Document Type : Case Report
Introduction
Paraneoplastic neurological syndromes (PNS) are rare immune-mediated disorders associated with systemic malignancies and are not attributable to direct tumor invasion, metastasis, infection, metabolic disturbances, or treatment toxicity. They result from an autoimmune response directed against shared antigens expressed by tumor cells and neural tissue (1).
The overall incidence of PNS is estimated to be less than 1% of all cancer patients, although underdiagnosis is likely (1, 2). PNS most commonly occur in association with small-cell lung carcinoma, breast cancer, thymoma, and hematologic malignancies; however, gynecologic cancers-particularly ovarian carcinoma-have also been implicated (3).
Among neurological presentations, paraneoplastic cerebellar degeneration (PCD) is one of the most severe and well-characterized syndromes, accounting for approximately 20–30% of PNS cases (4). In women, ovarian and breast carcinomas are frequently associated with anti-Yo-mediated cerebellar degeneration (5, 6). Clinically, PCD presents with rapidly progressive gait ataxia, dysarthria, diplopia, vertigo, and imbalance. Brain MRI may initially appear normal, with cerebellar atrophy developing later in the disease course (7).
According to the updated diagnostic criteria proposed in 2021, a classical neurological syndrome occurring in a patient with known malignancy, after exclusion of alternative causes, strongly supports the diagnosis of PNS even in the absence of detectable onconeural antibodies (8). High-grade serous ovarian carcinoma (HGSOC) is characterized by marked genomic instability and immunogenic potential, which may trigger cross-reactive immune responses against neuronal antigens. Although PNS associated with ovarian carcinoma are uncommon, early recognition is essential because neurological deficits may become irreversible if treatment is delayed. Here, we report a rare case of probable paraneoplastic cerebellar syndrome developing during neoadjuvant chemotherapy in a patient with high-grade papillary serous ovarian carcinoma.
Case Presentation
A 41-year-old G2P2L2 woman presented with a five-month history of progressive abdominal pain and distension. Histopathological evaluation confirmed high-grade serous ovarian carcinoma with pelvic involvement. Due to the extent of disease at presentation, neoadjuvant platinum-based chemotherapy was initiated (carboplatin and paclitaxel). Dates have been converted to a relative timeline in accordance with journal standards.
Approximately two months after starting chemotherapy, she developed progressive dizziness, diplopia, blurred vision, headache, and voice changes, followed by gait instability. Neurological examination revealed horizontal nystagmus, dysmetria on finger-to-nose testing, a positive Romberg sign, and a wide-based ataxic gait. Cranial nerve examination showed diplopia without facial weakness or dysphagia. Motor and sensory examinations were within normal limits.
Laboratory investigations, including metabolic panel and infectious workup, were unremarkable. However, serological testing for paraneoplastic antibodies (Anti-Hu, Anti-Yo, Anti-Ri, Anti-Ma2) was not performed due to limited availability.
To exclude metastatic disease and structural causes, brain MRI and lumbosacral MRI were performed and showed no abnormalities (Figure 1).
Treatment
The patient received combined immunomodulatory therapy as follows: Intravenous immunoglobulin (IVIG): 0.4 g/kg/day for 5 consecutive days, Methylprednisolone: 1 g/day for 5 days followed by oral taper, Plasmapheresis: 5 sessions over 10 days. Clinical response was evaluated based on improvement in gait stability, reduction in diplopia, and ability to ambulate independently.
Fig 1: Brain MRI demonstrating no evidence of cerebellar metastasis or structural lesion at the time of neurological symptom onset.
Timeline
A chronological summary of clinical events is presented in (Table 1).
|
Table 1. Timeline of clinical events and interventions |
|
|
Timepoint |
Clinical Event |
|
Month 0 |
Diagnosis of ovarian carcinoma |
|
Month 1 |
Initiation of neoadjuvant chemotherapy |
|
Month 3 |
Onset of neurological symptoms |
|
Month 3.5 |
Initiation of immunotherapy |
|
Month 4 |
Partial improvement |
|
Month 5 |
Cytoreductive surgery |
|
Month 9 |
Gradual neurological recovery |
Diagnostic Reasoning
Differential diagnoses were systematically considered and excluded:
Chemotherapy-induced neurotoxicity (carboplatin/ paclitaxel): unlikely due to predominant cerebellar signs rather than peripheral neuropathy
Cerebellar stroke: ruled out by normal MRI findings
Multiple sclerosis relapse: no prior history and no demyelinating lesions on imaging
Metabolic/toxic encephalopathy: laboratory findings were within normal limits
Despite the absence of antibody testing, the diagnosis of probable PNS was supported by the following:
Subacute cerebellar syndrome
Presence of a known malignancy (high-grade serous ovarian carcinoma)
Exclusion of alternative etiologies
Partial clinical response to immunotherapy
Follow-up
At 4-month follow-up, the patient regained partial ambulation with assistance. No recurrence of neurological symptoms was observed during subsequent oncologic follow-up. However, mild gait instability persisted, indicating incomplete neurological recovery.
Discussion
Paraneoplastic neurological syndromes (PNS) are a group of immune-mediated disorders that occur in association with systemic malignancies but are not attributable to direct tumor invasion, metastatic spread, metabolic derangements, or treatment toxicities. These syndromes are believed to result from an autoimmune response driven by shared antigens between the tumor and components of the nervous system, particularly Purkinje cells in cases of cerebellar degeneration (9, 10).
Although PNS can affect any part of the nervous system, paraneoplastic cerebellar degeneration (PCD) remains one of the most frequently described neurological manifestations in patients with gynecologic malignancies, including ovarian carcinoma (10, 11). PCD accounts for a significant proportion of PNS cases and presents with subacute onset of cerebellar symptoms such as ataxia, dysarthria, diplopia, and gait instability. These symptoms may develop before, during, or after cancer diagnosis and treatment (10, 11). The prevalence of PNS in ovarian cancer is estimated to be less than 1%, although underdiagnosis is likely, and increased clinical awareness may reveal higher rates. This underscores the importance of considering PNS in patients with unexplained neurological symptoms, even in the absence of radiological abnormalities.
Importantly, PNS can occur without detectable metastatic disease on neuroimaging, as illustrated in this case where both brain and spinal MRI were normal despite significant cerebellar symptoms.
The pathogenesis of PCD involves immune-mediated damage to cerebellar Purkinje cells triggered by onconeural antibodies such as anti-Yo, anti-Hu, anti-Ri, and less commonly anti-CV2/CRMP5. Among these, anti-Yo antibodies are most frequently associated with ovarian cancer-related PCD, particularly in high-grade serous carcinoma. Although antibody testing was not performed in this case, similar antibody-negative presentations have been reported, and diagnosis may rely on clinical criteria and exclusion of alternative etiologies. Previous reports have described similar cases where neurological symptoms developed in the context of ovarian carcinoma without evidence of metastatic spread on imaging, reinforcing the concept that PNS is primarily an autoimmune phenomenon rather than direct tumor invasion (3, 11). A careful differential diagnosis is essential in such cases. Conditions including chemotherapy- induced neurotoxicity (particularly from carboplatin and paclitaxel), cerebellar stroke, multiple sclerosis relapse, and metabolic or toxic encephalopathy should be considered and excluded. In the present case, normal neuroimaging findings, absence of metabolic abnormalities, and the pattern of neurological involvement made these diagnoses unlikely, thereby supporting a probable diagnosis of PNS.
Compared to previously reported cases, this case is notable for the development of neurological symptoms during neoadjuvant chemotherapy, absence of radiological abnormalities, and partial reversibility following immunotherapy. These features distinguish it from many classical presentations reported in the literature.
High-grade serous ovarian carcinoma is known for its immunogenicity, which may predispose to autoimmune cross-reactivity against neuronal tissue. This may explain the occurrence of PNS in this patient and supports a potential biological link between tumor subtype and neurological manifestations.
Management of PNS involves both oncologic and immunomodulatory approaches. Early tumour resection and effective oncologic therapy may reduce the antigenic stimulus driving the immune response, potentially ameliorating neurological symptoms. Immunotherapies such as high-dose corticosteroids, intravenous immunoglobulin (IVIG), and plasma exchange are commonly used, although their efficacy varies and depends on the timeliness of initiation. Some patients experience partial neurological improvement following immunotherapy, as observed in the present case (12, 13).
Despite advances in cancer therapy and immunomodulation, the overall prognosis of PNS remains guarded, with many patients experiencing persistent neurological dysfunction even after treatment of the underlying malignancy (3, 11). Long-term follow-up and multidisciplinary management, including physical therapy and supportive care, are essential for optimizing functional outcomes.
In this case, early initiation of immunotherapy resulted in partial neurological recovery, although residual deficits persisted. This is consistent with previous studies indicating that early treatment may improve outcomes but does not always lead to complete recovery.
This case has several limitations, including the absence of paraneoplastic antibody testing and lack of cerebrospinal fluid analysis, which may have strengthened diagnostic certainty.
Conclusion
Paraneoplastic cerebellar degeneration should be considered in patients with ovarian cancer who develop subacute neurological symptoms in the absence of radiological abnormalities. This case highlights the diagnostic challenges of antibody-negative PNS and emphasizes the importance of early recognition, prompt immunotherapy, and multidisciplinary management. Increased awareness may facilitate earlier diagnosis and improve neurological outcomes.
Declarations
Availability of data and materials
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Competing interests
The authors declare no competing interests.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Authors' contribution
All authors were participated in the concept and design, analysis and interpretation, data collection, writing the article, critical revision, final approval, statistical analysis, overall responsibility.
Acknowledgment
We thanks to Clinical Research Development Unit of Rouhani Hospital.
Ethics approval and consent to participate
N/A
