ObjectiveInvestigate the value of including cerebellar degeneration-related protein 2-like (CDR2L) as a marker in commercial diagnostic tests for anti-Yo–associated paraneoplastic cerebellar degeneration (PCD).MethodsWe included sera and CSF samples from 24 patients with suspected PCD (6 of whom had PCD with underlying gynecologic or breast cancer), who were positive for Yo antibodies using the commercially available, paraneoplastic neurologic syndromes (PNS) 14 Line Assay from Ravo Diagnostika. The samples were further evaluated using the EUROLINE PNS 12 Ag Line Assay and a cell-based assay (CBA) from Euroimmun. For confirmation of positive lineblot results, we used indirect immunofluorescence of rat cerebellar sections. We also tested all samples in 2 assays developed in-house: a CBA for CDR2L and a Western blot analysis using recombinant cerebellar degeneration-related protein 2 (CDR2) and CDR2L proteins.ResultsIn PNS 14 and PNS 12 Ag Line Assays, anti-CDR2 reactivity was observed for 24 (100%) and 20 (83%) of the 24 samples, respectively. Thirteen of 24 subjects (54%) were also positive using the Euroimmun CBA. Rat cerebellar immunofluorescence was the best confirmatory test. In our in-house CBA for CDR2L and Western blot for CDR2 and CDR2L, only the 6 patients with confirmed PCD reacted with CDR2L.ConclusionsCommercially available tests for Yo antibody detection have low specificity for PCD because these assays use CDR2 as antigen. By adding a test for CDR2L, which is the major Yo antigen, the accuracy of PCD diagnosis greatly improved.Classification of EvidenceThis study provides Class III evidence that a CBA for CDR2L accurately identifies patients with PCD.

Paraneoplastic cerebellar degeneration (PCD) is an unusual, remote effect of certain systemic cancers and is characterized by subacute cerebellar symptoms. PCD cases exhibit varying clinical features: In some cases only cerebellar involvement is noted, whereas in others, cerebellar involvement is accompanied by nervous system involvement at various levels. This article describes the knowledge on PCD, with emphasis on certain clinical-immunological associations. Recent studies have revealed the presence of various autoantibodies in the serum or cerebrospinal fluid of PCD patients. The antibodies associated with PCD are Yo, Hu, Ri, Ma, CV2/CRMP-5, P/Q-type VGCC, GAD, mGluR, ANNA-3, PCA-2, Tr, Zic and CARPVIII antibodies. The antigens recognized by these autoantibodies are membrane proteins or proteins expressed within cerebellar neurons. The pathogenic role played by the autoantibodies in PCD is unknown. In some PCD cases, it is unlikely that these autoantibodies play a pathogenic role; in such cases, cytotoxic T cells are assumed to play a crucial role in the pathogenesis of PCD. However, some autoantibodies, especially those directed against membrane proteins, have been shown to be directly involved in the pathogenesis of PCD. Detection of these autoantibodies is important for a correct diagnosis of PCD. The effect of immunotherapy is unclear in most PCD cases. Clarification of the relevant clinical-immunological associations is crucial for the developent of new therapeutic strategies for PCD.

Six patients developed a pancerebellar syndrome with symptoms preceding the diagnosis of neoplasia in five (median - 4 months) and following in one (2 years). In all patients, the initial cranial computed tomographic (CT) scans were normal. Five patients had repeat CTs and of these three were abnormal; cerebellar atrophy appearing 7 to 25 months following the initial CT. Median follow-up was 31 months (range 12–84 months) without evidence of CNS metastatic disease. In five of six patients the neurologic impairment did not progress. One patient's neurologic signs improved markedly with mantle radiation therapy of her Hodgkin's disease. An initially negative CT does not preclude the diagnosis of remote effect cerebellar atrophy. Paraneoplastic cerebellar degeneration is a self-limited nonprogressive process in the majority of patients.