(中英)临床推理：儿童期松果体母细胞瘤治疗后引起左侧轻偏瘫，共济失调和视神经炎一例--徐志强

SECTION 1      第1部分

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岁女性，因松果体瘤引起梗阻性脑积水，出现急性发作性头痛及颅内压增高症状。经内镜下第三脑室造瘘术及松果腺组织活检后，诊断为：松果体母细胞瘤。患者接受外科手术切除瘤体、颅脊柱放疗并且之后又进行了化疗治疗。手术后3个月病情稳定，颅脑MRI显示无新病灶或肿瘤残留的迹象。化疗6个月后随访MRI显示幕上皮质区以及颈髓C7水平出现白质无强化的损害，此时患者并没有神经系统症状。三个月后白质损害加重。

 

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个月后，突然出现左臂、左腿无力及视物模糊。神经系统检查证实患者出现左侧视神经炎及左侧轻偏瘫。常规实验室检查未见异常。再次行MRI显示脑和脊髓出现新发和强化病灶，包括：小脑半球、左侧小脑脚、皮质下白质、左侧眼神经和多节段（胸段、腰段）脊髓病变（图A，B）。一些损害表现为类圆形且完全环形强化。弥散成像和PWI成像未能明确病变性质（强化区域ADC值正常并且存在灌流轻微增高）。光谱学无异常。磁共振血管造影提示无血管狭窄。患者及家属拒绝行腰椎穿刺术。经过大剂量静脉应用激素治疗后，6-8周后，检查结果恢复正常。

 

Question for consideration:

1. What is your differential diagnosis regarding her second neurologic presentation?

 

问题思考：

1.对于患者第二次出现的神经系统症状，你的鉴别诊断是什么？

SECTION 2     第2部分

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.

 

松果体母细胞瘤属于WHO分级IV级肿瘤。具有恶性程度高，浸润性强，并且具有较强的扩散特性。尽管颅照射已被证明可以防止软脑膜扩散复发，但预后差^[1]。松果体母细胞瘤倾向于在神经组织表面复发，而非脑实质内部，并且所有转移灶都远离松果腺体，尽管有些病例报道指出转移可能与立体定向内镜活检相关^[2]。在本次病例报道中，在首次MRI显示白质改变后，肿瘤可能复发，但是没有经过特异性的治疗，症状出现了好转，在恶性疾病中难以预料。此外，MRI提示病变复发是手术后一年多才出现的，不可能是手术操作引起恶性病变的转移。

 

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，放射可以对脑白质产生延迟损伤（损伤在照射后几个月到几年出现），并且随后的化疗也可以增加脑损伤的风险。目前已经报道描述了多种放射损伤模式。脑和脊髓的MRI显示无ADC低信号和灌注不足的特征，提示无放射性坏死，磁共振波普分析未显示NAA降低^[3]。另一种辐射增强引起的迟发性放射损伤，其通常发生在室周旁的白质区域，但很难被强化，并且其临床症状和MRI表现特征往往具有进展性和不可逆性等特征。尽管有些病例报道指出延迟性的放射损伤可能存在改善和波动性，但是并不会出现症状完全恢复^[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.

 

考虑到化疗药物也可能对大脑和脊髓具有毒副作用，化学药物相关的神经毒性也被考虑。然而，临床上神经毒性通常发生在用药后的几周内出现，此患者症状出现在化疗药物结束后的几个月后出现的，因此化疗药物引起的毒性损害机制也不成立[^5]。

 

四个月后，患者出现2次亚急性发作性的左侧肢体无力持续时间超过1周，第二次发作是在上呼吸道感染期间。再次行MRI显示右侧脑桥、中脑、小脑蚓部出现一些新的强化病灶（图C），脊髓没有出现新发病灶。腰穿结果提示：8个白细胞（90%是淋巴细胞），蛋白、糖含量正常，脑脊液培养阴性，10个寡克隆带及IgG指数上升，CSF中细胞学检查未找到恶性细胞，使用激素后患者症状改善但没有完全恢复。

 

 

Question for consideration:

1. How has your differential diagnosis changed and what further investigations should be done?

 

问题思考：

1.你的鉴别诊断有什么改变，需要进一步做哪些检查？

SECTION 3     第三部分

              

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.

 

此患者由于脑、视神经和脊髓的受累表现为复发-缓解的症状。随访的MRI提示在中枢神经系统中出现强化和非强化的白质病变。鉴别诊断如下^[6]：

 

• 尽管神经系统的症状可能是某些自身免疫性疾病的首发症状，此患者无系统性红斑狼疮、白塞综合症和硬皮病的客观证据，大量的实验室检查结果示阴性的（抗核抗体、ds-DNA、抗中性粒细胞胞质抗体、抗心磷脂抗体、平滑肌抗体、anti-Ro, anti-La, 水通道蛋白4抗体）而且红细胞沉降率、C反应蛋白、TSH、补体C3、C4都是正常水平。完整了神经眼科检查也没有证据提示眼结节病，24小时的尿钙水平或者血清和脑脊液血管紧张素转化酶水平也无异常。患者无典型的症状和自身抗体阴性，Sj?gren 综合症（校审注：干燥综合征）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.

 

• 中枢神经系统血管炎可以由于血管恢复等因素出现症状波动，从而出现复发缓解的方式。然而不能解释视神经炎和脊髓受累。在磁共振血管成像中没有提示中枢神经系统血管炎特征。此外在未使用免疫抑制剂是中枢神经系统血管炎病情将是快速进展。

• 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.

 

• 脑脊液分析提示与感染不符。感染性疾病时如不使用抗感染治疗，比如结核、疱疹病毒、神经系统囊虫病，症状不会改善。前期用药化疗可使免疫受损的情况，从而导致典型的感染（真菌或者弓形虫），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.

 

• 中枢神经系统淋巴瘤也可以侵犯大脑、脊髓和视神经，通常在使用激素后MRI出现改善。然而，淋巴瘤通常侵犯基底节区和软脑膜，累及颅后窝的情况是非常罕见。淋巴瘤在MRI上通常表现为环形强化损害，但是通常是ADC低信号和NAA下降。脑脊液检测场出现蛋白水平升高和淋巴细胞增多，这些特征也不符合。

• 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.

 

• 其他引起儿童脱髓鞘性疾病，比如脑白质营养不良（对称性和进展性病程）和线粒体疾病（多系统受累）也不成立。

 

• 患者不符合视神经脊髓炎的诊断标准且水通道蛋白4抗体阴性。

Questions for consideration:

1. Could the development of multiple sclerosis (MS)be related to previous brain radiotherapy?

2. Would you recommend starting any long-term therapeutics?

 

问题思考：

1.先前的脑部放疗可能引起多发性硬化吗？

2.你推荐启动长期的治疗？

SECTION 4      第4部分

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].

 

在儿童和成人中，多发性硬化的诊断依据是基于中枢神经系在不同的时间和空间上出现炎性脱髓鞘。根据临床病程及神经影像学，多发性硬化患者的MRI显示大于2个T2序列的病灶在多个部位侵犯（侧脑室周、近皮质、脑干、脊髓）伴临床上非活动强化或不强化病灶，但须排除自身免疫、感染和占位病变。此患者符合儿童型多发性硬化的诊断标准^[7]。此外，脑脊液中OCBs和IgG指数增高符合多发性硬化的特征，且激素治疗症状改善。尽管上述情况对多发性硬化的诊断都是非特异性的，但均支持MS的诊断^[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.

 

此病例给我们带来有趣的问题，是否放射治疗后期增加MS的风险，已有报道表明颅脑放射治疗增加了MS的发生，但是其潜在的机制尚不清楚。研究表明MS患者对放射诱导的中枢神经系统的脱髓鞘进行修复更困难，这使得MS对脑放射治疗易感^[9]。另一方面，放射治疗可以诱发血脑屏障改变，从而使被放射照射的脑区产生免疫介导效应[^10]。此病例是一个例子，新发现的放射治疗触发的多发性硬化或者既往存在MS因放射治疗后出现临床症状。

 

复发缓解型MS是慢性疾病，出现再次复发，首选的药物是皮下注射干扰素-β-1a。在前6个月的治疗中此患者并没有留下出现临床症状或者MRI证据，患者最近检查符合之前左视神经炎和轻度左侧肢体偏瘫的后遗症。

References

[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.

编辑：李会琪