To describe the demographics, clinical characteristics, treatments and outcomes of seronegative stiff person spectrum disorders (SPSD) in a single-center cohort.

Retrospective review was performed at our SPSD center from 2004-2024. We included all those with confirmed diagnosis of SPSD who were seronegative for commercially available SPS autoantibodies. Patients with autoimmune encephalitis and pure cerebellar ataxia were excluded. We used descriptive statistics to summarize demographics, clinical characteristics, and treatments. Non-parametric tests were used to compare outcomes at first and last follow up.

Out of 359 patients, 15 seronegative patients were identified. Seronegative phenotypes included 10 classic SPS, 1 partial onset (one limb), 3 SPS-plus, and 1 PERM. The cohort was predominantly white (80%) and female (73%) with a median age of onset of 36 years (range, 16-67). All patients experienced leg spasms, anxiety and pain, and none had a history of malignancy. Most common exam findings were paravertebral stiffness, rigidity, hyperlordosis, spasticity and hyperreflexia. Six patients seroconverted to having low-titer GAD65 antibodies following IVIG treatment (false positive). Seven cases had positive confirmatory EMG. All patients received benzodiazepines and antispasmodics, 9 received symptomatic botulinum toxin, and 8 received immunotherapy. Median timed 25-foot walk at first visit vs last follow-up was 4.9 seconds vs 6.5 seconds (z = -1.712, p = 0.0869). The median modified Rankin scale was 2, at both first and last visit.

This case series highlights the rarity of seronegative SPSD. Future studies are needed to assess the true prevalence and other pathophysiological mechanisms involved in seronegative SPSD.