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A 54-year-old man presented with pain in the left chest for 3 days. His medical history was remarkable for hyperlipidemia managed with diet and statin. He denied tobacco smoking and consumption of alcohol. Physical examination was unrevealing. The patient was diagnosed with an adenocarcinoma of the lung harboring an epidermal growth factor receptor (EGFR) mutation that metastasized to T2-T4 levels. He was treated with radiotherapy and dexamethasone followed by Gefitinib.
54岁男性主因左侧胸痛3天入院。其病史有显著的高脂血症，正在接受饮食和他汀治疗。病人否认吸烟饮酒史。体格检查未见明显异常。病人被诊断为表皮生长因子受体（EGFR）突变阳性的肺腺癌，并且转移至T2-T4水平。我们对他采用了放疗和地塞米松治疗，继之给予口服吉非替尼。
In the subsequent weeks, the patient developed flaccid paraparesis with Medical Research Council (MRC) graded strength of 3/5 in most muscles of the lower limbs and normal power (MRC of 5/5) in the upper limbs. Deep tendon reflexes were symmetrical and grade 1 in the lower limbs and 2 in the upper limbs. Plantar responses were flexor. Sensory examination revealed impaired pinprick caudal to the T4 level. Cranial nerve examination was unremarkable. The patient was diagnosed with a T2-T4 pathologic fracture causing spinal cord compression He underwent urgent T2-T4 laminectomy, T3-T4 vertebrectomy, and resection of epidural tumor with partial recovery (MRC of 4/5 at most in muscles of the lower limbs and MRC of 5/5 in the upper limbs) after rehabilitation.
在随后的几周中，病人发生迟缓性截瘫，下肢大部分肌肉肌力MRC分级3/5级，上肢肌力正常（MRC分级5/5级）。腱反射双侧对称，下肢减弱（ ），上肢正常（ ）。跖反射呈屈曲反应。感觉检查显示T4水平以下针刺觉减退。颅神经检查未见明显异常。病人被诊断为T2-T4病理性骨折引起脊髓压迫。我们给他进行了T2-T4椎板切除术、T3-T4椎骨切除术和硬膜外肿瘤切除术。康复治疗后病人肌力部分恢复（下肢肌肉最大肌力：MRC分级4/5级，上肢：MRC分级5/5级）。
Approximately 2 weeks after his surgery, the patient developed rapidly progressive, severe weakness affecting lower and upper limbs with increasing respiratory discomfort over a 3-day period. The patient was intubated and transferred to the intensive care unit due to respiratory distress. He was alert without obvious cranial nerve dysfunction. Neurologic examination was remarkable for a severe, flaccid tetraparesis (MRC of 1/5 at most in all tested muscles in the lower limbs and MRC of 2/5 at most in all tested muscles in the upper limbs) in addition to diffuse areflexia and neutral plantar responses.
大约术后2周，病人在3天时间内发生了快速进展的严重的四肢瘫痪，并且伴有进行性呼吸困难。我们对他进行了气管插管；因为呼吸窘迫，将他转至重症监护病房。病人始终是清醒的，并且没有明显的颅神经功能障碍。神经系统检查显示明显的四肢迟缓性瘫痪（下肢所有测试肌肉最大肌力：MRC分级1/5级，上肢所有测试肌肉最大肌力：MRC分级2/5级），合并弥漫的反射消失和跖反射中性反应。 1. What is your differential? 2. What investigations would you recommend?
思考问题： 1. 你的鉴别诊断是什么？ 2. 你会建议什么辅助检查？ In cases of rapidly progressive tetraparesis, the clinician contemplates neurologic dysfunction at different levels of the nervous system from the motor and sensory long tracts to the spinal nerve roots, peripheral nerves, neuromuscular junction, and muscles. The nonpyramidal distribution of the weakness, lack of involvement of other supratentorial functions, and normal cranial nerve examination argued against a supraspinal localization. A reasonable etiologic differential diagnosis would include (1) progression of the spinal cancer with cervical involvement cranial to C5; (2) leptomeningeal metastasis; (3) Guillain-Barré syndrome (acute inflammatory demyelinating polyradiculoneuropathy [AIDP]) secondary to postinfectious state, paraneoplastic disease, or chemotherapy; (4) paraneoplastic neuromuscular junction disorders, e.g., Lambert-Eaton myasthenic syndrome; and (5) drug-induced myopathy due to steroids or statin. It is also worth mentioning metabolic causes of weakness with hyporeflexia or areflexia including electrolyte disturbances (e.g., hyperpotassemia, hypermagnesemia).1
对于快速进展的四肢瘫痪，临床医师在神经系统不同水平周密地考虑了神经功能缺损，从长的运动和感觉传导束到脊神经根、周围神经、神经肌肉接头和肌肉。非锥体束分布的无力、缺少其它幕上神经功能受累和颅神经正常不支持脊髓以上定位。合理的病因鉴别诊断应该包括：（1）脊柱肿瘤进展累及C5以上；（2）软脊膜肿瘤转移；（3）继发于前驱感染、副肿瘤疾病或肿瘤化疗的格林巴利综合征（急性炎症性脱髓鞘性多发性周围神经病[AIDP]）（4）副肿瘤性神经肌肉接头疾病，例如Lambert-Eaton肌无力综合征；（5）激素或者他汀诱发的肌病。另外值得一提的是引起无力伴随反射减低或消失的代谢性因素，这包括电解质紊乱（例如高钾血症，高镁血症）[1]。
The clinician should initially consider laboratory tests and neuroimaging of the spine followed by lumbar puncture with CSF analysis and electrodiagnostic studies. Indeed, the initial investigations revealed normal blood tests (i.e., complete blood count, electrolyte concentrations, creatine kinase, creatinine, and liver functions), and no evidence of progression of the metastatic spine disease on MRI (figure 1). CSF analysis was unrevealing for cell count and differential, biochemistry, infectious panel, and cytology. Of note, CSF was collected 9 weeks after cancer diagnosis and only 3 days following the first symptom the tetraparesis. Electrodiagnostic testing revealed (1) markedly reduced median, ulnar, and tibial compound motor unit potential (CMAP) amplitudes with prolonged distal latency and conduction velocity slowing; (2) conduction block of the ipsilateral ulnar nerve between the below elbow site and upper arm; (3) nonrecordable ipsilateral fibular motor responses at the extensor digitorum brevis and marked reduced CMAP and conduction block in the tibialis anterior at the knee; (4) absent ipsilateral median and ulnar F-wave responses; (5) absent ipsilateral median and sural sensory nerve action potentials; and (6) evidence of active denervation in the ipsilateral tibialis, soleus, and first dorsal interosseous muscles with relative preservation of the ipsilateral vastus medialis and pronator teres muscles (distal . proximal gradient of axonal loss) on needle examination.
临床医师应该首先考虑实验室和脊柱影像检查，然后进行脑脊液分析和电生理检查。事实上，最初进行的血液检查（亦即全血细胞计数、电解质浓度、磷酸肌酸激酶、肌酐和肝功能）是正常的，MRI未见脊柱转移瘤进展证据（图1）。脑脊液分析显示细胞计数和分类、生化、感染谱和细胞学未见异常。值得一提的是，脑脊液取自肿瘤诊断9周以后，并且距发生四肢瘫痪仅有3天。电生理检查显示：（1）正中神经、尺神经、胫神经的复合肌肉动作电位（CMAP）的波幅显著降低、远端潜伏期延长及传导速度减慢；（2）同侧尺神经在肘下和上臂段存在传导阻滞；（3）同侧的腓神经在趾短伸肌未记录到反应电位，在胫前肌未记录到CMAP的波幅显著降低及有明显的传导阻滞；（4）同侧正中神经及尺神经的F波未引出；（5）同侧正中神经和尺神经感觉神经动作电位消失；（6）在同侧的胫骨肌、比目鱼肌及第一骨间背侧肌针电极检测可见明确的失神经电位，而同侧股内侧肌和旋前圆肌相对保留。 1. What is your interpretation? 2. What are your next steps in management?
思考问题： 1. 你目前如何理解？ 2. 下一步如何处理？ Figure 1 MRI of the cervical and high thoracic spine 图1 颈椎和上胸椎MRI Sagittal T1-weighted (A) and T2-weighted (B–D) MRI of the cervical and high thoracic spine show metastatic cancer infiltrating the vertebral bodies and compression of the spinal cord from T2 to T4 levels. There was no significant interval change when compared with the patient’s initial MRI (not shown). 矢状位T1WI（A）和T2WI（B-D）MRI显示T2-T4水平转移瘤浸润椎体并压迫脊髓。相较于最初的MRI（未提供），病灶无明显变化。 Electrodiagnostic testing revealed a length-dependent, segmental, primarily demyelinating polyneuropathy, which was suggestive of AIDP. The patient denied history of recent symptoms and signs of infectious diseases. Paraneoplastic panel was negative for anti-Hu, anti-Yo, anti-Ri, anti-CASPR2, and anti-LGI1 antibodies. Gefitinib was held.
电生理检查显示长度依赖性、节段性、脱髓鞘为主的多发性神经病，这提示AIDP。这个病人否认前驱感染病史。包括抗Hu、抗Yo、抗Ri、抗CASPR2和抗LGI1抗体在内的副肿瘤抗体谱是阴性的。病人服用了吉非替尼。
Given the diagnosis of AIDP, IV immunoglobulin therapy (1 g/kg for 2 days) was instituted. Over the following 4 weeks, the patient recovered considerably from his motor deficits (MRC of 2/5 at most in the lower limbs and MRC of 4 /5in most of the upper limbs) with partial recovery of the deep tendon reflexes of the upper limbs. He was eventually transferred to a rehabilitation center.
考虑诊断AIDP，我们给予了静脉输注丙种球蛋白治疗（1克/天，共2天）。在接下来的4周中，病人运动功能有了相当的恢复（下肢最大肌力：MRC分级2/5，上肢大部分肌肉肌力：MRC分级4 /5），上肢腱反射也有部分恢复。他最后被转至康复中心。 1. What other neurologic complications should you expect? 2. How would you manage these?
思考问题： 1. 你还能想到其它什么神经系统并发症？ 2. 对这些并发症你将如何处理？ In addition to the sensorimotor deficits, patients with high thoracic or cervical lesions (at T6 or more cranial level) can develop cardiovascular complications due to loss of supraspinal sympathetic control. Furthermore, this patient was diagnosed with AIDP, which also affects motor, sensory, and autonomic nervous systems.
除了感觉运动神经功能障碍，高位胸髓或颈髓损伤（T6或以上）病人还可由于失去上位交感神经控制发生心血管并发症。此外，这个病人诊断为AIDP，这也可以影响感觉、运动和自主神经系统。
The patient initially presented with labile arterial blood pressure with a trend to hypotension and frequent hypertensive episodes (figure 2A). The patient showed no clinical or laboratory findings suggestive of shock. While low resting arterial blood pressure can be seen in patients with high thoracic spinal cord compression or AIDP, the sudden-onset hypertensive episodes are characteristic of autonomic dysreflexia that commonly occurs in patients with severe cervical or high thoracic spinal cord injury (SCI). The patient underwent a search for potential triggers of autonomic dysreflexia caudal to the level of SCI. Abdominal CT revealed fecal impaction (figure 2B). The resolution of the impaction was accompanied by stabilization in blood pressure (figure 2C).
这个病人最初血压不稳定，总体趋向低血压，但频发阵发性高血压（图2A）。其临床和实验室发现均不支持休克。尽管较低的静息血压可见于高位胸髓压迫或AIDP病人，阵发性高血压是自主神经反射异常的特点，这常发生于严重的颈髓或高位胸髓损伤病人。我们探查了引起脊髓损伤平面以下自主神经反射异常的可能诱因。腹部CT显示肠道积粪（图2B）。病人血压在肠道积粪解决之后恢复平稳（图2C）。
Figure 2 Variations in blood pressure (BP) and heart rate 图2 血压和心率变化 Hourly variations in BP and heart rate within 24hours before (A) and after (C) treatment of fecal impaction; autonomicdysreflexia characterized by hypertensive episodes is seen (A). The axial andcoronal CT images of the abdomen show impaction in the descending colon andrectum (B). 肠道积粪治疗前（A）和治疗后（C）24小时内每小时血压和心率变化；可见以阵发性高血压为特点的自主神经反射异常（A）。轴位和冠状位腹部CT显示降结肠和直肠积粪（B）。 This case illustrates potential neurologic complications of lung cancer: metastatic spinal cord compression (MSCC) and AIDP. Both conditions are associated with motor, sensory, and autonomic dysfunction.
本病例描述了肺癌可能的神经系统并发症：转移性脊髓压迫（MSCC）和AIDP。这两种情况都可以引起感觉、运动和自主神经功能障碍。
The occurrence of MSCC was estimated to be between 0.23% and 0.36% of patients with cancer.2,3 Lung, prostate, and breast cancer account for approximately two-thirds of cases.2 Nonoperative treatment of MSCC with corticosteroids and radiotherapy was considered the standard of care until the 1990s. The benefits of direct decompressive surgical resection followed by radiotherapy for management of patients with a single area of MSCC were shown in a randomized clinical trial in 2005.4 These benefits included a longer survival time, more commonly remaining ambulatory and continent, and improved pain symptoms when compared with patients who underwent radiotherapy alone.4 Although the adoption of this combined palliative approach would most likely increase health care costs, its benefits should be compassionately considered before making treatment decisions.5 While several specialists treating these patients widely recommend the combined palliative approach, there is no consensus on its indication for a multilevel MSCC. The most recent Cochrane Review indicated that “decompressive surgery followed by radiotherapy may benefit ambulant and nonambulant adults younger than 65 years of age, with poor prognostic factors for radiotherapy, a single area of compression, paraplegia for less than 48 hours, and a predicted survival of more than 6 months.” Given that this patient had multilevel metastatic spine cancer with no neurologic deficits at presentation, a multidisciplinary team recommended radiotherapy and corticosteroid therapy followed by chemotherapy.
据估计癌症病人中MSCC的发生率为0.23%~0.36%[2,3]。其中肺癌、前列腺癌和乳腺癌占了将近2/3[2]。直至20世纪90年代，采用皮质类固醇激素和放疗等非手术治疗都是MSCC的标准治疗方案。2005年一项随机临床试验展示了对单个部位MSCC病人进行直接减压手术切除继之放疗治疗的益处[4]。相较于单纯进行放疗，这些益处包括：更长的存活时间，更高的生活质量（避免长期卧床和二便失禁）和疼痛症状减轻[4]。尽管采用手术联合保守治疗很有可能增加健康护理费用，在做治疗决定之前我们也应该从关爱病人角度考虑它的益处[5]。尽管有专家广泛推荐采用手术联合保守治疗方案，如何处理多水平MSCC尚未达成共识。最新的Cochrane综述指出减压手术联合放疗可能对符合下列条件的65岁以下成人有益：存在放疗预后不佳的危险因素，单个部位压迫，截瘫48小时以内和预期存活时间超过6个月。考虑到这个病人存在多水平的脊椎肿瘤转移且入院时没有神经功能缺损，多学科团队建议采用放疗和皮质类固醇激素并继之化疗的治疗方案。
The potential clinical consequences of loss of supraspinal sympathetic control are well-recognized among patients after traumatic, severe, cervical, or high thoracic SCI.6,7 In addition to low resting blood pressure and orthostatic hypotension, individuals commonly develop hypertensive episodes associated with a variety of autonomic symptoms and signs (i.e., autonomic dysreflexia).6,7 The management of an episode of autonomic dysreflexia includes cardiovascular monitoring, assumption of the sitting position, loosening clothing or constrictive devices, and searching for potential triggers such as pressure sores, urinary complications, and other abdominal pathologies.6 Pharmacologic treatment is recommended only if the patient has persistently elevated systolic pressure (≥150 mmHg). Despite the severe potential complications of autonomic dysreflexia (e.g., retinal detachment, posterior reversible encephalopathy syndrome, seizures, stroke, and death), studies have shown that this entity is often unrecognized by individuals with SCI, caregivers, and health care professionals.6
在创伤引起严重的颈段或上胸段脊髓损伤的病人中，失去上位交感神经控制所可能导致的临床结果已可被很好地识别[6,7]。除了较低的静息血压和直立性低血压之外，具体病人还常见阵发性高血压，这与很多自主神经症状和体征相关（亦即自主神经反射异常）[6,7]。对自主神经反射异常发生的管理包括心血管监护，采取坐位，放松衣物或束缚装置，和寻找诸如压疮、尿路并发症及其它腹部疾病等可能的诱因[6]。仅在病人收缩压持续升高≥150mmHg时才推荐进行药物治疗。尽管自主神经反射异常可能引起严重的并发症（例如视网膜脱离，后部可逆性脑病综合征，癫痫发作，卒中和死亡），研究表明这个疾病实体并不为病人、照顾人员和医护人员所熟知[6]。
AIDP is also recognized as a cause of motor and sensory dysfunction as well as autonomic instability. The patient showed significant neurologic recovery after IV immunoglobulin therapy. Neurologists should have a high index of suspicion for paraneoplastic syndromes when evaluating a patient with known or suspected malignancy, even though only up to 1% of patients with cancer have an obvious paraneoplastic disorder.8 Moreover, meningeal disease, coagulopathy, metastasis, toxic, metabolic, and chemotherapy-induced causes should be ruled out before attributing a paraneoplastic diagnosis.8,9 While positive antibodies in patients with a suspected paraneoplastic syndrome are generally diagnostic, undetected antibodies occur in approximately 20% of patients with paraneoplastic syndromes of the CNS and most of the patients with paraneoplastic syndromesof the peripheral nervous system.8–10 CSF analysis is advisable in cases of a suspected paraneoplastic syndrome involving the CNS, nerve roots, or spinal sensory ganglia. In 90% of those cases, there is an inflammatory CSF change including lymphocytic pleocytosis, oligoclonal bands, and/or elevated protein, even though the sensitivity decreases with time. Normal CSF analysis is seen in only 7% of cases.8
AIDP也被认为是引起感觉、运动和自主神经功能障碍的原因之一。在静脉输注丙种球蛋白治疗之后，这个病人神经功能明显好转。尽管仅有总计1%的癌症病人合并明确的副肿瘤性疾病，神经科医师在对确诊或可疑恶性肿瘤病人进行评估时应高度警惕副肿瘤综合征[8]。此外，在诊断副肿瘤性疾病之前，我们应该排除脑膜疾病、凝血障碍、肿瘤转移、中毒、代谢性疾病和化疗诱导等因素[8,9]。尽管对于可疑的副肿瘤综合征抗体阳性具有诊断意义，大约20%的中枢神经系统副肿瘤综合征和大多数周围神经系统副肿瘤综合征抗体阴性[8~10]。我们建议对累及中枢神经系统、神经根和脊神经节的可疑的副肿瘤综合征病例进行脑脊液分析。其中有90%存在脑脊液炎性改变，这包括：淋巴细胞计数升高，寡克隆区带，和/或总蛋白升高；尽管其敏感性随时间下降。仅有7%脑脊液是正常的[8]。
The association of non-small-cell or small-cell lung carcinoma with AIDP has been reported in few cases.9,11–14 While coincidental occurrence of postinfectious AIDP and lung cancer is possible, the search for a paraneoplastic cause or drug side effect seems more appealing because “plurality must not be posited without necessity” (Occam’s razor).15 In a recent publication, a patient with adenocarcinoma of lung developed AIDP that was attributed to CASPR2 antibodies.13 Our patient tested negative for voltage-gated potassium channel antibodies (i.e., anti-CASPR2 and anti-LGI1) and anti-Hu antibodies, which are more commonly seen in patients with paraneoplastic peripheral neuropathy due to lung cancer.16 Another potential but rare cause of AIDP important in our case is the presumed association of Gefitinib with AIDP. A single case of AIDP has been noted as a potential side effect of the drug. Of note, Gefitinib is a tyrosine kinase inhibitor that has been recently approved by the Food and Drug Administration as a first-line option for the treatment of patients with advanced non-small-cell lung cancer with mutated EGFR, due to the improvement of progression-free survival.17
非小细胞或小细胞肺癌与AIDP之间的关联少见报告[9,11~14]。尽管合并存在肺癌和感染后AIDP是可能的，但从“一元论”考虑探寻副肿瘤因素或者化疗药副作用似乎更合理[15]。最近报告一例肺腺癌病人发生AIDP，被认为与CASPR2抗体相关[13]。我们的病例电压门控钾通道抗体（即抗CASPR2和抗LGI1抗体）和抗Hu抗体检测阴性，这些抗体在肺癌相关副肿瘤性周围神经病是更常见的[16]。我们病例中另一个可能但少见的引起AIDP的因素是吉非替尼。已有文献报告AIDP为吉非替尼可能的副作用。值得一提的是，吉非替尼是一种酪氨酸激酶抑制剂，最近已获FDA批准作为EGFR突变阳性的晚期非小细胞肺癌病人的一线治疗药物，因为它可以延长病人的无进展生存期[17]。
This case emphasizes a need for a greater awareness of potential secondary complications of patients with spinal metastatic lung cancer. Occam’s razor should always be used, but there is not always a clean shave. Similar to neurologic presentations of HIV, parsimony of localization and diagnosis is not always prudent. Early recognition and treatment of AIDP associated with cancer can prevent serious consequences of a potentially reversible disease. Timely diagnosis of episodes of autonomic dysreflexia can prevent complications of this lifethreatening entity.
这个病例强调我们应该更熟悉脊柱转移性肺癌病人可能的继发并发症。我们应该尽可能采用“一元论”，但也不尽然。类似的如HIV的神经系统表现，简化其定位和诊断并不总是合理的。早期识别和治疗癌症相关AIDP可以预防这种可能可逆疾病的严重后果。及时诊断阵发性自主神经反射异常可以预防这种威胁生命疾病的并发症。   编辑：李会琪 |
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来自： 雨林医风 > 《李神经群临床推理系列》
