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Youmans:脊髓受損疾病與治療-2

WCH | 2021-06-20 13:14:09 | 巴幣 104 | 人氣 187


纖維化與膠細胞結疤

  • Scar is a second major inhibitory element within the CNS. Its importance in inhibiting regeneration was recognized prior to the discovery of myelin and ECM inhibitors, but scarring has posed a greater therapeutic challenge. The reasons are that scar is both a physical and a chemical barrier, is heterogenous in composition, and has both beneficial and harmful characteristics.
結疤是第二主要抑制中樞神經生長的原因,在治療上是很難去除的。疤同時是身體和化學上的異質性屏障,對人體有好處也有壞處。
  • At a minimum scarring in the CNS must be thought of in terms of its glial and fibrous components. Glial scarring results when hypertrophied astrocytes form a physical barrier at the periphery of the lesion, walling off injured tissue from healthy tissue. These reactive astrocytes elaborate large cytoplasmic processes that interweave to form a barrier. The astrocytes of the scar also form a chemical barrier by secreting a number of growth inhibitory CSPGs, including neurocan, versican, aggecan, brevican, phosphacan, and neural/glial antigen 2 (NG2). Glial scarring is of additional clinical significance because it has been associated with neuropathic pain. The fibrous component of scar has a more potent inhibitory effect on neurite outgrowth than the glial component. The fibrous scar is located at the lesion core. It is associated with fibroblast infiltration and the deposition of inhibitory ECM molecules. These molecules function as chemical barriers to axonal regeneration in the same fashion as myelin inhibitors.
疤可以根據它的組成分成膠細胞型和纖維化型。膠細胞型疤是因為星狀細胞過度增生所形成,會在病灶周圍形成身體上的屏障以阻擋受傷組織。受影響的星狀細胞細胞質會變大然後交織一起形成屏障。而膠細胞型疤也是化學屏障,會分泌生長抑制物質CSPGs。膠細胞疤在臨床上很容易發現因為會出現神經痛。而纖維化疤則比膠細胞疤來得更有潛在的抑制效果。纖維化疤在病灶中心形成,跟纖維母細胞的浸潤以及抑制性細胞外間質分子有關,後者則會形成化學屏障。
  • Scarring after SCI has a number of beneficial qualities. Reactive astrocytes reestablish both ionic homeostasis and the integrity of the blood-brain barrier (BBB), steps important for resolving edema and limiting the infiltration of immune cells. Although much of the glial scar contains inhibitory CSPGs, there are regions that are instead rich in growth-promoting ECM molecules such as laminin and fibronectin. Indeed, astroglial scar remote from the lesion has been shown to support axonal growth. Astrocytes are also thought to supply neurons with energy and to elaborate growth factors and beneficial cytokines. Moreover, reactive astrocytes are believed to sequester excess glutamate and potassium, which can be harmful after injury.
脊髓損傷後的結疤有很多好處。首先對應的星狀細胞會修復離子的體內平衡以及血腦屏障,這對水腫的消退以及預防免疫細胞的浸潤是很重要的。雖然多數的膠細胞疤含有抑制因子CSPGs,但也有一些區域是包含生長促進的細胞外基質因子。確實星狀膠細胞疤在病灶的遠端還是有支持軸突生長的能力。星狀細胞同時也供應神經元能量、生長因子以及有利的細胞激素。此外也有研究認為這些星狀細胞會分泌過多的glutamate和鉀離子,對受損後細胞是有害的。
  • The most convincing evidence demonstrating the importance of the glial scar comes from a classic experiment performed by Faulkner and colleagues. In their study, transgenic mice expressing a glial fibrillary acidic protein (GFAP)–herpes simplex virus—thymidine kinase transgene were given ganciclovir following SCI. The result was ablation of reactive, transgene-expressing astrocytes, which led to exacerbated tissue disruption as well as neuronal and oligodendrocyte death. The investigators also noted failure of wound contraction and severe persisting motor deficits.
對於膠細胞疤的重要性有個最使人信服的證據,來自於一個經典的實驗。在這個實驗基因轉換過的老鼠能夠表現出GFAP-HSV-TK的基因,在老鼠脊髓受損後給予ganciclovir這個抗病毒藥物(會因為HSV被抑制而同樣使得膠細胞疤被抑制)。結果發現這老鼠有基因轉換過星狀細胞會出現惡化的組織破壞,以及神經元和寡樹突細胞的死亡。這實驗同時也發現傷口無法癒合同時嚴重持久的運動傷害。
  • It is thus easy to see why astrogliosis is a challenging target following injury—it will be difficult to preserve the beneficial effects of astrocytes while preventing those that inhibit regeneration. Appropriate timing may be key to therapeutic strategies targeting the glial scar. Employed strategies to date include irradiation, photoablation, and surgical resection; however, little success has been seen with any of these approaches as yet.
這實驗可以看到為甚麼星狀膠細胞在受傷後很具有治療挑戰的目標,因為它會同時有對星狀細胞好的影響以及抑制再生的功能。適當的時機介入對膠細胞疤的治療是關鍵,對於治療方式可以有放射治療、光剝離治療以及手術切除。但這些治療都還沒有很大的成功。

幹細胞和原始細胞

  • A long-held belief—once again dating back to Cajal—viewed the mature CNS as incapable of neurogenesis. This entrenched idea was refuted when contemporary research proved the existence of adult neurogenesis and its importance in avian song learning. Subsequent research localized regions of intense neurogenesis to the subependymal region and the subgranular cell layer of the hippocampus. Moreover, neurogenesis has been demonstrated in the brains of rodents and mammals, providing further evidence that the adult CNS has a greater capacity for repair than was previously recognized. The ependymal region of the spinal cord appears to function in a capacity similar to that of the subependymal region of the brain but is less well characterized as yet. Unfortunately native adult neurogenesis is insufficient for robust neural repair.
有很長一段時間研究認為成熟的中樞神經沒有神經生長的能力,但最近的研究卻推翻這個想法。研究發現在海馬迴的室管膜下區域以及顆粒下細胞層都有很密集的神經生長。此外,在齧齒類和哺乳類動物也有發現神經生長的功能,提供了證據說明了成人的中樞神經有更好的能力去自行修復。脊髓的室管膜區域跟室管膜下區域有一樣的修復功能,但在修復的角色扮演上還不清楚。研究也發現成人神經修復能力比齧齒類動物來得差。
  • The discovery of adult neurogenesis was coincident with the birth of stem cell science, which has recognized the presence of multipotent cells in adult tissues capable of differentiating into the various mature cell types of their resident organs. Evidence has also emerged to support the notion of tumor stem cells that drive the growth of tumors. The prospect of augmenting the function of native stem cells or transplanting them to assist tissue repair has spawned the field of regenerative medicine. Hopes for regenerative medicine have been very high in neurotrauma, given the severe deficits that accompany injury as well as the limited endogenous repair inherent to the CNS.
成人神經修復跟幹細胞的發現時間很接近,可能是因為幹細胞發現同時也發現了細胞有發展成多種組織的潛能。研究也顯示腫瘤幹細胞可以發展成腫瘤。對於幹細胞如何幫助組織修復的研究也產生了再生醫學的概念。再生醫學的應用給了神經傷害很大的希望,有鑑於中樞神經受損會發生很嚴重的神經缺損以及內生性修復的限制。

神經受損的分類

  • Classification systems are intimately linked to the diagnosis and treatment of medical conditions. They facilitate research and assist with outcome prediction, and their sophistication tends to mimic our understanding of the condition they characterize. Developing a sensitive scale that precisely, accurately, and reliably captures the innumerable functions of the spinal cord has been a great challenge. Considerable advances have occurred in the development of valid, objective assessment techniques to measure changes in spinal cord function in the setting of injury or disease.
脊髓損傷的分類往往取決於診斷與治療,這分類對研究以及治療後果的預測有很大的幫助。同時很精緻的分類也模仿出我們對疾病特性的了解。要擬定出一個很精確的分類是具有挑戰性的。大量的建議以及檢測技術也被應用進了脊髓損傷和疾病之中。
  • The first widely accepted classification scheme to assess neurological function following SCI was not described until 1967, when Frankel published his classic work. Frankel described a simple and convenient five-grade scale that classified SCI as Complete (A), Sensory Only (B), Motor Useless (C), Motor Useful (D), or Recovery (E). This work has had considerable influence in that it provides an easy scheme for classifying patients on the basis of obvious and easily assessed aspects of neurological function. Its general framework lives on in more modern classification schemes. A major shortcoming of this scale, however, is the subjectivity inherent in judging what constitutes “useful.” This scale also fails to recognize laterality and the independence with which motor and sensory functions can be lost. Furthermore, the grades C and D have a ceiling effect or discontinuity, whereby disproportionately few patients improve beyond them.
第一個最廣泛使用於了解神經功能的脊髓損傷分類Frankel量表創立於1967年,透過神經功能分成A(完全受損)、B(感覺受損)、C(運動受損)、D(運動完整)或是E(復原)。這個分類提供了簡單的框架用基本的神經功能發現去區分病人。而這個很廣泛的框架在現今的分類中也被應用到。但這個框架卻太強調「有用與否」,使得無法去辨識部分的運動感覺缺損。此外,C和D分類跟E有著很大的斷層,使得少數病患很難改善到E分類去。
  • The American Spinal Injury Association scale, alternatively known as the International Standard for Neurological Classification of Spinal Cord Injury (ISNCSCI), was first published in 1982 and now forms the international standard for post-injury evaluation of neurological function. The scale is endorsed by the International Medical Society of Paraplegia (IMSOP) and has undergone numerous revisions over the years. The ASIA scale tests five key muscles in each extremity, each scored up to 5 points, thus totaling 100. It also allows for optional testing of the diaphragm, deltoids, abdominals, medial hamstrings, and hip adductors. Sensory testing results are graded as normal (2 points), decreased (1 point), or absent (0) for pinprick and light touch in the C2 through S5 dermatomes, allowing the generation of scores for each up to a total of 112 points. Testing of position sense and awareness of deep pressure/pain is considered. The result is a sensitive score useful for clinical research that can be presented in simplified form via the ASIA Impairment Scale, which is essentially a modernization of the Frankel scale. In this scale, grade A remains a complete injury and grade E remains normal neurological function. Intervening scores have been made more objective, with a muscle power grade of 3 used to discriminate among them. Unfortunately the complexity of the ASIA scale makes it time-consuming to perform, and special training is required for personnel who employ it. As well, it neglects bowel, bladder, and other autonomic functions and lacks sensitivity related to hand function and thoracic injuries. Moreover, it does not assess pain or other aspects of quality of life.
美國脊髓損傷協會量表(ASIA),又被稱為脊髓損傷神經學分類國際標準檢查表(ISNCSCI)最早在1982年出版,現在已經成為國際標準的脊髓損傷後評估。這個事由國際癱瘓醫學會(IMSOP)所擬定,也修改了數次。美國脊髓損傷協會量表有五大項目,每一項20分,依此滿分為100分。這量表給予醫師選擇要不要測試橫膈膜、三角肌、腹肌、大腿後內側肌以及骨盆內收肌。感覺測試則以正常(2分)、減弱(1分)以及缺失(0分)來做區別。滿分為112分。同時量表也要求測試本體感覺跟深部壓覺/痛覺。這個在臨床上有用的簡單表格還是源自於Frankel量表。在美國脊髓損傷協會量表之中,A級代表完全損傷而E級代表正常。而評估分數的介入也使得這量表變得更客觀。例如透過肌肉力量有無大於3紛來做肌力有無的區別。但美國脊髓損傷協會量表的缺點在於要花很長的時間去做評估,同時對於評估者也需要先進行特殊的訓練。此外它也忽視了腸道、膀胱和其他自主神經支配的器官。在手部功能與胸椎受損也缺乏靈敏度。最後它也無法對疼痛或是其他生活品質進行評估。
  • Given the importance of quality of life measures in modern medical research, scales that assess it are frequently employed alongside the ASIA scale in SCI studies. The Functional Independence Measure (FIM) has been perhaps most widely used in the SCI literature despite the fact that it was designed for widespread application to all rehabilitation recipients. It evaluates areas of self-care, sphincter control, mobility, locomotion, and communication because it was largely designed to determine burden of care. It grossly scores patients as independent or dependent .
有鑑於評估生活品質在現在醫學研究的重要性,開始出現了有別於美國脊髓損傷協會量表的研究。功能自主評估表(FIM)可能是脊髓受損中被廣泛使用的量表,用在受傷後受復建者身上。它評估了病患的自主照顧能力、括約肌控制能力、活動度、局部動作以及溝通能力。它的評估決定了病患是否有自主照顧能力。
  • In 2001 Catz and associates published the Spinal Cord Independence Measure (SCIM) as a means of better assessing patients with SCI. The SCIM assesses self-care, respiration, sphincter management, and mobility. The SCIM has demonstrated more sensitivity to functional changes in patients with SCI than the FIM, and it has been revised to increase interobserver reliability with respect to bathing, dressing, bowel management, and mobility in bed.
在2001年脊髓獨立量表(SCIM)被出版,是為了評估病人的自主照顧能力、呼吸功能、括約肌控制以及致病率。脊髓獨立量表比起功能自主評估表來得更有靈敏度,同時也可以增加對於病患洗澡、換裝、解便以及床上活動度的評估。
  • Also emerging are scales that assess walking after SCI. The Walking Index for Spinal Cord Injury (WISCI) was published in 2000 and revised a year later. Other walking tests include the Timed Up and Go (TUG), the 10 Meter Walk test, and the 6 Minute Walk Test, all three of which have been compared in the same cohort of patients and found to be valid and reliable.
同時在脊髓獨立量表後也開始重視行走功能,因此在2000年多增加了脊髓損傷的行走評估(WISCI)。另外還有坐站起走測試(TUG)、10公尺行走測試以及6分鐘行走測試。這些都在研究上證實對病患評估是有用的。

急性脊髓損傷的次級傷害以及現在臨床處置

  • Clinical management of acute SCI is largely aimed at preventing further injury and optimizing the provision of nutrients to the injured tissue. A detailed discussion of the management of acute SCI is found elsewhere in this textbook; however, there is value to reviewing clinical management principles as they relate to the scientific perspective.
急性脊髓損傷的臨床處置主要是為了預防更長遠的傷害以及給予受損組織最優化的營養。其他參考書有詳細討論臨床處置,但這裡還是要回顧臨床處置有無科學根據。

次級侵害以及如何避免

  • Secondary insults are distinct from secondary injury. They occur at the level of the organism and lead to deficient provision of nutrients to injured CNS tissue. Hypotension and hypoxia, two secondary insults commonly seen after SCI, are believed to exacerbate secondary injury processes and worsen neurological injury. There is strong evidence that secondary insults markedly worsen outcome from TBI. Data supporting ill effects from secondary insults in SCI are fewer, but avoiding such additional insults is central to the clinical management of acute SCI. Ideally such insults are prevented; next best is recognizing harmful clinical events rapidly and treating them expediently.
次級侵害與次級傷害有所不同,但他們都會造成器官的損傷同時使得受傷的中樞神經組織缺營養。低血壓和缺氧,這兩個脊髓受傷後的次級侵害,被認為會惡化次級傷害的影響而使得神經傷害更嚴重。有很強的證據證明次級侵害會顯著造成創傷性腦傷的惡化。但支持次級侵害會造成脊髓損傷的資料很少,不過預防次級侵害還是被認為是急性脊髓受損的重點臨床處置。一旦次級侵害被預防了,個別處理突發的有害的臨床事件便輕鬆許多。
  • The top priority in managing acute SCI is assessment and stabilization of vital signs, with strict adherence to Advanced Trauma Life Support (ATLS) protocol and managing the ABCs ( a irway, b reathing, and c irculation) in that order or priority. Securing the airway and protecting the cervical spine share top priority. The next priority is breathing, which deserves special attention in patients with cervical spinal cord injuries, in whom compromise of the diaphragm and intercostal musculature can markedly impair respiratory effort. Paralysis of intercostal musculature is associated with an approximate 70% decrease in forced vital capacity and maximal inspiratory force because inspiration causes chest wall collapse until the onset of spasticity. Patients whose bodies compensate initially can rapidly fatigue, and indeed, a third of patients with cervical injuries require intubation in the first 24 hours. It is thus useful to monitor vital capacity in such patients; intubation should be considered in patients whose vital capacity is less than 1L, particularly if there is evidence of fatigue.
最先要處理急性脊髓損傷的便是維持生命徵象,跟ATLS流程和維持ABC(呼吸道、呼吸與循環)。保持呼吸道暢通和固定頸椎是最優先的,再來就是維持呼吸,尤其是對於頸椎受傷的病患,因為他們橫膈膜和肋間肌肉都會受到很大的影響。這些病人的肋間肌肉通常產生吸氣能力會少70%,進而造成胸腔塌陷。病人因此會急速感到疲勞,而1/3的頸椎受傷病患也因次需要在24小時內插管。因此這類病人監控肺活量很有幫助。肺活量少於1L的病患需要考慮插管,尤其是開始出現疲勞的症狀。

神經性休克與脊髓休克

  • Hypotension is an additional secondary insult that is critical to avoid after SCI. Two causes deserve special consideration in the context of SCI. First, neurogenic shock refers to hypotension and bradycardia due to interruption of the descending sympathetic tracts after severe CNS damage (brain or cervical or high thoracic [T6 or above] SCI). Neurogenic shock is typified by preserved urine output and warm extremities. Care must be taken to ensure that hypotension from other causes is excluded, in particular occult hemorrhage, which can be challenging to detect in patients with sensorimotor deficits. Fluid administration is generally considered first-line therapy in this situation,  although restricted heart rate makes patients with neurogenic shock susceptible to fluid overload. Early consideration of vasoactive agents is thus recommended. In the Clinical Practice Guidelines of the Consortium for Spinal Cord Medicine, this approach is recommended to maintain systolic blood pressure above 90mmHg, with at least level II evidence supporting this recommendation. Largely on the basis of a study by Vale and colleagues, SCI guidelines currently recommend efforts to optimize spinal cord perfusion by maintaining mean arterial pressures higher than 85mmHg for the first 7 days after injury.
低血壓是脊髓損傷後很需要預防的次級侵害,有兩種可能原因。首先神經性休克會造成低血壓以及心跳變慢,因為在嚴重的中樞神經受損後會影響到交感神經的下降路徑(下圖所示,尤其是傷害在第6胸椎以上)。神經性休克往往會保留解尿功能以及四肢溫熱。在處理低血壓之前需要排除其他會造成低血壓的可能性,尤其是失血的可能,這在有感覺運動缺損的病患身上不好診斷。輸液的提供被視為一線治療,也可以早期提供刺激血管的藥物治療。在脊髓醫學協會的臨床處理指引中,建議血壓要高於90mmHg(等級II)。研究也指出在受傷前七天維持血壓超過85mmHg是可以促進脊髓的血液灌流。

  • Spinal shock, which is not to be confused with neurogenic shock, is characterized by the loss of reflexes, bladder function, and muscle tone below the level of injury. Spinal shock usually lasts for days or weeks after SCI, the average duration being 4 to 12 weeks. The identification of clinical signs that define the duration of spinal shock is controversial. Different writers have defined the termination of spinal shock as the appearance of the bulbocavernosus reflex, the recovery of deep tendon reflexes, or the return of reflex detrusor functions. In 2004, Ditunno and colleagues proposed a four-phase model for spinal shock: areflexia or hyporeflexia (0 to 24 hours), initial reflex return (1 to 3 days), early hyperreflexia (4 days to 1 month), and spasticity (1 to 12 months).
脊髓休克,和神經性休克不同,跟反射、膀胱功能以及受傷處以下的肌肉張力喪失有關。通常發生於脊髓損傷數天到數周後,一般會持續4-12周。對於脊髓休克的結束的時間點還是有爭議的,定在球海綿體肌反射的出現、深層肌腱反射的出現或是逼尿肌功能的恢復都有提過。在2004年有學者將脊髓休克分為四個階段:無反射或低反射(0-24小時),反射開始恢復(1-3天),早期過度反射(4天-1個月)以及痙攣(1-12個月)。


脊髓減壓的時機

  • Spinal cord compression is frequently seen after spinal injuries and can impair blood flow, causing spinal ischemia. Given the exquisite sensitivity of the CNS to ischemia, it seems logical that efforts to mitigate this compression and ischemia as quickly as possible should reduce secondary SCI and improve outcome. A significant body of animal research has indeed demonstrated neurological benefit to early decompression of the injured spinal cord; however, such benefit is less clear in the human, particularly in patients with polytrauma, who are often medically unstable in the acute postinjury phase. Despite the fact that early spine surgery appears safe in patients with polytrauma, the question whether early decompression for acute human SCI is beneficial has been viewed as incompletely answered.
脊髓壓迫常見於脊髓損傷,會導致血液流通不良而造成脊髓缺血。有鑑於中樞神經很容易被缺血所影響,理論上盡速脊髓減壓是可以減少次級脊髓損傷的。一個大型動物實驗有發現早期減壓能夠減少脊髓的傷害。但這個好處對人類還是未知的,尤其是對有多處創傷的病患,往往病情不穩定不適合減壓。雖然早期脊髓手術對於多處創傷的病患而言是安全的,但早期減壓對人類脊髓損傷的好處還是未知的。
  • The Surgical Treatment of Acute Spinal Cord Injury Study (STASCIS) was initiated in 2003 to investigate the putative efficacy of early decompression. This trial was designed to be randomized, but resistance to randomly assigning patients to intentionally delayed decompression led to the trial's restructuring as a prospective observational study. The results of the study were published in 2012. A total of 313 patients were enrolled, of whom underwent early surgery, defined as within 24 hours of SCI; underwent late decompressive surgery. Univariate analysis showed that patients who had early decompression were 2.6 times more likely to have a two-grade improvement in ASIA Impairment Score by 6 months after injury (95% confidence interval [CI], 1.11-5.97). In multivariate analysis, the odds of two-grade improvement in ASIA Impairment Score increased to 2.8 with early decompression (95% CI, 1.10-7.28). Early surgery was associated with a nonsignificant decrease in the risk of complications.
急性脊髓手術治療研究小組(STASCIS)在2003年啟動早期減壓的研究,原本設計成隨機試驗,但沒有故意對病患延後治療的考量所以改成前瞻性研究。結果發表於2012年,有313個病患參與,被區分成受傷前24小時的早期治療以及24小時候的延後治療。結果顯示早期減壓比起延後治療多了2.6倍的可能在受傷後6個月有所改善。進一步分析則發現高出2.8倍。但早期治療也沒有顯著降低併發症的風險。
  • Central cord syndrome is uniquely challenging with respect to determining the optimal timing of intervention, given that most patients present without spinal instability and experience substantial spontaneous neurological improvement. Also, a historic and influential publication from Schneider and colleagues in 1954, which first described central cord syndrome, reported several poor outcomes arising from early decompression. The result was a recommendation to consider central cord syndrome a unique clinical entity and to avoid early procedures because of perceived risk to the spinal cord. Despite the tenuous evidence supporting it, this recommendation has persisted in the literature, although later evidence challenges this conclusion.
中央脊髓症候群開刀時機往往都有爭議,有鑑於多數病患脊髓不穩定以及會經歷到自發性神經改善。一個1954年的歷史且影響深遠的研究最先提到了中央脊髓症候群以及有些早期開刀後結果很差的。這個研究建議不應該早期開刀因為會對脊髓有風險。雖然沒有太多證據支持,但該文章還是堅持早期開刀。只是最新的研究質疑了這個說法。
  • It is our opinion that unless compelling evidence to the contrary arises in the future, central cord syndrome should be treated in the same fashion as other spinal cord injuries.
本書建議除非未來有更顯著的證據,不然最好還是跟脊髓損傷一樣的治療方式。

類固醇(Methylprednisolone)

  • Numerous putative neuroprotective drugs targeting secondary injury processes have been tested in large multicenter prospective randomized controlled trials for human SCI. Tested agents include methylprednisolone sodium succinate (MPSS), tirilazad mesylate, GM-1 ganglioside, thyrotropin-releasing hormone (TRH), gacyclidine, naloxone, and nimodipine. GM-1 ganglioside, also known as Sygen, is a complex glycolipid abundant in the membranes of nervous tissue that demonstrated inconsistent results in human clinical trials. Thyrotropin-releasing hormone demonstrated statistically significant benefit in patients with incomplete SCI, but this finding may represent type I error, given the attrition seen in the study. Gacyclidine, or GK-11, is a glutamate antagonist that failed to show a sustained benefit in a phase 2 human trial, although this finding may represent type II error. Nimodipine was tested in a French human trial in 1996 but did not show benefit. The opioid antagonist naloxone was tested in two human clinical trials but also did not demonstrate convincing benefit.
許多被認為對神經有保護作用的藥物用來治療次級傷害,也開始被進行大型隨機試驗的研究。其中GM-1神經節苷脂,又被稱作Sygen是個複雜的醣脂質其中富含著神經組織,在許多試驗中有著不一致的結果。甲狀腺促素釋素顯示對於不完全脊髓損傷的病患有顯著的好處,但該試驗有出現誤差。Gacyclidine或稱作GK-11,是個glutamate抑制劑在第二期人體試驗中被發現沒有好處,不過也可能有誤差。Nimodipine血壓要在1996年被試驗但沒有太大效益。鴉片類抑制劑naloxone在兩個人體試驗中也诶出現明確效益。
  • Methylprednisolone sodium succinate, (Solu-Medrol, Pfizer, Inc., New York) is the only agent from completed clinical trials that has entered clinical use for SCI, but this use is controversial. MPSS is a corticosteroid. Corticosteroids have been employed in neurotrauma for decades but have only lately been subject to intensive scientific scrutiny. Their described neuroprotective effects include antioxidant properties, enhancement of spinal cord blood flow, reduced cellular calcium influx, reduced axonal dieback, and attenuated lipid peroxidation. Following the accumulation of preclinical data that were generally supportive of a neuroprotective role in animal models of acute SCI, MPSS was studied in five prospective human acute SCI trials, making it the most extensively studied drug for acute SCI.
類固醇MPSS是唯一有完成臨床試驗並投入臨床治療的藥物,但治療效果還是備受爭議。類固醇被用在神經創傷已積數十年有,但直到最近才開始有科學上的推敲。他們認為類固醇有著抗氧化、增加脊髓灌流、減少細胞鈣離子流入、減少軸突死亡以及減少脂質過氧化體的神經保護功能。MPSS除了在動物試驗普遍被測是,也包含五個人體試驗,可以說是最廣泛被研究的藥物。
  • The landmark National Acute Spinal Cord Injury Study (NASCIS) and its two later versions examined the use of MPSS for acute SCI. The first study, published in 1984, compared high-dose with low-dose MPSS ; the use of placebo was judged unethical because benefit from steroids was presumed. Neurological improvement was not significantly different in the two treatment groups, although a statistically significant higher rate of wound infection was noted in the high-dose group as well as higher rates of gastrointestinal hemorrhage, sepsis, pulmonary embolism, delayed wound healing, and death.
很有決定性的國家急性脊髓損傷研究公布的兩個最新的研究檢視了MPSS在急性脊髓損傷的使用。第一篇發表於1984年,用高劑量和低劑量的MPSS來比較。不跟安慰劑比較是因為類固醇被預期是有益處的,只用安慰劑實在太過於不人道。比較後發現沒有太大差異,在高劑量也被發現有顯著的傷口感染以及腸胃出血、敗血症、肺栓塞、傷口治療延後甚至死亡。
  • Animal studies completed subsequent to the first NASCIS suggested that higher MPSS doses may be required for neuroprotection. NASCIS II was thus designed to compare a higher dose of MPSS with placebo and with the opioid antagonist naloxone given within 24 hours of injury. In the overall analysis there was no neurological benefit in the MPSS-treated group; however, a post hoc analysis performed as part of the original plan found that patients receiving the drug within 8 hours of injury benefited neurologically—including those with complete injuries. As in NASCIS I, MPSS administration was associated with higher rates of wound infection and pulmonary embolism.
這研究之後又完成了動物試驗,發現高劑量MPSS也有神經保護功能。因此在第二次研究中用高劑量MPSS加上安慰劑以及加上naloxone,在脊髓損傷24小時內給予治療。兩整沒有太大的差異。但事後分析卻發現在8小時內使用MPSS對神經益處,即便病患是完全損傷。
  • NASCIS III was designed and powered to explore the beneficial effects of administration of MPSS within 8 hours of injury, as reported in NASCIS II. This was the only NASCIS to assess functional outcome, employing the FIM. NASCIS III compared the 24-hour MPSS infusion used in NASCIS II with a 48-hour MPSS infusion and with tirilazad mesylate, a 21-aminosteroid with antioxidant but not glucocorticoid effects. Overall this trial demonstrated no sustained benefit to MPSS administration. A post hoc analysis noted that patients receiving MPSS 3 to 8 hours after injury demonstrated improved neurological function at 6 weeks and 6 months but not at 1 year, when administered MPSS for 48 hours rather than 24 hours. This finding led to the recommendation that if MPSS were given within 3 hours of injury, the 24-hour infusion would suffice, but if treatment was initiated between 3 and 8 hours after injury, a 48-hour MPSS regimen was better than the 24-hour regimen. The 48-hour regimen represents the highest dose of MPSS prescribed for any clinical condition and was associated with a two-times-higher rate of severe pneumonia, a four-times-higher rate of severe sepsis, and a six-times-higher incidence of death in comparison with the 24-hour regimen.
第三次研究為了討論在8小時內使用MPSS的好處,透過FIM做評估。第三次研究MPSS給24小時、48小時以及給予tirilazad mesylate,一個抗氧化類固醇但沒有糖皮質激素效果的藥物做比較。事後分析發現8小時內給予MPSS可以在6周至6個月改善神經功能但一年後就沒了。這只有在給48小時的才有,但給24小時的沒有這個效果。研究顯示如果在3小時內給予,給24小時就足夠了。不過如果是3-8小時給予,48小時的會比24小時來得有效益。同時也有研究發現48小時給予高劑量MPSS相比於24小時有2倍機會導致嚴重肺炎,4倍機會導致嚴重敗血症,以及6倍機會導致死亡
  • Two other prospective human SCI trials involving corticosteroids have been published. Although Otani and colleagues reported benefit from MPSS administration, Pointillart and associates  reported none. Nonetheless, both studies were small and plagued by methodologic problems that limit the interpretation of their results as either positive or negative.
兩個人體試驗其中一個表示MPSS有幫助,但一個則表示沒有。但這兩個研究規模太小且有瑕疵。
  • Later evidence further informs the use of MPSS for SCI. A 2012 Cochrane meta-analysis and review concluded that the benefit of MPSS for acute SCI is not associated with a significant increase in the risk of complications or mortality although a trend is apparent. As well, the STASCIS noted a benefit to MPSS administration and the researchers had to control for this effect in their analysis.
最新的研究2012年的多項數據分析與回顧發現MPSS有好處且跟顯著增加併發症或死亡是沒有太大關係。同時急性脊髓手術治療研究小組也註明使用MPSS是有效的。
  • Two predominant concerns regarding the use of MPSS for acute SCI have arisen. First, the benefits noted have been modest and have come from secondary analyses for which the studies were not designed or powered. Second, high rates of adverse events were consistently associated with MPSS administration. The latest version of the acute SCI guidelines now provide a level I recommendation against the administration of MPSS, a marked change from the previous version despite little change in the evidence considered. Our personal view is that given the severity of SCI deficits and current lack of alternatives, administration of MPSS (NASCIS II protocol) remains justified for selected patients with acute SCI if begun within 8 hours of injury.
兩個關於MPSS治療的重要考量也被提出,首先是MPSS的好處都被低估,而這些結果也是來自於那些沒倍設計過或是強化過的研究。再者使用MPSS有很高的機率會出現副作用。急性脊髓損傷指引的最新版本將MPSS的使用訂為強烈建議。本書的個人觀點是有鑑於脊髓損傷的嚴重性以及沒有其他藥物取代,8小時內使用MPSS是合理的。

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