This single-institution case series of six patients highlights several scenarios in which PCD developed in established cancer patients, either in remission, undergoing treatment, or prior to the diagnosis with recurrent malignancy. These findings offer several insights when approaching patients with suspected PCD, most importantly that early recognition and treatment is critical. Patients who were diagnosed and treated aggressively early appeared to have better outcomes than those with delays in diagnosis. Additionally, PCD may herald a new or recurrent cancer, and treatment of the underlying malignancy remains a critical component of therapy.
Diagnosing subacute ataxia and, later, identifying its specific cause can prove challenging. First, subacute ataxias must be differentiated from other neurologic disease categories, such as peripheral neuropathies, which is quite difficult given the overlap in exam findings. Case #1, for example, was suspected to be secondary to inflammatory neuritis, and case #6 had findings of peripheral demyelination on testing, despite their eventual diagnosis of PCD. Even when symptoms are suspected to be secondary to a cerebellar process, 58% of ataxic adult patients go without a definitive diagnosis.15 Case #3 exemplifies this circumstance, where the patient was diagnosed after repeating workup at a second academic institution. The challenge of diagnosis can be exacerbated by delays inherent in outpatient care. 3 of our 6 patients received their diagnosis of PCD from studies obtained while in the inpatient setting. It is possible that overlapping clinical entities caused by PCA-1 exist.
The primary means by which PCD is diagnosed is testing for antibodies in the CSF or serum.10 CSF antibody tests are preferred, but serum tests are more convenient to obtain. The variability of presentation of PCD may account for delayed work up. For example, case #2 had visual changes with suspicion for cranial nerve III involvement and case #1 was originally diagnosed with inflammatory neuritis. Rare but positive brain imaging findings that needs further work up are sometimes noted, like in patient 5. Irrespective of imaging, which can be normal at initial work up CSF cytology, assessment for leptomeningeal disease is recommended. Cerebellar atrophy can be present in subsequent brain MRI. CSF analysis is highly recommended and initial CSF indices showing inflammation (increased WBC, increased protein, increased oligoclonal bands) with negative infection and negative malignancy while pending antibody results could suggest paraneoplastic syndrome.16
These cases may provide insight into factors that may precipitate the development of PCD in established cancer patients. Intriguingly, the development of PCD after chemotherapy or surgery are very rare and may be due to de novo antigen exposure, triggering a rapid inflammation. It is unclear if underlying autoimmune disorders are a precipitating factor for PCD; but these were not observed in our case series, favoring de novo antigen exposure as likely mechanism.
Future advances in this rare disease will be challenging, with too few patients to conduct prospective clinical trials. However, biological insight from small numbers of patients can be informative and help guide further research and clinical care. For example, as a pathognomonic feature of this disease is the presence of autoantibodies, a major therapeutic treatment strategy has been antibody-mitigating therapy with plasmapheresis and IVIG. There may be a role for therapy directed toward B cells, such as with rituximab. In one investigation, 3 of 9 patients had improvement with this therapy based on their neurologic symptoms measured by the Rankin Scale.17 Additionally, the presence of infiltrating T and B cells in the brain raises questions of whether the lymphocytes are encountering antigen in the brain or in the periphery, clonally expanding, and then migrating into the brain.18,19 This could potentially be studied by comparative T cell receptor (TCR) and B cell receptor (BCR) sequencing in blood and CSF or directly in brain parenchyma from autopsy specimens. These observations have potential therapeutic implications, as therapies in multiple sclerosis that target lymphocyte trafficking, such as fingolimod and natalizumab may be beneficial in this disease.20,21 Finally, though immunosuppression has primarily focused on B cell-derived autoantibodies, perhaps the T cell component is equally important and stronger T cell directed immunosuppression may be considered as an adjunct (for example, the addition of tacrolimus, azathioprine or cyclophosphamide). Such immunosuppression must be considered concurrently with treatment of the underlying malignancy, which appears to be the most effective way to treat PCD.
Paraneoplastic cerebellar degeneration (PCD) associated with PCA-1 antibody is an important component in the differential diagnosis for new cerebellar findings in patients with cancer. This case series highlights the importance of prompt recognition, comprehensive neurologic work-up, and early immunosuppressive treatment. PCD may be a harbinger of a new or recurrent cancer diagnosis in patients and treatment of the underlying malignancy is essential. Breast cancer patients need work up for ovarian cancer in addition to screening for recurrence and vice versa for ovarian cancer patients who develop this specific antibody mediated PCD. Further research should focus on the mechanisms of this autoimmune disease to better target immunosuppression and improve outcomes for patients.