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Significance of Monoclonal Band in Cerebral Spinal Fluid

Special reports from Xin Yi, PhD, DABCC, FAACC, Associate Professor, Co-Director of Clinical Chemistry, Weill Cornell Medical College, Houston Methodist Hospital ; ZhiCheng, Jin, PhD, DABCC, Assistant Professor, Director of Toxicology, Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin – Madison



In the February 2022 issue of Clinical Chemistry, the flagship journal of the American Association of Clinical Chemistry, authors from the Houston Methodist Hospital, Drs. Xin Yi and Zhicheng Jin (currently at the University of Wisconsin, Madison), described a 72-year-old female presented with acute mental status changes and a 1-week history of periorbital eye and neck swelling. She had a medical history of stage 3 IgA kappa multiple myeloma considered in remission post stem cell transplant.

Cerebrospinal fluid (CSF) high-resolution electrophoresis detected a monoclonal band, and the CSF immunofixation (IFE) revealed monoclonal IgA kappa (Figure 1) with a migration pattern similar to the original serum studies from 6 years ago. Monoclonal IgA kappa seen in the gamma region on CSF IFE without corresponding bands on serum protein electrophoresis or IFE suggested the possibility of intrathecal production of a monoclonal immunoglobulin and ultimately led to the diagnosis of leptomeningeal myelomatosis (LMM), a very rare relapse isolated to the central nervous system (CNS).

Diagnosis of multiple myeloma relapse with CNS involvement is based on cytologic identification of clonal plasma cells in the CSF and leptomeningeal enhancement on magnetic resonance imaging. Overall, the incidence of multiple myeloma external to bone marrow ranges from 3% (newly diagnosed) to 20% (initial appearance in recurrent disease). Multiple myeloma in the central nervous system (CNS-MM) occurs in less than 1% of the cases and heralds a poor prognosis with an overall median survival of 8 months from onset. This LMM case had isolated CNS relapse prior to systemic relapse, which is even rarer and portends a very poor prognosis. A combination of radiation and intrathecal chemotherapy using methotrexate and liposomal ARA-C, and systemic treatment is usually necessary.

The known indication of CSF protein electrophoresis and IFE has been limited in the condition of multiple sclerosis. This case highlights a minimally reported but possible indication for CSF protein electrophoresis and IFE. When CNS-MM is suspected, especially with serum protein electrophoresis/IFE findings negative for an M-spike, CSF protein electrophoresis/IFE studies may be warranted along with CSF cytology and flow cytometry to evaluate for a possible CNS monoclonal process. In fact, this case raises the possibility that CSF protein electrophoresis/IFE in appropriate clinical conditions (e.g., myeloma with significant neurologic findings) might uncover cases of occult CNS-MM, increasing its reported incidence.

In this case, high-resolution protein electrophoresis is used for CSF oligoclonal band analysis. Separating proteins on agarose gel in an electric field followed by staining with amino black, high-resolution protein electrophoresis allows better protein resolution than standard protein gel electrophoresis.

The trend in the serum free light chains could also have been a relapse clue for the clinical team: even though the free light chain ratio was only 3.87 at 55 months post-diagnosis and the modest increase attributed to renal impairment, there was a significant change with 3-fold increase in kappa concentration from 41 to 46 months, while the renal function remained stable as suggested by estimated glomerular filtration rate. This would have met the progressive disease criteria, since the absolute increase of the involved free light chain was >10 mg/L. The finding could be interpreted as a light chain escape, a characteristic reported in other instances of extramedullary relapse of myeloma with poor disease prognosis. Measurement of free light chains is indicated as an important disease monitoring tool. Furthermore, total IgA was above the reference interval in serum at 55 months. Without evidence of a monoclonal IgA kappa protein on serum IFE, however, the earlier evidence suggesting relapse was likely not acted on and could have gone undiagnosed except for the insightful CSF testing that undeniably defined monoclonality for this case.

This case report received comments from David Alter at Emory University and Maria Alice Vieira Willrich at Mayo Clinic Laboratories.


Figure 1. CSF and serum protein electrophoresis with reflex to immunofixation electrophoresis. (A) high-resolution protein electrophoresis of patient’s recent CSF sample along with a positive CSF control and negative CSF sample; (B) immunofixation of the CSF sample; (C) immunofixation of the serum sample.

图 1. CSF 和血清蛋白电泳与免疫固定电泳。 (A) 患者 CSF 样本的高分辨率蛋白电泳以及阳性 CSF和阴性 CSF 对照; (B) CSF 样本的免疫固定; (C) 血清样本的免疫固定



脑脊液单克隆带的意义

在美国临床化学协会的旗舰期刊《临床化学》2022 年 2 月号上,来自休斯顿卫理公会医院的 易欣和金志成教授(现就职于威斯康星大学麦迪逊分校),介绍了一名 72 岁的女性,入院时神智不清,有 1 周的眼圈及颈部肿胀病史。她有 3 期 IgA kappa 多发性骨髓瘤的病史,在干细胞移植治疗后,症状有所缓解。

脑脊液 (CSF) 高分辨率电泳检测到单克隆条带,CSF 免疫固定 (CIFE) 显示单克隆 IgA kappa,其迁移模式与 6 年前的原始血清结果相似。在脑脊液 IFE (CIFE) 的伽玛区看到的单克隆 IgA kappa,但是 在血清蛋白电泳 或 IFE 上没有相应的带表明鞘内产生单克隆免疫球蛋白的可能性,并最终确诊为软脑膜骨髓瘤病 (LMM) ,这是一种非常罕见的中枢神经系统 (CNS)孤立复发。

多发性骨髓瘤复发伴中枢神经系统受累的诊断基于 CSF 中浆细胞的细胞学鉴定和磁共振成像上的软脑膜增强。总体而言,骨髓外多发性骨髓瘤的发病率从 3%(初次诊断)到 20%(复发性疾病的初始表现)不等。中枢神经系统多发性骨髓瘤 (CNS-MM) 发生在不到 1% 的病例中,预后不良,总体中位生存期为发病后 8 个月。这个 LMM 病例在未发现全身复发之前有孤立的 CNS 复发,这种情况更为罕见,预后非常差。通常需要结合使用甲氨蝶呤和脂质体 ARA-C 的放疗和鞘内化疗,以及全身治疗。

CSF 蛋白电泳 (CPEP)/CIFE 的已知适应症局限于多发性硬化症。该案例强调了 CPEP/CIFE 的一个报道很少,但可能的适应症。当怀疑 CNS-MM 时,尤其是血清蛋白电泳/IFE 发现 M-spike 阴性时,可能需要 CPEP/CIFE以及 CSF 细胞学和流式细胞术来评估可能的 CNS 单克隆病程。事实上,该病例提出了这样一种可能性,即 CPEP/CIFE 在适当的临床条件下(例如,具有显着神经系统发现的骨髓瘤)可能会发现隐匿性 CNS-MM 病例,从而增加其报告的发病率。

在这一病例中,实验室使用高分辨电泳进行 CSF 克隆带分析。通过在电场中分离琼脂糖凝胶上的蛋白质,然后用​​氨基黑染色,高分辨电泳比标准蛋白质凝胶电泳具有更好的蛋白质分辨率。

血清游离轻链的浓度变化也可以给临床团队提供线索:尽管游离轻链比率在诊断后 55 个月时仅为 3.87,并且因肾功能损害而适度增加,但随着 kappa 浓度从 41到 46 个月增加3倍,而肾功能基本保持稳定,这符合进行性疾病标准,因为所涉及的游离轻链的绝对值增加>10mg/L。这一发现可以解释为轻链逃逸,这是在其他预后不良的骨髓瘤髓外复发病例中的特征。游离轻链的测量应当被认为是一种重要的疾病监测工具。此外,血清总 IgA 在 55 个月时高于参考区间。然而,在此病例中,由于血清 IFE 上没有单克隆 IgA kappa 蛋白的证据,这些预示复发的早期证据可能无法得到证实,因而很难确诊和治疗;最终是关键的 CSF 检测确诊了多发性骨髓瘤在中枢神经系统内复发。


本病例报告收到了埃默里大学的 David Alter 和妙佑医疗国际的 Maria Alice Vieira Willrich的评论。


References:

  1. ZhichengJin, Roger L Bertholf, Xin Yi. Significance of Monoclonal Band in Cerebral Spinal Fluid. Clinical Chemistry, Volume 68, Issue 2, February 2022, Pages 276–281.

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