Prolonged Diagnostic Latency and Long-term Surveillance in Anti-Ri Antibody-positive Opsoclonus-myoclonus Syndrome with Carcinoma of Unknown Primary.

Introduction
Opsoclonus-myoclonus syndrome (OMS) is a rare neurological disorder that is clinically characterized by rapid, multidirectional saccadic eye movements (opsoclonus), limb myoclonus, and ataxia. In adults, OMS is commonly associated with neoplasms [paraneoplastic opsoclonus–myoclonus syndrome (POMS)] and is often associated with anti-Ri antibodies (1-4). As the neurological symptoms of POMS can precede the diagnosis of an underlying tumor by 1-6 months (5), POMS can potentially serve as an early indicator of occult malignancies. Carcinoma of unknown primary origin is a metastatic malignancy in which the primary tumor remains unidentified despite thorough systemic evaluation (6,7). Metastasis to the lymph nodes, liver, lungs, or bones is frequent, and the common histological types include adenocarcinomas, squamous cell carcinomas, and poorly differentiated carcinomas (6-8).
We herein report the unique case of a female patient with anti-Ri antibody-positive POMS in whom the primary site of underlying malignancy remained undetectable for approximately 3 years after the onset of OMS.

Case Report
A 71-year-old woman with a history of chronic obstructive pulmonary disease (COPD) and uterine fibroids was referred to our hospital with a 3-week history of progressive dizziness and unsteady gait. A neurological examination revealed truncal ataxia, increased deep tendon reflexes in both lower extremities, and vertical saccadic nystagmus in all gaze directions, consistent with opsoclonus. Laboratory tests, including thyroid function, vitamin levels, and autoimmune screening (e.g., antinuclear antibodies and antineutrophil cytoplasmic antibodies) yielded unremarkable results. The patient’s serum carcinoembryonic antigen (CEA) level was mildly elevated (11.2 ng/mL; normal, 0-5.8 ng/mL), while the remaining tumor markers tested were within reference ranges. A cerebrospinal fluid (CSF) analysis revealed lymphocytic pleocytosis (27 /μL), elevated protein (59 mg/dL), and an extremely high immunoglobulin G index level (3.02), along with positive oligoclonal bands. CSF cytology yielded negative results. These findings suggest an underlying abnormal immune-mediated mechanism. Serum testing for paraneoplastic antibodies was positive for anti-Ri antibody (3+), while negative results were obtained for all other neural antibodies tested, including anti-Hu, anti-Yo, anti-Ma2, and anti-collapsin response mediator protein 5 antibody. The assay was performed using an immunodot assay (PNS+2 blot; Ravo Diagnostika, Freiburg, Germany). Magnetic resonance imaging (MRI) of the brain revealed T2 hyperintensity in the periaqueductal gray matter (Figure A; arrow), pontine and medullary tegmentum (Figure B; arrow), and bilateral inferior olivary nuclei (Figure C, arrows) with no evidence of intracranial mass lesions. No cerebellar or brainstem atrophy was observed, and contrast-enhanced MRI revealed no abnormal intracranial enhancement. No signs of malignancy were observed on other imaging studies, including contrast-enhanced computed tomography (eCT) of the neck, chest, abdomen, and pelvis; ultrasound and contrast-enhanced MRI of the breast; MRI of the pelvis; and gallium scintigraphy. Colonoscopy (CS) did not reveal any significant findings, whereas esophagogastroduodenoscopy (EGD) revealed early Helicobacter pylori-positive gastric adenocarcinoma. Immunohistochemical staining for Ri antigens was not performed.
According to the paraneoplastic neurologic syndrome (PNS) -Care Score (9), the patient scored 7 points: 3 points for the high-risk phenotype (opsoclonus-myoclonus syndrome), 3 points for the high-risk antibody (anti-Ri antibody), and 1 point for a tumor (gastric adenocarcinoma), which was not consistent with the phenotype or antibody and lacked the expression of known Ri-related neuronal antigens. This score supported the diagnosis of probable PNS, and the patient was diagnosed with Ri antibody-positive PNS.
Following the initiation of corticosteroid pulse therapy with intravenous methylprednisolone (1.0 g/day; five days in the first course and three days in the second and third courses), the patient showed progressive improvements in neurological symptoms.
Truncal ataxia improved from the inability to maintain a standing posture to being able to stand unassisted. Opsoclonus-myoclonus became limited to visual fixation after the first course and resolved completely after the second, at which point she regained independent gait. Ultimately, only mild dysmetria of the right upper limb persisted. This was followed by oral prednisolone (20 mg/day), which was gradually tapered. T2 hyperintensity observed in the brainstem at the time of admission showed improvement following the initiation of immunosuppressive therapy (Figure D-F). These MRI findings were consistent with previous reports of anti-Ri antibody-positive OMS, in which brain MRI typically shows no abnormalities but may rarely demonstrate reversible brainstem lesions (10). After endoscopic resection of the gastric adenocarcinoma, remission of OMS symptoms was maintained on oral prednisolone (5 mg/day) and the patient was consequently discharged.
The patient subsequently experienced two relapses of OMS at 4 and 9 months, while on methylprednisolone (1.0 g/day) and intravenous immunoglobulin (400 mg/kg/day) for five days in each case. She remained free of neurological symptoms for over 1.5 years on oral prednisolone (15 mg/day) and cyclosporine (100 mg/day). During hospitalization for the two relapses, repeated blood tests, whole-body computed tomography (CT), and positron emission tomography (PET)/CT revealed no malignancy. An 18-mm left supraclavicular lymph node was present on imaging 28 months after onset; however, no clinical or radiological findings suggested malignant progression (Figure G, H). Except during relapse, the neurological condition of the patient remained essentially unchanged.
Thirty months after the initial onset of OMS, the patient was hospitalized for an exacerbation of COPD. No neurological abnormalities were observed upon admission. On hospital day 25, the patient developed fever. Computed tomography of the chest and abdomen as a fever work-up revealed that the left supraclavicular lymph node (30 mm in diameter) (Figure I; arrow) had increased in size in comparison to that 5 months earlier (diameter: 18 mm) and multiple hepatic masses (Figure J; arrows), which had not been previously detected. This indicated rapid metastatic progression of a malignant tumor. Serum tumor marker assays revealed elevated levels of CEA (17.8 ng/mL), cancer antigen 125 (195 U/mL), cytokeratin fragment 21-1 (15.1 ng/mL), and neuron-specific enolase (68.9 ng/mL), whereas levels of carbohydrate antigen 19-9, pro-gastrin releasing peptide, alpha-fetoprotein, and squamous cell carcinoma (SCC) antigen were within normal limits. No additional malignancy was detected on further imaging studies, including eCT from the neck to the pelvis, breast ultrasound, pelvic MRI, and PET/CT. EGD and CS revealed no significant findings. Needle biopsy of the left supraclavicular lymph node performed 33 months after the onset of symptoms revealed a poorly differentiated carcinoma, predominantly SCC with a small component of adenocarcinoma. The tumor cells were positive for CAM5.2, p40, cytokeratin 5/6, CD56, and focal GATA3 and negative for thyroid transcription factor-1, insulinoma-associated protein 1, synaptophysin, and chromogranin A, with several markers demonstrating only weak or focal positivity. Because the tumor lacked overt glandular differentiation, in contrast to previously diagnosed gastric adenocarcinoma, lymph node metastasis was considered histologically unrelated to gastric cancer. These pathological findings could not identify the primary cancer site; therefore, carcinoma of unknown primary origin was diagnosed. During hospitalization, the functional status of the patient gradually declined due to disuse and reduced physical activity, resulting in a deterioration of the Eastern Cooperative Oncology Group performance status of three. Given this level of functional impairment, the best supportive care without chemotherapy or radiotherapy was chosen as the most appropriate management strategy.

Discussion
POMS is generally associated with breast cancer and small cell lung carcinoma (1,4,11). Underlying malignancy is typically detected within 1-6 months of the onset of symptoms (5). Reports in which the primary tumor remains undetected are extremely rare, with only one previously documented case involving metastatic melanoma from an occult primary tumor (12).
In this case, the underlying tumor was initially suspected to be an early gastric carcinoma. However, multiple relapses after resection of the gastric carcinoma indicated that the true underlying tumor was likely a different carcinoma, with metastases identified in the supraclavicular lymph nodes and the liver. Notably, the primary tumor remained undetected, even 33 months after the initial onset of OMS, representing a significantly prolonged diagnostic delay rarely reported in the relevant literature. This atypically long latency may be explained by heightened tumor immunogenicity, particularly in poorly differentiated tumors, as observed in some lung adenocarcinoma cases (13). Such immunogenicity may provoke the early onset of neurological symptoms, even when the tumor burden is minimal. However, since not all poorly differentiated tumors are immunogenic, this remains hypothetical, and no systematic studies have addressed whether tumor differentiation influences the latency between the onset of symptoms and tumor identification in PNS. The concept of ‘immunologically active' tumors eliciting paraneoplastic symptoms despite a low tumor burden has been supported in other PNS types, although large-scale evidence remains lacking.
Furthermore, this case exhibited another atypical feature: despite rapid metastatic progression, no new neurological symptoms were evident at the time of tumor detection. According to the cancer immunoediting framework (14), persistent immune pressure can lead to selective elimination of antigen-expressing tumor cells, followed by the emergence of antigen-loss variants. Conceivably, the tumor in our patient initially expressed neuronal antigens that triggered anti-Ri antibody-mediated neurological symptoms but subsequently lost these antigens over time. This loss could explain the absence of neurological relapse despite rapid tumor progression at the time of detection.
Although the neurological symptoms in this patient remained stable for a prolonged period with immunosuppressive therapy alone, durable neurological recovery is generally recognized as the requirement for tumor-directed therapy in PNS (15). Thus, early identification of associated malignancy plays a critical role in improving clinical outcomes. Therefore, the present case underscores the diagnostic challenge posed by malignancies of unknown primary origin and highlights the importance of long-term surveillance in patients with paraneoplastic syndromes of unclear etiology. Given that such tumors often originate from small or clinically occult lesions, conventional imaging modalities and tumor markers may be insufficient for their early detection (8,16). Further research is warranted to refine rapid diagnostic strategies and establish optimal follow-up intervals to detect tumors earlier and improve the prognosis.

Conclusion
In this report, we present a case of anti-Ri antibody-positive POMS associated with carcinoma of unknown primary origin, in which the diagnostic latency for the underlying tumor was markedly prolonged. Although the neurological manifestations remained stable for an extended period under immunosuppressive therapy, the overall outcome for the patient was poor due to progressive malignancy. These findings emphasize that neurological stability does not necessarily equate to a favorable prognosis in patients with paraneoplastic syndrome. Therefore, long-term surveillance is essential, even in cases in which the primary tumor is not initially detected.

Written informed consent was obtained from the patient for publication of this case report.

The authors state that they have no Conflict of Interest (COI).