CLIPPERS is a rare and heterogeneous spectrum of central nervous system diseases still remains poorly understood. While some diagnostic criteria have been proposed, they may not fully encompass the complexities of clinical situations [2]. In this case study, we present a patient with CLIPPERS who exhibited prodromal infection, atypical imaging findings, and persistent oligoclonal bands, prompting further investigation.
With the absence of a definitive biomarker, CLIPPERS presents a range of differential diagnoses, including vasculitis, CNS lymphoma, intravascular lymphoma, neurosarcoidosis, CNS demyelinating disease, hemophagocytic lymphohistiocytosis, Behcet’s disease, and autoimmune GFAP astrocytopathy, among others [3, 4]. Furthermore, alternative diagnoses are frequently encountered during the follow-up for CLIPPERS. A systematic review involving 140 CLIPPERS patients revealed that 16% cases were ultimately diagnosed with cancer, especially hematological maligancies such as lymphoma [5]. Consequently, CLIPPERS is increasingly recognized as a pre-tumor state. A study from Zhang et al. suggested that the relapse of CLIPPERS between two months and one year after treatment, elevated protein levels in CSF, and presence of positive pyramid signs may serve as predictive factors for associated lymphoma [8]. A separate review corroborated these findings and additionally noted that males were more commonly affected by malignancy-associated CLIPPERS, with four cases yielded a positive CSF test for EBV within this cohort [6]. In the present case, the male patient exhibited nearly all of the aforementioned risk factors. Therefore, regular follow up id deemed necessary, and it is anticipated that the patient still meet the CLIPPERS diagnostic criteria up to now.
Multiple prior studies have documented cases of EB virus positive CNS lymphoma initially misdiagnosed as CLIPPERS [7–9]. Furthermore, EBV infection or reactivation in the CNS may be associated with the core features of CLIPPERS, such as punctate “peppering” enhanced lesions or perivascular T-cell infiltration, which are also present in instances of EBV + diffuse large B-cell lymphoma or CNS lymphomatoid granulomatosis. Schmidt and colleagues have posited the potential for diminished T-lymphocyte immunosurveillance as a result of chronic or transient T-cell dysfunction, which may lead to the latent activation of EBV-infected B-lymphoid cells [10]. Consequently, some researchers speculate on the potential involvement of chronic or transient T-cell dysfunction in the development of CLIPPERS, which could result in EBV antigen stimulation. In light of these findings, it is recommended that EBV testing be conducted in patients diagnosed with CLIPPERS. Furthermore, in cases where EBV is detected in CSF, prompt consideration should be given to referring patients for a brain biopsy.
Previous research has indicated a lower prevalence of OCBs in individuals diagnosed with CLIPPERS. In our specific case, the presence of persistent OCB II and an elevated IgG index has garnered our attention. The accompanying schematic diagram can be found in Fig. 2. OCBs are composed of clone restricted immunoglobulins (Igs) detected by isoelectric focusing (IEF) and are key features of ongoing CNS inflammatory processes in various neuroinflammatory conditions, notably multiple sclerosis and other CNS infection related disorders [11]. The proteins will undergo migration in response to a pH gradient and an electric field until they reach a region where the pH equals their pI (net charge of the protein is zero) [12]. According to this principle, we compared changes in the distribution of the oligoclonal bands in the electric field across 6 instances of detection results, as depicted in Fig. 2. It is evident that CSF Igs in this patient consistently accumulated in the pH range of 7–9 throughout the longitudinal follow-up period. Unexpectedly, a portion of Igs was observed at a pH of 5.6 in the fourth CSF test, indicating potential physiological processes related to the disease.
OCBs serve as reservoirs of IgG antibodies in CNS. Research has shown the presence of two distinct populations of antibody secreting cells (ASCs), consisting of short-lived fully differentiated plasmablasts with the ability to divide, and long-lived plasma cells that are incapable of proliferation. Plasmablasts disappear rapidly after antigen clearance, whereas long-lived plasma cells persist in CNS and are capable of producing Igs even in the absence of antigens and DNA synthesis [13]. The inflammatory CNS scenario provides many mediators essential for the maintenance of long-lived plasma cells, such as CXCL12, IL-6, TNF-ɑ, BAFF, vascular cell adhesion molecule-1(VCAM-1) and so on [14]. Following initial antigen exposure, the survival of long-lived plasma cells is primarily reliant on the apoptotic factors in the niche and these cells may expell from survival niches during competitive challenges [15, 16]. This phenomenon likely underlies the persistence of OCBs in the CSF of patients with multiple sclerosis (MS) and other CNS inflammation disorders. The alterations in banding patterns suggest potential competition among plasma cells for limited survival niches. It is possible that ASCs in the CNS may derive from peripheral lymphoid organs through plasmablasts or lymphoid follicles in the meninges. Further, a higher proportion of B cells in CNS exhibit a memory B cell phenotype compared to those in peripheral blood [17]. Therefore, these memory B cells might differentiate into ACSs in the presence of T cells upon antigen reactivation, or through a bystander reaction in an antigen-independent manner [18, 19].
OCBs are commonly considered as markers for MS, but their presence is not exclusive to MS patients, thus raising debate about their antigen specificity or potential non-specific activation of B cells in the CNS. Up to now, myelin proteins and viruses, particularly EBV, are among the leading antigen candidates for OCBs. EBV has been suggested as both an environmental trigger and a direct causative factor in CNS immunopathology. Numerous studies have documented clonally expanded B cells in MS that are capable of binding EBV proteins [20, 21]. However, the Igs targeting the virus exhibit distinct characteristics form the primary components of OCB in CSF, thereby limiting their ability to fully account for the origins of OCBs. Previous discussion has proposed that myelin specific recombinant antibodies are generated from clonal expanded plasma cells in CSF of MS patients, with OCBs typically targeting commonly presented auto-proteins and intracellular antigens [22, 23]. The available evidence suggests that production of IgG OCBs may function as a secondary immune response to tissue damage rather than playing a role in mediating major pathogenic effects.
In the case of our patient, it is hypothesized that latent EBV infection may contribute to the production of CSF restricted OCBs through antigen antibody reactions and subsequent autoimmune processes. The initial EBV infection likely led to an inflammatory CNS environment, where B cells from both peripheral and central sources differentiated into ASCs secreting IgG. These antibodies may target EBV virus proteins or non-specific cell surface antigens. The continued presence of long-lived plasma cells in this microenvironment likely sustains the persistence of OCBs. Changes in the longitudinal follow-up process of the bands may remind us the antigen of unknown origin reactivation, as illustrated in Fig. 3. Finally, that presence of OCBs in CSF may suggest intrathecal polymorphous lymphoproliferation, facilitating the identification of non-monoclonal lymphoproliferation disorders [24]. Accordingly, the detection of OCBs in CLIPPERS may unveil underlying pathophysiological mechanisms.