Spinal Cord Injury The Clinical Problem Keith DK

脊髓損傷 – 臨床上的問題 Spinal Cord Injury The Clinical Problem Keith DK Luk Chair Professor & Head Dept of Orthopedics & Traumatology University of Hong Kong

Anatomy 解剖學脊髓中樞神經系統 Spinal cord C 1 to L 1 (central nervous system) vs 馬尾叢周邊神經系統 Cauda equina (peripheral nervous system) L 2 to S 4

脊髓損傷的發病率 Incidence of Spinal Cord Injury • 在美國，每百萬人口約有40宗新病例　 (每年 10, 000宗病例) 40 new cases / million population in USA 　(about 10, 000 cases per year) 　 • 在歐洲, 台灣及香港，每百萬人口約有20宗新病例 20 new cases / million population in Europe, Taiwan & Hong Kong 　　 National Spinal Injury Statistical Center, USA. 2004 http: //www. spinalcord. uab. edu

一九九八至九九年度衛生署年報 Department of Health Annual Report 1998/99 脊髓損傷 – 365 病人 Spinal Cord Injury – 365 patients

2000年衛生署資料 Department of Health Website Information 脊髓及神經受損 – 452 病人 Injury to nerves and spinal cord – 452 patients

嚴重脊髓損傷 More Severe SCI 二零零四年上半年共有71個病例 First 6 months/2004 71 cases

常見脊髓損傷的原因 Common causes of spinal cord injury • 交通意外 Motor vehicular accident • 高處墜下 Fall from height • 運動創傷 Sports & recreational injuries • 暴力 Violence

香港常見導致脊髓受損的原因 Common Causes of Spinal Cord Impairment in Hong Kong • 退化病 Degenerative diseases • 創傷 Traumatic injuries • 腫瘤性疾病 Neoplastic diseases • 發炎性疾病 Inflammatory diseases

殘疾的程度 Disability relates to: • 受損水平 Level of injury • 受損程度 Degree of injury – 四肢癱瘓 Quadriplegia – 部份受損 Incomplete – 下肢癱瘓 Paraplegia – 完全受損 Complete

高位脊髓受損 High Spinal Cord Injury • 依賴呼吸機 Ventilator dependent • 呼吸併發症 Respiratory complication • 完全依賴 Totally dependent

臨床問題 Clinical Problems • 生理問題 Physical • 心理問題 – 病人, 家屬 Psychological – Patient, Family • 社交問題 – 就業, 參與社會活動 Socio-economical – Employment, Community access

生理問題 Physical Problems • 喪失活動能力 Loss of motion • 失去感覺 Loss of sensation - Pressure ulcers 褥瘡 • 痛楚 Pain

生理問題 Physical Problems • 交感神經功能 Autonomic dysreflexia - 膀胱 – 尿滯留或小便失禁 Bladder – retention or incontinence - 大腸 – 便秘或失禁 Bowel – constipation or incontinence - 功能性障礙 Sexual dysfunction • 痙攣 Spasticity

Natural history • 完全癱瘓者: – 一年內: • 約5 -10%的病人約有兩節段的改善 • 90% 的病人有一節段的改善 • 少於 1%的病人有兩節段以上的改善: • For complete SCI: – In one year: • 90% of SCI patients improve one level. • ~5 -10% of SCI patients improve two levels. • less than 1% of SCI patients improve more than two levels • 半癱瘓者: – 比較難估計, 不過整體比完全癱瘓者優勝 • For incomplete SCI – less predictable, tends to be better than complete injuries NSCISC, 2004. http: //www. spinalcord. uab. edu

傳統的療法 Conventional management • 脊髓是不能被修補或再生 Repair, regeneration of the spinal cord is not possible • 集中復康治療 – – 主流治療方向增強殘餘功能恢復功能減低傷殘 Focus on rehabilitation – Main stream management – Maximize residual functions – Functional restoration – Minimize disabilities

截癱性步行 Paraplegic walking

半癱瘓 Incomplete Paraplegia

家居改善 Home modification

公共交通具 Transportation

香港現有的服務 Current Services in Hong Kong • 幾乎所有的脊髓復康服務均由醫院管理局提供 Nearly all spinal cord rehabilitation are provided by HA • 三間由醫管局提供的脊髓復康醫院 3 SCI units under the Hospital Authority – 香港區：麥理浩復康院, Mac. Lehose Rehabilitation Centre – 九龍區：九龍醫院, Kowloon Hospital – 新界區：大埔醫院, Tai Po Hospital • 高技術水準的設備 - FES, 矯具等 • State-of- the-art facilities – FES, orthosis, etc

脊髓損傷的治療及再生的可能 Potential for spinal cord repair and regeneration 再生療法 Regenerative therapies

脊髓損傷研究的重要性 Importance of Spinal Cord Injury (SCI) Research

v 研究脊髓損傷的病理組織學 To investigate pathohistology of Spinal Cord Injury： • 損傷後神經元如何、為何死亡？ how and why neurons die after injury? • 甚麼因素阻止了脊髓損傷後軸突的再生？ What stop axonal regeneration in Spinal Cord Injury? • 如何促進脊髓損傷受損神經元的存活和再生？ How to enhance survival and regeneration of injured neurons in Spinal Cord Injury? • 這些問題的答案將會給脊髓損傷病人提供新的療法。 Answer to these questions will contribute significantly for the new treatment methods for Spinal Cord Injury patients.

v 確定已用於脊髓損傷病人臨床試驗的幹細胞、施萬細胞以及Oefactory Ensheathing Cells 細胞 (OEC - 嗅鞘上皮細胞)移植等治療方法的機制。 To confirm and prove mechanisms of treatment methods that have been used in clinical trial study for the Spinal Cord Injury patients, such as stem cell, Schwann’s cell and OEC cell (Oefactory Ensheathing Cells) transplantations. v 為脊髓損傷新藥的檢測提供動物模型。 To provide animal models for testing effects of new drugs for Spinal Cord Injury.

脊髓的主要功能（Main Functions of the Spinal Cord） • 將感覺訊息從外周傳向腦，運動訊息從腦傳向外周。 To convey sensory impulses from periphery to the brain and to convey motor impulses from the brain to the periphery. • 構成局部回路和反射。 To perform locomotion and reflex. Neuroscience Exploring the Brain, Second Edition. Bear MF, Connors BW, Paradiso MA

2 5 3 2 1 a 1 b 脊髓損傷後有侍解決的問題 1. 神經细胞死亡（Neuronal cell death） a. 原發損傷 Primary injury (空洞cavity) b. 繼發損傷 Secondary injury 2. 軸突切斷（Axotomy） 3. 脱髓鞘（Demyelination） 4. 膠質癍痕（Glial scar） 5. 抑制性分子（Inhibit molecules , NI-35, NI-250） 6. 血液供應不良（Poor Blood supply） 4, 5, 6 4 2 1 3

脊髓損傷的突破性研究 (一) （Breakthrough Studies on the Field of Spinal Cord Injury ） 2. 軸突切断（Axotomy）的治療增强軸突切斷神經元的再生能力。 Enhance regeneration ability of axotomized neurons (Pears Nature Medicine, 2004; Yick, J Neurotrauma, 2004). 2 5 3 2 1 a 1 b 4, 5, 6 2 1. 神經细胞死亡（Neuronal cell death）波尼松龍治療减少细胞死亡，利用嗅鞘上皮細胞或幹细胞移植替代死亡的细胞。Reduce cell death by therapy with methylprednisolone (Young 1990) and replace death cells with OEC transplantation (Li, J of Neurosci. 1998; Huang, 2003) or Stem cells transplantation (Harper, PNAS 2004).

脊髓损傷的突破性研究(二) （Breakthrough Studies on the Field of Spinal Cord Injury ） 3. 去髓鞘（Demyelination）的治療通過施萬细胞移植重建髓鞘。 Rebuild myelination by Schwann’s cell transplantation (Xu, EJN 1999; Sivasankaran, Nature Neurosci. 2004). 2 5 3 2 1 a 1 b 3 4, 5, 6 4 2 1 4, 5, 6. 膠質癍痕及抑制性分子（Glial scar and Inhibit molecules）通過改變局部化學環境减少癍痕形成，去除抑制因子。 Reduce glial scar and remove inhibitor molecules by changing the local chemical environment (Yick, Neuroreport, 2000; Moon, Nature Neurosci. 2001).

Clinical Trials Centre Faculty of Medicine The University of Hong Kong 8/F Clinical Pathology Building Queen Mary Hospital, Hong Kong Tel: (852) 2855 4664 Fax: (852) 2974 1248 E-mail: ctcentre@hkucc. hku. hk www. hku. hk/ctc 香港大學醫學院臨床試驗中心

Study sites 試驗場地 Drug development has become a global activity 由於研究員及合適参與臨床試驗的病人在已發展地區均出現短缺，臨床試驗正趨向全球化。 due to the lack of investigators and patients in the established regions.

ICH GCP Guideline 良好臨床試驗管理規範 1980 1996

Our aim 我們的目標 Global clinical trials Into China and HK from other regions 吸引世界各地之科研機構到中、港進行臨床試驗

Why Hong Kong? 為何選擇香港? • Highly qualified clinical investigators 高質素之臨床研究員 • Scientific expertise 科學專業知識 • Experienced in clinical research 豐富之臨床研究經驗 • High population density 高人口密度 • Excellent infrastructure 優良之基建 … and more …及其他有利條件

Clinical Trial / Research Experience 臨床試驗/研究經驗 Clinical Sciences –Number of Publications (1991 -2002) 臨床科學 – 出版數目 (1991 -2002)

Hong Kong Hospital Authority Clusters 香港醫院管理局聯網 7 Clusters 七個聯網 HA 43 Hospitals/Institutions 四十三間醫院/機構 29, 022 Beds 二萬九千零二十二個床位 6. 8 Million Population 六百八十萬人口

Hong Kong Hospital Authority Clusters 香港醫院管理局聯網 Ethics Committees 倫理委員會 • Compliance with ICH GCP • • 符合良好臨床試驗管理規範之標準 Uniform operations 統一運作標準 HA Guidelines 醫院管理局指引 SOPs 標準運作程序 Trained EC members 曾受訓之倫理委員會會員

Clinical Trials Centre 臨床試驗中心 Established in 1998 under the Faculty of Medicine of The University of Hong Kong (founded in 1887) 於一九九八年在香港大學醫學院之下成立 The first full-service Academic Research Organization (ARO) in clinical trials in Asia 亞洲首間一站式臨床試驗學術研究機構 Objective: To offer one-stop solutions to clinical trial sponsors and investigators 目標: 提供一站式服務予臨床試驗贊助商及研究員

Organization Structure 組織架構 Faculty of Medicine 醫學院 Board of Directors 理事會 Clinical Trials Centre 臨床試驗中心 Research and Consultation 研究及諮詢 Business and Development 業務發展 Trial Network Management 試驗網絡管理 Project Management 項目管理 Site Management 研究基地管理 Data Management and Medical Statistics 數據處理及統計分析 Laboratory and Research Pharmacy 實驗室及藥品管理 Education 教育及培訓 Advisory Committee 諮詢委員會

Sponsors with a Master Clinical Trial Contract with HKU 部份已與香港大學訂定標準合約之贊助商

Services 服務 Research Consultation Contract & Budget Regulatory Affairs 研究諮詢合約及財務預算法規事務 Subject Recruitment Site Management Trial Monitoring 受試者招募研究基地管理試驗監察 Research Pharmacy Project Management Data Management 藥品管理項目管理數據處理 Medical Statistics Training & Education Laboratory Services 統計分析教育及培訓實驗室服務

Clinical Trials 臨床試驗 CTC – No. of Sponsored Trials Contracted Per Year 受贊助之臨床試驗總數(每年)

Laboratory Facilities 實驗室設備 5 clinical laboratories: Anatomical Pathology Clinical Biochemistry Clinical Immunology Haematology Microbiology 五大臨床實驗室：組織及細胞病理臨床生化臨床免疫血液微生物學 Fully accredited by the College of American Pathologists (CAP) (under the category of large multidiscipline laboratory) 得到美國病理學家學會(CAP) 之認証 (隸屬大型多功能實驗室組別)

Educational Activities 教育活動 Master of Medical Sciences / Pg. Dip / Pg. Cert 醫療科學碩士/研究院文憑/研究院證書 - Clinical Trials Research Methodology 臨床試驗研究方法學 - Medical Statistics 統計分析 GCP courses 良好臨床試驗管理規範課程 EC members training 倫理委員會會員之培訓 Symposia / International conferences 講座/國際會議 Web-based Investigators Certification Programme 研究員網上訓練課程

Spinal Cord I. Research 脊骨創傷研究 On the conduct of Clinical Trials 臨床試驗程序 Pre-study activities 試驗前 Study activities 試驗中 Protocol 試驗方案 CRFs 病例報告表 Investigator Training 研究者培訓 GMP 藥品生產質量管理規範 Finance Post-study activities 試驗後財務 Approvals 批核 Insurance 保險 Logistics 物流

Spinal Cord I. Research 脊骨創傷研究 On the conduct of Clinical Trials 臨床試驗程序 Pre-study activities 試驗前 Study activities 試驗中 Post-study activities 試驗後 Site activities 研究單位活動 Project Manag. (QA) 項目管理(品質保証) Data Manag. 數據處理 Safety Monitoring 安全監控

Spinal Cord I. Research 脊骨創傷研究 On the conduct of Clinical Trials 臨床試驗程序 Pre-study activities 試驗前 Study activities 試驗中 Post-study activities 試驗後 Data Manag. 數據處理 Medical Statistics 統計分析 Medical Writing 醫學報告撰寫 Reporting 報告