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A 37-year-old man presented with a 7-month history of vertigo, nausea, dysphagia, right-sided tinnitus, and hearing loss. He denied headache, paresthesias, change in vision, or problems with cognition. He endorsed a history of progressive fatigue, generalized weakness, and poor libido. His symptoms left him functionally impaired and bedridden.
37岁男性，近7个月出现眩晕、恶心、吞咽困难、右侧耳鸣和听力受损。患者否认有头痛、感觉异常、视力变化或认知障碍等症状，诉既往有进行性疲惫、全身乏力感、性功能障碍等病史。这些症状使患者机能受损，长期卧床。
His medical history was remarkable for dyslipidemia, obesity hypoventilation syndrome, nephrolithiasis, and an episode of bilateral anterior uveitis 6 years prior. In addition, he had been in a motor vehicle collision that caused a facial degloving injury requiring multiple operations, leaving the patient with vision loss in his left eye.
患者既往有明显的血脂异常、肥胖低通气综合征、肾结石病史，6年前曾患双侧前葡萄膜炎。此外，患者在一次车祸中引起面部套状撕脱伤，需要多次手术，遗留左眼视力丧失。
On examination, the patient was morbidly obese with extensive scarring on the left side of his face. There was decreased visual acuity and left exotropia. The right pupil was dilated with a sluggish response to light. The left pupil could not be reliably examined due to the changes from his prior facial degloving injury. There was also lower lid scarring on the left with lagophthalmos, again secondary to his prior injury. The right lid was normal. There was a mild left-sided facial weakness in a lower motor neuron pat-tern. His speech was dysarthric. Examination of the remaining cranial nerves (CNs) was normal. Strength was 5/5 in the upper extremities bilaterally and 4 /5 in the lower extremities bilaterally. Muscle bulk and tone were normal, as were coordination and fine motor movements. Sensation and reflexes were intact. Rom-berg test was negative. Bilateral sensorineural hearing loss, mild to moderate on the left and moderate to severe on the right, was confirmed objectively with audiometry.
查体：患者病态肥胖、左侧面部大片疤痕、视力下降、左眼外斜视，右眼瞳孔扩大、对光反射迟钝。因为之前面部撕脱伤引起的后遗症，左眼不能被可靠地检测。左眼闭合不全，下眼睑瘢痕，也是继发于先前的外伤。右眼睑正常。左侧轻度下运动神经元性面瘫，构音障碍。其他颅神经检查正常。双上肢肌力5/5级，双下肢肌力4 /5级。肌容积和肌张力正常，共济和精细运动正常。感觉和反射检查正常。闭目难立征阴性。通过客观的测听检测证实双耳感音性听力减退，左耳轻到中度，右耳中重度。
Question for consideration: 1. Can you localize the lesion based on the patient’s constellation of findings? 思考问题： 1. 你能根据患者的临床表现定位病变部位吗？
CT of the head (figure ,1 A and B) demonstrated multiple enhancing intra-axial lesions. The largest measured up to 12×15×12 mm and was located in the lentiform nucleus. There were multiple other lesions involving the anterior parasagittal region of the right frontal lobe, the rostrum of the corpus callosum, and the hypothalamus. There were also findings suspicious for leptomeningeal enhancement, particularly in the basal cisterns. There was no evidence of hydrocephalus or herniation. MRI (figure 1, C and D) confirmed the presence of multiple enhancing parenchymal lesions and leptomeningeal enhancement in the posterior fossa.
头CT（图1，A和B）显示多发颅内强化病灶。最大的位于豆状核，达到12×15×12mm大小。其他病灶累及右额叶旁矢状面的前部、胼胝体嘴和下丘脑。头CT上也发现可疑柔脑膜强化，特别是基底池部位。无脑积水或脑疝迹象。磁共振（图1，C和D）证实存在多发脑实质强化病灶，以及后颅窝柔脑膜强化。 图1 头CT、MRI 增强CT（A，B）和T1加权MRI（C，D）轴位层面显示遍布脑实质的多发强化病灶。图B中显示的右额病灶为被活检病灶部位。柔脑膜强化在MRI钆增强序列上显示最清楚（白色箭头）。
Questions for consideration: 1. What is your differential diagnosis at this point? 2. What further investigations would you order at this point?
思考问题： 1、 此刻，你的鉴别诊断有哪些？ 2、 基于这点，你还要进一步做哪些检查？ The differential diagnosis for multiple cranial neuropathies with evidence of several intracranial lesions is extensive. This presentation is particularly worrisome for an underlying neoplastic process, particularly primary CNS lymphoma. Leptomeningeal carcinomatosis or metastatic disease are also possibilities. Alternatively, granulomatous disease, and infections such as tuberculosis, histoplasmosis, toxoplasmosis, blastomycosis, and HIV, are diagnostic considerations.
多发颅神经病变伴数个颅内病灶的鉴别诊断很多。其临床表现特别让人担心是潜在的肿瘤病变，特别是原发性中枢神经系统淋巴瘤，也有可能是软脑膜癌病或转移瘤。其他要考虑的鉴别诊断有肉芽肿病、感染性疾病，如结核、组织胞浆菌病、弓形体病、芽生菌病和HIV。
Further imaging tests were performed to identify a possible primary malignancy or other sites of disease involvement. CT chest demonstrated mediastinal and hilar lymphadenopathy with scattered small pulmonary nodules. CT abdomen showed retroperitoneal lymphadenopathy, with normal liver and skeletal structures.
给予进一步的影像检查来鉴别可能存在的原发性恶性肿瘤或其他部位受累疾病。胸部CT显示纵膈和肺门淋巴结肿大，肺内散在的小结节。腹部CT显示腹膜后淋巴结肿大，肝和骨骼结构正常。
Blood cultures were persistently negative, as were serologies sent for HIV, histoplasmosis, toxoplasmosis, and blastomycosis. CSF examination showed lymphocytic predominance with low glucose (0.6 mmol/L) and high protein (3.15 g/L). CSF flow cytometry was negative. Serum and CSF angiotensin-converting enzyme (ACE) levels were not elevated (22 U/L and 18U/L, respectively). CSF was sent for acid-fast bacilli stain, which was negative, as were mycobacterial cultures. Tuberculin skin test and interferon-gamma release assays were negative.
血培养持续呈阴性，针对HIV、组织胞浆菌病、弓形体病和芽生菌病的血清学检验也是阴性。脑脊液检测以淋巴细胞为主，糖降低（0.6mmol/L），蛋白升高（3.15g/L）。脑脊液流式细胞仪检测阴性。血清和脑脊液血管紧张素转换酶水平没有升高（分别是22U/L和18U/L）。送检脑脊液抗酸杆菌染色阴性，分枝杆菌培养也呈阴性。结核菌素皮肤试验和γ-干扰素释放试验均阴性。
Multiple attempts at biopsy of the mediastinal lymphadenopathy yielded nondiagnostic results. A biopsy of the most accessible intracranial lesion located in the right frontal lobe showed necrotizing granulomatous inflammation (figure 2). Stains for infection were negative. There was no evidence of neoplasia.
多次尝试纵膈肿大淋巴结活检没有获得有助诊断的结果。右侧额叶的病灶最容易取材，活检显示坏死的肉芽肿炎症（图2），感染相关的染色呈阴性，未发现肿瘤证据。 图2 脑活检的组织病理 （A）活检脑组织的低倍视野显微镜下显示多发的肉芽肿（选取标本上的黑星）。（B）高倍视野下的一个肉芽肿，可见多核巨细胞（箭头）和一个中心坏死区（白星）。HPS染色。A，40倍；B，185倍。
Question for consideration: 1. What is the final diagnosis?
思考问题： 1、 最后诊断是什么？
Given the history of prior anterior uveitis, multiple cranial neuropathies, and bilateral hilar and mediastinal lymphadenopathy, the patient’s presentation is most compatible with neurosarcoidosis. The necrosis seen on biopsy, though unusual with sarcoidosis, is consistent with necrotizing sarcoid granulomatosis, a rare subtype.1 Though serum and CSF ACE levels were normal, both tests have poor sensitivity and specificity.2
考虑到既往前葡萄膜炎病史、多颅神经病变、双侧肺门及纵膈淋巴结肿大，患者的临床表现最符合神经结节病。活检中见到的坏死，尽管在结节病中不常见，也符合坏死性结节性肉芽肿病，这是一种罕见的亚型。虽然血清和脑脊液血管紧张素转换酶水平正常，这两项检验的敏感性和特异性都不高。
Sarcoidosis is an uncommon disease with protean manifestations characterized by the appearance of noncaseating granulomas in involved organs.3 The etiology is poorly understood, but thought to be related to an exaggerated immune response to unidentified antigens, occurring in genetically predisposed individuals.3 The most common site of disease involvement is the pulmonary parenchyma and mediastinal and hilar lymph nodes (90%). However, up to 50% of patients will have extrapulmonary manifestations, including the anterior uvea (10%–30%), peripheral lymph nodes (10%–20%), and skin (15%).3–5 The CNS is an unusual site of granuloma formation, affecting only 5% of patients, but carries significant morbidity.3–5 Our patient had evidence of neurologic and pulmonary involvement, based upon his radiologic findings.
结节病是一种罕见病，症状变化多样，以受累脏器出现非干酪样肉芽肿为特点。病因不甚明确，但认为与遗传易感个体对不能识别的抗原产生了过度免疫反应有关。疾病累及的最常见部位是肺实质、纵膈和肺门淋巴结（90%）。然而，多达50%的患者会有肺外表现，涉及前葡萄膜（10%-30%）、周围淋巴结（10%-20%）和皮肤（15%）。中枢神经系统是肉芽肿形成的罕见部位，虽仅5%的患者受累及，但发病率显著。根据其影像学表现，该患者存在神经系统和肺受累的证据。
Neurosarcoidosis is challenging to identify and is rarely a definitive diagnosis.2 The most common manifestation is cranial neuropathies, observed in50%–75% of cases.2,5 The CN dysfunction is a result of multiple mechanisms, including increased intracranial pressure, mass effect from granulomas, and basal meningitis causing compression of CNs traversing the subarachnoid space.2,5 CN VII is the most commonly affected, followed by CN II.2,5 Our patient’s facial droop, lateral gaze deviation, and hearing loss were indicative of CN VII and CN VIII dysfunction and a partial CN III palsy. Aseptic meningitis is observed in 10%–20% of cases, manifesting as a lymphocytic pleocytosis with elevated protein and low glucose.2,5 Our patient’s CSF analysis exhibited this pattern. Mass lesions are present in 50% of patients on imaging.2 These lesions preferentially involve the hypothalamus and pituitary gland, and up to 15% of patients will develop neuroendocrine manifestations.2,5 Our patient demonstrated elevated prolactin, presumably secondary to granulomatous involvement of the pituitary stalk. Additionally, our patient endorsed a history of poor libido and fatigue, and subsequent investigations were compatible with hypogonadotropic hypogonadism. Psychiatric symptoms, cerebellar ataxia, and peripheral neuropathy each represent other potential manifestations of neurosarcoidosis.2,5
神经结节病的识别具有挑战性，很少能明确诊断。最常见的表现是颅神经病变，见于50%-75%的患者中。颅神经病变是多种机制作用的结果，包括颅内压升高、肉芽肿的占位效应和颅底脑膜炎致穿越蛛网膜下腔的颅神经受压。面神经最常受累，其次是视神经。该患者面部肌肉下垂、外斜视和听力受损表明面神经、前庭蜗神经病变，动眼神经不全麻痹。无菌性脑膜炎见于10%-20%的患者，表现为脑脊液淋巴细胞增多、蛋白升高、糖降低。该患者脑脊液分析呈现的就是此种模式。占位病变见于50%患者的影像上。这些病变倾向于累及下丘脑、垂体。多达15%的患者会有神经内分泌症状。该患者催乳素水平升高，推测是因为肉芽肿累及垂体柄。另外，该患者诉性功能减退和疲劳病史，后来发现符合促性腺激素分泌不足引起的性腺功能减退症。精神症状、小脑性共济失调和周围神经病变，每一个症状都可能是神经结节病的其他临床表现。
The imaging modality of choice for neurosarcoidosis is MRI with gadolinium.2,5 Typical findings include periventricular white matter lesions and leptomeningeal enhancement, both present in our patient. However, numerous other processes can have an identical radiographic appearance, including lymphoma or leukemia and infectious and other inflammatory etiologies.5 Serum and CSF ACE levels are of limited diagnostic utility. Previous studies demonstrated that serum ACE levels are only elevated in 50% of patients with proven neurosarcoidosis.5 Similarly, CSF ACE levels are elevated in 55% of patients with known disease, and can be elevated in 5% of patients where disease is absent.5 Our patient’s serum and CSF ACE levels were both within normal limits.
神经结节病病的首选影像模式是MRI钆增强。典型表现为脑室周围白质病变和柔脑膜强化，这两种变化都出现在该患者影像上。然而，许多其他病变具有完全相同的影像学表现，包括淋巴瘤或白血病、感染性和其他炎症性病因。血清和脑脊液血管紧张素转换酶水平的诊断效用是有限的。先前的研究证实，血清血管紧张素转换酶水平仅在50%的确诊神经结节病患者中有升高。同样地，脑脊液血管紧张素转换酶水平升高见于55%的确诊神经结节病患者中，也见于5%未患此病的患者中。该患者血清和脑脊液血管紧张素转换酶水平均在正常范围。
The gold standard for diagnosis is a tissue biopsy of an involved site demonstrating noncaseating granulomas. Typically the most accessible site of disease involvement is biopsied first to minimize morbidity. In our patient, this was the mediastinal lymphadenopathy. Attempts to sample these lymph nodes via endoscopy and mediastinoscopy yielded nondiagnostic results. Ultimately, a brain biopsy was required to arrive at the final pathologic diagnosis of necrotizing sarcoid granulomatosis. The differential diagnosis of necrotizing granulomas involving the CNS is extensive, and includes numerous infectious agents (particularly fungi and mycobacteria) and noninfectious processes, such as Wegener granulomatosis and necrotizing sarcoid granulomatosis.6 To the authors’ knowledge, there are no clear data in the literature to indicate that the presence or absence of necrosis on histopathology influences the clinical behavior or response to therapy of neurosarcoidosis. Despite the lack of formal randomized controlled trials, corticosteroids are the first-line therapy of choice for neurosarcoidosis.7 The initial route of treatment is dictated by disease severity. Mild disease, such as isolated facial nerve palsy, can typically be treated with oral prednisone at a dose of 0.5–1 mg/kg/d. Severe, disabling disease is treated aggressively with IV pulse corticosteroids. A common regimen is methylprednisolone at a dose of 20 mg/kg for 3–5 days, followed by an oral regimen.2 A prolonged taper of up to 1 year may be required, but symptom recurrence is common as the corticosteroid dose nears 10–20 mg/d.5
诊断的金标准是病变部位活检证实非干酪样肉芽肿。通常最容易接近的病变部位被首先活检以减少并发症。该患者在纵膈肿大淋巴结取材。开始试图通过内窥镜和纵膈镜检查取材这些淋巴结，但没有取得有诊断价值的结果。最后进行了脑活检，得出了坏死性结节性肉芽肿病的病理诊断。累及中枢神经系统的坏死性肉芽肿病的鉴别诊断有很多，包括很多感染性病原体（特别是真菌和分枝杆菌）和非感染性疾病，如韦格纳肉芽肿和坏死性结节性肉芽肿病。据作者所知，文献中没有明确数据显示，组织病理有没有坏死对临床行为或神经结节病治疗的反应有影响。尽管缺乏正式的随机对照试验，皮质类固醇也是治疗神经类肉瘤病的一线选择药物。初始治疗路径由疾病严重性决定。轻微的病变，如孤立性面神经麻痹，通常可以用口服泼尼松治疗，剂量为0.5-1毫克/公斤/天。严重的、致残性病变积极地静脉应用皮质类固醇治疗。常用的方案是用甲基强的松龙，剂量20毫克/公斤，连用3-5天，然后改为口服。可能需要长期口服、逐渐减量达1年，但是当皮质类固醇减量至10-20毫克/公斤时，症状复发很常见。
Alternative therapies for neurosarcoidosis are typically reserved for cases where corticosteroids have been ineffective or poorly tolerated. Further, some experts have advocated for their use early in the course of treatment for those with disabling symptoms.7 These therapies are typically steroid-sparing immunosuppressive agents, such as methotrexate and azathioprine.
其他治疗神经系统结节病方法通常适用于糖皮质激素治疗无效或不能耐受的患者。此外，一些专家提倡早期应用治疗表现致残性症状的患者。这些治疗通常是类固醇节制免疫抑制剂，如氨甲喋呤、硫唑嘌呤。
In the case of our patient, he was initially treated with prednisone at a dose of 80 mg per day with a prolonged taper, and early in his course azathioprine was added and titrated to a target dose of 2.5 mg/kg/ d. The patient’s clinical response to treatment has been limited, which is not unusual with neurosarcoidosis. He was subsequently referred to an appropriate rehabilitation program.
该患者最初应用泼尼松治疗，剂量为80毫克/天，长期口服，逐渐减量；在疾病早期加用了硫唑嘌呤，逐渐加量至2.5毫克/公斤/天的靶剂量。患者对治疗的临床反应不理想，这在神经结节病中并非少见。随后该患者被安排合适的康复治疗。   猴年岁尾，收官之作 李神经群翻译中心猴年硕果累累 期待金鸡之年是个更大的丰收年！ 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》
