IVIG, Plasmapheresis Effective in Managing Non-Tumor Anti-Tr/DNER Antibody-Associated Ataxia

Intravenous immunoglobulin (IVIG) and plasmapheresis can provide significant benefit to patients with autoimmune cerebellar ataxia (ACA), specifically cases associated with anti-Tr/Delta/notch-like epidermal growth factor-related receptor (DNER) antibodies, according to a case report published in The Cerebellum.¹

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Anti-Tr/DNER cerebellar ataxia is a type of ACA, which is a non-hereditary condition and form of acquired ataxia. The phenomenon typically involves the cerebellum, causing progressive ataxia. Paraneoplastic cerebellar degeneration (PCD) being present along with anti-Tr/DNER antibody is typically associated with malignancy.¹

This type of ACA is rarely reported; even rarer is for a patient to present without a tumor. A systematic review conducted in 2021 by Campana et al found that 91% of the 85 patients with anti-Tr/DNER antibody-associated cerebellar ataxia included in their review presented an associated tumor, with Hodgkin lymphoma being the most common.²

In this case report, the patient--a 49-year-old woman--was admitted to the emergency department with slurred speech, headache, and dizziness, which she said had started 3 months prior and worsened over time. She had no significant medical history or family history, and had no history of substance abuse, according to the investigators.

Regarding her physical condition, she was found to have dysarthria and could not walk on her own feet, needing a wheelchair for movement. She also exhibited trunk and limb ataxia. Further investigations, though, revealed no major abnormalities--blood cell count, renal and liver tests, brain imaging, and other measurements were all normal and unremarkable.¹

She initiated intravenous methylprednisolone and showed slight improvement. The patient was discharged and prescribed with venlafaxine and tizanidine and recommended to revisit after 2 weeks, the study authors wrote.

Laboratory, paraneoplastic, and autoimmune tests were within normal ranges, except for testing positive for Tr (DNER) antibody. After that indication, she was recommended for admission for further investigation and treatment. She began serum plasmapheresis, with 9 sessions daily.¹

Her condition significantly improved, and she regained her ability to walk short distances, yet her cerebellar tests remained impaired. Therefore, she was discharged and prescribed 25 g of IVIG every month for 6 months. After these 6 doses, the patient’s ataxia resolved, her gait improved, and cerebellar tests normalized. She initiated rituximab treatment every 6 months.¹

The patient’s condition was determined to be non-tumor anti-Tr/DNER antibody-associated ataxia once it was not associated with any malignancy within 2 years of cancer screenings. “Extensive testing showed no signs of a tumor, which emphasizes the need to explore non-tumor causes for these symptoms,” according to the report authors.

Anti-neural antibodies that have been recently discovered have been confirmed to be associated with ACA, creating the category of antibody-related ACA. These antibodies likely serve as markers for a specific autoimmune process in the central nervous system, which serves as a major indicator for considering immunotherapy like IVIG.¹

There is a complex system behind the immunoregulatory effects of IVIG in autoimmune and inflammatory diseases. These mechanisms working in synergy gives rise to the therapeutic benefits of IVIG in these types of diseases.

A multitude of prior reports have been published indicating the potential benefits of IVIG in autoimmune diseases. One such report from Widdess-Walsh et al, which analyzed 15 cases of autoantibody-mediated PCD, found that “most patients that were treated with IVIG and had what was defined as a good response were treated within 1 month of symptoms.” This emphasizes the importance of early treatment in ACA.³

Another case, reported by David et al, documented an 81-year-old woman with recurrent ovarian carcinoma and PCD who, with plasma exchanges and IVIG, had significant improvement within several weeks.⁴ After discussing this case, the investigators of the current case noted that theirs is the only instance where both IVIG and plasma therapy was utilized specifically for anti Tr/DNER-associated diseases.¹

“It seems that TPE along with IVIG provides significant benefits in patients with anti TR/DNER and can be considered at the initiation of treatment to achieve rapid lowering of circulating paraneoplastic autoantibodies,” the report authors wrote.

References

1. Adibi A, Rastegar-Kashkouli A, Yousefi P, et al. Plasmapheresis and IVIG for treatment of non-tumor anti-Tr/DNER antibody-associated ataxia: a case report. Cerebellum. 2024. doi:10.1007/s12311-024-01711-z

2. Campana IG, Silva GD. Anti-Tr/DNER antibody–associated cerebellar ataxia: a systematic review. Cerebellum. 2022;21:1085–109. doi:10.1007/s12311-021-01346-4

3. Widdess-Walsh P, Tavee JO, Schuele S, et al. Response to intravenous immunoglobulin in Anti-Yo associated paraneoplastic cerebellar degeneration: case report and review of the literature. J Neurooncol. 2003;63:187–190. doi:10.1023/A:1023931501503

4. David YB, Warner E, Levitan M, et al. Autoimmune paraneoplastic cerebellar degeneration in ovarian carcinoma patients treated with plasmapheresis and immunoglobulin: a case report. Cancer. 1996.doi:10.1002/(SICI)1097-0142(19961115)78:10<2153::AID-CNCR16>3.0.CO;2-Y