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Original Investigation |

Clinical and Immunologic Investigations in Patients With Stiff-Person Spectrum Disorder

Eugenia Martinez-Hernandez, MD, PhD1,2; Helena Ariño, MD1,2; Andrew McKeon, MD3; Takahiro Iizuka, MD4; Maarten J. Titulaer, MD, PhD5; Mateus M. Simabukuro, MD6; Eric Lancaster, MD, PhD7; Mar Petit-Pedrol, MS2; Jesús Planagumà, PhD2; Yolanda Blanco, MD, PhD1; Robert J. Harvey, BSc, PhD8; Albert Saiz, MD, PhD1,2; Francesc Graus, MD, PhD1,2; Josep Dalmau, MD, PhD2,7,9
[+] Author Affiliations
1Department of Neurology, Hospital Clínic, University of Barcelona, Barcelona, Spain
2Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
3Departments of Neurology, Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
4Department of Neurology, Kitasato University School of Medicine, Sagamihara, Japan
5Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands
6Neurology Division, Hospital das Clinicas, São Paulo University, São Paulo, Brazil
7Department of Neurology, University of Pennsylvania, Philadelphia
8Department of Pharmacology, UCL School of Pharmacy, London, England
9Institució Catalana de Recerca i Estudis Avançats (ICREA), Catalonia, Spain
JAMA Neurol. 2016;73(6):714-720. doi:10.1001/jamaneurol.2016.0133.
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Importance  Symptoms of stiff-person syndrome (SPS), stiff-limb syndrome (SLS), or progressive encephalomyelitis with rigidity, myoclonus, or other symptoms (SPS-plus) can occur with several autoantibodies, but the relative frequency of each antibody, syndrome specificity, and prognostic implications are unclear.

Objective  To report the clinical and immunologic findings of a large cohort of patients with stiff-person spectrum disorder (SPSD), including SPS, SLS, and SPS-plus.

Design, Setting, and Patients  This study retrospectively examined a case series (January 1, 1998, through December 31, 2014) of immunologic investigations performed in a neuroimmunology referral center. The study included 121 patients with clinical features of SPSD. Data analysis was performed from July 1, 2015, through November 1, 2015.

Main Outcomes and Measures  Analysis of clinical-immunologic associations, including autoantibodies to 8 proteins expressed in inhibitory synapses.

Results  The median age of the patients was 51 years (interquartile range, 40-61 years), and 75 (62.0%) were female. Fifty (41.3%) had SPS, 37 (30.6%) had SPS-plus, 24 (19.8%) had SLS, and 10 (8.3%) had SPS or SLS overlapping with ataxia, epilepsy, or encephalitis. Fifty-two patients (43.0%) had glutamic acid decarboxylase (GAD65) antibodies (2 with γ-aminobutyric acid–A [GABA-A] receptor antibodies), 24 (19.8%) had α1-subunit of the glycine receptor (GlyR) antibodies (2 with GAD65 antibodies), 5 (4.1%) had other antibodies, and 40 (33.1%) tested negative for antibodies. None had gephyrin or glycine transporter antibodies. Among the main immunologic groups (GAD65 antibodies, GlyR antibodies, and antibody negative), those with GAD65 antibodies were more likely to be female (45 [86.5%] of 52, 8 [36.4%] of 22, and 18 [45.0%] of 40, respectively; P < .001), have systemic autoimmunity (34 [65.4%] of 52, 7 [31.8%] of 22, and 13 [32.5%] of 40, respectively; P = .004), and have longer delays in being tested for antibodies (median, 3 vs 0.5 and 1 year; P < .001). Patients with GAD65 antibodies were more likely to develop SPS (27 [51.9%] of 52) or overlapping syndromes (8 [15.4%] of 52) than patients with GlyR antibodies (5 [22.7%] and 0 [0%] of 22, respectively), who more often developed SPS-plus (12 [54.5%] of 22 vs 7 [13.5%] in those with GAD65 antibodies); antibody-negative patients had an intermediate syndrome distribution. In multivariable analysis, symptom severity (P = .001) and immunologic group (P = .01) were independently associated with outcome. Compared with patients with GlyR antibodies, those with GAD65 antibodies (odds ratio, 11.1, 95% CI, 2.3-53.7; P = .003) had worse outcome. Patients without antibodies had similar outcome than patients with GlyR antibodies (odds ratio, 4.2, 95% CI, 0.9-20.0; P = .07).

Conclusions and Relevance  In SPSD, symptom severity and presence and type of antibodies are predictors of outcome.

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