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歲男性，近7個(gè)月出現(xiàn)眩暈、惡心、吞咽困難、右側(cè)耳鳴和聽力受損?；颊叻裾J(rèn)有頭痛、感覺異常、視力變化或認(rèn)知障礙等癥狀，訴既往有進(jìn)行性疲憊、全身乏力感、性功能障礙等病史。這些癥狀使患者機(jī)能受損，長期臥床。
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.
患者既往有明顯的血脂異常、肥胖低通氣綜合征、腎結(jié)石病史，6年前曾患雙側(cè)前葡萄膜炎。此外，患者在一次車禍中引起面部套狀撕脫傷，需要多次手術(shù)，遺留左眼視力喪失。
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.
查體：患者病態(tài)肥胖、左側(cè)面部大片疤痕、視力下降、左眼外斜視，右眼瞳孔擴(kuò)大、對(duì)光反射遲鈍。因?yàn)橹懊娌克好搨鸬暮筮z癥，左眼不能被可靠地檢測(cè)。左眼閉合不全，下眼瞼瘢痕，也是繼發(fā)于先前的外傷。右眼瞼正常。左側(cè)輕度下運(yùn)動(dòng)神經(jīng)元性面癱，構(gòu)音障礙。其他顱神經(jīng)檢查正常。雙上肢肌力5/5級(jí)，雙下肢肌力4 /5級(jí)。肌容積和肌張力正常，共濟(jì)和精細(xì)運(yùn)動(dòng)正常。感覺和反射檢查正常。閉目難立征陰性。通過客觀的測(cè)聽檢測(cè)證實(shí)雙耳感音性聽力減退，左耳輕到中度，右耳中重度。
Question for consideration:
1. Can you localize the lesion based on the patient’s constellation of findings?
思考問題：
1. 你能根據(jù)患者的臨床表現(xiàn)定位病變部位嗎？
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.
頭CT（圖1，A和B）顯示多發(fā)顱內(nèi)強(qiáng)化病灶。最大的位于豆?fàn)詈?，達(dá)到12×15×12mm大小。其他病灶累及右額葉旁矢狀面的前部、胼胝體嘴和下丘腦。頭CT上也發(fā)現(xiàn)可疑柔腦膜強(qiáng)化，特別是基底池部位。無腦積水或腦疝跡象。磁共振（圖1，C和D）證實(shí)存在多發(fā)腦實(shí)質(zhì)強(qiáng)化病灶，以及后顱窩柔腦膜強(qiáng)化。
圖1 頭CT、MRI
增強(qiáng)CT（A，B）和T1加權(quán)MRI（C，D）軸位層面顯示遍布腦實(shí)質(zhì)的多發(fā)強(qiáng)化病灶。圖B中顯示的右額病灶為被活檢病灶部位。柔腦膜強(qiáng)化在MRI釓增強(qiáng)序列上顯示最清楚（白色箭頭）。
Questions for consideration:
1. What is your differential diagnosis at this point?
2. What further investigations would you order at this point?
思考問題：
1、 此刻，你的鑒別診斷有哪些？
2、 基于這點(diǎn)，你還要進(jìn)一步做哪些檢查？
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.
多發(fā)顱神經(jīng)病變伴數(shù)個(gè)顱內(nèi)病灶的鑒別診斷很多。其臨床表現(xiàn)特別讓人擔(dān)心是潛在的腫瘤病變，特別是原發(fā)性中樞神經(jīng)系統(tǒng)淋巴瘤，也有可能是軟腦膜癌病或轉(zhuǎn)移瘤。其他要考慮的鑒別診斷有肉芽腫病、感染性疾病，如結(jié)核、組織胞漿菌病、弓形體病、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.
給予進(jìn)一步的影像檢查來鑒別可能存在的原發(fā)性惡性腫瘤或其他部位受累疾病。胸部CT顯示縱膈和肺門淋巴結(jié)腫大，肺內(nèi)散在的小結(jié)節(jié)。腹部CT顯示腹膜后淋巴結(jié)腫大，肝和骨骼結(jié)構(gòu)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.
血培養(yǎng)持續(xù)呈陰性，針對(duì)HIV、組織胞漿菌病、弓形體病和芽生菌病的血清學(xué)檢驗(yàn)也是陰性。腦脊液檢測(cè)以淋巴細(xì)胞為主，糖降低（0.6mmol/L），蛋白升高（3.15g/L）。腦脊液流式細(xì)胞儀檢測(cè)陰性。血清和腦脊液血管緊張素轉(zhuǎn)換酶水平?jīng)]有升高（分別是22U/L和18U/L）。送檢腦脊液抗酸桿菌染色陰性，分枝桿菌培養(yǎng)也呈陰性。結(jié)核菌素皮膚試驗(yàn)和γ-干擾素釋放試驗(yàn)均陰性。
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.
多次嘗試縱膈腫大淋巴結(jié)活檢沒有獲得有助診斷的結(jié)果。右側(cè)額葉的病灶最容易取材，活檢顯示壞死的肉芽腫炎癥（圖2），感染相關(guān)的染色呈陰性，未發(fā)現(xiàn)腫瘤證據(jù)。
圖2 腦活檢的組織病理
（A）活檢腦組織的低倍視野顯微鏡下顯示多發(fā)的肉芽腫（選取標(biāo)本上的黑星）。（B）高倍視野下的一個(gè)肉芽腫，可見多核巨細(xì)胞（箭頭）和一個(gè)中心壞死區(qū)（白星）。HPS染色。A，40倍；B，185倍。
Question for consideration:
1. What is the final diagnosis?
思考問題：
1、 最后診斷是什么？
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
考慮到既往前葡萄膜炎病史、多顱神經(jīng)病變、雙側(cè)肺門及縱膈淋巴結(jié)腫大，患者的臨床表現(xiàn)最符合神經(jīng)結(jié)節(jié)病。活檢中見到的壞死，盡管在結(jié)節(jié)病中不常見，也符合壞死性結(jié)節(jié)性肉芽腫病，這是一種罕見的亞型。雖然血清和腦脊液血管緊張素轉(zhuǎn)換酶水平正常，這兩項(xiàng)檢驗(yàn)的敏感性和特異性都不高。
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.
結(jié)節(jié)病是一種罕見病，癥狀變化多樣，以受累臟器出現(xiàn)非干酪樣肉芽腫為特點(diǎn)。病因不甚明確，但認(rèn)為與遺傳易感個(gè)體對(duì)不能識(shí)別的抗原產(chǎn)生了過度免疫反應(yīng)有關(guān)。疾病累及的最常見部位是肺實(shí)質(zhì)、縱膈和肺門淋巴結(jié)（90%）。然而，多達(dá)50%的患者會(huì)有肺外表現(xiàn)，涉及前葡萄膜（10%-30%）、周圍淋巴結(jié)（10%-20%）和皮膚（15%）。中樞神經(jīng)系統(tǒng)是肉芽腫形成的罕見部位，雖僅5%的患者受累及，但發(fā)病率顯著。根據(jù)其影像學(xué)表現(xiàn)，該患者存在神經(jīng)系統(tǒng)和肺受累的證據(jù)。
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
神經(jīng)結(jié)節(jié)病的識(shí)別具有挑戰(zhàn)性，很少能明確診斷。最常見的表現(xiàn)是顱神經(jīng)病變，見于50%-75%的患者中。顱神經(jīng)病變是多種機(jī)制作用的結(jié)果，包括顱內(nèi)壓升高、肉芽腫的占位效應(yīng)和顱底腦膜炎致穿越蛛網(wǎng)膜下腔的顱神經(jīng)受壓。面神經(jīng)最常受累，其次是視神經(jīng)。該患者面部肌肉下垂、外斜視和聽力受損表明面神經(jīng)、前庭蝸神經(jīng)病變，動(dòng)眼神經(jīng)不全麻痹。無菌性腦膜炎見于10%-20%的患者，表現(xiàn)為腦脊液淋巴細(xì)胞增多、蛋白升高、糖降低。該患者腦脊液分析呈現(xiàn)的就是此種模式。占位病變見于50%患者的影像上。這些病變傾向于累及下丘腦、垂體。多達(dá)15%的患者會(huì)有神經(jīng)內(nèi)分泌癥狀。該患者催乳素水平升高，推測(cè)是因?yàn)槿庋磕[累及垂體柄。另外，該患者訴性功能減退和疲勞病史，后來發(fā)現(xiàn)符合促性腺激素分泌不足引起的性腺功能減退癥。精神癥狀、小腦性共濟(jì)失調(diào)和周圍神經(jīng)病變，每一個(gè)癥狀都可能是神經(jīng)結(jié)節(jié)病的其他臨床表現(xiàn)。
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.
神經(jīng)結(jié)節(jié)病病的首選影像模式是MRI釓增強(qiáng)。典型表現(xiàn)為腦室周圍白質(zhì)病變和柔腦膜強(qiáng)化，這兩種變化都出現(xiàn)在該患者影像上。然而，許多其他病變具有完全相同的影像學(xué)表現(xiàn)，包括淋巴瘤或白血病、感染性和其他炎癥性病因。血清和腦脊液血管緊張素轉(zhuǎn)換酶水平的診斷效用是有限的。先前的研究證實(shí)，血清血管緊張素轉(zhuǎn)換酶水平僅在50%的確診神經(jīng)結(jié)節(jié)病患者中有升高。同樣地，腦脊液血管緊張素轉(zhuǎn)換酶水平升高見于55%的確診神經(jīng)結(jié)節(jié)病患者中，也見于5%未患此病的患者中。該患者血清和腦脊液血管緊張素轉(zhuǎn)換酶水平均在正常范圍。
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
診斷的金標(biāo)準(zhǔn)是病變部位活檢證實(shí)非干酪樣肉芽腫。通常最容易接近的病變部位被首先活檢以減少并發(fā)癥。該患者在縱膈腫大淋巴結(jié)取材。開始試圖通過內(nèi)窺鏡和縱膈鏡檢查取材這些淋巴結(jié)，但沒有取得有診斷價(jià)值的結(jié)果。最后進(jìn)行了腦活檢，得出了壞死性結(jié)節(jié)性肉芽腫病的病理診斷。累及中樞神經(jīng)系統(tǒng)的壞死性肉芽腫病的鑒別診斷有很多，包括很多感染性病原體（特別是真菌和分枝桿菌）和非感染性疾病，如韋格納肉芽腫和壞死性結(jié)節(jié)性肉芽腫病。據(jù)作者所知，文獻(xiàn)中沒有明確數(shù)據(jù)顯示，組織病理有沒有壞死對(duì)臨床行為或神經(jīng)結(jié)節(jié)病治療的反應(yīng)有影響。盡管缺乏正式的隨機(jī)對(duì)照試驗(yàn)，皮質(zhì)類固醇也是治療神經(jīng)類肉瘤病的一線選擇藥物。初始治療路徑由疾病嚴(yán)重性決定。輕微的病變，如孤立性面神經(jīng)麻痹，通常可以用口服潑尼松治療，劑量為0.5-1毫克/公斤/天。嚴(yán)重的、致殘性病變積極地靜脈應(yīng)用皮質(zhì)類固醇治療。常用的方案是用甲基強(qiáng)的松龍，劑量20毫克/公斤，連用3-5天，然后改為口服?？赡苄枰L期口服、逐漸減量達(dá)1年，但是當(dāng)皮質(zhì)類固醇減量至10-20毫克/公斤時(shí)，癥狀復(fù)發(fā)很常見。
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.
其他治療神經(jīng)系統(tǒng)結(jié)節(jié)病方法通常適用于糖皮質(zhì)激素治療無效或不能耐受的患者。此外，一些專家提倡早期應(yīng)用治療表現(xiàn)致殘性癥狀的患者。這些治療通常是類固醇節(jié)制免疫抑制劑，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.
該患者最初應(yīng)用潑尼松治療，劑量為80毫克/天，長期口服，逐漸減量；在疾病早期加用了硫唑嘌呤，逐漸加量至2.5毫克/公斤/天的靶劑量。患者對(duì)治療的臨床反應(yīng)不理想，這在神經(jīng)結(jié)節(jié)病中并非少見。隨后該患者被安排合適的康復(fù)治療。
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