Case Report: A False Negative Case of Anti-Yo Paraneoplastic Myelopathy

Abstract

The development of autoimmune antibody panels has improved the diagnosis of paraneoplastic neurological disorders (PNDs) of the brain and spinal cord. Here, we present a case of a woman with a history of breast cancer who presented with a subacute sensory ataxia that progressed over 18 months. Her examination and diagnostic studies were consistent with a myelopathy. Metabolic, infectious, and autoimmune testing were non-diagnostic. However, she responded to empirical immunosuppression, prompting further workup for an autoimmune etiology. An unbiased autoantibody screen utilizing phage display immunoprecipitation sequencing (PhIP-Seq) identified antibodies to the anti-Yo antigens cerebellar degeneration related protein 2 like (CDR2L) and CDR2, which were subsequently validated by immunoblot and cell-based overexpression assays. Furthermore, CDR2L protein expression was restricted to HER2 expressing tumor cells in the patient's breast tissue. Recent evidence suggests that CDR2L is likely the primary antigen in anti-Yo paraneoplastic cerebellar degeneration, but anti-Yo myelopathy is poorly characterized. By immunostaining, we detected neuronal CDR2L protein expression in the murine and human spinal cord. This case demonstrates the diagnostic utility of unbiased assays in patients with suspected PNDs, supports prior observations that anti-Yo PND can be associated with isolated myelopathy, and implicates CDR2L as a potential antigen in the spinal cord.

Detection of High‐Risk Paraneoplastic Antibodies against TRIM9 and TRIM67 Proteins

“…This study highlights some additional benefits of complementing traditional autoantibody discovery and validation methods with PhIP‐Seq. As demonstrated here, PhIP‐Seq epitope mapping aids direct comparison of paraneoplastic polyclonal antibody responses to paralogous gene pairs like TRIM9/TRIM67; as was also done for CDR2L/CDR2 in anti‐Yo paraneoplastic cerebellar degeneration 4,35 . PhIP‐Seq may be particularly well suited to identify autoantibodies elicited by cancer‐associated neoantigens, even against a background of systemic autoimmunity 36 .…”

“…As demonstrated here, PhIP-Seq epitope mapping aids direct comparison of paraneoplastic polyclonal antibody responses to paralogous gene pairs like TRIM9/TRIM67; as was also done for CDR2L/CDR2 in anti-Yo paraneoplastic cerebellar degeneration. 4,35 PhIP-Seq may be particularly well suited to identify autoantibodies elicited by cancer-associated neoantigens, even against a background of systemic autoimmunity. 36 As a massively parallel antibody detection method, PhIP-Seq may also aid in identifying autoimmune neurological patients who harbor additional antibodies that may contribute to illness presentation.…”

“…36 As a massively parallel antibody detection method, PhIP-Seq may also aid in identifying autoimmune neurological patients who harbor additional antibodies that may contribute to illness presentation. 37 Moreover, PhIP-Seq has detected autoantibodies that fail to bind rodent brain tissue 35 or novel autoantibodies that do not recognize a rodent ortholog, 38 or for which a rodent ortholog does not exist. 39 However, the sensitivity of PhIP-Seq is hampered by the absence of post- Although PhIP-Seq identified the homologous TRIM9/TRIM67 B-box 2 domains as immunodominant peptide epitopes, not all cases were immunoreactive to this epitope.…”

Update in autoimmune and paraneoplastic myelopathies: Newly described antigen targets and antibody testing

“…However, there have been reports of other neurologic syndromes including myelopathy ( 44 ). One case report of a 36-year-old woman with breast cancer and progressive lower extremity sensory loss revealed a longitudinally-extensive, dorsal-predominant T2 hyperintensity from T5 to T10 ( 45 ). Another case report with available neuropathology demonstrated inflammatory infiltrates and demyelination of the spinal cord tissue ( 46 ).…”