硬膜囊內(nèi)減壓治療創(chuàng)傷性脊髓損傷的研究進(jìn)展

梁兵　董健　唐家廣

硬膜囊內(nèi)減壓治療創(chuàng)傷性脊髓損傷的研究進(jìn)展

梁兵董健唐家廣

脊髓損傷；病理過(guò)程；減壓術(shù)，外科；治療學(xué)

創(chuàng)傷性脊髓損傷 ( traumatic spinal cord injury，TSCI )多見(jiàn)于交通事故、砸傷、摔傷、運(yùn)動(dòng)性損傷等，由直接作用于脊柱或脊髓的機(jī)械性損害所致，可導(dǎo)致全身多器官、系統(tǒng)長(zhǎng)期的功能紊亂，甚至永久性的功能改變，如損傷平面以下的感覺(jué)、運(yùn)動(dòng)功能障礙，致使患者生活質(zhì)量明顯下降，給個(gè)人、家庭和社會(huì)帶來(lái)沉重負(fù)擔(dān)，在全球呈現(xiàn)高發(fā)生率與高致殘率[1-4]。

TSCI 的發(fā)生主要是由于原發(fā)機(jī)械性損傷和繼發(fā)性缺血性損傷導(dǎo)致脊髓組織破壞。原發(fā)性損傷發(fā)生在機(jī)械性損傷的即刻，它是不可逆的過(guò)程。繼發(fā)性損傷是一種細(xì)胞分子水平的主動(dòng)調(diào)節(jié)過(guò)程，具有可逆性和可控性。因此，早期正確積極的干預(yù)，對(duì)于保留殘存神經(jīng)組織的功能至關(guān)重要。藥物學(xué)方法促進(jìn)神經(jīng)再生進(jìn)程、抑制炎癥有害方面，是目前脊髓損傷 ( spinal cord injury，SCI ) 治療研究的前沿；然而，迄今為止，國(guó)際上雖然已經(jīng)有 5 種藥物學(xué)治療方案用于臨床試驗(yàn)，但它們并沒(méi)有任何一種成為有效的治療方法[5]，尚未發(fā)現(xiàn)任何藥物在脊髓損傷臨床轉(zhuǎn)化應(yīng)用治療中具有顯著療效[6-9]。因此，外科手術(shù)干預(yù)，硬膜囊內(nèi)減壓，清除血腫，解除壓迫，釋放壞死物質(zhì)，以減輕脊髓組織水腫、恢復(fù)脊髓血流灌注以及降低繼發(fā)性損害，是有希望治療脊髓損傷的途徑之一，也是未來(lái)脊髓損傷治療研究的重要發(fā)展方向。筆者對(duì)硬膜囊內(nèi)減壓的作用及手術(shù)時(shí)機(jī)的研究進(jìn)行如下綜述。

一、脊髓損傷的病理生理學(xué)

TSCI 的病理生理改變主要由兩大機(jī)制引起：原發(fā)性損傷機(jī)制 ( 即刻的機(jī)械性損傷 ) 和繼發(fā)性損傷機(jī)制 ( 由血管、細(xì)胞和生化事件改變引發(fā)的一系列級(jí)聯(lián)瀑布反應(yīng) )[10-14]。

原發(fā)性損傷指即刻的機(jī)械物理性損傷，以脊髓內(nèi)微脈管系統(tǒng)、神經(jīng)細(xì)胞損傷壞死以及軸突斷裂為特征，具體表現(xiàn)為血管痙攣、脊髓內(nèi)微血管破裂致灰白質(zhì)內(nèi)出血、實(shí)質(zhì)細(xì)胞出血性壞死、白質(zhì)水腫、軸突的斷裂以及凝血因子和血管活性胺的釋放等，其可導(dǎo)致血栓形成，加重血管痙攣，進(jìn)一步引起脊髓組織缺氧、壞死，引起繼發(fā)性損傷[10]。而原發(fā)性損傷的機(jī)械物理學(xué)機(jī)制可分為 4 種類型：( 1 ) 擠壓 / 挫傷型；( 2 ) 牽張型；( 3 ) 撕裂或橫斷型；( 4 )剪切型[15]。

繼發(fā)性損傷是指在原發(fā)損傷基礎(chǔ)上，主要是由原發(fā)性水腫的擴(kuò)展，激發(fā)一系列細(xì)胞和分子機(jī)制，觸發(fā)細(xì)胞壞死和凋亡等系列效應(yīng)，最終造成了不可逆性的損傷，包括局部缺血、谷氨酸受體過(guò)度激活、脂質(zhì)過(guò)氧化作用、鈣離子超載等，導(dǎo)致殘存或未完全損傷的神經(jīng)細(xì)胞繼續(xù)破壞死亡[11,16]。原發(fā)性損傷發(fā)生在損傷即刻，是不可逆的；而繼發(fā)性損傷是一種細(xì)胞分子水平的主動(dòng)調(diào)節(jié)過(guò)程，具有可逆性和可控性[17]。脊髓損傷后的繼發(fā)性變化是非常復(fù)雜的，由多種機(jī)制混合而成，它們之間相互作用、相互影響。

二、脊髓損傷的分期

根據(jù)脊髓損傷后的病理生理學(xué)改變，其發(fā)生發(fā)展過(guò)程被分為五期：

1. 速發(fā)期 ( immediate phase )：為原發(fā)損傷后 2 h 內(nèi)[18]。其特點(diǎn)是原發(fā)機(jī)械性損傷導(dǎo)致脊髓實(shí)質(zhì)內(nèi)血管破裂，灰質(zhì)和白質(zhì)內(nèi)出血、水腫[11,19]；血腫進(jìn)一步加重局部缺血和神經(jīng)元及膠質(zhì)細(xì)胞死亡[15,20]。軸突發(fā)生創(chuàng)傷性斷裂、水腫。創(chuàng)傷導(dǎo)致脊髓內(nèi)的小膠質(zhì)細(xì)胞活化，同時(shí)細(xì)胞膜的破壞導(dǎo)致離子平衡紊亂、大量細(xì)胞基質(zhì)和細(xì)胞因子釋放，如白介素-1 ( IL-1β )、白介素-6 ( IL-6 ) 和腫瘤壞死因子-α等[21-24]。局部缺血低氧增加神經(jīng)元和膠質(zhì)細(xì)胞對(duì)谷氨酸鹽的敏感性，導(dǎo)致興奮期延長(zhǎng)，神經(jīng)細(xì)胞壞死[25-30]。神經(jīng)元細(xì)胞破壞，釋放出的促炎性細(xì)胞因子進(jìn)入脊髓損傷區(qū)域，預(yù)示速發(fā)期的終結(jié)。

2. 急性早期 ( early acute phase )：為損傷后 2～48 h。其特點(diǎn)為脊髓持續(xù)出血和壞死；血管和細(xì)胞水腫；自由基產(chǎn)生，尤其是氧自由基和活性氧簇 ( ROS )，導(dǎo)致脂質(zhì)過(guò)氧化[31-33]；谷氨酸興奮性毒性作用[27-30,34]；血－腦屏障破壞，通透性增加[23,35]；嗜中性粒細(xì)胞、單核－巨噬細(xì)胞、淋巴細(xì)胞等浸潤(rùn)，導(dǎo)致炎癥反應(yīng)更明顯；少突膠質(zhì)細(xì)胞死亡，導(dǎo)致早期的脫髓鞘作用[21-24]；軸突水腫加重；并發(fā)全身系統(tǒng)事件，如休克、脊髓休克、低血壓和組織缺氧等[10-11,36-37]。這個(gè)時(shí)期自由基的產(chǎn)生和谷氨酸興奮性毒性作用達(dá)到高峰。

3. 亞急性期 ( subacute phase )：緊隨在急性期之后，為損傷后 2 天至 2 周。其特點(diǎn)為脊髓損傷區(qū)域巨噬細(xì)胞浸潤(rùn)加重，吞噬清理壞死組織，另外損傷區(qū)域星形膠質(zhì)細(xì)胞增生、活化為反應(yīng)性星形膠質(zhì)細(xì)胞，形成膠質(zhì)瘢痕，重建障血－腦屏障和恢復(fù)離子平衡[23,38-39]。星形膠質(zhì)瘢痕不僅阻止巨噬細(xì)胞和中性粒細(xì)胞的進(jìn)一步浸潤(rùn)，而且可以減少組織水腫。另一方面，星形膠質(zhì)瘢痕同時(shí)也抑制了神經(jīng)元軸突的再生。

4. 中期 ( intermediate phase )：為損傷后 2 周至 6 個(gè)月。其特點(diǎn)為膠質(zhì)瘢痕繼續(xù)形成，脊髓內(nèi)空洞囊腔形成，脊髓損傷區(qū)域趨于穩(wěn)定[40-41]。在可能存活的地方持續(xù)的軸突再生，同時(shí)膠質(zhì)瘢痕也在生長(zhǎng)和成熟[41]。

5. 慢性期 ( chronic / late phase )：開(kāi)始于傷后 6 個(gè)月，可能持續(xù)到 1～2 年。其特點(diǎn)為持久的瓦勒氏變性( Wallerian degeneration ) 出現(xiàn)，伴隨膠質(zhì)瘢痕最終成熟、軸突脫髓鞘病變、脊髓囊性空洞形成以及殘存脊髓組織的結(jié)構(gòu)和功能重塑[40,42-44]。脊髓損傷最終病變特點(diǎn)表現(xiàn)為脊髓軟化壞死和囊性空洞形成。

然而，相對(duì)于基礎(chǔ)病理生理學(xué)研究，臨床上的急性期( acute phase ) 通常被定義為受傷后的 4～5 周[45]。

三、硬膜囊內(nèi)減壓的必要性與機(jī)制

TSCI 的治療策略包括手術(shù)、藥物、細(xì)胞療法、組織工程和再生修復(fù)等[46]。手術(shù)療法的目的主要是用于脊髓減壓，此外還用于維持脊柱正常序列和穩(wěn)定性。然而，手術(shù)去除骨組織和韌帶的硬脊膜外減壓并不能解除脊髓實(shí)質(zhì)內(nèi)的血腫和腫脹，而這也是脊髓創(chuàng)傷后導(dǎo)致硬膜囊完整患者中髓內(nèi)壓力增高、脊髓局部缺血和缺氧加重的原因。迄今為止，雖然研究脊髓損傷治療的藥物療法、細(xì)胞療法，乃至組織工程修復(fù)等方法種類繁多，但尚未形成治療脊髓損傷的診療標(biāo)準(zhǔn)或指南。

1911 年，Allen[47]利用犬類的脊髓損傷模型，證明了脊髓背部縱向切口可以改善脊髓的運(yùn)動(dòng)功能和結(jié)構(gòu)。此后，大量的實(shí)驗(yàn)研究和臨床研究結(jié)果也證明硬膜內(nèi)減壓在治療脊髓損傷中的作用，可以改善脊髓損傷后的功能恢復(fù)，降低脊髓損傷后的繼發(fā)性損傷[47-60]。

1988 年，Perkins 和 Deane[51]對(duì) 6 例急性脊髓損傷患者采用了硬脊膜切開(kāi)方式進(jìn)行硬膜囊內(nèi)減壓，術(shù)中見(jiàn)硬膜囊正常搏動(dòng)消失，硬脊膜表面靜脈充盈；硬脊膜縱行切開(kāi)后，可見(jiàn)腦脊液自硬膜囊內(nèi)以約 15 mm Hg ( 1 mm Hg＝0.133 kPa ) 的壓力“射”出；術(shù)后隨訪 4～5 年，患者神經(jīng)功能 ASIA 分級(jí)獲得明顯改善。作者認(rèn)為，急性脊髓損傷后的組織水腫限制了正常的腦脊液循環(huán)和動(dòng)脈灌注，加重硬脊膜內(nèi)的壓力，最終引起類似“骨筋膜室綜合征”的“脊髓筋膜室綜合征”，這一結(jié)果被認(rèn)為是硬脊膜切開(kāi)減壓阻斷繼發(fā)性損害的有力措施。

1989 年，日本學(xué)者 Koyanagi 等[58]對(duì) 4 例急性頸脊髓損傷患者采用脊髓切開(kāi)的方式進(jìn)行硬膜囊內(nèi)減壓，術(shù)后患者上肢運(yùn)動(dòng)功能均有所恢復(fù)，感覺(jué)障礙有一定程度的減退。

Zhu 等[49]對(duì) 30 例急性完全性脊髓損傷的患者 ( ASIA A 級(jí) ) 采用硬脊膜切開(kāi)、蛛網(wǎng)膜下腔松解和脊髓切開(kāi)的方式進(jìn)行硬膜囊內(nèi)減壓治療，術(shù)后所有患者均獲得一定的步行功能，其中 43% 的患者 ( 13 例 ) 可借助拐杖、手杖或不需要任何支撐行走，40% 的患者 ( 12 例 ) 可在輪式步行練習(xí)器的輔助下行走。

外科手術(shù)減壓在脊髓損傷功能恢復(fù)中具有重要作用[61-63]。TSCI 發(fā)生時(shí)，脊髓受到硬膜外骨折碎片、脊髓剪切力等原發(fā)性損傷和硬膜內(nèi)脊髓水腫、血腫等繼發(fā)性損傷作用，同時(shí)受到骨性椎管和硬脊膜囊限制，導(dǎo)致脊髓內(nèi)、外同時(shí)受壓，引起髓內(nèi)壓力增高，使硬膜囊或蛛網(wǎng)膜下腔狹窄粘連、腦脊液阻斷、動(dòng)靜脈阻塞，進(jìn)而促使局部缺血、缺氧和加重繼發(fā)性損傷，而缺血缺氧反過(guò)來(lái)又加重水腫蔓延、血腫壞死以及髓內(nèi)高壓，形成惡性循環(huán)。因此，硬膜囊內(nèi)減壓可減輕受傷脊髓節(jié)段水腫或血腫引起的硬膜內(nèi)壓力，清除病灶部位的出血、壞死的組織，進(jìn)而增加脊髓的血流灌注，減輕缺血，減少炎性介質(zhì)持續(xù)對(duì)脊髓的刺激，阻斷或終止脊髓的繼發(fā)性損傷過(guò)程，為脊髓的神經(jīng)恢復(fù)、再生創(chuàng)造一個(gè)良好的微環(huán)境[49,51,64]。國(guó)內(nèi)鞠躬院士認(rèn)為，硬脊膜內(nèi)減壓能夠終止繼發(fā)性脊髓損傷，而解除壓迫也有利于殘余神經(jīng)的恢復(fù)[65-67]。亦有研究認(rèn)為，脊髓損傷處的軟化病灶或出血具有占位性病變的損傷效果，可持續(xù)性壓迫其周?chē)Ｉ窠?jīng)組織；清除病灶或出血可減輕周?chē)窠?jīng)組織的壓迫，改變正常組織中神經(jīng)元及軸突生存的微環(huán)境，恢復(fù)脊髓血流灌注，有利于殘存神經(jīng)組織的功能恢復(fù)[49,68-69]。

四、硬膜囊內(nèi)減壓的手術(shù)時(shí)機(jī)

盡管許多基礎(chǔ)研究結(jié)果表明，脊髓減壓能夠明顯改善神經(jīng)功能，降低繼發(fā)性損傷，但對(duì)于手術(shù)時(shí)機(jī)還存在不同的意見(jiàn)。Batchelor 等[70]薈萃分析結(jié)果提示，傷后 12 h 內(nèi)減壓可以獲得穩(wěn)定受益，而在傷后 12～24 h 內(nèi)減壓，其受益較少。最近的臨床研究亦提示，傷后 24 h 內(nèi)減壓可使 15%～20% 的患者獲得穩(wěn)定受益，而超過(guò) 24 h 后的減壓效果不甚明顯，也有學(xué)者認(rèn)為在脊髓休克期過(guò)后再行手術(shù)[62,68,71-76]。Fehlings 等[77]學(xué)者基于手術(shù)減壓時(shí)間的研究認(rèn)為，早期減壓 ( ＜24 h 或＜72 h ) 可以促進(jìn)脊髓損傷后的功能恢復(fù)，具有統(tǒng)計(jì)學(xué)意義。La Rosa 等[78]Meta 薈萃分析結(jié)果證實(shí)，與保守治療和延期 ( 晚期 ) 手術(shù)減壓 ( ＞24 h )相比，24 h 內(nèi)手術(shù)減壓可使脊髓損傷的患者的 ASIA 分級(jí)得到顯著改善。Fehlings 和 Perrin[79]檢索了 1966～2004 年間 Medline 所收錄的關(guān)于脊髓損傷的文獻(xiàn)進(jìn)行回顧分析，研究發(fā)現(xiàn)“早期減壓對(duì)脊髓損傷治療有效”的文獻(xiàn)數(shù)量要較“治療結(jié)果無(wú)效或消極”的文獻(xiàn)數(shù)量多，進(jìn)一步說(shuō)明早期減壓有益于脊髓損傷的功能恢復(fù)。盡管支持盡早手術(shù)的研究占多數(shù)，但缺乏充分的證據(jù)證明早期手術(shù)的益處，手術(shù)是否存在時(shí)間窗還存在很多的爭(zhēng)議；而且急診來(lái)院患者往往處于應(yīng)激狀態(tài)，需要調(diào)節(jié)全身狀況，防止術(shù)中、術(shù)后并發(fā)癥，因此不一定適合急診手術(shù)，應(yīng)選擇最佳手術(shù)時(shí)機(jī)。

筆者認(rèn)為脊髓損傷后應(yīng)積極手術(shù)，不放棄任何能夠減輕患者傷殘程度、降低致殘率的微小機(jī)會(huì)。最好于傷后24 h 內(nèi)行手術(shù)減壓治療，由于各種原因不能早期手術(shù)時(shí)，可在傷后 2 個(gè)月內(nèi)，最遲也不要晚于傷后 12 個(gè)月手術(shù)，因?yàn)榈竭_(dá)脊髓恢復(fù)平臺(tái)期 ( 停滯不前 ) 中位時(shí)間為 1.8 個(gè)月。而當(dāng)脊髓恢復(fù)到達(dá)平臺(tái)期 ( 停滯不前 )，但影像學(xué)顯示仍有脊髓受壓時(shí)，亦應(yīng)行手術(shù)治療[80-81]。

目前，開(kāi)展針對(duì)手術(shù)干預(yù)治療脊髓損傷的臨床與實(shí)驗(yàn)研究，尤其側(cè)重于手術(shù)減壓的時(shí)機(jī)、最佳的減壓組合方式( 椎板切除的硬膜囊外骨性減壓、硬脊膜切開(kāi)或脊髓切開(kāi)的硬膜囊內(nèi)減壓 ) 以及是否聯(lián)合藥物輔助療法，為將來(lái)研究脊髓損傷治療的策略、模式提供了潛在、有效的方向。硬膜囊內(nèi)減壓可釋放硬脊膜等膜結(jié)構(gòu)對(duì)脊髓組織的約束，清除血腫和壞死組織，減輕受傷脊髓的壓迫，降低硬膜囊內(nèi)壓，促進(jìn)脊髓的血流灌注，減少脊髓組織缺血、缺氧，減少或抑制繼發(fā)性損傷的蔓延，防止細(xì)胞的進(jìn)一步壞死，保存殘余的脊髓組織，促進(jìn)神經(jīng)功能的恢復(fù)。未來(lái)，利用動(dòng)物模型及臨床試驗(yàn)，研究外科手術(shù)減壓的時(shí)間窗、最佳的減壓方式，以及減壓對(duì)受傷脊髓節(jié)段繼發(fā)的炎癥、瘢痕形成的影響及其組織學(xué)和神經(jīng)學(xué)結(jié)果，具有良好的前景。

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( 本文編輯：王萌 )

Research progress on intra-dural decompression for traumatic spinal cord injury

LIANG Bing, DONG Jian, TANG Jia-guang. Department of Orthopaedics, Zhongshan Hospital of Fudan University, Shanghai, 200032, PRC Corresponding author: TANG Jia-guang, Email: tangjiaguang2013@163.com

Traumatic spinal cord injury ( TSCI ) consists of primary spinal cord injury and secondary spinal cord injury, with a high morbidity and disability rate globally. Primary spinal cord injury occurs at the time of theinjury, which is an irreversible process. And it cannot be improved. Following the primary injury, secondary injury is a kind of molecular and cellular level of active adjustment process. It is reversible and controllable. Currently, the treatment options for spinal cord injury ( SCI ) include pharmacological agents, surgical intervention, cellular therapies and rehabilitative care. Nonetheless, SCI is still a harmful condition for which there is yet no cure. None of pharmacologic therapies have become the standard of care. Nevertheless, recent clinical and basic science research has shown surgical decompression is a potentially valuable modality for the treatment of SCI. This review provides an overview of research progress on intra-dural decompression for SCI, covering areas from pathophysiology and phases to the role and timing of surgical decompression.

Spinal cord injuries; Pathologic processes; Decompression, surgical; Therapeutics

10.3969/j.issn.2095-252X.2016.11.012

R683.2

200032 上海，復(fù)旦大學(xué)附屬中山醫(yī)院骨科 ( 梁兵、董健 )；100048 北京，解放軍總醫(yī)院第一附屬醫(yī)院骨科( 梁兵、唐家廣 )

唐家廣，Email: tangjiaguang2013@163.com

2016-08-31 )