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A 48-year-old football referee presented with a 6-week history of bilateral distal leg weakness, numbness, and worsening mobility, and a 4-week history of tingling in all fingers. Six months earlier he had noted bouts of generalized tiredness lasting minutes at a time although he had continued to complete football games. One month later, he developed bilateral calf tightness and occasional imbalance while walking, and the generalized periods of tiredness were more prolonged, lasting up to 2 hours.
一位48岁男性足球裁判员主因双下肢远端无力、麻木、走路不稳6周，手指刺痛4周入院。6个月前曾在足球比赛中出现持续数分钟的全身乏力，但他仍坚持完成了比赛。1个月前出现双侧小腿肚紧皱感，行走时有时会出现不平衡，全身乏力的持续时间也延长到2小时。
On presentation, the numbness had advanced proximally from the feet to the knees. He had developed a broad-based gait and needed aids to walk. Bladder and bowel function were normal. His appetite was unaffected with no weight loss. On further questioning, he reported erectile dysfunction for more than 1 year. He had a history of hemochromatosis (C282Y homozygote) and received venesections every 3 months. He was a nonsmoker and drank 12 units of alcohol a week.
入院时，患者麻木感从脚进展到膝部，并逐渐出现了宽基底步态，需要帮助才能行走。大小便功能正常，食欲没有影响，体重没有下降。进一步询问病史，患者1年多前就出现了勃起功能障碍。既往有血色素沉着症（C282Y纯合子），每3个月接受一次静脉切开放血治疗。患者无吸烟史，每周饮酒12单位（96克酒精）。
Clinical examination revealed normal cranial nerves and upper limbs and bilateral pitting pedal edema up to the midshin. Medical Research Council power was 4/5 hip flexors and extensors, 3/5 at knees, and 1–2/5 at ankles bilaterally. Deep tendon reflexes were absent. Plantar responses were mute. Pinprick sensation was reduced in both feet. Joint position and vibration sense were impaired up to the ankles and knees, respectively. Romberg test was positive with broad-based and high stepping gait. Systemic examination revealed hepatomegaly with no lymphadenopathy.
体格检查示颅神经和上肢正常，累及到胫骨中部的双侧凹陷性足部水肿，双侧髋部肌力4/5级，膝部肌力3/5级，踝部肌力1-2/5级，腱反射消失，跖反射消失，双侧足部针刺觉减弱，踝部及膝部以下关节位置觉及震动觉减弱，Romberg征阳性，并有宽基底步态和高抬步步态。全身系统查体示肝大，无淋巴结肿大。
Questions for consideration: 1. Would you want to clarify any aspect of the patient’s history? 2. What is the differential diagnosis for his presentation?
问题思考： 1. 该患者的病史是否明确？ 2. 鉴别诊断有哪些？
Hepatomegaly might be expected in hemochromatosis, but regular venesection points toward the possibility of this being an independent feature. Erectile dysfunction suggests autonomic involvement or hormonal deficiencies. To delineate this, it is worthwhile revisiting the history to enquire about change in shaving frequency, body hair, or gynecomastia, which would suggest sex hormone abnormalities, or palpitations, postural hypotension, diarrhea, or constipation, which would suggest autonomic dysfunction. In our patient, there were no specific features of either.
血色素沉着症可能引起肝大，但规律的静脉切开放血治疗提示肝大可能独立于血色素沉着症。勃起功能障碍考虑有自主神经功能障碍或性激素分泌异常。为进一步明确是哪种原因，需再追问患者有无刮须频率、体毛及乳房变化，若出现这些情况，考虑性激素分泌异常。若患者有心悸、体位性低血压、腹泻或者便秘的情况，则考虑自主神经功能障碍。该患者上述两种表现都没有。
The findings suggest a length-dependent, sensorimotor, symmetrical polyneuropathy with sensory ataxia. Lack of upper motor neuron signs rules out cord pathology such as transverse myelitis. Diabetes is the most common cause of neuropathy in the Western world, but the speed of onset and sensory ataxia would be unusual. Both of these features could be explained by chronic inflammatory demyelinating polyradiculoneuropathy, although classically this would preferentially affect proximal power. The absence of bowel or bladder dysfunction, a sensory level or saddle anesthesia makes cauda equina pathology unlikely.
根据患者的临床表现，支持是一个长度依赖性、感觉运动均受累、对称性的并有感觉性共济失调的多发性神经病。没有上运动神经元受损的体征，可排除横贯性脊髓炎等脊髓病变。糖尿病是西方国家最常见的引起周围神经病变的原因，但该患者的起病速度和感觉性共济失调的表现在糖尿病性周围神经病变中是少见的。尽管慢性炎症性脱髓鞘性多发性神经根神经病（CIDP）可解释患者的起病速度和感觉性共济失调，但典型的CIDP更容易影响近端肌力。患者没有二便障碍、鞍区感觉缺失、感觉平面，不考虑马尾病变。
Toxic neuropathies secondary to alcohol, lead (predominant motor involvement), thallium (pain, paresthesias, autonomic dysfunction), dimethylaminopropionitrile (sexual dysfunction, distal sensory impairment), carbondisulfide (sensory ataxia), orethylene oxide (leg cramps, weakness, numbness, gait ataxia) are possible, but no such exposure was reported. Nutritional deficiency-related neuropathies could cause these features but often present with mixed upper and lower motor neuron signs. Neurosarcoidosis frequently presents with cranial nerve dysfunction. Paraneoplastic etiology should be considered, and progressive bouts of fatigue could point toward systemic involvement, in particular hematologic malignancies. Amyloid neuropathy is a possibility but is often associated with autonomic dysfunction.
继发于酒精、铅（以运动受累为主）、铊（疼痛、感觉异常、自主神经功能障碍）、二甲氨基丙腈（性功能障碍、远端感觉障碍）、二硫化碳（感觉性共济失调）、环氧乙烷（腿痉挛、乏力、麻木、步态共济失调）的中毒性神经病是可能的，但患者既往没有暴露史。营养缺乏性神经病可出现类似该患者临床表现，但多合并上下运动神经元受损体征。神经系统结节病多以颅神经受损多见。副肿瘤综合征需要考虑，但进行性短阵性乏力提示有全身系统受累，尤其是血液系统恶性肿瘤可能。淀粉样变性神经病也有可能，但多合并自主神经功能障碍。
The presence of sensory impairment without ocular involvement, upper extremity weakness, respiratory compromise, or a fluctuating course makes a neuromuscular junction disorder highly unlikely. Common muscle disorders would tend to have more proximal involvement, a more chronic course, and no large fiber sensory involvement.
该患者存在感觉障碍，没有眼肌受累、上肢无力、呼吸困难或者波动性病程，考虑神经肌肉接头疾病可能性很小。肌肉病变通常近端肌肉受累，病程更长，而且没有大感觉神经纤维受累。
Hemochromatosis has been independently associated with sensorimotor neuropathy with 26% patients having neuropathy in an observational study.1 No prospective studies exist to ascertain a causal relationship.
在一项观察性研究中发现血色素沉着症与感觉运动性神经病独立相关，其中26%血色素沉着症患者合并神经病[1]。目前尚没有前瞻性研究来证实其因果关系。
Questions for consideration: 1. What investigations are needed for this patient? 2. How would you sequence them?
问题思考： 1. 该患者还需进行哪些检查？ 2. 如何来安排这些检查？
Nerve conduction studies showed delayed F waves in the upper limbs and motor and sensory conduction abnormalities in lower limbs with no conduction block, suggestive of a distal axonal neuropathy.
神经传导速度检查显示上肢F波延迟，下肢感觉、运动神经传导异常，但没有传导阻滞，支持远端轴索性神经病。
Raised CSF protein at 2.76 g/L (normal range 0.1–0.5) with normal glucose and cell counts suggested an inflammatory process at the level of the nerve root.
脑脊液蛋白数升高至2.76g/L（正常范围0.1-0.5），糖和细胞数是正常的，提示为累及神经根的炎性病变。
Our patient had a normal complete blood count except for platelets of 431×109/L (normal range 150–400). Erythrocyte sedimentation rate, C-reactive protein, creatine kinase, vitamin B12, folate, immunoglobulins (Ig), thyroid function, and electrolytes including calcium were all within normal limits. Serology for HIV, hepatitis, and syphilis were negative, as were cryoglobulins and anti-nuclear, anti-neutrophil cytoplasmic and anti-ganglioside antibodies. Albumin was reduced at 31 g/L. IgG level was raised at 3.8 g/L with raised k (26.9 mg/L, normal range 3–19) and λ (41.3 mg/L, normal range 5–26), but a preserved k/λ ratio. An IgG λ paraprotein was present on immunofixation. Raised IgG or IgA can be seen in chronic inflammatory demyelinating polyradiculoneuropathy, raised IgM (with a paraprotein) in distal acquired demyelinating sensory neuropathy, and raised IgG λ in POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) syndrome.
该患者除血小板为431×109/L（正常范围150-400）外，其余血细胞计数正常。血沉、C反应蛋白、肌酸激酶、维生素B12、叶酸、免疫球蛋白、甲状腺功能、电解质都是正常的。HIV、肝炎、梅毒都是阴性，冷球蛋白、抗核抗体、抗中性粒细胞胞浆抗体、抗神经节苷脂抗体也是阴性的。白蛋白降低至31g/L。IgG水平升高至3.8g/L，并有κ（26.9mg/L，正常范围3-19）和λ（41.3mg/L，正常范围5-26）升高，但κ/λ比值正常。免疫固定电泳出现IgGλ副蛋白。慢性炎性脱髓鞘性多发性神经根神经病可出现IgG或IgA升高，远端获得性脱髓鞘性感觉神经病可出现IgM（合并副蛋白）升高，POEMS综合征（多发性神经病、脏器肿大、内分泌疾病、单克隆丙种球蛋白病、皮肤改变）可出现IgGλ升高。
Spine MRI revealed abnormal low T1-weighted and T2-weighted signal and high STIR (short T1 inversion recovery) signal of the T7 vertebral body, and CT showed loss of the normal trabecular pattern but no cortical destruction. A whole-body fluorodeoxyglucose (FDG)-PET scan showed high metabolic activity in the T7 vertebra. Other vertebrae were normal. Bone marrow aspiration was normal. Skeletal survey, renal function, bone profile, and urine Bence Jones protein (myeloma screen) were normal.
脊髓MRI显示在T7椎体有异常低T1、T2信号和高STIR（短时间翻转恢复序列）信号。CT显示正常骨小梁结构消失，但没有皮质骨破坏。全身FDG-PET扫描显示T7脊椎有高代谢活动，其他脊椎是正常的。骨髓穿刺是正常的。骨骼检查、肾功能、骨轮廓、尿本周蛋白（骨髓瘤筛查）都是正常的。
Hormonal profile showed a reduced free testosterone of 146 pmol/L (normal>200) and an abnormal cortisol response to a short Synacthen test(200nmol/ L, normal>450) suggesting adrenal insufficiency. Serum vascular endothelial growth factor (VEGF) was markedly raised at 1,698 pg/mL (normal<771). The β2 microglobulin was normal.
激素系列显示游离睾酮减少到146pmol/L（正常>200），以及对快速法促肾上腺皮质激素兴奋实验产生异常皮质醇反应（200nmol/L，正常>450），提示肾上腺功能不全。血清VEGF异常升高达1698pg/ml（正常<771），β2微球蛋白是正常的。
Sensory and motor lower limb responses were absent on nerve conduction studies 3 months later, confirming definite progression.
3个月后神经传导速度检查显示下肢感觉运动反应消失，确认病程进展。
Questions for consideration: 1. What would your next management steps be? 2. What is the likely diagnosis? 3. What are the therapeutic options?
问题思考： 1. 下一步采取什么措施？ 2. 可能的诊断是什么？ 3. 可选择哪些治疗方案？
This patient presented with progressive symmetrical distal lower limb weakness with electrophysiologic evidence of a progressive axonal sensorimotor polyneuropathy. CSF analysis suggested an inflammatory cause. Raised IgG level with an IgG paraprotein and raised k and λ light chains were observed. Since the k/λ ratio was normal, our hematologists thought that this was likely to represent monoclonal gammopathy of unknown significance. Bone marrow aspiration was non diagnostic. IVIg and plasma exchange were not considered because they are ineffective in paraproteinemic neuropathies.
该患者表现为进展性对称性下肢远端无力，并有进展性轴索性运动感觉多神经病的电生理学证据。脑脊液分析提示是一个炎性病变。检查发现伴有IgGλ副蛋白的IgG水平升高，以及κ和λ轻链的升高。因为κ/λ比值正常，血液病专家认为这很有可能代表一种意义未明的单克隆丙种球蛋白病。骨髓穿刺不具有诊断性。不考虑应用IVIG和血浆置换治疗是因为它们对副蛋白性神经病是无效的。
A strong suspicion of a hematologic malignancy driving the neuropathy led us to revisit the imaging. The CT scan of the T7 vertebra showed an expansile lesion with possible sclerotic margins (figure). Musculoskeletal oncologists agreed to biopsy the vertebra.
因为高度怀疑是由于恶性血液病引起的神经病，我们重新复习患者的影像学检查。CT扫描显示在T7脊椎有一个可能为边缘硬化的膨胀性病灶（见图），骨骼肌肉系统肿瘤专家同意行脊椎活检检查。
(A)T1像显示低信号 （B）STIR像显示T7椎体高信号 (C) CT轴位显示T7脊椎硬化 (D) H-E染色 (200×) 显示单一的浆细胞群 (T7 活检) (E) 免疫细胞化学法显示CD38阳性细胞 The biopsy showed a monotonous population of plasma cells with CD38-positive and λ-positive cells on immunocytochemistry. This confirmed a solitary T7 plasmacytoma as the likely etiology for the progressive axonal polyneuropathy, mediated by increased cytokine VEGF production.
活检显示为免疫细胞化学CD38阳性和λ阳性的单一浆细胞群，证实了孤立的T7浆细胞瘤为进展性轴索性多神经病的可能病因，且为升高的VEGF所介导。
POEMS syndrome was diagnosed because the required criteria were fulfilled (table). The patient was initiated on a 3-day IV course of methylprednisolone followed by oral prednisolone at 1 mg/kg body weight per day, which was gradually weaned over 6 months. The T7 vertebra was irradiated with a dose of 45 Gy in 25 fractions over a month with no complications.
本例满足POEMS综合征诊断标准（见表）。开始先给予静脉应用甲泼尼龙治疗3天，后续给予口服泼尼松1mg/Kg/天，并在6个月内逐渐减量后停掉。应用总剂量为45Gy的放疗量行T7脊椎放疗，在1个月内分25次完成，没有出现并发症。
表 诊断标准[4]（至少2个主要标准和1个次要标准)
缩写：VEGF=血管内皮生长因子
VEGF levels returned to normal. At 6-month follow-up, there were minor improvements in muscle power, and the patient was managing to mobilize with 2 crutches and bilateral ankle–foot orthoses.
VEGF水平恢复正常。6个月后患者肌力轻微恢复，能够应用2个拐杖及双侧踝足矫形器行走。
POEMS syndrome 2 is a rare multisystem paraneoplastic disorder caused by an underlying plasma cell neoplasia. This is most commonly seen in men (2:1) aged between 20 and 83 years (median 46 years). At least 2 major and 1 minor criteria are needed for diagnosis (table).3 Patients may present to a variety of specialists depending on symptoms, and a progressive neuropathy is most frequently encountered by a neurologist. Endocrine dysfunction commonly involves the gonadal axis followed by the adrenal glands. Hyperpigmentation or hypertrichosis are commonly observed skin changes.
POEMS综合征[2]是由潜在的浆细胞瘤引起的一种罕见的累及多系统的副肿瘤性疾病。最常见于男性患者（2:1），发病年龄在20岁到83岁之间（平均年龄46岁）。诊断POEMS需要至少2个主要诊断标准和1个次要标准（见表）[3]。患者会因出现不同的症状就诊于多个科室，因进展性神经病会最常就诊于神经科。内分泌功能障碍常见于生殖腺轴，其次为肾上腺。色素沉着或多毛症为常见的皮肤病变。
A high degree of suspicion and thorough systemic examination are required for diagnosis. Monoclonal gammopathy identified in peripheral blood gives a definite clue, but identifying the neoplastic lesion can be a challenge. Blood paraprotein can be undetectable. Immunofixation, a more sensitive measure than electrophoresis for identifying low-concentration light-chain Ig, is recommended. Identifying solitary tumors is challenging, and FDG-PET can be very helpful in such situations.
高度怀疑本病以及全面的体格检查对诊断POEMS综合征是必要的。外周血发现丙种球蛋白给我们一个明确的提示，但确定肿瘤病灶具有挑战性。血副蛋白不容易检测，推荐比电泳更敏感的免疫固定法测定低浓度轻链Ig。明确孤立的肿瘤具有挑战性，FDG-PET在这种情况下可提供很好地帮助。
VEGF levels usually normalize 1 month4 after treatment, but trends rather than absolute values are considered useful for therapeutic decisions. VEGF is a cytokine secreted by plasma cells and platelets that promotes vascular permeability, angiogenesis, and migration of monocytes and macrophages. Polyneuropathy is believed to be a consequence of neural ischemia caused by thrombosed endoneurial vessels.5
VEGF水平通常在治疗1个月后恢复正常[4]，但是在治疗决策方面VEGF变化趋势比其绝对值更有帮助。VEGF是由浆细胞和血小板分泌的细胞因子，可以增强血管渗透性、血管再生以及单核巨噬细胞迁移。多发性神经病被认为是由神经内膜血管血栓形成导致的神经缺血而引起的并发症[5]。
There are no randomized controlled trials for best practice management.6 Solitary bone lesions as in our patient are managed with localized radiotherapy. In a Mayo Clinic series, complete or partial hematologic, VEGF, FDG-PET, and clinical responses were documented in 31%, 14%, 22%, and 47% of patients treated with radiotherapy, respectively.7 Diffuse bone marrow neoplasia is treated with systemic chemotherapy. Case series of dexamethasone combined with several other agents including melphalan, cyclophosphamide, thalidomide, lenalidomide, and bevacizumab have reported a 50% to 80% hematologic response and some neurologic response.
目前还没有随机对照实验探索其最佳的临床实践管理方案[6]。我们这个患者的脊椎孤立病灶给予了局灶性放射治疗。在一个梅奥诊所的病例系列研究中，31%患者应用放射治疗可出现完全或部分血液反应，14%患者可出现完全或部分VEGF反应，22%患者出现完全或部分FDG-PET反应，47%的患者出现完全或部分临床反应[7]。弥漫性骨髓瘤应用系统性化疗治疗。病例系列中应用地塞米松联合其他制剂包括美法仑、环磷酰胺、沙利度胺、来那度胺、贝伐单抗等药物可产生50%-80%血液反应和一些神经反应。
The course of POEMS syndrome is usually chronic with one Japanese series reporting survival greater than 10 years, although estimates range from 33 months (n=102)8 to 165 months (n=99)2 in different case series. A Cochrane review of both solitary and diffuse disease with therapies including corticosteroids, chemotherapy, radiotherapy, and stem cell transplants reported mild to moderate improvement in limb function and nerve conduction velocities.6 Case series of stem cell transplants have reported substantial neurologic improvement or stabilization.4
POEMS综合征病程通常比较长。一项日本病例研究报道生存期可超过10年，尽管有估计范围在33个月（n=102)[8]到165个月（n=99）[2]之间。在一项Cochrane综述中认为，所有孤立和弥漫性病变在应用包括激素、化疗、放疗以及干细胞移植等治疗后，可出现肢体功能及神经传导速度轻度到中度改善[6]。有报道认为干细胞移植病例可产生显著地神经功能恢复或病情稳定。[4]  编辑：李会琪 阅读更多  |
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来自： 雨林医风 > 《李神经群临床推理系列》
