Prevalence, Clinical Profiles, and Prognosis of Stiff-Person Syndrome in a Japanese Nationwide Survey

Abstract

Background and objectives: To elucidate current epidemiologic, clinical, and immunologic profiles and treatments of stiff-person syndrome (SPS) in Japan.

Methods: A nationwide mail survey was conducted using an established method. Data processing sheets were sent to randomly selected departments of internal medicine, neurology, pediatrics, psychiatry, and neurosurgery in hospitals and clinics throughout Japan to identify patients with SPS who were seen between January 2015 and December 2017.

Results: Thirty cases were identified as glutamic acid decarboxylase 65 (GAD65)-positive SPS cases on the basis of detailed clinical data of 55 cases. Four patients had α₁ subunit of glycine receptor (GlyR) antibodies, and 1 patient had both GAD65 and GlyR antibodies. The total estimated number of patients with GAD65-positive SPS was 140, and the estimated prevalence was 0.11 per 100,000 population. The median age at onset was 51 years (range, 26-83 years), and 23 (76%) were female. Of these, 70% had classic SPS, and 30% had stiff-limb syndrome. The median time from symptom onset to diagnosis was significantly longer in the high-titer GAD65 antibody group than in the low-titer group (13 months vs 2.5 months, p = 0.01). The median modified Rankin Scale (mRS) at baseline was 4, and the median mRS at the last follow-up was 2. Among the 29 GAD65-positive patients with ≥1 year follow-up, 7 received only symptomatic treatment, 9 underwent immunotherapy without long-term immunotherapy, and 13 received long-term immunotherapy such as oral prednisolone. The coexistence of type 1 diabetes mellitus and the lack of long-term immunotherapy were independent risk factors for poor outcome (mRS ≥3) in the GAD65-positive patients (odds ratio, 15.0; 95% CI 2.6-131.6; p = 0.001; odds ratio, 19.8; 95% CI 3.2-191.5; p = 0.001, respectively).

Discussion: This study provides the current epidemiologic and clinical status of SPS in Japan. The symptom onset to the diagnosis of SPS was longer in patients with high-titer GAD65 antibodies than in those with low-titer GAD65 antibodies. The outcome of patients with SPS was generally favorable, but more aggressive immunotherapies are necessary for GAD65-positive patients with SPS.

Figure 1. Flowchart of the Nationwide Survey

SPS = stiff-person syndrome.

Figure 2. Flowchart of the Clinical Study

GAD65 = glutamic acid decarboxylase 65; GlyR = glycine receptor α1 subunit. # Lack of antagonist inhibition on EMG is defined by continuous co-contraction of agonist and antagonist muscles (inhibitory to relax) as confirmed by EMG.