By Ulrike W. Kaunzner, MD, and Jai Perumal, MD

Dr. Kaunzner is a Fellow in Neurology, Weill Cornell Medical College, and Dr. Perumal is Assistant Professor of Neurology, Weill Cornell Medical College

Dr. Kaunzner reports no financial relationships relevant to this field of study. Dr. Perumal reports she is on the speakers bureau for Biogen Idec, Teva Pharmaceuticals, Genzyme Corp., and Acorda Therapeutics.

Synopsis: This study analyzed patients diagnosed with antibody-mediated paraneoplastic and non-paraneoplastic cerebellar ataxia, and treatment benefit was seen predominantly in the non-paraneoplastic group.

Source: Jones AL, et al. Responses to and outcomes of treatment of autoimmune cerebellar ataxia in adults. JAMA Neurol 2015; Sep 28:1-10. doi: 10.1001/jamaneurol.2015.2378.

Autoimmune cerebellar ataxia belongs to a heterogeneous group of neurological diseases caused by a variety of autoantibodies. It can occur as paraneoplastic syndrome, appearing in association with malignancy, commonly with lung tumors, gynecologic tumors, and lymphoma, especially Hodgkin’s lymphoma, and can precede the cancer diagnosis for years.1 On the other hand, it can develop without any relation to malignancy and is referred to as non-paraneoplastic syndrome. At least 17 autoantibodies have been associated with this entity, and anti-Yo and anti-Tr antibodies exclusively affect the cerebellum.2 Symptoms may be acute or subacute, and may include classic brain stem findings. The disease has a poor prognosis and often results in severe disability. Treatments have been variable and unpredictable.

This study by Jones et al from the Mayo Clinic investigated the treatment response of patients with paraneoplastic and non-paraneoplastic cerebellar ataxia, and measured the ability to ambulate as a primary outcome. This retrospective cohort study analyzed patients who were included in a database between 1989 and 2013. The 118 selected patients were 18 years of age, positive for at least one antibody, presented with cerebellar ataxia, and were treated with either immunotherapy or chemotherapy. All patients had cerebellar signs, with gait ataxia present in all 118 patients, and other common symptoms including dysmetria, nystagmus, and dysarthria. Extra-cerebellar signs were found in 63 patients (53.4%), with myelopathy and neuropathy the most frequently documented symptoms. Interestingly, 35 patients (29.7%) had neurological diagnoses other than autoimmune cerebellar ataxia prior to evaluation at the Mayo Clinic. All 118 patients had at least one autoantibody detected in serum, and of the 45 patients who underwent lumbar puncture, 25 had CSF autoantibodies. Common antibodies included GAD65, anti-Yo, CRMP-5 and anti-Hu. Out of 118 tested patients, 63 (53.4%) were diagnosed with paraneoplastic syndrome, and in 29 patients malignancy was discovered after antibody detection, with a median range of 3 months until cancer diagnosis. The remaining 55 patients (46.6%) were considered non-paraneoplastic.

Neurological improvement attributed to therapy was reported in 54 out of 118 patients (45.8%) and treatment included either immunotherapy (n = 51) or chemotherapy and radiation therapy (n = 3). While corticosteroids, intravenous immunoglobulin, and plasma exchange appeared efficacious in both groups and showed higher treatment effects in the non-paraneoplastic group, difference in treatment was statistically significant only for steroids. Improvement following steroid treatment was seen in 20.5% of patients with paraneoplastic disorder vs 55.6% of patients with non-paraneoplastic disorder. Cyclophosphamide was only beneficial in the paraneoplastic group, and rituximab did not show any effect in either group.

Overall, 22 patients had a robust response, which was defined as sustained improvement from one ambulation level to the next. Out of these 22 patients, eight required more than one immunotherapy, and 16 patients needed continued immunotherapy, including mycophenolate mofetil or cyclophosphamide. Beneficial outcome was associated with PMP channel or receptor antibodies (e.g., NMDA). In the case of positive GAD65 antibodies, earlier initiation of treatment showed a better outcome. Non-paraneoplastic disorder was the single strongest predictor of positive response to immunotherapy, and 76.4% of patients within this group remained ambulatory.


This study documents a positive response to immunotherapy in a large cohort that previously had been described in anecdotal reports or small series. There were treatment benefits in 45.8% of all patients, with better results in those with a non-paraneoplastic presentation. Limitations of this study are that it was retrospective and did not address therapy of the underlying cancer in the paraneoplastic group and how this affected recovery. The rarity of these disorders and the variability of treatment response, often based on the underlying antibody, make the design of a prospective study difficult, but it would be ideal to compare individual and combined immunotherapies in a prospective trial.

In summary, the results from this study are encouraging. The authors emphasized that treatment should be initiated in both non-paraneoplastic and paraneoplastic syndromes as soon as autoimmune cerebellar ataxia is diagnosed, while a search for underlying malignancy is undertaken. Moreover, sequential or maintenance immunotherapy might be required to preserve and maintain a positive treatment effect.


  1. Darnell RB, Posner JB. Paraneoplastic syndromes affecting the nervous system. Semin Oncol 2006;33:270-298.
  2. Hoftberger R, et al. Update on neurological paraneoplastic syndromes. Curr Opin Oncol 2015;27:489-495.