A 13-year-old girl presented acutely with an episode of headache and signs of elevated intracranial pressure from a pineal gland tumor causing obstructive hydrocephalus. After an endoscopic third ventriculostomy and pineal gland biopsy, she was diagnosed with pineoblastoma. She was treated with surgical resection,craniospinal radiotherapy, and subsequent chemo-therapy. Brain MRIs were performed every 3 monthsafter surgery and remained stable with no new lesionsor signs of residual tumor. However, a follow-up brain MRI performed 6 months after chemotherapy showed some small white matter nonenhancing lesions in supratentorial subcortical areas and within the cord at C7. She had no neurologic symptoms at that time and the white matter lesions improved over the next 3 months.

患者13歲女性，因松果體瘤引起梗阻性腦積水，出現(xiàn)急性發(fā)作性頭痛及顱內(nèi)壓增高癥狀。經(jīng)內(nèi)鏡下第三腦室造瘺術(shù)及松果腺組織活檢后，診斷為：松果體母細(xì)胞瘤?；颊呓邮芡饪剖中g(shù)切除瘤體、顱脊柱放療并且之后又進(jìn)行了化療治療。手術(shù)后3個(gè)月病情穩(wěn)定，顱腦MRI顯示無新病灶或腫瘤殘留的跡象。化療6個(gè)月后隨訪MRI顯示幕上皮質(zhì)區(qū)以及頸髓C7水平出現(xiàn)白質(zhì)無強(qiáng)化的損害，此時(shí)患者并沒有神經(jīng)系統(tǒng)癥狀。三個(gè)月后白質(zhì)損害加重。

However, 10 months later, she developed acute weakness of her left arm and leg and blurry vision.Her neurologic examination confirmed left optic neuritis and moderate left hemiparesis. Routine laboratories did not show any abnormalities. A new brain MRI showed new and enhancing lesions in the brain and spinal cord, including cerebellar hemispheres, left cerebellar peduncle, subcortical white matter, left opticnerve, and multilevel (thoracic and lumbar) intramedullary spinal cord lesions (figure, A and B). Some ofthem were round and had a complete ring-enhancingpattern. Additional MRI sequences such as diffusion-weighted imaging and perfusion-weighted imaging didnot clarify the nature of the lesions (normal apparentdiffusion coefficient [ADC] values and slightlyincreased perfusion in enhancing areas). Spectroscopywas normal. Magnetic resonance angiography demon-strated no flow-limiting stenosis. The patient and herfamily declined a lumbar puncture. She was empiri-cally treated with high-dose IV steroids and her exam-ination results returned to normal after 6–8 weeks.

10個(gè)月后，突然出現(xiàn)左臂、左腿無力及視物模糊。神經(jīng)系統(tǒng)檢查證實(shí)患者出現(xiàn)左側(cè)視神經(jīng)炎及左側(cè)輕偏癱。常規(guī)實(shí)驗(yàn)室檢查未見異常。再次行MRI顯示腦和脊髓出現(xiàn)新發(fā)和強(qiáng)化病灶，包括：小腦半球、左側(cè)小腦腳、皮質(zhì)下白質(zhì)、左側(cè)眼神經(jīng)和多節(jié)段（胸段、腰段）脊髓病變（圖A，B）。一些損害表現(xiàn)為類圓形且完全環(huán)形強(qiáng)化。彌散成像和PWI成像未能明確病變性質(zhì)（強(qiáng)化區(qū)域ADC值正常并且存在灌流輕微增高）。光譜學(xué)無異常。磁共振血管造影提示無血管狹窄。患者及家屬拒絕行腰椎穿刺術(shù)。經(jīng)過大劑量靜脈應(yīng)用激素治療后，6-8周后，檢查結(jié)果恢復(fù)正常。

Pineoblastomas correspond to WHO grade IV tumors, being highly malignant and infiltrative, with a significant potential for dissemination. Although craniospinal irradiation has been shown to prevent leptomeningeal recurrence, pineoblastomas are known to have a poor prognosis^[1]. Pineoblastomas tend to recuron the surfaces of the neural tissue rather than in the parenchyma and all the lesions identified in the patient were far from the pineal gland, although the reare case reports of brain metastasis related to the manipulation of a pineoblastoma after stereotacticor endoscopic biopsy^[2]. In this case, tumor recurrence was considered after the first MRI showing whitematter changes, but the subsequent improvement without specific treatment is not expected in a malignant condition. Moreover, the pineoblastoma surgerywas performed more than a year before the appear-ance of lesions on MRI, making it much less likely that the procedure caused dissemination of the malignancy.

松果體母細(xì)胞瘤屬于WHO分級(jí)IV級(jí)腫瘤。具有惡性程度高，浸潤性強(qiáng)，并且具有較強(qiáng)的擴(kuò)散特性。盡管顱照射已被證明可以防止軟腦膜擴(kuò)散復(fù)發(fā)，但預(yù)后差^[1]。松果體母細(xì)胞瘤傾向于在神經(jīng)組織表面復(fù)發(fā)，而非腦實(shí)質(zhì)內(nèi)部，并且所有轉(zhuǎn)移灶都遠(yuǎn)離松果腺體，盡管有些病例報(bào)道指出轉(zhuǎn)移可能與立體定向內(nèi)鏡活檢相關(guān)^[2]。在本次病例報(bào)道中，在首次MRI顯示白質(zhì)改變后，腫瘤可能復(fù)發(fā)，但是沒有經(jīng)過特異性的治療，癥狀出現(xiàn)了好轉(zhuǎn)，在惡性疾病中難以預(yù)料。此外，MRI提示病變復(fù)發(fā)是手術(shù)后一年多才出現(xiàn)的，不可能是手術(shù)操作引起惡性病變的轉(zhuǎn)移。

On the other hand, radiation to the brain is known to produce late delayed changes in the white matter (from several months to years after exposure) and subsequent administration of chemotherapy may increase the risk of cerebral injury. A variety of patterns of radiation-induced injury have been described. The brain and spinal cord MRIs were not suggestive of radionecrosis, lacking signs of low ADC signal and hypoperfusion. Magnetic resonance spectroscopy did not show a decrease in NAA as istypically seen^[3]. Another form of delayed radiotoxicity called radiation-induced enhancement usually occurs within the periventricular white matter and has different patterns of enhancement, although its clinicalcourse and MRI findings are usually progressive and irreversible. Despite the fact that some cases ofimprovement or fluctuation have been reported, acomplete resolution of the lesions is not expected^[4].

另一方面，放射可以對(duì)腦白質(zhì)產(chǎn)生延遲損傷（損傷在照射后幾個(gè)月到幾年出現(xiàn)），并且隨后的化療也可以增加腦損傷的風(fēng)險(xiǎn)。目前已經(jīng)報(bào)道描述了多種放射損傷模式。腦和脊髓的MRI顯示無ADC低信號(hào)和灌注不足的特征，提示無放射性壞死，磁共振波普分析未顯示NAA降低^[3]。另一種輻射增強(qiáng)引起的遲發(fā)性放射損傷，其通常發(fā)生在室周旁的白質(zhì)區(qū)域，但很難被強(qiáng)化，并且其臨床癥狀和MRI表現(xiàn)特征往往具有進(jìn)展性和不可逆性等特征。盡管有些病例報(bào)道指出延遲性的放射損傷可能存在改善和波動(dòng)性，但是并不會(huì)出現(xiàn)癥狀完全恢復(fù)^[4]。

Considering that chemotherapeutic drugs administered to the patient might be potentially toxic to the brain and spinal cord, the possibility of chemotherapy-related neurotoxicity was also taken into consideration. However, in this setting neurotoxicity usually developsa few weeks after the chemotherapy and progresses,while the patient’s symptoms started months after the end of the chemotherapy, rendering a toxic mechanism unlikely^[5].

Four months later, the patient developed 2 episodes of subacute left-sided weakness lasting more than a week. The second episode occurred during an upper respiratory infection. A new brain MRI showed several new enhancing lesions affecting the right pons, mid-brain, and cerebellar vermis, with improvement ofthe previous lesions (figure, C), without new lesionsin the spinal cord. A lumbar puncture was performedand showed 8 leukocytes (90% lymphocytes), normal protein and glucose levels, negative cultures, and 10 unique oligoclonal bands (OCBs) with elevated immu-noglobulin G (Ig G) index. Cytology was negative for malignant cells in the CSF. The patient improved with steroids but did not return to her baseline.

考慮到化療藥物也可能對(duì)大腦和脊髓具有毒副作用，化學(xué)藥物相關(guān)的神經(jīng)毒性也被考慮。然而，臨床上神經(jīng)毒性通常發(fā)生在用藥后的幾周內(nèi)出現(xiàn)，此患者癥狀出現(xiàn)在化療藥物結(jié)束后的幾個(gè)月后出現(xiàn)的，因此化療藥物引起的毒性損害機(jī)制也不成立[^5]。

四個(gè)月后，患者出現(xiàn)2次亞急性發(fā)作性的左側(cè)肢體無力持續(xù)時(shí)間超過1周，第二次發(fā)作是在上呼吸道感染期間。再次行MRI顯示右側(cè)腦橋、中腦、小腦蚓部出現(xiàn)一些新的強(qiáng)化病灶（圖C），脊髓沒有出現(xiàn)新發(fā)病灶。腰穿結(jié)果提示：8個(gè)白細(xì)胞（90%是淋巴細(xì)胞），蛋白、糖含量正常，腦脊液培養(yǎng)陰性，10個(gè)寡克隆帶及IgG指數(shù)上升，CSF中細(xì)胞學(xué)檢查未找到惡性細(xì)胞，使用激素后患者癥狀改善但沒有完全恢復(fù)。

This patient presented with relapsing-remitting symptoms due to brain, optic nerve, and spinal cord involvement. Follow-up MRIs have shown enhancing and nonenhancing white matter lesions in different areas of the CNS. Her differential diagnosis is broad^[6]:

• Although neurologic symptoms can be the first presentation of some autoimmune systemic disorders, the patient did not have features suggestive of systemic lupus erythematosus, Beh?et syndrome, or scleroderma. Extensive workup included negative autoantibodies (antinuclear antibodies, ds-DNA, antineutrophil cytoplasmic antibodies, anticardiolipin, smooth muscle anti-bodies, antiphospholipid, anti-Ro, anti-La, anti-aquaporin-4) and normal results for erythrocyte sedimentation rate, C-reactive protein, thyroid-stimulating hormone, C3, and C4. There was no evidence for sarcoidosis on complete neuro-ophthalmologic examination, 24-hour urine calcium levels, or serum or CSF angiotensin-converting enzyme. Sj?gren syndrome was ruled out as the patient had no typical symptoms and autoantibodies were also negative.

此患者由于腦、視神經(jīng)和脊髓的受累表現(xiàn)為復(fù)發(fā)-緩解的癥狀。隨訪的MRI提示在中樞神經(jīng)系統(tǒng)中出現(xiàn)強(qiáng)化和非強(qiáng)化的白質(zhì)病變。鑒別診斷如下^[6]：

• 盡管神經(jīng)系統(tǒng)的癥狀可能是某些自身免疫性疾病的首發(fā)癥狀，此患者無系統(tǒng)性紅斑狼瘡、白塞綜合癥和硬皮病的客觀證據(jù)，大量的實(shí)驗(yàn)室檢查結(jié)果示陰性的（抗核抗體、ds-DNA、抗中性粒細(xì)胞胞質(zhì)抗體、抗心磷脂抗體、平滑肌抗體、anti-Ro, anti-La, 水通道蛋白4抗體）而且紅細(xì)胞沉降率、C反應(yīng)蛋白、TSH、補(bǔ)體C3、C4都是正常水平。完整了神經(jīng)眼科檢查也沒有證據(jù)提示眼結(jié)節(jié)病，24小時(shí)的尿鈣水平或者血清和腦脊液血管緊張素轉(zhuǎn)化酶水平也無異常?；颊邿o典型的癥狀和自身抗體陰性，Sj?gren 綜合癥（校審注：干燥綜合征）被排除。

• CNS vasculitis is known to produce fluctuating symptoms in a relapsing-remitting manner due to vascular compromise. However, this entity does not explain the optic nerve and spinal cord involvement of this patient and there were no features suggestive of CNS angiitis on the magnetic resonance angiography. Additionally, rapid progression is expected without immunosuppressive medications.

• 中樞神經(jīng)系統(tǒng)血管炎可以由于血管恢復(fù)等因素出現(xiàn)癥狀波動(dòng)，從而出現(xiàn)復(fù)發(fā)緩解的方式。然而不能解釋視神經(jīng)炎和脊髓受累。在磁共振血管成像中沒有提示中樞神經(jīng)系統(tǒng)血管炎特征。此外在未使用免疫抑制劑是中樞神經(jīng)系統(tǒng)血管炎病情將是快速進(jìn)展。

• CSF analysis was not compatible with a CNS infection. Infections such as tuberculosis, herpesvirus, or neurocysticercosis would not have improved without antimicrobial therapy. Even considering the possibility of an immunocom-promised state related to the previous chemotherapy, a typical infections (such as fungal or toxoplasma) can be reasonably ruled out.

• 腦脊液分析提示與感染不符。感染性疾病時(shí)如不使用抗感染治療，比如結(jié)核、皰疹病毒、神經(jīng)系統(tǒng)囊蟲病，癥狀不會(huì)改善。前期用藥化療可使免疫受損的情況，從而導(dǎo)致典型的感染（真菌或者弓形蟲），也可以排除。

• CNS lymphomas can affect the brain, spinal cord, and optic nerves and MRI findings commonly improve with steroids. However, these neoplasms usually affect basal ganglia and leptomeninges, while posterior fossa involvementis very uncommon. On MRI, lymphomas can present as ring-enhancing lesions, but usually have low ADC values and decreased NAA,whereas the CSF often reveals an elevated protein concentration and a lymphocytic pleocytosis, features that were not present in the patient.

• 中樞神經(jīng)系統(tǒng)淋巴瘤也可以侵犯大腦、脊髓和視神經(jīng)，通常在使用激素后MRI出現(xiàn)改善。然而，淋巴瘤通常侵犯基底節(jié)區(qū)和軟腦膜，累及顱后窩的情況是非常罕見。淋巴瘤在MRI上通常表現(xiàn)為環(huán)形強(qiáng)化損害，但是通常是ADC低信號(hào)和NAA下降。腦脊液檢測場出現(xiàn)蛋白水平升高和淋巴細(xì)胞增多，這些特征也不符合。

• Other causes of demyelination in children such as leukodystrophies (symmetric and progressive course) and mitochondrial diseases (multisystem involvement) are very unlikely.

• The patient did not meet criteria for a diagnosis of neuromyelitis optica and aquaporin-4 anti-bodies were negative.

• 其他引起兒童脫髓鞘性疾病，比如腦白質(zhì)營養(yǎng)不良（對(duì)稱性和進(jìn)展性病程）和線粒體疾?。ǘ嘞到y(tǒng)受累）也不成立。

• 患者不符合視神經(jīng)脊髓炎的診斷標(biāo)準(zhǔn)且水通道蛋白4抗體陰性。

The diagnosis of MS in both children and adults restson the evidence of inflammatory demyelination in different regions of the CNS occurring over time. Considering the clinical course and the neuroimaging, the patient’s presentation was typical of relapsing-remitting MS. The MRI showed more than 2 T2 lesions in many locations commonly affected in patients with MS (peri-ventricular, juxtacortical, brainstem, and spinal cord),with clinically silent enhancing and nonenhancing lesions. Once autoimmune, infectious, and space-occupying lesions had been ruled out, this patient met the most current criteria for a diagnosis of pediatric MS^[7].Furthermore, detection of OCBs and elevated IgG index in the CSF are characteristic features of MS, and an improvement with steroids is expected. Although both circumstances are not specific for MS, they support the diagnosis^[8].

在兒童和成人中，多發(fā)性硬化的診斷依據(jù)是基于中樞神經(jīng)系在不同的時(shí)間和空間上出現(xiàn)炎性脫髓鞘。根據(jù)臨床病程及神經(jīng)影像學(xué)，多發(fā)性硬化患者的MRI顯示大于2個(gè)T2序列的病灶在多個(gè)部位侵犯（側(cè)腦室周、近皮質(zhì)、腦干、脊髓）伴臨床上非活動(dòng)強(qiáng)化或不強(qiáng)化病灶，但須排除自身免疫、感染和占位病變。此患者符合兒童型多發(fā)性硬化的診斷標(biāo)準(zhǔn)^[7]。此外，腦脊液中OCBs和IgG指數(shù)增高符合多發(fā)性硬化的特征，且激素治療癥狀改善。盡管上述情況對(duì)多發(fā)性硬化的診斷都是非特異性的，但均支持MS的診斷^[8]。

This case brings to light an interesting question of whether or not radiotherapy puts a patient at risk for later developing MS. It has been reported that brain radiotoxicity is higher in patients with MS. The underlying mechanism remains unclear. It has been suggested that patients with MS could have more difficulty in repairing radiation-induced demyelination of the CNS, which makes them more vulnerable to brain radiotoxicity^[9]. On the other hand, radiotherapy could induce changes in the blood–brain barrier that may allow immune-mediated effects on the irradiated brain^[10]. This case conceivably represents an example of either new demyelinating disease triggered by preceding brain radiotherapy or preexisting disease brought to the clinical surface after radiotherapy.

Based on the fact that relapsing-remitting MS is a chronic disease and new relapses are expected, the patient was started on a first-line disease-modifying therapy (subcutaneous interferon-b-1a). She has not shown clinical or MRI evidence of disease activity during the first 6 months on this treatment. The most recent examination of the patient is consistent with sequelae of previous left optic neuritis and mild left hemiparesis.

此病例給我們帶來有趣的問題，是否放射治療后期增加MS的風(fēng)險(xiǎn)，已有報(bào)道表明顱腦放射治療增加了MS的發(fā)生，但是其潛在的機(jī)制尚不清楚。研究表明MS患者對(duì)放射誘導(dǎo)的中樞神經(jīng)系統(tǒng)的脫髓鞘進(jìn)行修復(fù)更困難，這使得MS對(duì)腦放射治療易感^[9]。另一方面，放射治療可以誘發(fā)血腦屏障改變，從而使被放射照射的腦區(qū)產(chǎn)生免疫介導(dǎo)效應(yīng)[^10]。此病例是一個(gè)例子，新發(fā)現(xiàn)的放射治療觸發(fā)的多發(fā)性硬化或者既往存在MS因放射治療后出現(xiàn)臨床癥狀。

復(fù)發(fā)緩解型MS是慢性疾病，出現(xiàn)再次復(fù)發(fā)，首選的藥物是皮下注射干擾素-β-1a。在前6個(gè)月的治療中此患者并沒有留下出現(xiàn)臨床癥狀或者M(jìn)RI證據(jù)，患者最近檢查符合之前左視神經(jīng)炎和輕度左側(cè)肢體偏癱的后遺癥。

[1]       Tate M, Sughrue ME, Rutkowski MJ, et al. The long-term postsurgical prognosis of patients with pineoblastoma. Cancer. 2012. 118(1): 173-9.

[2]       Luther N, Stetler WR, Dunkel IJ, Christos PJ, Wellons JC, Souweidane MM. Subarachnoid dissemination of intraventricular tumors following simultaneous endoscopic biopsy and third ventriculostomy. J Neurosurg Pediatr. 2010. 5(1): 61-7.

[3]       Wang YX, King AD, Zhou H, et al. Evolution of radiation-induced brain injury: MR imaging-based study. Radiology. 2010. 254(1): 210-8.

[4]       Pruzincová L, Steno J, Srbecky M, et al. MR imaging of late radiation therapy- and chemotherapy-induced injury: a pictorial essay. Eur Radiol. 2009. 19(11): 2716-27.

[5]       Sul JK, Deangelis LM. Neurologic complications of cancer chemotherapy. Semin Oncol. 2006. 33(3): 324-32.

[6]       Hahn JS, Pohl D, Rensel M, Rao S. Differential diagnosis and evaluation in pediatric multiple sclerosis. Neurology. 2007. 68(16 Suppl 2): S13-22.

[7]       Waldman A, Ghezzi A, Bar-Or A, Mikaeloff Y, Tardieu M, Banwell B. Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research. Lancet Neurol. 2014. 13(9): 936-48.

[8]       Krupp LB, Banwell B, Tenembaum S. Consensus definitions proposed for pediatric multiple sclerosis and related disorders. Neurology. 2007. 68(16 Suppl 2): S7-12.

[9]       D'hooghe MB, Nagels G, Bissay V, De Keyser J. Modifiable factors influencing relapses and disability in multiple sclerosis. Mult Scler. 2010. 16(7): 773-85.

[10]     Miller RC, Lachance DH, Lucchinetti CF, et al. Multiple sclerosis, brain radiotherapy, and risk of neurotoxicity: the Mayo Clinic experience. Int J Radiat Oncol Biol Phys. 2006. 66(4): 1178-86.

編輯：李會(huì)琪