Case
An 18-month-old Japanese boy without significant past history was
admitted to our hospital with a 1-week history of limb tremor,
opsoclonus and ataxia. He was unable to sit or walk without support. He
had no history of vaccinations or infections within the preceding month.
Computed tomography revealed a localized anterior sacral tumor and no
lesions of the central nervous system. The anterior sacral tumor showed
avid uptake of 123I-metaiodobenzylguanidine
(123I-MIBG). Blood testing revealed none of the
autoantibodies reported in association with paraneoplastic neurological
syndromes such as anti-Hu, anti-Ri, anti-Yo, anti-amphiphysin,
anti-PNMA2, anti-CV2, anti-recoverin, anti-SOX1, anti-titin, anti-zic4,
anti-GAD65 and anti-Tr.[5] CSF analysis revealed an increased number
and ratio of CD20-positive B cells, at 0.66 cells/µl and 12%,
respectively (reference B-cell ratio in CSF: 0.00–0.03%[6]). In
addition, oligoclonal bands and anti-GluRδ2 antibodies were detected in
CSF.[2,3] The anterior sacral tumor was resected completely and
diagnosed pathologically as neuroblastoma without MYCNamplification, classified as very low risk group in the International
Neuroblastoma Risk Group Classification. In addition, detailed
pathological analysis revealed multiple lymphoid follicles containing
abundant CD20-positive B cells in the neuroblastoma tissue (Fig. 1). The
increased CD20-positive B cells, oligoclonal bands and anti-GluRδ2
antibodies in CSF, and multiple lymphoid follicles containing abundant
CD20-positive B cells in neuroblastoma tissue led us to consider the
possibility that humoral immunity may contribute to OMS.
OMS has been reported to persist after
complete resection of neuroblastoma and to require immunosuppressive
therapy after tumor resection. We started administration of monthly
dexamethasone (DEX) (20 mg/m2/day for 3 days) pulses
and IVIg (1 g/kg/day) according to a previous report.[7] To assess
the effectiveness of treatment, we monitored the severity of OMS
symptoms using “OMS Rating Scales”, comprising evaluations of six
symptoms: stance, gait, arm function, opsoclonus, mood/behavior and
speech (Supplementary Table S1).[8] Simultaneously, we monitored
CD20-positive B cells and oligoclonal bands in CSF over time, as factors
reported to reflect the disease activity of OMS. After starting
immunosuppressive therapy, limb tremor, ataxia and opsoclonus gradually
remitted. After three cycles, the patient was able to walk again without
support. OMS Rating Scales score also improved to 2, from 8 at the first
visit. Although oligoclonal bands in CSF had been detected persistently,
the B-cell ratio in CSF declined in parallel with symptom improvement
(Fig. 2).
Since significant improvements by DEX pulse and IVIg therapy and
increased CD20-positive B cells in CSF and multiple lymphoid follicles
with abundant CD20-positive B cells in tumor tissue were observed, we
considered the existence of identical B-cell clones contributed to the
pathogenesis of OMS in both CSF and tumor tissues. We therefore
performed BCR repertoire analysis of B-cells in both CSF and tumor
tissue using unbiased amplification of BCR genes followed by
next-generation sequencing (Repertoire Genesis Inc., Osaka, Japan) as
previously described.[9] Consequently, the existence of identical
B-cell clone was confirmed in both CSF and tumor tissue (Supplemental
Table S2). Intriguingly, the identical B-cell clone was the dominant
clone in both CSF and tumor tissue. Moreover, various diversity indices
including the Shannon Weaver index, inverse Simpson index, Pielou’s
evenness and Diversity Evenness 50 were applied to evaluate the
diversity and clonality of B-cells in both CSF and tumor tissue. As a
result, every diversity index confirmed that B-cells in CSF showed low
diversity and B-cells in tumor tissue showed high diversity
(Supplemental Table S3). These data suggested that low-diversity B-cell
clones migrating into the central nervous system from tumor tissue may
express autoantibodies such as anti-GluRδ2 antibodies, leading to the
pathogenesis of OMS.