陳會,劉平,胡文廣,鄧佳,陳嘉蕾,趙立力
·學(xué)術(shù)交流·
兒童眼球陣攣-肌陣攣綜合征的臨床特點
陳會,劉平,胡文廣,鄧佳,陳嘉蕾,趙立力
目的 探討兒童眼球陣攣-肌陣攣綜合征(OMS)的臨床特點。方法 回顧性分析4例OMS患兒臨床資料。結(jié)果 本組4例OMS患兒臨床均伴有眼球陣攣、肌陣攣、共濟失調(diào)及行為異常,其中3例伴有睡眠障礙,1例伴有語言障礙,1例伴有智力倒退。其中3例患兒胸腹部CT提示胸腹腔占位,病理提示低分化神經(jīng)母細胞瘤。3例患兒均予腫瘤切除治療及術(shù)后化學(xué)治療,腫瘤均未復(fù)發(fā)。其中1例患兒在化療后半年給予免疫治療,目前OMS癥狀明顯緩解,但遺留語言表達下降及智力倒退;另外未加用免疫治療的2例患兒目前OMS癥狀仍持續(xù)存在。未合并神經(jīng)母細胞瘤的患兒在確診后給予人免疫球蛋白及激素治療,目前OMS癥狀好轉(zhuǎn),無腫瘤新發(fā)。結(jié)論 OMS是一種罕見的神經(jīng)系統(tǒng)自身免疫性疾病,兒童常合并神經(jīng)母細胞瘤,手術(shù)后腫瘤預(yù)后良好,但多數(shù)仍需要進一步接受免疫治療才能長期改善OMS癥狀,且OMS已導(dǎo)致的神經(jīng)系統(tǒng)后遺癥預(yù)后不良。
眼球陣攣-肌陣攣綜合征;神經(jīng)母細胞瘤;臨床特點
眼球陣攣-肌陣攣綜合征(OMS)是一種罕見的神經(jīng)系統(tǒng)疾病,臨床以眼球陣攣、肌陣攣、共濟失調(diào)和行為改變?yōu)橹饕攸c。文獻報道[1]成人OMS與不同類型的癌癥相關(guān),如乳腺癌、肺細胞癌、睪丸和卵巢腫瘤等;而在兒童, 2%~3%的神經(jīng)母細胞瘤患兒合并OMS,50%~80%的OMS患兒合并神經(jīng)母細胞瘤[2]?,F(xiàn)分析4例OMS患兒的臨床特點,以期能為臨床工作提供診治經(jīng)驗,增加對本病的認識。
1.1 一般資料 系2011年1月~2015年7月我科診斷為OMS的4例患兒,診斷標準符合國際共識[3]:具備以下4條中的3條,且第1條為必備診斷條件:(1)眼球陣攣;(2)肌陣攣/共濟失調(diào);(3)行為改變/睡眠障礙;(4)神經(jīng)母細胞瘤。其中男2例,女2例;年齡10~43個月,平均24個月;病程20 d~3個月,平均1.5個月。
1.2 臨床表現(xiàn) 患兒均無前驅(qū)感染,表現(xiàn)為眼球震顫4例,肌陣攣4例,共濟失調(diào)4例,睡眠障礙3例,語言障礙1例,智力倒退1例。4例患兒均有行為異常,其中怕生3例,易激惹3例。
1.3 實驗室檢查 入院后完善血尿便常規(guī),全血生化,免疫相關(guān)檢查(IgA、IgG、IgM、C3、C4),CSF檢查,EEG檢查未見明顯異常。1例患兒頭顱MRI提示兩側(cè)側(cè)腦室后角旁散在斑點、斑片狀T2高信號,T2Flair稍高信號。3例患兒胸腹部CT示1例腹膜右腎前方占位,1例T11-12水平脊柱右前方占位灶,1例左側(cè)腹膜后軟組織密度腫塊影,內(nèi)見少許點條狀鈣化影;3例患兒病理切片均提示低分化神經(jīng)母細胞瘤。
1.4 治療方法 3例發(fā)現(xiàn)胸腔或腹腔占位的患兒在我院外科行手術(shù)治療,術(shù)后病理報告確診為神經(jīng)母細胞瘤。3例患兒術(shù)后均給予化學(xué)治療(長春新堿+環(huán)玲酰胺方案),其中2例患兒完成6次化療療程,1例完成4次化療;其中1例患兒化療結(jié)束后半年由于眼球陣攣、肌陣攣癥狀緩解不明顯,語言表達能力下降,智力倒退,繼續(xù)在外院予人免疫球蛋白及大劑量糖皮質(zhì)激素等治療(具體劑量不詳)。另外1例未合并神經(jīng)母細胞瘤患兒確診后在我院給予2 g/kg人免疫球蛋白治療及3個療程大劑量糖皮質(zhì)激素沖擊治療[1個療程為甲基潑尼松龍20 mg/(kg·d)×3 d],后改用醋酸潑尼松片口服[2 mg/(kg·d)×4 d](計劃糖皮質(zhì)激素總療程6個月)。
1.5 隨訪 隨訪合并神經(jīng)母細胞瘤的3例患兒4個月~4.5年,目前腫瘤均未復(fù)發(fā)。其中未加用免疫治療的2例患兒目前眼球陣攣、肌陣攣癥狀仍持續(xù)存在,有不同程度行為異常(哭鬧不安,怕生等);應(yīng)用免疫治療的1例患兒眼球陣攣及肌陣攣癥狀明顯緩解,無明顯行為異?;蛩哒系K,但遺留語言表達下降,智力倒退無明顯好轉(zhuǎn)。不伴神經(jīng)母細胞瘤的1例患兒在大劑量激素沖擊療程完成時臨床癥狀即有明顯緩解,最后1次隨訪(5個月)時口服糖皮質(zhì)激素(醋酸潑尼松片)已減量至5 mg/d,患兒偶有眼球陣攣及肌陣攣發(fā)生,較發(fā)病時明顯好轉(zhuǎn),能獨走,步態(tài)基本正常,情緒好轉(zhuǎn),無明顯煩躁不安。
OMS是一種罕見的神經(jīng)系統(tǒng)自身免疫性疾病,自Kinsbourne于1962年首次報道以來[4],國外關(guān)于本病的報道逐漸增多。我國自2008年北京大學(xué)第一醫(yī)院熊暉等[5]報道該綜合征開始,國內(nèi)的報道逐漸增多[6-9]。本病大多數(shù)伴有惡性腫瘤,其中50%~80%的OMS患兒合并神經(jīng)母細胞瘤[2]。本組中3例患兒合并神經(jīng)母細胞瘤。
目前研究[10-11]認為,OMS發(fā)病機制與免疫功能異常有關(guān),但具體機制和作用靶點尚不完全清楚。B細胞活化因子是B細胞存活的一個所必需的關(guān)鍵分子,參與鞘內(nèi)B細胞擴增。研究[12]發(fā)現(xiàn),CSF中B細胞過度表達或“擴增”是OMS疾病活動期的生物標記物,與臨床嚴重程度相關(guān)。患兒常表現(xiàn)出持續(xù)癥狀,且常規(guī)治療無效。已有相關(guān)研究[13]報道,OMS患者的CSF中B細胞活化因子顯著升高,可能在OMS發(fā)病中擔任關(guān)鍵作用。但B細胞活化因子缺少特異性抗體,且一些OMS患兒血清學(xué)抗體呈陰性,提示還有其他因素參與疾病的發(fā)生發(fā)展。Pranzatelli等[14]發(fā)現(xiàn),多數(shù)OMS患兒CSF細胞數(shù)正常,但CD4/CD8比值下降,提示細胞介導(dǎo)的免疫機制也參與了OMS的發(fā)生。
OMS的診斷以臨床診斷為主,沒有明確的實驗室指標。本病的臨床診斷標準國際共識[3]為必須具備以下4條中的3條,且第1條為必備診斷條件:(1)眼球陣攣;(2)肌陣攣/共濟失調(diào);(3)行為改變/睡眠障礙;(4)神經(jīng)母細胞瘤。其中眼球陣攣主要表現(xiàn)為雙眼球呈快速、粗大、雜亂的不自主運動,在掃視目標時最明顯,當眼球已經(jīng)固定于注視目標后,異常運動減輕,合眼或睡眠中持續(xù)存在,故OMS又被稱為“舞蹈眼綜合征”。肌陣攣表現(xiàn)為軀干、四肢和頭面部抖動,在運動或情緒激動時加重,是一種非癲癇性肌陣攣,通過EEG可以鑒別。本組4例OMS患兒均伴有眼球陣攣、肌陣攣、共濟失調(diào)及行為異常,其中3例伴有睡眠障礙,1例伴有語言障礙,1例伴有智力倒退;3例患兒胸腹部CT提示胸腹腔占位,病理切片均提示低分化神經(jīng)母細胞瘤,均符合OMS的臨床標準。本組4例患兒的眼球陣攣均為“舞蹈眼”樣表現(xiàn),且4例患兒的肌陣攣表現(xiàn)EEG提示均為非癲癇性事件,故結(jié)合患兒的臨床表現(xiàn)及實驗室結(jié)果,不難與其他疾病相鑒別。
研究[15]發(fā)現(xiàn),極少數(shù)與感染有關(guān)的OMS患兒病情可自發(fā)緩解,但大多數(shù)OMS患者需要接受免疫抑制治療。目前臨床治療以類固醇、促腎上腺皮質(zhì)激素、免疫球蛋白、硫唑嘌呤、利妥昔單抗、環(huán)磷酰胺治療為主。研究[16-17]發(fā)現(xiàn),利妥昔單抗對復(fù)發(fā)性O(shè)MS是有效的免疫抑制治療。有報道[18]稱,發(fā)病超過30周后才開始治療的OMS患者,其遺留嚴重的神經(jīng)系統(tǒng)后遺癥的比率明顯高于30周之前開始治療者。本組2例接受免疫治療的患兒OMS癥狀均有明顯好轉(zhuǎn),其中1例發(fā)病2個月即開始治療,目前尚未發(fā)現(xiàn)遺留明顯神經(jīng)系統(tǒng)后遺癥,另外1例在發(fā)病后1年才開始免疫治療,雖OMS癥狀有緩解,但已遺留明顯的神經(jīng)系統(tǒng)后遺癥。故早期診斷,早期治療非常重要。
神經(jīng)母細胞瘤與OMS癥狀輕重無相關(guān)性,多數(shù)伴OMS的神經(jīng)母細胞瘤患者手術(shù)切除腫瘤后預(yù)后良好,但這部分患兒多數(shù)需要進一步接受免疫抑制劑治療才能長期改善OMS癥狀,且OMS已導(dǎo)致的神經(jīng)系統(tǒng)后遺癥預(yù)后不良[19-21]。本組3例伴有神經(jīng)母細胞瘤患兒在切除腫瘤后,最長隨訪4年5個月腫瘤無復(fù)發(fā),但OMS癥狀仍持續(xù)存在,其中1例在經(jīng)免疫治療后癥狀開始好轉(zhuǎn),但仍遺留了明顯的語言表達下降及智力倒退。
OMS是一種罕見的嚴重的神經(jīng)系統(tǒng)疾病,多數(shù)患兒合并神經(jīng)母細胞瘤。在臨床上如遇見眼球陣攣伴共濟失調(diào)或肌陣攣的患兒應(yīng)高度警惕本病,應(yīng)早期篩查胸腹部CT以早期發(fā)現(xiàn)腫瘤,并早期給予免疫治療以減少遺留嚴重的神經(jīng)系統(tǒng)后遺癥的可能。
[1]Titulaer MJ, Soffietti R, Dalmau J, et al. Screening for tumours in paraneoplastic syndromes: report of an EFNS task force[J]. Eur J Neurol, 2011,18:19.
[2]Rudnick E, Khakoo Y, Antunes NL, et al. Opsoclonus-myoclonus-ataxia syndrome in neuroblastoma: clinical outcome and antineuronal antibodies-a report from the Children’s Cancer Group Study[J]. Med Pediatr Oncol, 2001,36:612.
[3]Matthay KK, Blaes F, Hero B, et al. Opsoclonus myoclonus syndrome in neuroblastoma a report from a workshop on the dancing eyes syndrome at the advances in neuroblastoma meeting in Genoa, Italy, 2004[J]. Cancer Lett, 2005,228:275.
[4] Kinsbourne M. Myoclonic encephalopathy of infants[J]. J Neurol Neurosurg Psychiatry, 1962, 25: 271.
[5]熊暉, 彭鏡,張月華, 等. 眼球陣攣-肌陣攣綜合征的臨床診治分析[J]. 中華兒科雜志, 2008,46:570.
[6]林希, 包新華, 常杏芝.兒童眼球陣攣-肌陣攣綜合征14例臨床特征及治療分析[J].中國實用兒科雜志,2011,26:47.
[7]劉穎, 程士凱, 付大軍, 等. 神經(jīng)母細胞瘤相關(guān)的眼陣攣-肌陣攣綜合征1例[J]. 實用兒科臨床雜志, 2011,26:1207.
[8]劉平,吳懼.兒童神經(jīng)母細胞瘤合并眼球陣攣-肌陣攣綜合征1例[J].中國實用兒科雜志,2011,26:875.
[9]劉京京, 王永霞, 馬秀偉. 眼球陣攣-肌陣攣綜合征1例并文獻復(fù)習[J]. 發(fā)育醫(yī)學(xué)電子雜志, 2014, 12: 234.
[10]Raffaghello L, Conte M, De Grandis E, et al. Immunological mechanisms in opsoclonus-myoclonus associated neuroblastoma[J]. Eur J Paediatr Neurol, 2009,13:219.
[11]Matsumoto H, Ugawa Y.Paraneoplastic opsoclonus-myoclonus syndrome—a review[J]. Brain Nerve, 2010,62:365.
[12]Pranzatelli MR, Travelstead AL, Tate ED, et al. CSF B-cell expansion in opsoclonus-myoclonus syndrome: a biomarker of disease activity[J]. Mov Disord, 2004,19:770.
[13]Pranzatelli MR, Tate ED, McGee NR, et al. BAFF/APRIL system in pediatric OMS: relation to severity, neuroinflammation, and immunotherapy[J]. J Neuroinflammation, 2013,10:10.
[14]Pranzatelli MR, Travelstead AL, Tate ED, et al. B- and T-cell markers in opsoclonus-myoclonus syndrome: immunophenotyping of CSF lymphocytes[J]. Neurology, 2004,62:1526.
[15]Ki PK, Lynch BJ, Osborne JP, et al. Dancing Eye Syndrome associated with spontaneous recovery and normal neurodevelopment[J]. Eur J Paediatr Neurol, 2010,14:178.
[16]Battaglia T, de Grandis E, Mirabelli-Badenier M, et al. Response to rituximab in 3 children with opsoclonus-myoclonus syndrome resistant to conventional treatments[J]. Eur J Paediatr Neurol, 2012,16:192.
[17]Mitchell WG, Wooten AA, O’Neil SH, et al. Effect of Increased Immunosuppression on Developmental Outcome of Opsoclonus Myoclonus Syndrome (OMS)[J]. J Child Neurol, 2015,30:976.
[18]Hasegawa S, Matsushige T, Kajimoto M, et al. A nationwide survey of opsoclonus-myoclonus syndrome in Japanese children[J]. Brain Dev, 2015,37:656.
[19]Mitchell WG, Davalos-Gonzalez Y, Brumm VL, et al. Opsoclonus-ataxia caused by childhood neuroblastoma: developmental and neurologic sequelae[J]. Pediatrics, 2002,109:86.
[20]Krug P, Schleiermacher G, Michon J, et al. Opsoclonus-myoclonus in children associated or not with neuroblastoma[J]. Eur J Paediatr Neurol, 2010,14:400.
[21]Hayward K, Jeremy RJ, Jenkins S, et al. Long-term neurobehavioral outcomes in children with neuroblastoma and opsoclonus-myoclonus-ataxia syndrome: relationship to MRI findings and anti-neuronal antibodies[J]. J Pediatr, 2001,139:552.
Clinical features of opsoclonus-myoclonus syndrome in children
CHENHui,LIUPing,HUWen-Guang,etal.
DepartmentofNeurology,ChengduWomenandChildren’sCentralHospital,Chengdu610019,China
Objective To discuss the clinical features of opsoclonus myoclonus syndrome (OMS) in children. Methods Clinical date of 4 patients with OMS were analyzed retrospectively. Results Four cases in this group had opsoclonus, myoclonus, ataxia and abnormal behavior. Three of the patients were with sleep disorder, 1 case with the language barrier, 1 case with intelligence. The chest and abdominal CT revealed that 3 cases had a placeholder in the chest or abdomen. Pathologic examination showed low differentiated neuroblastoma. Three cases confirmed with neuroblastoma were given tumor resection and postoperative chemotherapy; all of them had no recurrence of tumor so far. One case was given immunotherapy half a year after chemotherapy, the OMS symptoms had significantly relieved, but the decline of language expression and mental regression were persisted. Two cases without immunotherapy had OMS symptoms persisting. And 1 case without neuroblastoma was given immunoglobulin and hormone therapy after diagnosed, the symptoms was improved after immunotherapy, and there was no new-onset tumor. Conclusions OMS is a rare autoimmune disease of the nervous system, often associated with neuroblastoma in children. The tumor has good prognosis after surgery, but most of them still need to be given further immunotherapy to improve OMS symptoms. Existing neurological sequelae has poor prognosis.
opsoclonus-myoclonus syndrome;neuroblastoma;clinical features
610091成都市婦女兒童中心醫(yī)院神經(jīng)內(nèi)科
劉平
R742.1
A
1004-1648(2017)01-0064-03
2016-03-04
2016-07-31)