decompression for traumatic evidence is needed to support this results. cervical spinal cord injury: results of the Surgical Timing On the other hand, this favorable outcomes of early in Acute Spinal Cord Injury Study (STASCIS). PLoS One decompression after SCI are rather limited to those whom 2012;7:e32037. present ASIA B or C. ASIA D neurologic complete deficits 6. Kepler CK, Kong C, Schroeder GD, Hjelm N, Sayadipour failed to show any difference of improvement even after early A, Vaccaro AR, et al. Early outcome and predictors of early surgery7). Another group of patients whom seem that they outcome in patients treated surgically for central cord less likely benefit from early surgical decompression are those syndrome. J Neurosurg Spine 2015;23:490–494. with central cord syndromes. Central cord syndrome patients 7. Lenehan B, Fisher CG, Vaccaro A, Fehlings M, Aarabi B, whom had early decompression did not show significant clinical Dvorak MF. The urgency of surgical decompression in acute difference according to the timing of surgery11). central cord injuries with spondylosis and without instability. Spine 2010;35:S180–186. SUMMARY 8. Liu JM, Long XH, Zhou Y, Peng HW, Liu ZL, Huang SH. Is urgent decompression superior to delayed surgery for SCI usually results in devastating clinical outcomes, and traumatic spinal cord injury? A Meta-Analysis. World proper neurocritical care is essential while managing these Neurosurg 2016;87:124–131. patients. Although there are still some debate regarding the 9. Rath N, Balain B. Spinal cord injury-The role of surgical optimal timing for surgery in SCI patients, it is clear by previous treatment for neurological improvement. J Clin Orthop literature that surgery has a specific benefit for neurocritical care Trauma 2017;8:99–102. in SCI patients. The goals of surgery in SCI are correcting and 10. Rowland JW, Hawryluk GW, Kwon B, Fehlings MG. Current reducing the broken biomechanical alignment and stabilizing it status of acute spinal cord injury pathophysiology and by instrumentation while decompressing the neural structures. emerging therapies: promise on the horizon. Neurosurg Furthermore, by stabilization and decompression, minimizing Focus 2008;25:E2. the possible progressive secondary injuries to the spinal cord are 11. Stevens EA, Marsh R, Wilson JA, Sweasey TA, Branch CL, the key role of surgery. Powers AK. A review of surgical intervention in the setting of traumatic central cord syndrome. Spine J 2010;10:874–880. CONFLICT OF INTEREST 12. Tator CH, Fehlings MG. Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular No potential conflict of interest relevant to this article was mechanisms. J Neurosurg 1991;75:15–26. reported. 13. Vaccaro AR, Hulbert RJ, Patel AA, Fisher C, Dvorak M, Lehman RA, et al. The subaxial cervical spine injury REFERENCES classification system: a novel approach to recognize the importance of morphology, neurology, and integrity of 1. Ackery A, Tator C, Krassioukov A. A global perspective the disco-ligamentous complex. Spine (Phila Pa 1976) on spinal cord injury epidemiology. J Neurotrauma 2007;32:2365–2374. 2004;21:1355–1370. 14. Vaccaro AR, Lehman RA, Hurlbert RJ, Anderson PA, Harris 2. Amar AP, Levy ML. Pathogenesis and pharmacological M, Hedlund R, et al. A new classification of thoracolumbar

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injuries: the importance of injury morphology, the integrity surgical management of acute traumatic spinal cord injury. of the posterior ligamentous complex, and neurologic status. Neurotherapeutics 2011;8:187–194. Spine (Phila Pa 1976) 2005;30:2325–2333. 16. Witiw CD, Fehlings MG. Acute Spinal Cord Injury. J Spinal 15. Wilson JR, Fehlings MG. Emerging approaches to the Disord Tech 2015;28:202–210.

www.e-jnic.org 19 eISSN 2635-5280 Review Article J Neurointensive Care 2018;1(1):20-24. https://doi.org/10.32587/jnic.2018.00066

Deep Vein Thrombosis and Pulmonary Embolism following Hemorrhagic Stroke Sung Ho Lee, Won Joo Jeong, Seok Keun Choi, Byung Duk Kwun Department of Neurosurgery, School of Medicine, Kyung Hee University, Seoul, Korea

Received: September 22, 2018 Accepted: September 27, 2018 Venous thromboembolism (VTE) after stroke is an infrequent but potentially fatal medical Published: October 10, 2018 complication. The incidence of VTE was shown to be higher in hemorrhagic stroke than in ischemic stroke by several studies; however, no strategy for VTE screening and prophylaxis has been Corresponding Author: established. Lower extremity ultrasonography (US) is the diagnostic method of choice, but rou- Sung Ho Lee, M.D., Ph.D. tine application for stroke patients is still debated. For prevention, graduated compression stock- Department of Neurosurgery, ings (GCS) have little effect on VTE, and thigh-high GCS should be selected. Early use of inter- School of Medicine, Kyung Hee mittent pneumatic compression (IPC) has strong evidence for preventing VTE and is recom- University, 23 Kyung Hee Dae Ro, Dongdaemoon-gu, Seoul 02447, mended in several clinical guidelines for managing intracerebral hemorrhage (ICH) and sub- Korea arachnoid hemorrhage (SAH). Prophylactic heparin products are still debated for preventing Tel: +82-2-958-8385 VTE despite the risk of rebleeding or hematoma enlargement. To date, administering low-dose, Fax: +82-2-958-8380 low-molecular-weight heparin (LMWH) seems the best method to prevent VTE with less risk Email:[email protected]; of hemorrhagic complications. However, the optimal product, dose, and timing are unclear. [email protected] Keywords: Venous thromboembolism; Deep Vein Thrombosis; Pulmonary Embolism; Stroke; Intracerebral hemorrhage

BACKGROUND REVIEW

Venous thromboembolism (VTE) including deep vein Incidence and risk factors thrombosis (DVT) and pulmonary embolism (PE) are The incidence of VTE after stroke varies from 10-75% potentenially fatal medical complications following intracerebral depending on the diagnostic criteria, tools, and study hemorrhage (ICH) and subarachnoid hemorrhage (SAH). design3,13,21,24). Many studies have reported a higher incidence The incidence of PE after stroke (including both ischemic and of DVT or PE after ICH and SAH than after cerebral infarction hemorrhagic) is less than 1%; however, PE causes more than or transient ischemic attack39). In 2003, Gregory et al. 50% of early deaths after stroke1). As in ischemic stroke, patients retrospectively reported the incidence of DVT after hemorrhagic with hemorrhagic stroke are prone to DVT due to immobility, (n=1,926) and thromboembolic (n=15,599) stroke as 1.9% and possible hemiplegia, and older age. 0.5%, respectively18). Hemorrhagic stroke and length of hospital Methods to prevent and properly manage VTE after ischemic stay were independent risk factors for DVT. Skaf et al. reported stroke are relatively well established3,4); however, strategies for a VTE incidence of 1.93% (1.37% of DVT and 0.68% of PE) hemorrhage stroke are not. in 1,605,000 ICH patients in 200538). In 2014, Stecker et al.

20 www.e-jnic.org Sung Ho Lee et al. Venous thromboembolism after Hemorrhagic stroke reported that the VTE incidence was 1.3% (33 of 2613 stroke pneumatic compression (IPC) patients, DVT=25, PE=3, both=5) and was higher in SAH The CLOTS (Clots in Legs or Stockings After Stroke) trials and ICH than in ischemic patients. Higher National Institutes included three randomized trials assessing the preventive effect of Health Stroke Scale (NIHSS) score and heart failure were of graduated compression stockings (GCS) and intermittent statistically significant risk factors in their study. pneumatic compression (IPC) in DVT in stroke patients. In Meanwhile, the incidence of DVT is much higher in studies CLOTS 1, 2518 stroke patients (including 232 ICH patients) that used lower extremity ultrasonography (US). Lacut et al. were enrolled to investigate the preventive effect of thigh-high reported a DVT incidence of 15.9% up to 10 days after ICH GCS and did not show reduced DVT, PE, or death8). In CLOTS development27). Yablon et al. reported 16% DVT up to 120 2, the effectiveness of below-knee GCS and thigh-high GCS days43). In a Japanese series, Ogata et al. reported that 21 of 52 were compared in 1406 stroke patients. The incidence of DVT ICH patients developed DVT32). Kawase et al. performed venous was higher in the below-knee GCS group (8.8% versus 6.3%; duplex US to detect DVT in 81 ICH patients, and 4, 9, and 17 absolute difference, 2.5% points; 95% confidence interval, (21%) patients were diagnosed at 1, 7, and 14 days, respectively. [CI] 0.7 to 4.4)9). Finally, CLOTS 3 enrolled 2876 stroke Female sex was the only independent predictor of DVT. patients (including 376 ICH patients) and found that applying Although risk factors for stroke-related DVT are still debated, IPC as soon as possible reduced the incidence of DVT. The advanced age, high NIHSS score, hemiparesis, immobility, preventive effect was more prominent in ICH patients (6.7% female sex, atrial fibrillation, intravenous or intra-arterial tissue versus 17.0%; odds ratio [OR], 0.36; 95% CI 0.17–0.75)10,14). plasminogen activator (tPA), and length of hospital stay have In the 2015 American Heart Association (AHA)/ American been identified16,28,29). Male sex is considered to be highly Stroke Association (ASA) Guidelines for the Management of associated with DVT in the general population2,12,26,30,31,37). Spontaneous ICH19), GCS is considered not beneficial (Class III, level of evidence [LOE] A), but IPC should be used just Diagnosis after admission (Class I, LOE A). AHA/ASA Guidelines for the The location and extent of DVT should be identified, because Management of Aneurysmal SAH do not describe the use IPC DVT in infra-popliteal calf veins (below-knee or distal DVT) or GCS11), but European Stroke Organization (ESO) Guidelines can spontaneously resolve and seldom results in PE22). However, for the Management of Intracranial Aneurysms and SAH40) in continuous monitoring is crucial because 1 in 6 distal DVTs 2012 and Korean Clinical Practice Guidelines for Aneurysmal progresses to proximal DVT, which carries a greater risk of PE20). SAH7) in 2018 recommended applying IPC, GCS, or both to Clinical symptoms of DVT appear as local pain or tenderness prevent DVT. and local leg edema in approximately 2/3 of DVT patients; however, these symptoms can be hidden in unalert hemorrhagic Unfractionated heparin (UFH) / low-molecular-weight stroke patients. A clinical DVT prediction score (Wells score) heparin (LMWH) can be useful but is still limited. Thus, it should be combined In ischemic stroke, prophylactic use of heparin or heparinoids with D-dimer, (i.e., increased serum C-reactive protein [CRP] has been broadly recommended36). Kamphuisen et al. performed with normal fibrinogen with a fever of unknown origin3)) for a meta-analysis of 16 randomized controlled trials dealing with evaluation4,42). heparin use to prevent VTE after acute ischemic stroke. They The most important diagnostic tool is venous duplex US, defined low-dose, unfractionated heparin (UFH) as ≤ 15,000 which is accurate, safe, simple, and portable. Directly watching IU/day and low-dose, low-molecular-weight heparin (LMWH) flow physiology with real-time Doppler imaging (duplex, as ≤ 6000 IU/day or weight-adjusted dose ≤ 86 IU/kg/day. continuous-wave and color-flow Doppler imaging) provides High-dose UFH reduced PE but increased ICH or extracranial another advantage20). To detect DVT, US has high sensitivity hemorrhage (ECH), and low-dose UFH reduced thrombosis but (93.2-95.0%) and specificity (93.1-94.4%)17). The limitation of not PE and increased the risk of ICH or ECH. Meanwhile, high- US is that it is only suitable to detect proximal DVT, not distal dose LMWH decreased both DVT and PE but increased the risk DVT or DVT above the inguinal canal. In those cases, MR and of ICH or ECH, and low-dose LMWH decreased the risk of both CT venography of the lower extremity and pelvis with contrast DVT (OR=0.34, 95%; CI=0.19—0.59) and PE (OR=0.36, 95%; provide high sensitivity and specificity35,41). CI=0.15—0.87) without increased risk of ICH (OR=1.39, 95% CI=0.53—3.67) or ECH (OR=1.44, 95% CI=0.13—16). ESO Prophylaxis & treatment guidelines for VTE in immobile patients with acute ischemic Graduated compression stockings (GCS) / intermittent stoke recommend prophylactic anticoagulation with UFH www.e-jnic.org 21 Venous thromboembolism after Hemorrhagic stroke Sung Ho Lee et al.

(5000IU q 12 or 8 hours), LMWH, or a heparinoid15). filter insertion does not eliminate the need for anticoagulation. Prophylactic use of heparin or heparinoids to prevent DVT Nevertheless, AHA/ASA Guidelines for the Management of after hemorrhagic stroke has not received consensus agreement Spontaneous ICH recommend IVC filter placement in ICH due to the increased risk of hemorrhage or rebleeding6). In 1991, patients with symptomatic DVT or PE (Class IIa, LOE C)19). Boeer et al. administered low-dose UFH (5000 IU per 8 hours) 2 and 10 days after ICH in 68 patients and reported significantly CONCLUSION reduced PE without increasing ICH5). They suggested that heparin can re-open occluded vessels in cerebral infarctions Because DVT following hemorrhagic stroke is an uncommon but seldom expands hematomas surrounding cerebral tissue but fatal complication, early detection is crucial. Lower extremity due to elevated pressure. They ultimately recommend its use. US is the most recommended diagnostic tool, but clinical signs Despite several limitations of the study design, several small are preferred for immobile patients. IPC should be applied prospective studies were performed thereafter. Kiphuth et al. just after admission to the intensive care unit to prevent DVT. reported no fatal PE and a moderate increase in hematoma (20- Although, the evidence is still limited, heparin could be used 30%) after using LMWH (Enoxafarin 4000IU, dalteparin 2500 for high-risk patients; low-dose LMWH seems to be the most IU) within 36 hours for 97 ICH patients25). Orken et al. showed preferred form. that administering LMWH did not increase ICH but failed to decrease VTE compared to GCS only. In 2011, Paciaroni et al. Abbreviation reported a meta-analysis of four controlled (randomized or non- ICH Intracerebral hemorrhage randomized) studies of heparin use to prevent DVT in ICH SAH Subarachnoid hemorrhage patients and found that heparin (UFH or LMWH) significantly PE Pulmonary embolism reduced PE (1.7% vs. 2.9%; RR, 0.37; 95% CI, 0.17–0.80; DVT Deep vein thrombosis p = 0.01) but not DVT (4.2% vs 3.3% [RR, 0.77]; 95%CI, VTE Venous thromboembolism 0.44–1.34; p = 0.36). However, hemorrhage did not increase CT Computed tomography significantly (8.0%vs. 4.0%; RR, 1.42; 95% CI, 0.57–3.53; p MRI Magnetic resonance imaging = 0.45) and mortality decreased non-significantly (16.1% vs. US Ultrasonography 20.9%; RR, 0.76; 95% CI, 0.57–1.03; p = 0.07). They concluded UFH Unfractionated heparin that heparin use should be considered with caution for high- LMWH Low-molecular-weight heparin risk patients33). Khan et al. performed a systematic review of GCS Graduated compression stockings DVT in acute stroke and concluded that UFH administration IPC Intermittent pneumatic compression should be considered for high-risk patients even in ICH and SAH. However, their conclusion does not seem to be clear. CONFLICT OF INTEREST AHA/ASA Guidelines for the Management of Aneurysmal SAH and Korean Clinical Practice Guidelines for Aneurysmal No potential conflict of interest relevant to this article was SAH also indicate a lack of sufficient evidence for heparin use reported. in SAH patients7,11). However, the AHA/ASA Guidelines for the Management of Spontaneous ICH recommend low-dose REFERENCES LMWH or UFH for immobile ICH patients 1-4 days from onset until after bleeding stops (Class IIb, LOE B)19). To date, real- 1. The international stroke trial (IST): a randomised trial of world recommendations for low-dose LMWH use are unclear, aspirin, subcutaneous heparin, both, or neither among 19435 including optimal timing, dose, and products. patients with acute ischaemic stroke. International stroke trial collaborative group. Lancet 1997;349:1569– 1581. Inferior vena cava (IVC) filter 2. Anderson FA Jr, Wheeler HB, Goldberg RJ, Hosmer DW, Inferior vena cava (IVC) filter insertion is a common method Patwardhan NA, Jovanovic B, et al. A population-based to prevent PE when therapeutic anticoagulation is impossible. perspective of the hospital incidence and case-fatality rates of However, information comparing IVC filter and anticoagulation deep vein thrombosis and pulmonary embolism. The worcester is extremely limited23). Moreover, the IVC filter itself can dvt study. Arch Intern Med 1991;151:933– 938. induce thrombosis at the insertion site, perforation of the IVC 3. Bembenek J, Karlinski M, Kobayashi A, Czlonkowska A. Early and adjacent tissue, fracture, or migration. Additionally, IVC stroke-related deep venous thrombosis: Risk factors and influence

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on outcome. J Thromb Thrombolysis 2011;32:96–102. Incidence and patterns of prophylaxis. J Stroke Cerebrovasc Dis 4. Beyer J, Schellong S. Deep vein thrombosis: Current diagnostic 2014;23:123–129. strategy. Eur J Intern Med 2005;16:238–246. 17. Goodacre S, Sampson F, Stevenson M, Wailoo A, Sutton 5. Boeer A, Voth E, Henze T, Prange HW. Early heparin therapy in A, Thomas S, et al. Measurement of the clinical and cost- patients with spontaneous intracerebral haemorrhage. J Neurol effectiveness of non-invasive diagnostic testing strategies for deep Neurosurg Psychiatry 1991;54:466–467. vein thrombosis. Health Technol Assess 2006;10:1–168; iii-iv. 6. Chang SH, Shin HS, Lee SH, Koh HC, Koh JS. Rebleeding of 18. Gregory PC, Kuhlemeier KV. Prevalence of venous ruptured intracranial aneurysms in the immediate postoperative thromboembolism in acute hemorrhagic and thromboembolic period after coil embolization. J Cerebrovasc Endovasc stroke. Am J Phys Med Rehabil 2003;82:364–369. Neurosurg 2015;17:209–216. 19. Hemphill JC 3rd, Greenberg SM, Anderson CS, Becker K, 7. Cho WS, Kim JE, Park SQ, Ko JK, Kim DW, Park JC, et al. Bendok BR, Cushman M, et al. Guidelines for the management Korean clinical practice guidelines for aneurysmal subarachnoid of spontaneous intracerebral hemorrhage: A guideline for hemorrhage. J Korean Neurosurg Soc 2018;61:127–166. healthcare professionals from the american heart association/ 8. Collaboration CT, Dennis M, Sandercock PA, Reid J, Graham american stroke association. Stroke 2015;46:2032–2060. C, Murray G, et al. Effectiveness of thigh-length graduated 20. Ho VB, van Geertruyden PH, Yucel EK, Rybicki FJ, Baum RA, compression stockings to reduce the risk of deep vein Desjardins B, et al. Acr appropriateness criteria(®) on suspected thrombosis after stroke (clots trial 1): A multicentre, randomised lower extremity deep vein thrombosis. J Am Coll Radiol controlled trial. Lancet 2009;373:1958–1965. 2011;8:383–387. 9. Collaboration CT. Thigh-length versus below-knee stockings for 21. Kamran SI, Downey D, Ruff RL. Pneumatic sequential deep venous thrombosis prophylaxis after stroke: A randomized compression reduces the risk of deep vein thrombosis in stroke trial. Ann Intern Med 2010;153:553–562. patients. Neurology 1998;50:1683–1688. 10. Collaboration CT, Dennis M, Sandercock P, Reid J, Graham 22. Kearon C. Natural history of venous thromboembolism. C, Forbes J, et al. Effectiveness of intermittent pneumatic Circulation 2003;107(23 Suppl 1):I22–30. compression in reduction of risk of deep vein thrombosis 23. Kelly J, Hunt BJ, Lewis RR, Rudd A. Anticoagulation or inferior in patients who have had a stroke (clots 3): A multicentre vena cava filter placement for patients with primary intracerebral randomised controlled trial. Lancet 2013;382:516–524. hemorrhage developing venous thromboembolism? Stroke 11. Connolly ES, Rabinstein AA, Carhuapoma JR, Derdeyn CP, 2003;34:2999–3005. Dion J, Higashida RT, et al. Guidelines for the management 24. Kelly J, Rudd A, Lewis RR, Coshall C, Moody A, Hunt BJ. of aneurysmal subarachnoid hemorrhage: A guideline for Venous thromboembolism after acute ischemic stroke: A healthcare professionals from the american heart association/ prospective study using magnetic resonance direct thrombus american stroke association. Stroke 2012;43:1711–1737. imaging. Stroke 2004;35:2320–2325. 12. Cushman M, Tsai AW, White RH, Heckbert SR, Rosamond 25. Kiphuth IC, Staykov D, Kohrmann M, Struffert T, Richter G, WD, Enright P, et al. Deep vein thrombosis and pulmonary Bardutzky J, et al. Early administration of low molecular weight embolism in two cohorts: The longitudinal investigation of heparin after spontaneous intracerebral hemorrhage. A safety thromboembolism etiology. Am J Med 2004;117:19–25. analysis. Cerebrovasc Dis 2009;27:146–150. 13. Davenport RJ, Dennis MS, Wellwood I, Warlow CP. 26. Kyrle PA, Minar E, Bialonczyk C, Hirschl M, Weltermann A, Complications after acute stroke. Stroke 1996;27:415– 420. Eichinger S. The risk of recurrent venous thromboembolism in 14. Dennis M, Sandercock P, Murray G, Forbes J, Collaboration CT. men and women. N Engl J Med 2004;350:2558–2563. Does intermittent pneumatic compression reduce the risk of 27. Lacut K, Bressollette L, Le Gal G, Etienne E, De Tinteniac A, post stroke deep vein thrombosis? The clots 3 trial: Statistical Renault A, et al. Prevention of venous thrombosis in patients analysis plan. Trials 2013;14:66. with acute intracerebral hemorrhage. Neurology 2005;65:865– 15. Dennis M, Caso V, Kappelle LJ, Pavlovic A, Sandercock P. 869. European stroke organisation (eso) guidelines for prophylaxis 28. Li Z, Liu L, Wang Y, Zhao X, Wang DZ, Wang C, et al. Factors for venous thromboembolism in immobile patients with acute impact the adherence rate of prophylaxis for deep venous ischaemic stroke. 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A prospective study using clinical factors. CNS Neurosci Ther versus unfractionated heparin for the prevention of venous 2014;20:403–410. thromboembolism after acute ischaemic stroke (prevail study): 30. McRae S, Tran H, Schulman S, Ginsberg J, Kearon C. Effect of An open-label randomised patient's sex on risk of recurrent venous thromboembolism: A 37. Silverstein MD, Heit JA, Mohr DN, Petterson TM, O'Fallon meta-analysis. Lancet 2006;368:371–378. WM, Melton LJ. Trends in the incidence of deep vein 31. Moores L, Bilello KL, Murin S. Sex and gender issues and venous thrombosis and pulmonary embolism: A 25-year population- thromboembolism. Clin Chest Med 2004;25:281– 297. based study. Arch Intern Med 1998;158:585– 593. 32. Ogata T, Yasaka M, Wakugawa Y, Inoue T, Ibayashi S, Okada Y. 38. Skaf E, Stein PD, Beemath A, Sanchez J, Bustamante MA, Olson Deep venous thrombosis after acute intracerebral hemorrhage. J RE. Venous thromboembolism in patients with ischemic and Neurol Sci 2008;272:83–86. hemorrhagic stroke. Am J Cardiol 2005;96:1731–1733. 33. Paciaroni M, Agnelli G, Venti M, Alberti A, Acciarresi M, Caso V. 39. Stecker M, Michel K, Antaky K, Cherian S, Koyfmann F. Efficacy and safety of anticoagulants in the prevention of venous Risk factors for dvt/pe in patients with stroke and intracranial thromboembolism in patients with acute cerebral hemorrhage: hemorrhage. Open Neurol J 2014;8:1–6. A meta-analysis of controlled studies. J Thromb Haemost 40. Steiner T, Juvela S, Unterberg A, Jung C, Forsting M, Rinkel G, et 2011;9:893–898. al. European stroke organization guidelines for the management 34. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis of intracranial aneurysms and subarachnoid haemorrhage. NC, Becker K, et al. 2018 guidelines for the early management Cerebrovasc Dis 2013;35:93–112. of patients with acute ischemic stroke: A guideline for healthcare 41. Thomas SM, Goodacre SW, Sampson FC, van Beek EJ. Diagnostic professionals from the american heart association/american stroke value of ct for deep vein thrombosis: Results of a systematic association. Stroke 2018;49:e46–e110. review and meta-analysis. Clin Radiol 2008;63:299–304. 35. Sampson FC, Goodacre SW, Thomas SM, van Beek EJ. The 42. Wells PS, Owen C, Doucette S, Fergusson D, Tran H. Does this accuracy of mri in diagnosis of suspected deep vein thrombosis: patient have deep vein thrombosis? JAMA 2006;295:199–207. Systematic review and meta-analysis. Eur Radiol 2007;17:175– 43. Yablon SA, Rock WA, Nick TG, Sherer M, McGrath CM, 181. Goodson KH. Deep vein thrombosis: Prevalence and risk 36. Sherman DG, Albers GW, Bladin C, Fieschi C, Gabbai factors in rehabilitation admissions with brain injury. Neurology AA, Kase CS, et al. The efficacy and safety of enoxaparin 2004;63:485–491.

24 www.e-jnic.org eISSN 2635-5280 Original Article J Neurointensive Care 2018;1(1):25-31. https://doi.org/10.32587/jnic.2018.00031

The Prognostic Value of Optic Nerve Sheath Diameter in Patients with Poor-Grade Subarachnoid Hemorrhages Dong Gyun Ju1, Jeong-Am Ryu1, 2, Yong Oh Kim2, Sangkil Lee3, Ji Sun Baek4 1 Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Department of Critical Care Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 3 Department of Neurology, ChungBuk National University Hospital, Cheongju, Korea 4 Department of Ophthalmology, Konyang University, Kim’s Eye Hospital, Myung-Gok Eye Research Institute, Seoul, Korea

Received: August 30, 2018 Accepted: September 19, 2018 Objective Published: October 10, 2018 We evaluated if the optic nerve sheath diameter (ONSD) on brain computed tomography (CT) could be used to predict neurological outcomes of patients with poor-grade subarachnoid hem- Corresponding Author: orrhage (SAH). Ji Sun Baek, M.D. Department of Ophthalmology, Methods Konyang University, Kim’s Eye Hospital, Myung-Gok Eye This was a retrospective and observational study of adult patients with poor-grade SAH admit- Research Institute, 136 Yeongsin-ro, ted January 2012 through June 2017. Initial brain CT was performed within 12 hours from onset Yeongdeungpo-gu, Seoul 07260, of SAH. Follow-up brain CT was performed within 48 hours from onset of SAH and after aneu- Korea rysmal treatment. The primary outcome was neurological status upon six months later assessed Tel: +82-2-2639-7812 with Glasgow Outcome Scale (GOS, 1 to 5). Fax: +82-2-2633-3976 Results E-mail: [email protected] Among 59 patients with poor-grade SAH, survival to discharge was identified in 47 (79.7%) patients. Of these 47 survivors, 39 (66.1%) had good neurological outcomes (GOS of 3, 4 or 5). In this study, initial ONSDs and follow-up ONSDs in the poor neurological outcome group were significantly greater than those in the good neurological outcome group (all p<0.03). The intracranial pressure (ICP) was monitored in only 13 (22.0%) patients at that time of follow-CT scanning. Using simple correlation analysis, there was a linear correlation between ONSD and ICP (ρ=0.683, p=0.010). In ROC curve analysis for prediction of poor neurological outcome, ONSDs and ONSD indices had considerable predictive values (C-statistics: 0.683 to 0.804) and similar predictive performances for poor neurological outcome. Conclusion The ONSDs and ONSD indices measured on CT scanning may be beneficial for predicting neurological outcomes in patients with poor-grade SAH.

Keywords: Optic nerve sheath diameter; Brain computed tomography; Subarachnoid hemorrhage

INTRODUCTION given follow-up brain CT scan were performed after treatment of ruptured aneurysm. Of these patients, we excluded patients Subarachnoid hemorrhage (SAH) is a complex neurovascular under age 18, those with malignancy whose expected life span syndrome and a devastating condition with high mortality and was less than one year, those with insufficient medical records, morbidity rates for those that survive the initial hemorrhage2,6,8). those with a history of head trauma, neurosurgery, cardiac arrest, In SAH patients, the level of consciousness on admission is the or chronic neurological abnormality on admission, and those most critical early predictor of clinical outcome2). Patients with that transferred from other hospitals after more than one day of poor-grade SAH (World Federation of Neurosurgeons [WFNS] onset of SAH. In addition, we excluded patients with anomaly grade 4 and 5) could have high mortality and poor neurological of orbits, orbital mass lesions, and ocular or retro-orbital injury. outcome13). However, there are recent reports on patients A total of 59 patients with poor-grade SAH were analyzed in this with poor-grade SAH treated early and aggressively with coil study (Fig. 1). embolization and neurointensive care could achieve a good neurological outcome6,13). Therefore, to accurately evaluate the Definitions and outcomes prognosis of these patients, new predictors other than the initial In this study, poor-grade SAH was defined as World Federation level of consciousness are needed. of Neurosurgical Societies (WFNS) grade 4 and 52). The Poor neurological outcome is usually secondary to early brain primary outcome was neurological status upon six months later injury or delayed cerebral ischemia in SAH patients2). assessed with Glasgow Outcome Scale (GOS, 1 to 5)11). GOSs Uncontrolled intracranial hypertension results in decreased of 3, 4, and 5 were classified as good neurological outcomes. cerebral perfusion and transient global cerebral ischemia2,5). GOSs of 1 and 2 were considered poor neurological outcomes. Therefore, early monitoring of intracranial hypertension may We thoroughly reviewed medical records. Patients were graded be beneficial in predicting neurological outcomes of the patients on the GOS by two independent neurologists. Initial brain CT with poor-grade SAH. angiography was performed within 12 hours from onset of SAH. Measurement of optic nerve sheath diameter (ONSD) Follow-up brain CT was performed within 12-48 hours from has been proposed as an alternative method for detection onset of SAH and after aneurysmal treatment. If aneurysmal of intracranial hypertension4,11). However, if ONSD may be treatment was not possible, a follow-up brain CT scan was beneficial to systemically estimate neurological outcomes of performed within 48 hours. For all CT studies, 64-channel patients with poor-grade SAH has not been reported. Therefore, scanners (Light Speed VCT; GE Healthcare, Milwaukee, the objective of this study is to investigate if the ONSD with Wisconsin, USA) with a 5-mm slice width were used. Brain some modifications could be used to predict neurological CT images were reviewed by two independent neurologists. outcomes of patients with poor-grade SAH. Investigators blinded to clinical information opened these CT scans for each patient using commercial image-viewing software MATERIALS AND METHODS (Centricity RA1000 PACS Viewer; GE Healthcare, Milwaukee, Wisconsin, USA). Optic nerve sheath diameter (ONSD) and Study population eyeball transverse diameter (ETD) were measured using the This was a retrospective, single-center, and observational same initial CT scan and subsequent scan. ONSD was measured study of adult patients with poor-grade SAH admitted to the at a distance of 3 mm behind the eyeball, immediately below the neurosurgical intensive care unit at Samsung Medical Center sclera in a perpendicular vector in reference to the linear axis of January 2012 through June 2017. This study was approved by the nerve (Fig. 2A)4,7,11). The images were changed to the ‘chest/ the Institutional Review Board of Samsung Medical Center abdomen’ window (window width 300 & window level 10) (SMC 2018-07-154). The requirement for informed consent and were magnified threefold on the particular image slice that was waived due to its retrospective nature. Clinical and demonstrated the largest diameter of the optic nerve sheath11). laboratory data were collected by a trained study coordinator ONSD was measured from one side of the optic nerve sheath using a standardized case report form. We included patients with to the other as a section through the center of the optic nerve7). SAH admitted to the neurosurgical intensive care unit during The transverse diameter of the eyeball was chosen because the study period. Those that were obtunded or unconscious (a the ONSD is usually measured in the transverse plain15). ETD score of ≤12 on the Glasgow Coma Scale) on admission to the was defined as the maximal transverse diameter of the eyeball hospital and those given brain computed tomography (CT) measured from one side of the retina to the other (in-to-in, scan within 12 hours from onset of SAH were selected. Those Fig. 2B)1,15). The ONSD/ETD index was defined as multiplied

26 www.e-jnic.org Dong Gyun Ju et al. Optic nerve sheath diameter and SAH

Fig. 1. Study flow chart. SAH : subarachnoid hemorrhage, GCS : Glasgow Coma Scale, CT : computed tomography, GOS : Glasgow Outcome Scale.

A B Statistical analyses All data are presented as medians and interquartile ranges (IQRs) for continuous variables and numbers (percentages) for categorical variables. Data were compared using Mann- Whitney U test for continuous variables and Chi-square test or Fisher’s exact test for categorical variables. Simple linear regression was used to plot the relationship between simultaneously measured ONSD and ICP. Spearman's rank correlation coefficient (ρ) was calculated to evaluate correlation between ONSD and Fig. 2. A: Measurement of optic nerve sheath diameter and B : ICP. Predictive performances of ONSDs and ONSD indices eyeball transverse diameter on the brain computed tomography were assessed using area under the curve (AUC) of the receiver scan. operating characteristic (ROC) curves for sensitivity vs. 1-specificity. AUCs were compared using the nonparametric median ETD (22.5 mm) by average value of bilateral ONSDs approach published by DeLong et al.3) for two correlated AUCs. over average value of bilateral ETDs (22.5× ONSDaverage/ Optimal cut-off value of each ONSD and its modification for

ETDaverage). The intracranial pressure (ICP) at that time of predicting poor neurological outcome was obtained by ROC follow-up CT scanning was defined as immediately measured curve and Youden index9,10). All tests were two-sided and p ICP after the CT scanning. values < 0.05 were statistically significant. Data were analyzed using IBM SPSS statistics version 20 (IBM, Armonk, NY, USA). www.e-jnic.org 27 Optic nerve sheath diameter and SAH Dong Gyun Ju et al.

RESULTS

Baseline characteristics and clinical outcomes The median age of patients was 64 (IQR: 53-73 years). Of 59 p = 0.683, p= 0.010 patients, 18 (30.5%) were males. Hypertension (45.8%) and smoking (18.6%) were most common comorbidities among poor-grade SAH patients. Thirty-five (59.3%) patients were Hunt and Hess grade 5 and 32 (54.2%) patients were WFNS grade 5. Forty-two (71.2%) patients had ruptured aneurysms of anterior circulation. Around middle cerebral artery (27.1%) and anterior communicating artery (20.3%) were most common location of ruptured aneurysm. However, aneurysm or ruptured aneurysm was not detected in four patients (6.8%). Treatment of ruptured aneurysm was performed within 72 hours in most patients (83.1%). Endovascular coiling of the ruptured aneurysm was performed in 36 (61.0%) patients. Surgical Fig. 3. Scatter plot of intracranial pressure (ICP, mmHg) and optic nerve sheath diameter (ONSD, mm). Follow-up ONSDaverage was clipping was performed in 12 (20.3%) patients. Delayed used in simple correlation analysis. cerebral ischemia accompanied in 16 (27.1%) patients. Baseline characteristics of SAH patients are presented in Table 1. Survival to discharge was identified in 47 (79.7%) patients. Of these 47 survivors, 39 (66.1%) had good neurological outcomes (GOS of 3, 4 or 5, Fig. 1).

Optic nerve sheath diameters and their modifications In this study, initial ONSDs and follow-up ONSDs in the poor neurological outcome group were significantly greater than those in the good neurological outcome group (Table 2). However, initial ETD and follow-up ETD were not significant differences between the good neurological outcome group and poor neurological outcome group (p=0.227 and p=0.108, respectively). The ICP was monitored in only 13 (22.0%) patients at that time of follow-CT scanning. Using simple correlation analysis, there was linear correlation between ONSD and ICP (ρ=0.683, p=0.010) (Fig. 3). In ROC curve analysis for prediction of poor neurological outcome (Fig. 4), the C-statistic of initial ONSDmax was 0.729 (95% CI: 0.583 to 0.875). A cut- Fig. 4. Receiver operating characteristic (ROC) curves for the off > 6.33 mm had a sensitivity of 80.0% (95% CI: 56.3% to prediction of poor outcomes using the optic nerve sheath diameters 94.3%) and a specificity of 69.2% (95% CI: 52.4% to 83.0%). and their modifications. ONSD : optic nerve sheath diameter, ETD The C-statistic of follow-up ONSDaverage was 0.760 (95% CI: : eyeball transverse diameter. 0.633 to 0.887). A cut-off > 6.26 mm had a sensitivity of 70.0% (95% CI: 45.7% to 88.1%) and a specificity of 74.4% (95% CI:

57.9% to 87.0%). The C-statistic of follow-up ONSD/ETD significantly different compared to that of initial ONSDmax or was 0.804 (95% CI: 0.684 to 0.924). A cut-off > 6.46 had a follow-up ONSDaverage (p=0.199 and p=0.156, respectively). sensitivity of 65.0% (95% CI: 40.8% to 84.6%) and a specificity of 87.2% (95% CI: 72.6% to 98.7%). However, there were DISCUSSION similar predictive performances of ONSDs and ONSD indices for poor neurological outcome; the predictive performance of In this study, we evaluated if the ONSDs and their modifications follow-up ONSD/ETD for poor neurological outcome was not could be used to predict neurological outcomes of patients

28 www.e-jnic.org Dong Gyun Ju et al. Optic nerve sheath diameter and SAH

Table 1. Baseline characteristics Good neurological outcome Poor neurological outcome (n=39) (n=20) p-value Age (yr) — median (IQR) 58.0 (49.0 – 68.0) 72.0 (61.5 – 76.5) 0.005 Gender, male — no. of patients (%) 11 (28.2) 7 (35.0) 0.812 BMI (kg/m2) — median (IQR) 23.4 (21.1 – 26.5) 22.0 (20.2 – 24.0) 0.206 Comorbidities — no. of patients (%) Hypertension 20 (51.3) 7 (35.0) 0.362 Current smoker 8 (20.5) 3 (15.0) 0.872 Diabetes mellitus 3 (7.7) 4 (20.0) 0.338 Previous stroke 3 (7.7) 0 (0.0) 0.518 Hunt & Hess Classification — no. of patients (%) 0.002 4 22 (56.4) 2 (10.0) 5 17 (43.6) 18 (90.0) WFNS grade — no. of patients (%) 0.044 4 22 (56.4) 5 (25.0) 5 17 (43.6) 15 (75.0) Fisher classification — median (IQR) 4.0 (3.0 – 4.0) 4.0 (4.0 – 4.0) 0.010 Modified Fisher classification — median (IQR) 3.0 (3.0 – 4.0) 4.0 (3.5 – 4.0) 0.016 Glasgow Coma Scale — median (IQR) 7.0 (4.0 – 8.0) 4.0 (3.0 – 6.5) 0.010 Pupil reactivity — no. of patients (%) 0.012 Both intact pupil reflex 27 (69.2) 6 (30.0) One unreactive pupil 3 (7.7) 2 (10.0) Both unreactive pupil 9 (23.1) 12 (60.0) Aneurysm location — no. of patients (%) Anterior communicating artery 8 (20.5) 4 (20.0) Anterior cerebral artery & distal 5 (12.8) 2 (10.0) Middle cerebral artery & distal 14 (35.9) 2 (10.0) Internal carotid artery 1 (2.6) 6 (30.0) 0.016 Posterior communicating artery 6 (15.4) 3 (15.0) Posterior circulation 4 (10.3) 0 (0.0) No aneurysm 1 (2.6) 2 (10.0) Unknown 0 (0.0) 1 (5.0) Hydrocephalus — no. of patients (%) 23 (59.0) 16 (80.0) 0.185 Intraventricular hemorrhage — no. of patients (%) 18 (46.2) 15 (75.0) 0.066 EVD — no. of patients (%) 32 (82.1) 8 (40.0) 0.003 Vasospasm — no. of patients (%) 20 (51.3) 4 (20.2) 0.021 Delayed cerebral ischemia — no. of patients (%) 13 (33.3) 3 (15.0) 0.134 Early treatment within 72hr— no. of patients (%) 39 (100.0 ) 10 (50.0) <0.001 Aneurysm management — no. of patients (%) Coiling 27 (69.2) 9 (45.0) 0.127 Clip operation 10 (25.6) 2 (10.0) 0.284 Endotracheal intubation during over 24hr 23 (59.0) 20 (100.0) 0.002 Decompressive craniectomy — no. of patients (%) 5 (12.8) 3 (15.0) 0.999 Barbiturate coma therapy — no. of patients (%) 2 (5.1) 3 (15.0) 0.427 IQR : interquartile range, BMI : body mass index, WFNS : World Federation of Neurosurgeons, EVD : external ventricular drainage with poor-grade SAH. Major findings of this study were as ICP were moderately correlated; 3) In initial CT and follow- follows: 1) the patients with poor-grade SAH had considerable up CT, ONSDs and ONSD indices of the poor neurological survival rate (79.7%) and favorable neurological prognosis outcome group were significantly greater than those of the good (66.1%); 2) Simultaneous measurement of ONSD on CT and neurological outcome group and these markers could be used to www.e-jnic.org 29 Optic nerve sheath diameter and SAH Dong Gyun Ju et al.

Table 2. The optic nerve sheath diameters and their modifications according to neurological outcomes Good neurological outcome (n=39) Poor neurological outcome (n=20) p-value

ONSDaverage 6.07 (5.87 – 6.47) 6.62 (5.98 – 7.07) 0.022

ONSDmax 6.21 (5.93 – 6.71) 6.79 (6.39 – 7.36) 0.004

ETDaverage 22.7 (22.0 – 23.3) 22.3 (21.8 – 22.9) 0.227 ONSD/ETD 6.13 (5.86 – 6.32) 6.81 (5.99 – 7.11) 0.006

Follow-up ONSDaverage 5.81 (5.45 – 6.29) 6.52 (6.11 – 6.69) 0.001

Follow-up ONSDmax 6.21 (5.93 – 6.71) 6.79 (6.39 – 7.36) 0.004

Follow-up ETDaverage 22.7 (22.1 – 23.1) 22.2 (21.9 – 22.6) 0.108 Follow-up ONSD/ETD 5.85 (5.39 – 6.26) 6.63 (6.21 – 6.84) <0.001 ONSD : optic nerve sheath diameter, ETD : eyeball transverse diameter predict neurological outcomes of patients with poor-grade SAH. circulation of cerebrospinal fluid is not blocked4). ONSD on Although it is difficult to predict the outcome following SAH, initial brain CT may be correlated with neurologic outcomes level of consciousness on admission would be associated with after traumatic brain injury11,12). Simultaneous measurement of prognosis of SAH patients2,6,13). One widely accepted predictor ONSD on initial CT and intracranial pressure were correlated, is the WFNS grade based on the level of consciousness as and ONSD was indicative of intracranial hypertension in assessed by the Glasgow coma scale13,14). Especially, patients patients with severe traumatic brain injury11,12). In this study, with poor WFNS grade SAH 4 and 5 historically have had high ONSD measured on CT scanning may be also a good predictive mortality and poor neurological outcomes13). However, in recent marker associated with intracranial pressure and prognosis in years, a considerable number of patients with poor-grade SAH patient with poor-grade SAH. treated aggressively with early coil embolization and supportive This study has several limitations. First, it was a retrospective neurointensive care could achieve a favorable neurological review of medical records. Therefore, the GOS was also outcome and survival6,13). Therefore, to accurately evaluate the retrospectively determined based on medical records. Second, prognosis of patients with poor-grade SAH, other predictors the non-randomized nature of the registry data may have other than the initial level of consciousness are needed. resulted in selection bias. Although brain CT scans were In patients with poor-grade SAH, poor neurological outcome performed within 48 hours after SAH, a major limitation of this is usually secondary to early brain injury or delayed cerebral study may be that the CT scans were performed at different ischemia2). Secondary cerebral injury can occur, that is the time settings. Third, invasive ICP monitoring was performed additive cerebral injury characterized by an imbalance in post- in a limited number of patients after aneurysmal treatment. resuscitation cerebral oxygen delivery and use, ultimately Finally, our study was conducted at one institution and involved culminating in neuronal death5). In addition, cerebral a lesser number of subjects. Although there were no significant autoregulation may be disturbed to different extents and differences between ONSDs and their modifications in this disturbed autoregulation in SAH is associated with delayed study, there may be different outcomes in larger cohorts. cerebral ischemia, vasospasm and unfavorable outcome5). Therefore, future studies with larger cohorts are needed to Especially, uncontrolled intracranial hypertension results in validate these findings. decreased cerebral blood flow and transient global cerebral ischemia and associated with early brain injury and poor CONCLUSION neurological outcome2,5). Therefore, early monitoring of intracranial hypertension may be beneficial in predicting The ONSDs and ONSD indices measured on CT scanning neurological outcomes of the patients with poor-grade SAH. may be used to predict neurological outcomes of patients with Measurement of ONSD has been proposed as an alternative poor-grade SAH. method for the detection of increased intracranial pressure4). The optic nerve is surrounded by cerebrospinal fluid CONFLICT OF INTEREST because it is a part of the central nervous system. Therefore, increased intracranial pressure will be transmitted through No potential conflict of interest relevant to this article was the subarachnoid space surrounding the optic nerve, within reported. the nerve sheath, especially the retrobulbar segment, unless

30 www.e-jnic.org Dong Gyun Ju et al. Optic nerve sheath diameter and SAH

INFORMED CONSENT 2013;17:R61. 8. Naval NS, Chang T, Caserta F, Kowalski RG, Carhuapoma Informed consent was obtained from all individual participants JR, Tamargo RJ. Improved aneurysmal subarachnoid included in this study. hemorrhage outcomes: a comparison of 2 decades at an academic center. J Crit Care 2013;28:182–188. REFERENCES 9. Ruopp MD, Perkins NJ, Whitcomb BW, Schisterman EF. Youden Index and optimal cut-point estimated from 1. Bekerman I, Sigal T, Kimiagar I, Ben Ely A, Vaiman M. The observations affected by a lower limit of detection. Biom J quantitative evaluation of intracranial pressure by optic 50:2008;419–430. nerve sheath diameter/eye diameter CT measurement. Am J 10. Schisterman EF, Perkins NJ, Liu A, Bondell H. Optimal cut- Emerg Med 2016;34:2336–2342. point and its corresponding Youden Index to discriminate 2. de Oliveira Manoel AL, Goffi A, Marotta TR, Schweizer individuals using pooled blood samples. Epidemiology TA, Abrahamson S, Macdonald RL. The critical care 16:2005;73–81. management of poor-grade subarachnoid haemorrhage. Crit 11. Sekhon MS, Griesdale DE, Robba C, McGlashan N, Care 2016;20:21. Needham E, Walland K, et al. Optic nerve sheath diameter 3. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing on computed tomography is correlated with simultaneously the areas under two or more correlated receiver operating measured intracranial pressure in patients with severe characteristic curves: a nonparametric approach. Biometrics traumatic brain injury. Intensive Care Med 40:2014;1267– 1988;44:837–845. 1274. 4. Hwan Kim Y, Ho Lee J, Kun Hong C, Won Cho K, Hoon Yeo 12. Sekhon MS, McBeth P, Zou J, Qiao L, Kolmodin L, J, Ju Kang M, et al. Feasibility of optic nerve sheath diameter Henderson WR, et al. Association between optic nerve measured on initial brain computed tomography as an early sheath diameter and mortality in patients with severe neurologic outcome predictor after cardiac arrest. Acad traumatic brain injury. Neurocrit Care 2014;21:245–252. Emerg Med 2014;21:1121– 1128. 13. Taylor CJ, Robertson F, Brealey D, O'Shea F, Stephen T, Brew 5. Johnson U, Engquist H, Lewen A, Howells T, Nilsson P, S, et al. Outcome in poor grade subarachnoid hemorrhage Ronne-Engstrom E, et al. Increased risk of critical CBF levels patients treated with acute endovascular coiling of aneurysms in SAH patients with actual CPP below calculated optimal and aggressive intensive care. Neurocrit Care 2011;14:341– CPP. Acta Neurochir (Wien) 2017;159:1065–1071. 347. 6. Konczalla J, Seifert V, Beck J, Guresir E, Vatter H, Raabe A, 14. Teasdale GM, Drake CG, Hunt W, Kassell N, Sano K, et al. Outcome after Hunt and Hess Grade V subarachnoid Pertuiset B, et al. A universal subarachnoid hemorrhage hemorrhage: a comparison of pre-coiling era (1980- scale: report of a committee of the World Federation of 1995) versus post-ISAT era (2005-2014). J Neurosurg Neurosurgical Societies. J Neurol Neurosurg Psychiatry 2018;128:100–110. 1988;51:1457. 7. Legrand A, Jeanjean P, Delanghe F, Peltier J, Lecat B, Dupont 15. Vaiman M, Gottlieb P, Bekerman I. Quantitative relations H. Estimation of optic nerve sheath diameter on an initial between the eyeball, the optic nerve, and the optic canal brain computed tomography scan can contribute prognostic important for intracranial pressure monitoring. Head Face information in traumatic brain injury patients. Crit Care Med 2014;10:32.

www.e-jnic.org 31 eISSN 2635-5280 Original Article J Neurointensive Care 2018;1(1):32-39. https://doi.org/10.32587/jnic.2018.00010

Clinical Advantage of Propofol Compared with Barbiturate for the Coma Therapy in the Patients with Severe Traumatic Brain Injury Hye Jin Shin1, Geun Young Yang1, Young Zoon Kim2 1 Department of Anesthesiology and Pain Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea 2 Department of Neurosurgery, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea

Received: August 14, 2018 Accepted: September 19, 2018 Objective Published: October 10, 2018 Barbiturates have been demonstrated to reduce intracranial pressure (ICP), but adverse effects, Corresponding Author: which include hypotension and a long recovery time, make clinical applications difficult. Propo- Young Zoon Kim, M.D., Ph.D. fol is also known to have same effect. In the present study, we undertook coma therapy using Department of Neurosurgery, propofol or barbiturate and compared clinical value in the practical point. Samsung Changwon Hospital, Methods Sungkyunkwan University School of Medicine, 158 Paryong-ro, From June 2014 to April 2017, 38 patients with severe traumatic brain injury underwent thio- Masanhoewon-gu, Changwon pental or propofol coma therapy for the 3 days following neurosurgery. Seventeen patients were 51353, Korea treated with thiopental (group A) and 21 patients with propofol (group B). Tel: +82-55-233-5241 Fax: +82-55-233-8040 Results E-Mail: [email protected] Mean doses were 6.1 mg/kg/hr of thiopental and 4.4 mg/kg/hr of propofol. In group A, mean bispectral indexes were 29.4 on day 1, 27.4 on day 2, and 26.0 on day 3, and in group B, 31.4 on day 1, 29.9 on day 2, and 27.8 on day 3. Mean ICP was 16.8 cm on day 1, 24.4 cm on day 2 and 15.1 cm on day 3 in group A, and 18.3 cm on day 1, 25.4 cm on day 2 and 18.0 cm on day 3 in group B. To maintain systemic normotentsion, dopamine was infused continuously at mean doses of 10.2 μg/kg/min in group A and 4.4 μg/kg/min in group B. Mean times to stationary state were 32.9 hours in group A and 6.6 hours in group B. Conclusion The present study suggest that propofol coma therapy has less systemic hypotension and shorter time to stationary state than thiopental therapy for achieving the same depth of anesthesia and ICP-reducing effect.

Keywords: Propofol; Barbiturate; Coma therapy; Bispectral index; Traumatic brain injury

32 www.e-jnic.org Hye Jin Shin et al. Coma therapy for severe brain injury

INTRODUCTION 18 months (from June 2014 to November 2015), whereas, 21 patients (group B) underwent coma therapy with propofol The potential neuroprotective effects of barbiturates and (Fresofol 2%®) during the next 17 months (from December propofol have been long recognized. These drugs induce a dose- 2015 to April 2017). dependent reduction in the cerebral metabolic rate of oxygen Based on preoperative consciousness of patients and

(CMRO2) until silence on electroencephalography (EEG), intraoperative findings, the following conditions were after which additional doses have no beneficial effects.12,18) considered before deciding to perform neuroprotective coma Furthermore, they can reduce cerebral blood flow (CBF) in the therapy: 1) in severe TBI patients with Glasgow Coma Scale non-ischemic brain by increasing vascular resistance and reduce (GCS) score < 9; 2) in the case of that severe brain swelling and intracranial pressure (ICP) 1,11,12). midline shifting may lead to cerebral herniation; 3) in the case of Numerous theories have been proposed to explain the that discolarization of brain and weak or absent brain pulsation ability of barbiturates and propofol to prevent or treat cerebral of the operative findings ischemia. The most quoted major neuroprotective mechanism involves the dose-dependent diminution of CMRO2 (up to 50 Monitoring of burst-suppression patterns by EEG percent) in human and animals until EEG silence.15,21) Other After brain surgery, all the patients were transfer to a potential mechanisms of neuroprotection include: stabilization neurosurgical intensive care unit under a deep hypnotic state. of lysosomal membranes, the attenuation of intracellular The induction of coma therapy and anesthetic agent titration calcium concentrations, anti-oxidative and anti-excitotoxic targeted the appearance of EEG burst-suppression patterns. processes19,22,23). EEG signals were obtained using gold cup electrodes applied The general brief is that maximal neuroprotection is achieved to the scalp with cream, and were located according to the at doses producing silent EEG20,24). However, higher doses can international 10-20 systems. Skin impedance was maintained cause many complications in clinical practice. Moreover, smaller at < 5 KΩ. The following leads were recorded: left and right doses may be as efficacious as those required to obtain burst frontal-mastoid (FP1-A1, FP2-A2, channels 1 and 2), left and right suppression. This is important when considering the deleterious frontal-CZ (FP1-CZ, FP2-CZ, channels 3 and 4), plus a ground side effects of barbiturates, because of: 1) cardiopulmonary electrode placed at the center of the forehead. EEGs were dose-dependent depressant effects and the prolonged ventilation recorded using a portable Aspect A-1000 EEG monitor (Aspect required in patients receiving burst-suppression doses, 2) the Medical System, Inc., Natick, MA, USA). increased risk of infection attributable to barbiturates and the need for invasive monitoring, and 3) a depression of mental Setting of bispectral index (BISTM) status that obscures neurological evaluations13). After achieving a burst-suppression pattern on the portable However, propofol has a shorter recovery time and induces EEG, we replaced electrodes for the BISTM (BisSensor; less systemic hypotension than barbiturate2,12). Therefore, Aspect Medical Systems, Inc., Newton, MA, USA) on the coma therapy using propofol might be more convenient and forehead, as specified by the manufacturer, and measured less complicated than therapies based on barbiturate. In an signals using an Aspect A-2000 EEG monitor (software attempt to compare the clinical application of two drugs, such version 3.3; Aspect Medical System, Inc., Newton, MA, USA). as depth of anesthesia, changes of ICP, methods to maintain For polysomnography, we placed a midline frontoparietal systemic normotension, recovery time from coma therapy and electrode for EEG, an electrode at canthus and above unilateral their complications, we performed retrospective study of coma eye for electro-oculography and a submental electrode for therapy after craniotomy or craniectomy for severe traumatic electromyography. BIS scores on the monitor were recorded at brain injury (TBI) using propofol or thiopental as general 2-hours interval using a monitor and data were collected. And anesthetic agents in two patient groups. then we compared the scores between two groups.

MATERIAL AND METHODS Anesthetic procedures In group A, thiopental was administered in increments of From June 2014 to April 2017, 38 patients underwent coma 50-100 mg intravenously at 1- to 5-minutes intervals, and in therapy after brain surgery for the severe TBI at our institute. group B, propofol was administered in increments of 10-20 mg Of these, 17 patients (group A) underwent coma therapy with intravenous push at 5- to 10-minutes intervals in an attempt thiopental (Pentotal Sodium®) after brain surgery for the first to achieve an EEG burst-suppression pattern. BIS scores were www.e-jnic.org 33 Coma therapy for severe brain injury Hye Jin Shin et al. then recorded. Anesthetic doses were incrementally and slowly Statistical analysis adjusted upward to achieve the desired endpoint, i.e., an EEG The t-test, the Chi-square test and Fisher’s exact test were used burst-suppression pattern, and BIS scores were then recorded. to compare the two groups in terms of baseline characteristics After the induction of general anesthesia and loss of and each parameter for assessment. Results were considered consciousness (no response to verbal commends, loss of eyelid significant when p-values were less than 0.05. Statistical analyses reflex, and loss of self respiration), respiration was conducted were performed using SPSS version 20.0 (SPSS Institute, Inc, using a mechanical ventilator with 30~40% oxygen via an Chicago, IL) endotracheal tube. No other neuromuscular blockers were used. After determining target BIS scores below 40 with silence RESULTS on EEG, to maintain general anesthesia, patients in group A received thiopental and those in group B propofol at doses of Characteristics of the patient populations between the previously determined target BIS score +5 and –5. Table 1 summarizes patient characteristics and initial diagnoses. There were 16 male and 22 female patients of Other monitoring during therapy mean age of 54.5 years (range: 33-68) when coma therapy was Patient’s anesthetic states were clinically monitored using performed. In group A, there were 10 men and 7 women of the modified Observer Assessment of Alertness and Sedation mean age 55.5 years (range: 37-68), and in group B, there were (MOAAS) scale, i.e., when a patient responded readily to his/ 9 men and 12 women of mean age 53.7 years (range: 33-68). her name spoken in normal tone a score of 5 was allocated; Initial diagnoses were as follows; 16 acute subdural hemorrhages when a patient responded lethargically a score of 4 was (7 in group A and 9 in group B), 10 traumatic intracerebral allocated; when a patient responded only after calling in a loud hemorrhage (4 in group A and 6 in group B), 5 diffuse cerebral voice or repeatedly a score of 3 was allocated; when a patient hemorrhagic contusion (3 in group A and 2 in group B), 3 responded only after mild prodding or shaking a score of 2 was epidural hemorrhages (2 in group A and 1 in group B), 3 diffuse allocated; when a patient did not respond to mild prodding or cerebral edema with diffuse axonal injury (1 in group A and shaking a score of 1 was allocated; and a score of 0 was allocated 2 in group B), and 1 other disease. All the patients underwent when a patient did not respond to a noxious stimulus. craniotomy or craniectomy. The mean overall preoperative GCS ICP was monitored by use of epidural fiberoptic catheter and score was 6.6 (6.4 in group A and 6.8 in group B) and ranged sensor that was placed in the space between dura and craniected from 4 to 8. No significant difference was observed between muscle or scalp. Digitalized numbers on the ICP monitor were recorded every 2 hours. Vital signs were checked and recorded Table 1. Clinical features of the patients at initial presentation* every hour. When systolic blood pressure fell below 100 Total Group A Group B mmHg, a catecholamine (e.g., dopamine) was used to raise and (N = 38) (N = 17) (N = 21) maintain systolic blood pressure to at least 100 mmHg; doses Male 16 (42.1%) 10 (58.8%) 9 (42.9%) Gender administered were recorded. Female 22 (57.9%) 7 (41.2%) 12 (57.1%) Mean 54.5 55.5 53.7 Age (years) Recovery time from coma therapy to stationary state Range (33 - 68) (37 - 68) (33 - 68) Acute After the discontinuance of anesthetics, patient consciousness subdural 16 (42.1%) 7 (41.2%) 9 (42.9%) was checked every two hours using the MOAAS and GCS hematoma scores. Recovery time was calculated from the time of Traumatic intracerebral 10 (26.3%) 4 (23.5%) 6 (28.6%) stopping anesthesia to the point when these scales indicated a hematoma neurologically stationary state, which was checked at least 12 Diagnosis Hemorrhagic 5 (13.2%) 3 (17.6%) 2 (9.5%) times with 2-hours interval. When the patient recovers slowly contusion Epidural after a day, the identical results in the 6 times sequential repeated hematoma 3 (7.9%) 2 (11.8%) 1 (4.8%) tests was determined as stationary state. When a patient’s Diffuse vital signs, neurological signs, and respiration became stable, cerebral 3 (7.9%) 1 (5.9%) 2 (9.5%) edema mechanical ventilation was stopped. No thiopental or propofol Others 1 (2.6%) 0 (0.0%) 1 (4.8%) antagonists were administered. And then, the recovery time was Initial Mean 6.6 6.4 6.8 compared between two groups. GCS score Range (4 - 8) (4 - 8) (4 - 8) * GCS : Glasgow Coma Scale

34 www.e-jnic.org Hye Jin Shin et al. Coma therapy for severe brain injury

two groups in terms of demographic parameters, diseases, or the patients was increased to 24.9 cmH2O and 24.4 cmH2O in preoperative GCS scores. group A and 25.4 cmH2O in group B. In the last day, mean ICP

for all the patients was decreased again to 16.6 cmH2O and 15.1

BIS scores cmH2O in group A and 18.0 cmH2O in group B, respectively. After achieving a burst-suppression pattern on EEG, BIS scores No statistical difference was found between two groups in the were recorded every 2 hours for 3 days during coma therapy, ICP (Table 2). and average values were calculated (Table 2). For all patients, mean BIS scores were; 29.4 on the first day, 27.4 on the second Dose of anesthetics and cardiotonics day, and 26.0 on the last day. In group A, mean BIS scores were In group A, the mean dose of thiopental administered was 6.1 26.9 on the first day, 24.3 on the second day, and 23.7 on the last mg/kg/hr (range: 4.5-7.5 mg/kg/hr) and in group B, the mean day. In group B, mean BIS scores were 31.4 on the first day, 29.9 dose of propofol administered was 4.4 mg/kg/hr (range: 3.5-6.0 on the second day, and 27.8 on the last day. The two groups had mg/kg/hr). no differences in terms of BIS scores. To maintain systemic normotensive state, dopamine was administered to counter cardiac depression due to anesthetics. MOAAS scores Except for dopamine, no other agent was administered to Hypnotic depth was checked by physicians, and MOAAS increase systemic pressure. The mean overall dose of dopamine scores were recorded every 2 hours during coma therapy (Table administered was 7.0 μg/kg/min (range: 0.0-14.0 μg/kg/min). 2). For all patients, mean MOAAS scores were 0.66 on the first In group A, the mean dose of dopamine was 10.2 μg/kg/min day, 0.61 on the second day and 0.39 on the last day. In group (range: 8.0-14.0 μg/kg/min) and in group B, 4.4 μg/kg/min A, mean MOAAS scores were 0.24 on the first day, 0.17 on the (range: 0.0-8.0 μg/kg/min). Significantly less dopamine was second day and 0.00 on the last day. In group B, mean MOAAS administered to maintain systemic pressure in group B than in scores were 1.00 on the first day, 0.95 on the second day, and group A (p=0.000) (Table 2). 0.71 on the last day. In terms of MOAAS scores, no significant differences were found between the two groups and all the Recovery from anesthesia to the stationary state patients were well controlled under deep anesthesia. The mean overall recovery time was 18.4 hours (range: 4.0- 48.0 hours) and summarized on table 2. In group A, it was 32.9 Results of ICP monitoring hours (range: 20.0-48.0 hours) and in group B, 6.6 hours (range: In the first day of coma therapy, mean ICP for all the patients 4.0-10.0 hours). It took shorter time to recover from anesthesia was 17.5 cmH2O and 16.8 cmH2O in group A and 18.3 cmH2O for patients who were treated with propofol than those who in group B, respectively. In the second day, mean ICP for all were treated with barbiturate (p=0.000).

Table 2. Clinical features during coma therapy* Total (N = 38) Group A (N = 17) Group B (N = 21) p-value† Mean dose of anesthetics (mg/kg/hr) 6.1 (4.5 - 7.5) 4.4 (3.5 - 6.0) Day 1 29.4 (21.5 - 40.1) 26.9 (21.5 - 33.5) 31.4 (25.4 - 40.1) 0.752 Mean bispectral Index Day 2 27.4 (19.3 - 35.6) 24.3 (19.3 - 27.2) 29.9 (22.6 - 35.6) 0.691 Day 3 26.0 (20.7 - 37.0) 23.7 (20.7 - 30.2) 27.8 (21.0 - 37.0) 0.721 Day 1 0.66 (0.0-1.0) 0.24 (0.0-1.0) 1.00 (1.0-1.0) 0.882 Mean MOAAS Score Day 2 0.61 (0.0-1.0) 0.17 (0.0-1.0) 0.95 (0.0-1.0) 0.902 Day 3 0.39 (0.0-1.0) 0.00 (0.0-0.0) 0.71 (0.0-1.0) 0.880 Day 1 17.5 (11.6 - 28.6) 16.8 (11.6 - 24.0) 18.3 (14.0 - 28.6) 0.639

Intracranial pressure (cmH2O) Day 2 24.9 (13.6 - 35.4) 24.4 (13.6 - 33.5) 25.4 (17.3 - 35.4) 0.756 Day 3 16.6 (11.0 - 22.4) 15.1 (11.0 - 22.0) 18.0 (12.0 - 22.4) 0.108 Mean 7.0 10.2 4.4 <0.001 Dose of dopamine (μg/kg/min) Range (0.0 - 14.0) (8.0 - 14.0) (0.0 - 8.0) Mean 18.4 32.9 6.6 <0.001 Recovery time (hour) Range (4.0 - 48.0) (20.0 - 48.0) (4.0 - 10.0) * MOAAS : Modified Observer Assessment of Alertness and Sedation. † t-test. www.e-jnic.org 35 Coma therapy for severe brain injury Hye Jin Shin et al.

Outcome any patient. There was no statistical difference in complication GCS score after stationary condition from coma therapy between two groups. was not significantly different before coma therapy. The mean overall post-therapeutic GCS score was 6.8 (6.7 in group A and Illustration of case 7.0 in group B) and ranged from 3 to 10. Four patients (23.5%) A 64-year-old woman visited emergent care unit with acute in group A got worse than before and 4 patients (19.0%) in alteration of mentality after head trauma from fall-down. Her group B did. Seven patients (41.2%) in group A improved and pupils did not response to the light and she had decorticated 11 patients (52.4%) in group B did. However, the difference movement to noxious stimulation. GCS score was 6. On the between two groups did not have statistical significance computed tomographic (CT) scan, crescent-shaped, high- (p=0.352). density lesion on the left fronto-temporal area was found. And midline was shifted to the right side and sulci were Complications of coma therapy obliterated. Under impression of acute subdural hemorrhage, Table 3 presents the complications that occurred during coma she underwent decompressive craniectomy and subdural therapy. No patient died during therapy. Although all patients hemorrhage was removed. In the neurosurgical field, the experienced side effects to some degree, their complications brain was tense and swelling up severely and decreased brain were minimal and not life-threatening, i.e., systemic hypotension pulsation and discoloration was found. After brain surgery, (systolic blood pressure < 100 mmHg) occurred in 35 patients we started coma therapy using propofol with a dose of 4 mg/ (17 in group A and 18 in group B), electrolyte imbalances kg/hr to reduce intracranial pressure and lessen the brain (hyponatremia, hypokalemia, or hypercalcemia) occurred damage. Initially, the dose was titrated by use of portable EEG in 10 patients (4 in group A and 6 in group B), leukocytosis monitoring with confirmation of burst-suppression pattern (>10,000/μL) occurred in 7 patients (4 in group A and 3 in and then was maintained with a dose of 6 mg/kg/hr. BIS score group B), appearance of pneumonic consolidation on chest was ranged from 35 to 50 during coma therapy. Dopamine X-ray occurred in 6 patients (3 in group A and 3 in group B), with a dose of 4 μg/kg/min was administrated to maintain increased erythrocyte sedimentation rate (ESR) (> 20 mm/ normotensive systemic pressure. During coma therapy, she hr) or C-reactive protein (CRP) (> 5 mg/L) in 5 patients (3 in experienced increase of serum LDH (315 IU/mL), leukocytosis group A and 2 in group B), increased serum blood urea nitrogen (15,000/μL) and metabolic acidosis (serum pH 7.30). She (BUN) (> 25 mg/dL) or creatinine (> 1.5 mg/dL) in 4 patients recovered from coma therapy 6 hours to stationary state after (1 in group A and 3 in group B), acidosis in 4 patients (2 in discontinuance of propofol administration. Fortunately, she group A and 2 in group B), arrhythmia by electrocardiography improved minimally with withdraw movement to pain and (ECG) in 3 patients (2 in group A and 1 in group B), increased pupillary response to the light returned. But she was unable to lactate dehydrogenase H (LDH) in 2 patients (0 in group A cooperate with physician and GCS score was 8. Fig. 1 shows and 2 in group B) and deep vein thrombosis in 2 patients (1 in pre- and immediate postoperative imaging scan, EEG finding group A and 1 in group B). No fever (> 38.0℃) was found in and BIS setting.

Table 3. Complications of neuroprotective coma therapy* Total (N = 38) Group A (N = 17) Group B (N = 21) p-value† Hypotension (SBP<100 mmHg) 35 (92.1%) 17 (100%) 18 (85.7%) 0.752 Electrolyte imbalance 10 (26.3%) 4 (23.5%) 6 ((28.6%) 0.911 Leukocytosis (>10,000/μL) 7 (18.4%) 4 (23.5%) 3 (14.3%) 0.535 Pneumonic consolidation 6 (15.8%) 3 (17.6%) 3 (14.3%) 0.902 Increase of ESR or CRP 5 (13.2%) 3 (17.6%) 2 (9.5%) 0.887 Increase of BUN/Cr 4 (10.5%) 1 (5.9%) 3 (14.3%) 0.135 Acidosis 4 (10.5%. 2 (11.8%) 2 (9.5%) 0.826 Arrhythmia 3 (7.9%) 2 (11.8%) 1 (4.8%) 0.604 Increase of LDH 2 (5.3%) 0 (0.0%) 2 (9.5%) 0.078 Deep vein thrombosis 2 (5.3%) 1 (5.9%) 1 (4.8%) 0.921 * ESR : erythrocyte sedimentation rate; CRP : C-reactive protein; BUN : blood urea nitrogen; Cr : creatine; LDH : lactate dehydrogenase H. † Fisher’s exact test.

36 www.e-jnic.org Hye Jin Shin et al. Coma therapy for severe brain injury

DISCUSSION thiopental coma therapy. However, no difference was observed between the propofol and thiopental groups in terms of BIS In this study, we found that propofol coma therapy has a scores, MOAAS scores, changes in ICP, outcome, and side shorter recovery time from general anesthesia, induces less effects. systemic hypotension, and requires less dopamine than In general, propofol has similar neuroprotective effects as barbiturate, but also has several advantages18). First, propofol has a shorter half time and recovery time from anesthesia than barbiturate, which can facilitate early neurological evaluation. Second, the lower systemic hypotension associated with propofol can reduce catecholamine requirements. Third, some authors have suggested that the risk of infection may be lower for propofol than barbiturate. Finally, propofol provides an energy source due to its lipid content. With coincidence, in presenting study, patients who underwent propofol coma therapy had A B shorter recovery time and lower systemic hypotension and less catecholamine requirement. But, in terms of infection, there was no difference between two groups. Hatch DJ suggested that propofol coma therapy for > 2 days has much higher risk of infection7). In this study of 3 day-schedule coma therapy, as many as six patients gained pneumonic consolidation on chest X-ray without fever. However, despite the practical advantages of propofol, it is not completely safe, especially when administered at high doses, because at high levels propofol accentuates lactate accumulation and edema formation in cases of cerebral ischemia with hyperglycemia8). Moreover, propofol infusion syndrome is a

C rare but often fatal syndrome that was originally described in critically ill children undergoing long-term (>48 hours) propofol infusion at high doses (> 4 mg/kg/hr) 7). Its features consist of severe metabolic acidosis, rhabdomyolysis, renal failure, and fatal cardiac failure. Moreover, this pathologic condition can be aggravated by the combined use of glucocorticoid and catecholamine. In combination with glucocorticoid, high dose of propofol can exert profound effects on immunity and inflammation3). In combination with catecholamine, the negative inotropic effects of propofol can increase catecholamine requirement, and thus, create a vicious cycle that 3) D E results in a progressive myocardial depressive effect . For these reasons, high-dose propofol for prolonged period (>48 hours) is not recommended5,9). Therefore, determination of optimal Fig. 1. A 64-year-old woman visited emergency care unit with acute altered mentality after head trauma. A: At admission, precontrast barbiturate and propofol concentration is of considerable computed tomographic (CT) image showed crescent-formed, importance. high-density lesion on the left fronto-temporal area and midline shift to right side. B: After craniectomy and removal of hemorrhage, In this point of view, BIS scores can titrate the optimal dose there was aggravated midline shift on the immediate postoperative of barbiturate and propofol until burst-suppression pattern CT scan. C: In order to titrate propofol dosage, burst-suppression appear on the EEG. In fact, BIS scores were developed to pattern was confirmed by use of the portable EEG monitoring. ) D: BIS leads were placed on her forehead. E: BIS monitoring was measure the effects of anesthetic agents on the brain10 . Over started after titration of propofol dose. several years, a large database of high fidelity EEG recordings and clinical recordings from more than 2,000 patients that www.e-jnic.org 37 Coma therapy for severe brain injury Hye Jin Shin et al. received a wide variety of anesthetic regimens, were collected by ACKNOWLEDGEMENTS Aspect Medical Systems, Inc. This database contains recorded EEG segments and records of associated clinically derived I thank the following individuals: Young Min Kim, M.D., and hypnotic states. According to this setting, BIS score of 65-85 Mi-Ok Sunwoo, M.D., (Department of Radiology, Samsung have been recommended for sedation, score of 40-65 have been Changwon Hospital) for their review of the neuroradiological recommended for general anesthesia, and at the score of lower images; and Young Wook Kim, M.D., (Department of than 40, cortical suppression becomes discernible in EEG as Biostatistics, Samsung Changwon Hospital) for assistance with a burst suppression pattern. Almost patients in this study had the statistical analysis. the BIS score of lower 40 during coma therapy. Therefore, BIS scores can be used to manage anesthetics effectively and REFERENCES reduce drug usage, reduce recovery time, facilitate higher quality recovery, and reduce the side effects of prolonged anesthesia4). 1. Alali AS, Naimark DM, Wilson JR, Fowler RA, Scales DC, In presenting study, we monitored ICP with epidural catheter Golan E, et al. Economic evaluation of decompressive and sensor and performed coma therapy during continuous craniectomy versus barbiturate coma for refractory 3 days. However, according to guideline by Martin R. et al., intracranial hypertension following traumatic brain injury. severe TBI patients were recommended to monitor ICP with Crit Care Med 2014;42:2235–2243. ventricular catheter14). Although true ICP shows a potential 2. Alnemari AM, Krafcik BM, Mansour TR, Gaudin D. A to warn against the elevation of ICP, continuous analysis of comparison of pharmacologic therapeutic agents used for the intracranial pressure adds information to simple recording of reduction of intracranial pressure after traumatic brain injury. mean trend values actually6). In fact, there are no strict and World Neurosurg 2017;106:509–528. absolute guideline for coma therapy. In the traditional stair step 3. Beatrice V, Frank R, Andrea C, Nichola L. The physiology of treatment of intracranial hypertension, barbiturate coma therapy propofol infusion syndrome; a simple name for a complex has the most potential capacity to reduce ICP17). Therefore, syndrome. Intensive Care Med 2003;29:1417– 1425. many neurosurgeons consider barbiturate coma therapy for the 4. Bhargava AK, Setlur R. Correlation of bispectral index refractory high ICP16). In the point of limitation of this study, and Guedel’s stages of ether anesthesia. Anesth Analg 3-days coma therapies were performed without precise scientific 2004;98:132–124. considerations, and further comprehensive studies are needed 5. Cremer OL, Moons KGM, Bouman EAC, Kruijiswijk JE, to confine the duration of therapy and the time of weaning coma de Smet AM, Kalman CJ. Long-term propofol infusion therapy. and cardiac failure in adult head-injured patients. Lancet 2001;357:117–118. CONCLUSION 6. Czosnyka M, Steiner L, Balestreri M, Schmidt E, Smielewski P, Hutchinson PJ, et al. Concept of “true ICP” in monitoring Barbiturate and propofol coma therapy are known to have and prognostication in head trauma. Acta Neurochir Suppl similar important neuroprotective roles. However, in spite of the 2005;95:341–344. several practical advantages of propofol over barbiturate such as 7. Hatch DJ. Propofol infusion syndrome in children. Lancet less systemic hypotension during coma therapy and shorter time 1999;353:1117–1118. to stationary state, it is not a completely safe anesthetic agent. 8. Ishii H, Arai T, Segawa H, Morikawa S, Inubushi T, Kukuda The determination of the optimal dose required to maximize K. Effects of propofol on lactate and edema formation in its neuroprotective effects and avoid fatal complications is of focal cerebral ischemia in hyperglycemic rats. British J Anesth considerable importance. The findings of the present study 2002;88:412–417. suggest that BIS can be used to determine the optimal dose of 9. Jacobi J, Fraser GL, Coursion DB, Riker RR, Fontain D, propofol so as to increase its neuroprotective effects and reduce Wittbrodt ET, et al. Clinical practice guidelines for the its side effects during coma therapy. sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med 2002;30:119–141. CONFLICT OF INTEREST 10. Jay WJ, Peter SS. Development and clinical application of electroencephalographic bispectrum monitoring. The authors have no financial conflicts of interest. Anesthesiology 2000;93:1336–1344. 11. Kochs E, Hoffman WE, Werner C, Thomas C, Albrecht RF,

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Shulte am Esh J. The effects of propofol on brain electrical injury. In: Winn HR, editor. Youmans Neurosurgical Surgery. activity, neurologic outcome, and neuronal damage following 5th ed. Philadelphia: W.B. Saunders; 2004. 5:p. 5103–5144. incomplete ischemia in rats. Anesthesiology 1992;76:245– 18. Skoutelis A, Lianou P, Papageorgious E, Kokkinis K, 252. Alexopolous K, Bassaris H. Effects of propofol and 12. Lee JW, Woo JH, Baik HJ, Kim DY, Chae JS, Yang NR, et al. thiopentone on polymorphonuclear leukocyte functions in The effect of anesthetic agents on cerebral vasospasms after vitro. Acta Anesthsiol Scand 1994;38:858–862. subarachnoid hemorrhage: a retrospective study. Medicine 19. Smith DS, Rehncrona S. Siesjo BK. Barbiturates as protective (Baltimore) 2018;97:e11666. agents in brain ischemia and as free radical scavengers in vitro. 13. Levy ML, Rabb C, Couldwell WT, Zelman V, Apuzzo MLJ. Acta Physiol Scand Suppl 1980;492:129–134. Protection of the neural pool. In: Apuzzo MLJ, editor. Brain 20. Spetzler RF, Hadley MN. Protection against cerebral Surgery: Complication avoidance and management. New ischemia; the role of barbiturates. Cerebrovasc Brain Metab York: Churchill Livingston; 1993. p. 857–889. Rev 1989;1:212–229. 14. Martin R, Ivan J, Marek M, Ingrid W, Walter M. Severe 21. Steen PA, Michenfielder JD. Cerebral protection with traumatic brain injury in Austria VI; Effects of guideline-based barbiturate; relation to anesthetic effect. Stroke 1978;9:140– management. Wien Klin Wochenschr 2007;119:64–71. 142. 15. Michenfielder JF, Theye RA. The effects of anesthesia 22. Steen PA, Michenfeilder JD. Mechanisms of barbiturate and hypothermia on canine cerebral ATP and lactate protection. Anesthesiology 1980;53:183–185. during anoxia produced by decapitation. Anesthesiology 23. Teichberg VI, Tal N, Goldberg O, Luini A. Barbiturates, 1970;33:430–439. alcohols and the CNS excitatory neurotransmission; specific 16. Nilsson P, Enbald P, Chamber I, Citerio G, Fiddes H, Howells effects on the kainite and quisqualate receptors. Brain Res T, et al. Survey of traumatic brain injury management in 1984;291:285–292. European Brain-IT centers year 2001. Acta Neurochir Suppl 24. Zarchin N, Guggenheimer-Furman E, Meilin S, Ornstein E, 2005;95:51–53. Mayevsky A. Thiopental induced cerebral protection during 17. Robertson C. Critical care management of traumatic brain ischemia in gerbilis. Brain Res 1998;780:230–236.

www.e-jnic.org 39 eISSN 2635-5280 Original Article J Neurointensive Care 2018;1(1):40-46. https://doi.org/10.32587/jnic.2018.00059

Analysis of Predisposing Factors of the Treatment of Patients with Unruptured Intracranial Aneurysms Seong-woo Lee, Jin-Woo Park, Kyung-Jae Park, Shin-Hyuk Kang, Yong-Gu Jung, Jung-Yul Park, Dong- Hyuk Park Department of Neurosurgery, Korea University Medical Center, Korea university college of Medicine, Seoul, Korea

Received: September 14, 2018 Accepted: September 19, 2018 Objective Published: October 10, 2018 To investigate the factors that influence the determination of treatment of unruptured intracranial aneurysms (UIAs), we retrospectively compared various well-known risk factors that are asso- Corresponding Author: ciated with future rupture for treated and observed groups. Dong-Hyuk Park, M.D., Ph.D. Department of Neurosurgery, Methods Korea University Medical Center, Anam Hospital, Korea University Between January 2006 and December 2016, a total of 279 patients treated UIAs with surgical College of Medicine, 73 Inchonro clipping or coil embolization have been included in this study. In the same period, 100 patients Sungbuk-gu, Seoul 02841, Korea did undergo transfemoral cerebral angiograms and were initially managed with observation. An- Tel: +82-2-920-5729 eurysmal characteristics and patinets were compared between the treated and the observed Fax: +82-2-929-0629 group. The association between these factors and the decision of treatment was performed using E-mail: [email protected] a multivariate logistic regression analysis. Results 279 patients with treated unruptured aneurysms and the observation group included 100 patients with unruptured aneurysms. A multivariate study revealed that young age (OR=0.959 / p=0.001), high aneurysms height, (OR=1.906 / p=0.002), daughter sac (OR=4.072 / p=0.001), location of aneurysms (anterior communicating artery (OR=3.729 / p=0.022) and middle cerebral artery bifurcation (OR=4.110 / p=0.009) were significantly associated with the treatment group when compared to the observation group. Conclusion Young age, a small aspect ratio, a large aneurysmal height, a daughter sac, and the location of aneurysm were strongly associated with the treatment of unruptured aneurysms.

Keywords: Predisposing factors; Unruptured intracranial aneurysms; Rupture risk; Observa- tion; Treatment

40 www.e-jnic.org Seong-woo Lee et al. Predisposing factors of UIAs

INTRODUCTION artery bifurcation and the origin of the anterior choroidal artery, excluding those located at the origin of the posterior Autopsy studies have shown an occurrence of unruptured communicating. Aneurysmal factors included height, neck and intracranial aneurysms (UIAs) incidences in approximately 5 width of aneurysm, which were measured via TFCA images. percent of all performed autopsies6,13). 6 of 100,000 patients will The maximum diameter was defined as the longest diameter of have ruptured aneurysm induced subarachnoid hemorrhage UIA. Aspect ratio means the ratio of height to neck (Fig. 1). each year in the USA1,17). UIAs are a cerebrovascular condition that are commonly diagnosed due to improved imaging techniques. While the rupture risk of UIAs leads many neurosurgeons to advise its preventive treatment, the management of patients with UIAs remains controversial. Surgeon preference and experience as well as morphologic and anatomic considerations play important roles in the debates that continue over the controversy about whether to treat UIAs. Many studies have reported that certain patient characteristics increase the risk of rupture, including old age, female gender, and Japanese or Finnish descent. Aneurysms characteristics that increase the risk of rupture are location at the posterior circulation and increasing size10,22,32,33). Fig. 1. Size measurement of Aneurysmal neck(A), width(B), Thus, these factors affect the management of UIAs. In this height(C) in schematic diagram. study, we evaluated the association between these risk factors, which are involved in future rupture of UIAs and management Analysis of the patients factors decision. The following factors of the patients with aneurysms, whether treated or not, were collected and analyzed to examine their METHODS relationships with treatment indication. Included patient factors were age, sex, underlying disease: hypertension (previously Patient selection and inclusion criteria known, patient being treated with antihypertensive medications, The treatment group included a total of 279 patients with UIAs or blood pressure 140/90 mm Hg during the nonacute phase), and who were treated with surgical clipping or coil embolization and diabetes mellitus (DM) (fasting glucose > 7 mmol/L or between January 2006 and December 2016. In the same period, patient being treated with antidiabetic medication), smoking 100 patients who underwent transfemoral cerebral angiography history (current or past), alcohol history, and other diseases, (TFCA) and who were initially managed with observation such as history of ischemic stroke or cardiac disease (heart were included in the observation group. Patients with UIAs failure, arrhythmia). 18 patients of the treated group had who did not undergo TFCA were excluded16). Patients were multiple aneurysms (6.4%) and 7 patients of the observation also excluded if they had any of 1) Prior SAH, 2) symptomatic group had multiplicity (7%). The total number of treated aneurysm, and 3) fusiform aneurysm. Clinical outcomes, aneurysms was 297 and 108 aneurysms were observed. aneurysmal characteristics (location, size, and morphological characteristics of lesions) and clinical presentation parameters, Procedure: diagnosis and treatment methods underlying disease were evaluated for both groups. After patients were diagnosed with UIA through CT angiography or MR angiography, they were admitted and Analysis of aneurysmal characteristics underwent the TFCA. Based on the results, medical staff All UIAs were classified into the following categories based (neurosurgeon and neuroradiologist) consulted with the on location: 1. middle cerebral artery (MCA), 2. anterior patients and their caregivers to determine a treatment plan. communicating artery (ACoA) including distal anterior cerebral The methods of operation mean surgical clipping and artery, 3. cavernous ICA, 4. internal carotid artery (ICA), 5. endovascular treatment included coil embolization and stent posterior communicating artery (PCoA), 6. Basilar top, and assisted coiling26). 7. vertebrobasilar artery (VBA). ICA included the location between the cavernous portion of ICA and the internal carotid www.e-jnic.org 41 Predisposing factors of UIAs Seong-woo Lee et al.

Analysis of post-operative state and follow up of were considered statistically significant. Between-cohort observation group comparisons of the distributions of baseline characteristics were In the treated group, the outcome of each patient was assessed done with the Chi-squared test for categorical variables and with using the Glasgow Outcome Scale (GOS) 1 month after the the Mann-Whitney test for continuous variables. Analyses were operation day. A Glasgow Outcome score of 5 indicates no performed with SPSS ver. 23.0 (IBM corporation, Armonk, NY, disability, a score of 4 or 3 indicates both moderate disability, i.e., USA). no need for assistance in everyday life, employment is possible but may require special equipment, and severe disability, i.e., RESULTS severe injury with permanent need for help with daily living, a score of 1 to 2 indicates death or a persistent vegetative state. Comparison of risk factors between the treatment The mean follow up duration for the observation group was and observation groups 33.66 month. Table 1 showed the comparison of patient and aneurysmal characteristics between the treated and observation groups. Statistical analysis A statistical analysis was performed via binary logistic Patient characteristics regression to analyze any independent association between A total of 279 patients with newly diagnosed aneurysms that the groups, and odds ratio (ORs) and their 95% confidence underwent treatment for aneurysms were reviewed over a interval (CIs) were estimated. Both multivariate and univariate period of 10 years. The group included 84 men (31%) and 195 analysis were performed. The data are expressed as a mean ± women (69%) with an average age of 58.49 years (± 10.71). standard deviation (SD). P values of less than 0.05 (p<0.05) The observation group consisted of 27 men (27%) and 73

Table 1. Complications of neuroprotective coma therapy Treated group (279 patients) Observation group (100 patients) p-value Age Mean - yr 58.49 ± 10.71 61.9 ± 11.11 0.007 >70 yr – no (%) 47 (16%) 30 (30%) 0.002 No.of females (%) 195 (69%) 73 (73%) 0.610 Hypertension (%) 164 (58%) 52 (52%) 0.242 Diabetes mellitus (%) 29 (10%) 12 (12%) 0.708 Ischemic stroke (%) 9 (2%) 1 (1%) Cardiac disease (%) 17 (5%) 5 (5%) Smoke history (%) 70 (25%) 13 (13%) 0.011 Alcohol (%) 70 (25%) 24 (24%) 0.893 Others 53 (18%) 18 (18%) Size of aneurysms Mean ± SD – (mm) Neck 3.60±1.51 3.34±1.78 0.153 Height 5.13±3.39 3.37±3.30 0.001 Width 5.62±5.09 4.08±3.77 0.006 Maximum diameter 6.27±5.26 4.27±4.04 0.001 Aspect ratio (%) 1.46±0.79 1.18±1.61 0.027 Location of aneurysms (%) Anterior communicating artery 68 (24%) 12 (12%) 0.016 Posterior communicating artery 31 (11%) 11 (11%) 0.570 Middle cerebral artery 91 (32%) 19 (19%) 0.01 Cavernous ICA* 46 (16%) 34 (34%) 0.001 Internal carotid artery 26 (9%) 13 (13%) 0.338 Basi lar toptop 7 (2%) 6 (6%) 0.114 Vertebrobasilar artery 10 (3%) 5 (5%) 0.554 Daughter sac 56 (20%) 5 (5%) 0.001 * :Internal carotid artery

42 www.e-jnic.org Seong-woo Lee et al. Predisposing factors of UIAs women (73%) with an average of 61.9 years (± 11.11). Both 2 patients had a GOS 3 or 2 and showed hemiparesis and severe groups together included 77 patients who were older than cognitive dysfunction. 70 years (19%). Age and smoke history were statistically association in comparison between treated and observation Association between risk factors of rupture and group (p=0.007 and 0.011, respectively). 268 patients had treatment female gender, 216 patients had hypertension and 41 patients Tables 2 and 3 demonstrates the results of logistic regression had diabetes mellitus, however their distribution between analysis of associations between rupture risk factors and treated group and observation group was not statistically treatment. Univariate analyses showed that young patient age significant (p=0.610 for sex, p=0.242 for hypertension and (OR=0.970, p=0.007), smoke history (OR=2.252, p=0.013), p=0.708 for diabetes mellitus). The number of patients who high height of aneurysms (OR=1.340, p=0.001), large width with a history of drinking alcohol showed no difference between (OR=1.142, p=0.006), large maximum diameter (OR=1.192, two groups (p=0.893). p=0.001), large aspect ratio (OR=1.493, p=0.024), AcoA (OR=2.209, p=0.016), MCA (OR=2.064, p=0.011), and Aneurysms characteristics present daughter sac (OR=3.317, p=0.001) were significantly 160 patients underwent surgical clipping and 119 patients associated with the treated group. However, cavernous ICA was underwent endovascular treatment. Mean neck size which was associated with the observation group (OR=-0.420, p=0.001). 3.60±1.51 in treated group, was not significant higher than Multivariate analysis revealed that a high height of aneurysm the 3.34±1.78 of the observation group (p=0.153). However (OR=1.906, p=0.001), a small aspect ratio (OR=0.493, mean height was significantly different (5.13±3.39 in treated p=0.006), the presence of daughter sac (OR=4.072, p=0.001), grup and 3.37±3.30 in observation group, p=0.001). The and young age (OR=0.959, p=0.001) were significantly height of aneurysms was bigger than 5 mm in 94 patients. associated with the treated group. Further associated with the The mean width was also statistically higher in treated group treated group were AcoA and MCA (OR=3.729, p=0.022 and (5.62±5.09) than observation group (4.08±3.77) (p=0.006). OR=4.110, p=0.009, respectively). The maximum diameter (6.27±5.26 in treated group and 4.27±4.04 in observation group) and aspect ratio (1.46±0.79 DISCUSSION in treated group and 1.18±1.61 in observation group) were also significantly difference (p=0.001 in maximum diameter Our study found the following factors as significant between and p=0.027 in aspect ratio, respectively). The most common treated and observation group: age, smoke history, aneurysmal location of aneurysms in the surgical clipping group was the height and width, maximum diameter, aspect ratio, aneurysm MCA (49%, 79 patients), whereas that in the endovascular located in AcoA. treatment group was the cavernous ICA (35%, 42 patients). The MCA, Cavernous ICA and daughter sac. The significant most common location of aneurysms in the observation group factors for the treated group were different than those for the was the cavernous ICA artery (32%, 32 patients) and the MCA observation group and included the following: young mean age (19%, 19 patients). The distribution of location of UIA was (58.49 years vs 61.9 years), more patients with a smoke history significantly difference in AcoA (p=0.016), MCA (p=0.01), and (25% patients vs 13% patients), high height (5.13 mm vs 3.37 cavernous ICA (p=0.001). A total of 61 patients had daughter mm ) and width (5.62 mm vs 4.08 mm), a large maximum sac, of which 56 patients were in the treated group and 5 patients diameter (6.27 mm vs 4.27 mm), large aspect ratio(1.46 vs 1.18), were in the observation group. The ratio with daughter sac was more AcoA location (24% vs 12%), MCA (32% vs 19%), less statistically significant(p=0.001). cavernous ICA (16% vs 34%) and more daughter sac (56% vs 5%). Postoperative mortality and morbidity In a multivariate analysis, young age, high height, small aspect 266 patients (95%) achieved a good outcome (Glasgow ratio, presence of daughter sac, and UIA located in AcoA Outcome scale 5) at 1 month follow up. The mortality rate was and MCA were independently associated with the treatment 1%, and the overall surgical morbidity was 5%. In total 3 of the group. The effect of age as a risk factor of the rupture of UIA 279 patients died after the operation within 1 month. 1 death has been consistently reported in the past. Rinkel et al. and was due to intraoperative rupture and 2 due to sepsis. Twelve Vlak et al. described a higher incidence rate of SAH among patients had a GOS of 4 after 1 month, these patients showed older populations22,32). In our study, young age was significantly 3rd nerve palsy diplopia and short term memorial impairment. associated with the treated group. This is presumably due to www.e-jnic.org 43 Predisposing factors of UIAs Seong-woo Lee et al.

Table 2. Univariate analysis between treated group and observation group Univariate analysis Clinical characteristics OR p-value 95% CI for OR (Lower-upper) Age 0.970 0.949-0.992 0.007 No.of females 0.859 0.515-1.430 0.558 Hypertension (Positive) 0.760 0.480-1.202 0.241 Diabetes mellitus (Positive) 1.176 0.575-2.404 0.658 Smoke history (Positive) 2.252 1.184-4.283 0.013 Alcohol user (Positive) 0.921 0.541-1.568 0.761 Size of aneurysms Mean ± SD – (mm) Neck 1.126 0.956-1.325 0.155 Height 1.340 1.170-1.535 0.001 Width 1.142 1.038-1.256 0.006 Maximum diameter 1.192 1.077-1.319 0.001 Aspect ratio (%) 1.493 1.053-2.115 0.024 Location of aneurysms (Positive) Anterior communicating artery 2.209 1.161-4.204 0.016 Posterior communicating artery 1.011 0.488-2.097 0.976 Middle cerebral artery bifurcation 2.064 1.180-3.608 0.011 Cavernous ICA* 0.420 0.248-0.710 0.001 Internal carotid artery 0.688 0.388-1.397 0.301 Basilar top 0.403 0.132-1.230 0.110 Vertebrobasilar artery 0.706 0.235-2.119 0.535 Daughter sac (Positive) 3.317 2.028-5.427 0.001 OR: Odds ratio, CI: Confidence interval * :Internal carotid artery

Table 3. Multivariate analysis between treated group and observation group Multivariate analysis Clinical characteristics OR p-value 95% CI for OR (Lower-upper) Age 0.959 0.934-0.984 0.001 Height 1.906 1.445-2.513 0.001 Neck 0.783 0.611-1.004 0.054 Aspect ratio 0.493 0.299-0.814 0.006 Shape(Daughter sac; Positive) 4.072 2.295-7.223 0.001 Anterior communicating artery 3.729 1.213-11.463 0.022 Middle cerebral artery bifurcation 4.110 1.423-11.868 0.009 OR: Odds ratio, CI: Confidence interval the reason that treatment is recommended and implemented of aneurysm that are more than 4 mm in size and multilobular or in younger patients because of their better general condition aneurysms with bleb changes4), our study showed that the most than those of older patients. Several researchers reported that commonly treated location was the MCA and the maximum the size and location of aneurysm were predictors of UIA diameter was 6.27±5.26 mm. Further, the location of the rupture. The International Study of Unruptured Intracranial aneurysm in the AcoA and MCA is significantly associated with Aneurysms [ISUIA] in 1998 demonstrated a low rupture rate the treated group in the multivariate analysis. MCA was easier for an unruptured aneurysm smaller than 7 mm. A larger size to access in surgical clipping, and there were more cases of surg and a posterior circulation site were predictors as independent ery3,5,7,18,20,23,24,27,30). While the univariate study showed that high risk factors of aneurysm rupture, and patients with a history of aneurysmal height, large aneurysmal width, large maximum ruptured aneurysms were at higher risk9). A Japanese cohort diameter and large aspect ratio were significantly related to the study reported that the following factors increased the risk of treated group, the multivariate study showed that maximum rupture: aneurysms of 7 mm or larger, aneurysms located in diameter and aneurysmal width did not show any difference posterior circulation except for PcoA, and aneurysms with a and high aneurysmal height, small aspect ratio and daughter sac daughter sac10). While recent literature recommends treatment were significantly associated with the treatment group2,12,14,21).

44 www.e-jnic.org Seong-woo Lee et al. Predisposing factors of UIAs

Contrary to previous studies, our study implies that a low aspect large aneurysmal height, a daughter sac, and some locations ratio was related to the treatment group25,29). of aneurysm (AcoA, MCA) are associated with the treatment Some known risk factors did not show a significantly group. Prospective studies should be performed in larger sample difference. While a female gender has been reported as risk sizes and more concise evaluation to make better decisions for factor in some studies10,28), more incidences of ruptured the treatment of UIA. aneurysm are found in women than in men32), and, in our study the female gender was the dominant gender of total patients. CONFLICT OF INTEREST However the gender was not associated with the treated group. Hypertension was a controversial risk factor as hypertension No potential conflict of interest relevant to this article was did not significantly increase the risk of rupture10). However, in reported. other study hypertension is a major risk factor for subarachnoid hemorrhage19,32). In our study, hypertension did not show a REFERENCES significant difference between the treated and the observation group. Several researchers reported smoking history, alcohol 1. Bederson JB, Awad IA, Wiebers DO, Piepgras D, Haley EC history and previous episode of SAH as risk factors for UIA Jr, Brott T, et al. Recommendations for the management rupture8,10,11,15,31). In our analysis, the smoke history was of patients with unruptured intracranial aneurysms: A significantly related to the treated group in the univariate Statement for healthcare professionals from the Stroke study but not in the multivariate study, and alcohol use was Council of the American Heart Association. Stroke not statistically significant in both analyses. In our study, we 2000;31:2742–2750. excluded patients who underwent previous episodes of SAH 2. Byoun HS, Huh W, Oh CW, Bang JS, Hwang G, Kwon OK. and symptomatic aneurysm. Further investigations of a larger Natural history of unruptured intracranial aneurysms : a number of patients is warranted to determine any significant retrospective single center analysis. J Korean Neurosurg Soc relationships. 2016;59:11–16. The indication for UIA in our institution is for patients with 3. Chyatte D, Porterfield R. Nuances of middle cerebral artery a tolerable whole body condition, with an aneurysm height aneurysm microsurgery. Neurosurgery 2001;48:339–346. of 5 mm or more, and with the UIA located in AcoA or MCA 4. Seo DH, Kim DW, Park SQ, Song Y, You SH, Kwon SU, et al. with or without a daughter sac. Furthermore, treatment of UIA Guidelines for the management of unruptured intracranial located in MCA was usually performed by surgical clipping. aneurysm. Korean J Cerebrovasc Surg 2011;13:279–290. Conversely, Cavernous ICA or posterior circulation aneurysms 5. Dashti R, Hernesniemi J, Niemela M, Rinne J, Lehecka M, are performed mainly by endovascular treatment. Shen H, et al. Microneurosurgical management of distal Our study has some limitations. Patient data were collected middle cerebral artery aneurysms. Surg Neurol 2007;67:553– and analyzed at a single center, as a consequence, the potential 563. for bias in treatment choice and conservative management 6. Dusak A, Kamasak K, Goya C, Adin ME, Elbey MA, Bilici may exist. The number of patients who were enrolled in our A. Arterial distensibility in patients with ruptured and study was relatively small. Especially for the group of PcoA and unruptured intracranial aneurysms: is it a predisposing factor posterior circulation, which are known to have a high risk of for rupture risk? Med Sci Monit 2013;19:703–709. rupture, there was no difference between the treatment group 7. Guresir E, Schuss P, Berkefeld J, Vatter H, Seifert V. Treatment and the observation group. It is estimated that the bias was results for complex middle cerebral artery aneurysms. A generated fromthe limit that the subject was relatively small. We prospective single-center series. Acta Neurochir (Wien) did not consider statistical errors or differences in the tendency 2011;153:1247–1252. of the operator. 8. Guresir E, Vatter H, Schuss P, Platz J, Konczalla J, de Rochement Rdu M, et al. Natural history of small unruptured CONCLUSION anterior circulation aneurysms: a prospective cohort study. Stroke 2013;44:3027–3031. Management of UIA has never been straight forward. 9. The International Study of Unruptured Intracranial Decisions on treatment of UIA should be carefully made after Aneurysms Investigators. Unruptured intracranial investigation of many risk factors for rupturing. In the present aneurysms--risk of rupture and risks of surgical intervention. study, we conclude that a young age, a small aspect ratio, a N Engl J Med 1998;339:1725–1733. www.e-jnic.org 45 Predisposing factors of UIAs Seong-woo Lee et al.

10. Investigators UJ, Morita A, Kirino T, Hashi K, Aoki N, 23. Rinne J, Hernesniemi J, Niskanen M, Vapalahti M. Analysis Fukuhara S, et al. The natural course of unruptured of 561 patients with 690 middle cerebral artery aneurysms: cerebral aneurysms in a Japanese cohort. N Engl J Med anatomic and clinical features as correlated to management 2012;366:2474–2482. outcome. Neurosurgery 1996;38:2–11. 11. Ishibashi T, Murayama Y, Urashima M, Saguchi T, Ebara 24. Rodriguez-Hernandez A, Sughrue ME, Akhavan S, Habdank- M, Arakawa H, et al. Unruptured intracranial aneurysms: Kolaczkowski J, Lawton MT. Current management of middle incidence of rupture and risk factors. Stroke 2009;40:313– cerebral artery aneurysms: surgical results with a "clip first" 316. policy. Neurosurgery 2013;72:415–427. 12. Jang EW, Jung JY, Hong CK, Joo JY. Benefits of surgical 25. Ryu CW, Kwon OK, Koh JS, Kim EJ. Analysis of aneurysm treatment for unruptured intracranial aneurysms in elderly rupture in relation to the geometric indices: aspect ratio, patients. J Korean Neurosurg Soc 2011;49:20–25. volume, and volume-to-neck ratio. Neuroradiology 13. Jellinger K. Pathology of intracerebral hemorrhage. Zentralbl 2011;53:883–889. Neurochir 1977;38:29–42. 26. Slusarz R, Beuth W, Sniegocki M. Functional capacity 14. Joo SW, Lee SI, Noh SJ, Jeong YG, Kim MS, Jeong YT. What scale as a new tool for early functional assessment in is the significance of a large number of ruptured aneurysms patients after surgical treatment of intracranial aneurysms: smaller than 7 mm in diameter? J Korean Neurosurg Soc a prospective study involving 128 patients. Med Sci Monit 2009;45:85–89. 2012;18:CR680–686. 15. Juvela S, Poussa K, Lehto H, Porras M. Natural history of 27. Suzuki J, Yoshimoto T, Kayama T. Surgical treatment of unruptured intracranial aneurysms: a long-term follow-up middle cerebral artery aneurysms. J Neurosurg 1984;61:17–23. study. Stroke 2013;44:2414–2421. 28. Thompson BG, Brown RD Jr, Amin-Hanjani S, Broderick 16. Kovac JD, Stankovic A, Stankovic D, Kovac B, Saranovic D. JP, Cockroft KM, Connolly ES Jr, et al. Guidelines for Intracranial arterial variations: a comprehensive evaluation the management of patients with unruptured intracranial using CT angiography. Med Sci Monit 2014;20:420–427. aneurysms: a guideline for healthcare professionals from 17. Li Z, Zhang G, Huang G, Wang Z, Tan H, Liu J, et al. the american heart association/american stroke association. Intraoperative combined use of somatosensory evoked Stroke 2015;46:2368–2400. potential, microvascular doppler sonography, and 29. Ujiie H, Tachibana H, Hiramatsu O, Hazel AL, Matsumoto indocyanine green angiography in clipping of intracranial T, Ogasawara Y, et al. Effects of size and shape (aspect ratio) aneurysm. Med Sci Monit 2016;22:373–379. on the hemodynamics of saccular aneurysms: a possible 18. Morgan MK, Mahattanakul W, Davidson A, Reid J. Outcome index for surgical treatment of intracranial aneurysms. for middle cerebral artery aneurysm surgery. Neurosurgery Neurosurgery 1999;45:119–129; discussion 129-130. 2010;67:755–761; discussion 761. 30. van Dijk JM, Groen RJ, Ter Laan M, Jeltema JR, Mooij 19. Murayama Y, Takao H, Ishibashi T, Saguchi T, Ebara M, Yuki JJ, Metzemaekers JD. Surgical clipping as the preferred I, et al. Risk analysis of unruptured intracranial aneurysms: treatment for aneurysms of the middle cerebral artery. Acta prospective 10-year cohort study. Stroke 2016;47:365–371. Neurochir (Wien) 2011;153:2111–2117. 20. Ogilvy CS, Crowell RM, Heros RC. Surgical management 31. Vlak MH, Rinkel GJ, Greebe P, Algra A. Risk of rupture of an of middle cerebral artery aneurysms: experience with intracranial aneurysm based on patient characteristics: a case- transsylvian and superior temporal gyrus approaches. Surg control study. Stroke 2013;44:1256–1259. Neurol 1995;43:15–22; discussion 22-14. 32. Vlak MHM, Algra A, Brandenburg R, Rinkel GJE. Prevalence 21. Park SH, Yim MB, Lee CY, Kim E, Son EI. Intracranial of unruptured intracran ial aneurysms, with emphasis on fusiform aneurysms: it's pathogenesis, clinical characteristics sex, age, comorbidity, country, and time period: a systematic and managements. J Korean Neurosurg Soc 2008;44:116– review and meta-analysis. Lancet Neurol 2011;10:626–636. 123. 33. Wermer MJ, van der Schaaf IC, Algra A, Rinkel GJ. Risk of 22. Rinkel GJ, Djibuti M, Algra A, van Gijn J. Prevalence and risk rupture of unruptured intracranial aneurysms in relation of rupture of intracranial aneurysms: a systematic review. to patient and aneurysm characteristics: an updated meta- Stroke 1998;29:251–256. analysis. Stroke 2007;38:1404–1410.

46 www.e-jnic.org eISSN 2635-5280 Case Report J Neurointensive Care 2018;1(1):47-50. https://doi.org/10.32587/jnic.2018.00024

Posterior Reversible Encephalopathy Syndrome in a Patient with Spinal Metastasis Jin Wook Kim, Ju Ho Jeong Department of Neurosurgery, Dongguk University Gyeongju Hospital, Dongguk University College of Medicine, Gyeongju, Korea

Received: August 20, 2018 Accepted: September 19, 2018 Posterior reversible encephalopathy syndrome (PRES), also named reversible posterior leuko- Published: October 10, 2018 encephalopathy, is not a familiar term to neurosurgeon. The PRES is characterized by various kinds of neurologic signs and symptoms that include headache, seizure, altered mental status, le- Corresponding Author: thalgy, visual loss and focal neurological disability. A 63-year-old female visited with upper back Ju Ho Jeong, M.D., Ph.D. pain and both leg weakness. She has been receiving chemotherapy with gemcitabine and cispla- Department of Neurosurgery, tin for lung cancer with multiple bone metastasis. According to the imaging, we diagnosed the Dongguk University Gyeongju patient as T8 pathologic fracture. Five days after surgical decompression, she suddenly com- Hospital, Dongguk University College of Medicine, 87 Dongdae- plained of visual loss. Magnetic resonance imaging(MRI) of the brain showed bilateral subcorti- ro, Gyeongju 38067, Korea cal and cortical edema in the parieto-occipital area. Her MRI finding and symptoms suggested Tel: +82-54-770-8232 the PRES. Five days after conservative treatment, her visual disturbance was completely recov- Fax: +82-54-770-8378 ered. We believe that accurate and early detection of PRES and adequate treatment is very im- E-mail: [email protected] portant for the patient having a history of chemotherapy. Keywords: Posterior reversible encephalopathy syndrome; Blindness; Metastasis

INTRODUCTION chemotherapeutic agents, pre-eclampsia, eclampsia, electrolyte disturbance have been identified as risk factors2,3,5-7). PRES is In 1996, posterior reversible encephalopathy syndrome not familiar with neurosurgeon, so early diagnosis and prompt (PRES) was first described as reversible leukoencephalopathy treatment are very important because it can lead to permanent by Hinchey1). This syndrome is characterized by various kinds or severe neurological disability. And it is almost reversible and of neurologic signs and symptoms that include headache, can be treated with conservative therapy. We report a case of seizure, altered mental status, lethalgy, visual loss and focal PRES in patient with a history of chemotherapy. neurologic defects2-4). PRES presents a variety of symptoms, so it is sometimes difficult to diagnose accurately. Classic CASE REPORT neuroimaging of magnetic resonance imaging (MRI) and computed tomography (CT) characteristically show bilateral A 63-year-old woman was admitted to a department of cortical and subcortical edema, especially in the parieto-occipital neurosurgery with a history of upper back pain and both areas. Although the pathogenesis of this syndrome remains leg weakness for 2 months. About two years ago, she was controversial, hypertension, immunosuppressive therapy, diagnosed with lung cancer and multiple bone metastasis. And

Fig. 2. T2-weighted magnetic resonance imaging showing bilateral high signal intensity in parieto-occipital cortical and subcortical region(arrows).

DISCUSSION

We have reported a case of posterior reversible encephalopathy syndrome (PRES). Hinchey et al. were first described as a reversible posterior leukoencephalopathy syndrome in 1996, and the name was changed to PRES in 2000 and since then the terminology has been widely used1,8). But PRES is not still familiar to most of neurosurgeons due to their limited experience. PRES is generally associated with severe hypertension, eclampsia, preeclampsia, immunosuppressive treatment, electrolyte imbalance, chemotherapeutic agents and autoimmune Fig. 1. T2-weighted magnetic resonance imaging showing the disease. Especially, severe hypertension is regarded as the major spinal metastatic tumors compressing spinal cord at the level of 8th thoracic vertebra. risk factor in these patients. Some authors reported that about

48 www.e-jnic.org Jin Wook Kim et al. PRES in spinal metastasis

70~80% of these patients have severe hypertension9,10). But chemotherapy. similar to our case, PRES can occur even in the absence of severe hypertension. According to several studies, a few cases CONFLICT OF INTEREST of PRES are associated with chemotherapeutic agent such as gemcitabine, cisplatin, 5-fluoruracil, oxaliplatin, cytarabine2,11). No potential conflict of interest relevant to this article was Symptoms of PRES include headache, seizure, altered reported. mentality, visual disturbance and focal neurological signs. According to the report of Roth et al.12) the one of the most REFERENCES common symptoms of the patient with PRES is seizure, which occurred in 84% of the patients. Visual disturbance was also 1. Hinchey J, Chaves C, Appignani B, Breen J, Pao L, Wang A, et found in 60% of these patients13). Most symptoms of PRES al. A reversible posterior leukoencephalopathy syndrome. N usually occur suddenly, so accurate and early diagnosis is Engl J Med 1996;334:494–500. important. Typically, PRES can be diagnosed by brain MRI. 2. Kim CH, Kim CH, Chung CK, Jahng TA. Unexpected Cerebral edema involving the parieto-occipital area is seen as seizure attack in a patient with spinal metastasis diagnosed increased signal of T2 imaging and fluid attenuated inversion as posterior reversible encephalopathy syndrome. J Korean recovery(FLIAR) imaging13). Neurosurg Soc 2011;50:60–63. Although pathogenesis of PRES is still controversial, but the 3. Kim TK, Yoon JU, Park SC, Lee HJ, Kim WS, Yoon JY. most widely accepted hypothesis is that it is associated with Postoperative blindness associated with posterior reversible vasogenic edema14). If the blood pressure is increases more encephalopathy syndrome: a case report. J Anesth than a certain level, the cerebral autoregulation can fails. Acute 2010;24:783–785. failure of cerebral autoregulation lead to disruption of the blood 4. Nickels TJ, Manlapaz MR, Farag E. Perioperative visual loss brain barrier and cerebral vasodilatation. Consequent leakage of after spine surgery. World J Orthop 2014;5:100–106. transudation into the interstitium results in cerebral vasogenic 5. Kastrup O, Maschke M, Wanke I, Diener HC. Posterior edema. reversible encephalopathy syndrome due to severe Mechanism of chemotherapeutic agents related with PRES hypercalcemia. J Neurol 2002;249:1563–1566. is also unclear. Cisplatin and gemcitabine are commonly used 6. Shoji T, Bando T, Fujinaga T, Chen F, Kohno M, Yabe in many cancer patients, but it is not certain that which drug is M, et al. Posterior reversible encephalopathy syndrome main cause of PRES. Some authors have suggested that cisplatin due to immunosuppressant after living-donor lobar lung induced PRES may be related to hypomagnesemia15), but that is transplantation: report of a case. Gen Thorac Cardiovasc not yet clear. Surg 2012;60:514–517. Eventually, control of leading cause is very important to 7. Yi JH, Ha SH, Kim YK, Choi EM. Posterior reversible this syndrome. If there was a history of high blood pressure, encephalopathy syndrome in an untreated hypertensive controlling of blood pressure is needed. If the patient is in the patient after spinal surgery under general anesthesia -A case treatment of cancer chemotherapy, drug must be discontinued report. Korean J Anesthesiol 2011;60:369–372. or changed to other drug. Typically, radiologic findings and 8. Casey SO, Sampaio RC, Michel E, Truwit CL. Posterior clinical symptoms are reversible within 2 weeks after early and reversible encephalopathy syndrome: utility of fluid- accurate treatment9,11). But if adequate treatment is not initiated attenuated inversion recovery MR imaging in the detection or PRES is not diagnosed, irreversible ischemic damage may of cortical and subcortical lesions. AJNR Am J Neuroradiol occur. 2000;21:1199–1206. 9. Bartynski WS. Posterior reversible encephalopathy syndrome, CONCLUSION part 1: fundamental imaging and clinical features. AJNR Am J Neuroradiol 2008;29:1036–1042. Although PRES is not familiar with surgeon, it is reversible 10. Bartynski WS. Posterior reversible encephalopathy syndrome, with supportive therapy and control of leading cause. It is often part 2: controversies surrounding pathophysiology of vasogenic difficult to diagnosis early and it can be progressively result in edema. AJNR Am J Neuroradiol 2008;29:1043–1049. permanent neurologic damage. We believe that an accurate and 11. Kwon EJ, Kim SW, Kim KK, Seo HS, Kim DY. A case of prompt diagnosis of PRES is important to avoid permanent gemcitabine and cisplatin associated posterior reversible neurological disability for the patient having a history of encephalopathy syndrome. Cancer Res Treat 2009;41:53–55. www.e-jnic.org 49 PRES in spinal metastasis Jin Wook Kim et al.

12. Roth C, Ferbert A. Posterior reversible encephalopathy 14. Port JD, Beauchamp NJ Jr. Reversible intracerebral pathologic syndrome: long-term follow-up. J Neurol Neurosurg entities mediated by vascular autoregulatory dysfunction. Psychiatry 2010;81:773–777. Radiographics 1998;18:353–367. 13. Donmez FY, Basaran C, Kayahan Ulu EM, Yildirim 15. Ito Y, Arahata Y, Goto Y, Hirayama M, Nagamutsu M, Yasuda M, Coskun M. MRI features of posterior reversible T, et al. Cisplatin neurotoxicity presenting as reversible encephalopathy syndrome in 33 patients. J Neuroimaging posterior leukoencephalopathy syndrome. AJNR Am J 2010;20:22–28. Neuroradiol 1998;19:415–417.

50 www.e-jnic.org eISSN 2635-5280 Case Report J Neurointensive Care 2018;1(1):51-54 https://doi.org/10.32587/jnic.2018.00073

Concurrent Isolated Cortical Vein Thrombosis and Pulmonary Thromboembolism as an Initial Presentation of Protein S Deficiency Kun-Hee Han, Kyu-Sun Choi, Yong Ko, Hyeong-Joong Yi, Dae Hyo Song Department of Neurosurgery, Hanyang University Medical Center, College of Medicine, Hanyang University, Seoul, Korea

Received: October 1, 2018 Accepted: October 2, 2018 Protein S is a vitamin K-dependent anticoagulant protein. Its deficiency is a rare condition and Published: October 10, 2018 can lead to deep vein thrombosis, pulmonary embolism or stroke. The incidence of cerebral venous thrombosis (CVT) is low, and in particular, isolated cortical vein thrombosis (ICVT) is Corresponding Author: very rare. Early diagnosis and treatment are quite important, as ICVT is potentially fatal. There Kyu-Sun Choi, M.D., Ph.D. are many known risk factors as pregnancy, puerperium, using oral contraceptive and etc. Here Department of Neurosurgery, we report the case of a 59-year-old woman with isolated cortical vein thrombosis causing sub- College of Medicine, Hanyang arachnoid hemorrhage and intracerebral hemorrhage as clinical onset of Protein S deficiency. University, 17 Haengdang-dong, Seongdong-gu, Seoul 04713, Korea This case report discusses the possible mechanism and treatment of this extremely rare condi- Tel: +82-2-2290-8492 tion that is an association between ICVT and Protein S deficiency. Fax: +82-2-2281-0954 Keywords: Isolated cortical vein thrombosis; Pulmonary thromboembolism; Protein S defi- E-mail: [email protected] ciency

INTRODUCTION and has only been reported in case reports and small patient series. Here, we report an extremely rare case of an ICVT patient Protein S is a vitamin K-dependent anticoagulant protein. with type II Protein S deficiency Which prevents clotting by acting as a cofactor for activated protein C in the degradation of clotting factors Va and VIIa. CASE REPORT An inherited or acquired deficiency of protein S leads to a prothrombotic state, with predisposition to thrombosis. A 59-year-old woman, who was admitted to the emergency Its deficiency is a rare condition and can lead to deep vein department due to right-sided hemiparesis and aphasia. She thrombosis, pulmonary embolism or stroke. was alert, and had apparent right side motor weakness, when Cerebral venous thrombosis (CVT) is a relatively rare she woke up at 9 AM. She had no medical history and family cause of stroke, and it has been reported to cause 0.5–1.0 % history of cerebral infarction of hers mother. On admission, of all strokes1-2). Isolated cortical vein thrombosis (ICVT) is body temperature, heart rate, and blood pressure were 37 °C, the thrombosis of 1 or more cerebral cortical veins without 88 beats/ min, and 130/80 mmHg, respectively. An initial occlusion of the major dural venous sinuses or the deep cerebral computed tomography (CT) scan revealed acute intracerebral veins. ICVT accounts for less than 1% of all cerebral infarctions hemorrhage & subarachnoid hemorrhage in left frontal lobe

A B

Fig. 1. Intracranial imaging. A: Initial brain CT shows acute intracerebral hemorrhage & subarachnoid hemorrhage in left frontal lobe and cortical sulcus. B: Follow-up brain CT (postictal state) shows interval resolution of subarachnoid hemorrhage in left frontal region. and cortical sulcus (Fig. 1A). Considering the patient’s age and or chest discomfort symptom during admission. To address absence of a hypertension history, brain CT angiography was IVCT and PTE, systemic heparinization was promptly performed to rule out conditions such as a cerebral aneurysm, applied. arteriovenous malformation (AVM), or sinus thrombosis, and Although the resolution of pulmonary embolism was no such conditions were noted. Brain CT angiography showed confirmed after anticoagulation, she expired at hospital day 30th. diffuse narrowing of Lt ICA and severe stenosis (about 75%) at left supraclinoid ICA. Her ICH was treated with conservative medical therapy in order to maintain systolic BP below 130 mmHg, including immediate intravenous administration of mannitol. MRI and cerebral angiography were planned on another day to identify the definite etiology Magnetic resonance (MR) images and DSA confirmed a left frontal ICVT as the underlying disease. (Fig. 2) At admission, the coagulation profile was assessed, and blood laboratory studies were performed to check for connective tissue diseases. No abnormal data was found, except that the protein S activity was low at 31 %. In hospital day 7th, she had a GTC type seizure. After postictal period, follow up brain CT showed no specific change( Fig. 1B). However, her condition rapidly deteriorated and she went into a coma approximately 2 hours after seizure. Her consciousness level was E1V1M2 on the Glasgow Coma Scale (GCS). At chest CT, multifocal pulmonary thromboembolisms (PTE) in both lungs, acute Fig. 2. Digital subtraction angiography shows time delayed to chronic phase, combined pulmonary hypertension and RV contrast wash-out isolated cortical vein. This vein coincided with enlargement (Fig. 3). The patient had no significant dyspnea intracerebral hemorrhage area.

52 www.e-jnic.org Kun-Hee Han et al. Cortical vein thrombosis in protein S deficiency

A B

Fig. 3. Chest CT angiography shows multifocal pulmonary rhromboembolisms in both lungs, acute to chronic phase. Combined pulmonary hypertension and RV enlargement.

DISCUSSION with early seizures. Anticoagulation therapy for ICVT averts aggravation of the thrombus, and allows for improvement of ICVT is rare in developed countries, with an incidence the occlusion lesion. This therapy is supported by European rate ranging from 1:10,000 to 1:25,000.11). There are no Federation of Neurological Societies guidelines. However, specific symptoms for ICVT. Diagnosis is very difficult owing in cases of hemorrhagic presentation, appropriate therapy is to the condition’s rarity and the obscurity of symptoms. highly controversial. It has been reported that 39–41% of ICVT Of help, is to note a patient’s background and history. Risk patients present with ICH, hemorrhagic venous infarcts, or factors easily identifiable from a medical history included, isolated subarachnoid hemorrhage5). Although heparin and pregnancy, puerperium, connective tissue disease, malignancy, warfarin have been used for more than 50 years, newer oral contraceptive use, and infections such as, sinusitis, otitis, and anticoagulants (eg. dabigatran, rivaroxaban, apixaban) might mastoiditis4). Young individuals, especially young women, are offer an alternative to traditional therapies for ICVT, and more vulnerable. The International Study on ICVT reported pulmonary thromboembolism6). that 78% of all cases were aged less than 50 years, and that the Protein S (named in reference to its isolation and incidence of ICVT was three times greater in women than characterisation in Seattle in 1979) is a vitamin K-dependent men4). When a young, pregnant, or postpartum woman presents protein synthesised in the liver, vascular endothelium and with new onset, stroke-like symptoms, such as headaches and megakaryocytes. It helps in cleaving activated clotting factors Va seizure, it is significant to examine for the ICVT risk factors. and VIIa on vascular endothelium by acting in association with If ICVT is suspected, CT venography or MR venography protein C. PS deficiency is classified as type I (low total and free should be performed. However, due to its small size, ICVT is antigen, reduced activity), type II (normal total and free antigen, hard to detect using these conventional modalities. A recent reduced activity), and type III (normal total antigen, reduced study proved that T2*/susceptibility-weighted MR imaging free antigen and activity). Our patient was diagnosed with type sequences are very effective in detecting such lesions. Treatment II PS deficiency, which is an extremely rare disease8). Few case for ICVT is still controversial; however, heparin has been reports have also implicated protein S deficiency in recurrent reported as a safe and effective treatment. This is true even ischemic strokes in the young. Similarly, progressive intracranial when ICVT is accompanied by hemorrhagic lesions. Anti- occlusive disease has been reported in association with protein S seizure medication should be given to those who present deficiency. However, current data do not support an association www.e-jnic.org 53 Cortical vein thrombosis in protein S deficiency Kun-Hee Han et al. between hereditary protein S deficiency and an increased risk Engl J Med 2005;352:1791–1798. of arterial thrombosis. The recommended therapy for ICVT is 2. Bousser MG, Crassard I. Cerebral venous thrombosis, anticoagulation with heparin followed by oral anticoagulation, pregnancy and oral contraceptives. Thromb Res.130 Suppl which should be continued indefinitely for patients with 2012;1:S19–22. underlying thrombophilia. 3. Park DS, Moon CT, Chun YI, Koh YC, Kim HY, Roh HG. Clinical characteristics of cerebral venous thrombosis CONCLUSION in a single center in Korea. J Korean Neurosurg Soc 2014;56:289–294. Here, we presented an extremely rare case of an ICVT 4. Ferro JM, Canhão P, Stam J, Bousser MG, patient with type II PS deficiency. For early diagnosis, it is vital Barinagarrementeria F, ISCVT Investigators. Prognosis to suspect CVT, including ICVT, considering the patient’s of cerebral vein and dural sinus thrombosis: results of the background. In such a case, CT-DSA should be performed International Study on Cerebral Vein and Dural Sinus and the images should be thoroughly checked. A hematoma Thrombosis (ISCVT). Stroke 2004;35:664–670. associated with ICVT caused by a cortical vein might expand 5. Ghandehari K, Riasi HR, Noureddine A, Masoudinezhad without early anticoagulation therapy, as was noted in our case. S, Yazdani S, Mirzae MM, et al. Safety assessment of Therefore, early anticoagulation therapy might be essential, even anticoagulation therapy in patients with hemorrhagic in isolated cases involving ICH. cerebral venous thrombosis. Iran J Neurol 2013;12:87–91. 6. Gross PL, Weitz JI. New anticoagulants for treatment of CONFLICT OF INTEREST venous thromboembolism. Arterioscler Thromb Vasc Biol 2008;28:380–386. No potential conflict of interest relevant to this article was 7. Lanska DJ, Kryscio RJ. Risk factors for peripartum and reported. postpartum stroke and intracranial venous thrombosis. Stroke 2000;31:1274–1282. REFERENCES 8. Garcia de Frutos P, Fuentes-Prior P, Hurtado B, Sala N. Molecular basis of protein S deficiency. Thromb Haemost 1. Stam J. Thrombosis of the cerebral veins and sinuses. N 2007;98:543–556.

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