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Observational Study
. 2025 May;32(5):e70166.
doi: 10.1111/ene.70166.

Clinical Features and Outcomes of Glutamic Acid Decarboxylase-65 Antibody-Associated Pure Cerebellar Ataxia and Stiff Person Syndrome Spectrum Disorders: A Single-Center Cohort Study

Jonathan D Krett  1 , Yujie Wang  1   2 , Ashley Miles  1 , Herbert R Chen  1 , Hanyeh Afshar  1 , Aisha Elfasi  1 , Doris D Lin  3 , Scott D Newsome  1
Affiliations
Observational Study

Clinical Features and Outcomes of Glutamic Acid Decarboxylase-65 Antibody-Associated Pure Cerebellar Ataxia and Stiff Person Syndrome Spectrum Disorders: A Single-Center Cohort Study

Jonathan D Krett et al. Eur J Neurol. 2025 May.

Abstract

Background: Cerebellar ataxia is associated with greater disability in glutamic acid decarboxylase-65 (GAD65) antibody-associated neurological disorders and can occur in isolation or as part of stiff person syndrome (SPS) spectrum disorders (SPSD). We sought to phenotypically characterize this subpopulation with cerebellar dysfunction.

Methods: Observational study of GAD65 antibody-seropositive individuals with cerebellar involvement seen at Johns Hopkins (1997-2024). Subjects were divided into two groups based on cerebellar dysfunction in the presence (SPSD; SPS-plus and progressive encephalomyelitis with rigidity and myoclonus [PERM]) or absence (pure cerebellar ataxia [pCA]) of classic SPS features. Clinical and paraclinical findings were analyzed descriptively.

Results: Seventy-two patients were selected among 356 (62 SPSD, 10 pCA). Mean age for patients with pCA was 58 ± 16 years versus 46 ± 15 years for SPSD (p = 0.012). Males comprised 50% of the pCA group versus 19% SPSD (p = 0.049). High GAD65 antibody serum titers occurred in 76% without group differences, while cerebrospinal fluid antibody positivity occurred in 35/37 (95%) of SPSD versus 5/8 (62%) pCA (p = 0.033). Although the modified Rankin scale was similar (median 3, interquartile range 2-4) in both groups, the brief ataxia rating scale indicated a higher burden of cerebellar abnormalities in pCA versus SPSD, and there was a trend toward greater cerebellar atrophy by MRI in pCA (p = 0.44). Rituximab and benzodiazepine use was more frequent in SPSD versus pCA.

Conclusions: GAD65 antibody-associated ataxia is disabling irrespective of accompanying SPS features. Patients with pCA were older, more commonly male, and may have more frequent cerebellar atrophy than those with SPSD. Prospective validation of cerebellar outcomes and neuroimaging findings is needed.

Keywords: GAD‐65; autoimmune neurology; cerebellar ataxia; neuroimmunology; stiff person syndrome.

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Conflict of interest statement

J.D.K., A.M., H.R.C., H.A., A.E., and D.D.L. declare no conflicts of interest. Y.W. has received consultant fees from TG Therapeutics and has received research funding (paid directly to institution) from Genentech and uniQure. S.D.N. has received consultant fees for scientific advisory boards from Biogen, Genentech, Bristol Myers Squibb, Novartis, and TG Therapeutics, is the study lead PI for a Roche clinical trial program, and has received research funding (paid directly to institution) from Biogen, Roche, Lundbeck, Genentech, Sanofi, The Stiff Person Syndrome Research Foundation, National Multiple Sclerosis Society, Department of Defense, and Patient Centered Outcomes Research Institute.

Figures

FIGURE 1
FIGURE 1
STROBE diagram outlining the selection of patients with GAD65 antibody‐seropositive SPSD with cerebellar features and pCA (July 1, 1997–July 1, 2024). GAD65, anti‐glutamic acid decarboxylase‐65 antibodies; JH, Johns Hopkins; pCA, pure cerebellar ataxia; SPS, stiff person syndrome; SPSD, stiff person syndrome spectrum disorder.
FIGURE 2
FIGURE 2
Scatterplots showing GAD65 antibody titers in patients with SPSD with cerebellar features and pCA (1997–2024). (A) Serum GAD65 ELISA titers. (B) Serum GAD65 RIA titers. (C) CSF GAD65 RIA titers. Each point indicates a single subject. First and last available serum titers are displayed according to the color‐coded legend. CSF titers reflect a single instance. ELISA, enzyme‐linked immunosorbent assay; GAD65, anti‐glutamic acid decarboxylase‐65 antibodies; pCA, pure cerebellar ataxia; RIA, radioimmunoassay; SPSD, stiff person syndrome spectrum disorder.
FIGURE 3
FIGURE 3
Sagittal T1‐weighted MRI showing progressive midline cerebellar atrophy at (A) year 0 and (B) year 4 from symptom onset in a patient with SPS‐plus.
FIGURE 4
FIGURE 4
Box‐whisker plots displaying brief ataxia rating scale (BARS) results at first and last clinic visit for patients with GAD65 antibody‐seropositive SPSD with cerebellar features compared to pCA (1997–2024). BARS is scored out of 30, with higher scores indicating greater severity of cerebellar signs. Plots show median BARS+/−IQR over median 34 months of follow‐up for the total cohort. BARS first SPSD vs. pCA, p = 0.013. BARS last SPSD vs. pCA, p = 0.01. GAD65, anti‐glutamic acid decarboxylase‐65 antibodies; pCA, pure cerebellar ataxia; SPSD, stiff person syndrome spectrum disorder.
FIGURE 5
FIGURE 5
Box‐whisker plots displaying timed 25‐ft walk (T25FW) results at first and last clinic visit for patients with GAD65 antibody‐seropositive SPSD with cerebellar features compared to pCA (1997–2024). Plots show median T25FW+/−IQR over median 34 months of follow‐up for the total cohort. Group differences for first and last visit T25FW were not statistically significant. GAD65, anti‐glutamic acid decarboxylase‐65 antibodies; pCA, pure cerebellar ataxia; SPSD, stiff person syndrome spectrum disorder.
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