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. 2023 Jul;10(7):1083-1094.
doi: 10.1002/acn3.51791. Epub 2023 May 22.

Stiff person spectrum disorder diagnosis, misdiagnosis, and suggested diagnostic criteria

Nicholas H Chia  1 , Andrew McKeon  1   2   3 , Marinos C Dalakas  4   5 , Eoin P Flanagan  1   3 , James H Bower  1 , Bryan T Klassen  1 , Divyanshu Dubey  1   2   3 , Nicholas L Zalewski  3   6 , Dustin Duffy  3 , Sean J Pittock  1   2   3 , Anastasia Zekeridou  1   2   3
Affiliations

Stiff person spectrum disorder diagnosis, misdiagnosis, and suggested diagnostic criteria

Nicholas H Chia et al. Ann Clin Transl Neurol. 2023 Jul.

Abstract

Background: Stiff person spectrum disorder (SPSD) is heterogeneous, and accurate diagnosis can be challenging.

Methods: Patients referred for diagnosis/suspicion of SPSD at the Mayo Autoimmune Neurology Clinic from July 01, 2016, to June 30, 2021, were retrospectively identified. SPSD diagnosis was defined as clinical SPSD manifestations confirmed by an autoimmune neurologist and seropositivity for high-titer GAD65-IgG (>20.0 nmol/L), glycine-receptor-IgG or amphiphysin-IgG, and/or confirmatory electrodiagnostic studies (essential if seronegative). Clinical presentation, examination, and ancillary testing were compared to differentiate SPSD from non-SPSD.

Results: Of 173 cases, 48 (28%) were diagnosed with SPSD and 125 (72%) with non-SPSD. Most SPSD were seropositive (41/48: GAD65-IgG 28/41, glycine-receptor-IgG 12/41, amphiphysin-IgG 2/41). Pain syndromes or functional neurologic disorder were the most common non-SPSD diagnoses (81/125, 65%). SPSD patients more commonly reported exaggerated startle (81% vs. 56%, p = 0.02), unexplained falls (76% vs. 46%, p = 0.001), and other associated autoimmunity (50% vs. 27%, p = 0.005). SPSD more often had hypertonia (60% vs. 24%, p < 0.001), hyperreflexia (71% vs. 43%, p = 0.001), and lumbar hyperlordosis (67% vs. 9%, p < 0.001) and less likely functional neurologic signs (6% vs. 33%, p = 0.001). SPSD patients more frequently had electrodiagnostic abnormalities (74% vs. 17%, p < 0.001), and at least moderate symptomatic improvement with benzodiazepines (51% vs. 16%, p < 0.001) or immunotherapy (45% vs. 13% p < 0.001). Only 4/78 non-SPSD patients who received immunotherapy had alternative neurologic autoimmunity.

Interpretation: Misdiagnosis was threefold more common than confirmed SPSD. Functional or non-neurologic disorders accounted for most misdiagnoses. Clinical and ancillary testing factors can reduce misdiagnosis and exposure to unnecessary treatments. SPSD diagnostic criteria are suggested.

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Conflict of interest statement

Drs Chia, Klassen, Zalewski, and Mr Duffy report no relevant disclosures. Dr McKeon reports patent applications issued for MAP1B and GFAP‐IgGs and pending for Septin‐5, PDE10A, Kelchl11‐IgGS as biomarkers of autoimmune neurologic disease. He has consulted for Grifols, Medimmune, and Euroimmun; and received research support from Grifols, Medimmune, Alexion, and Euroimmun but has not received personal compensation. He also received research funding from the NIH (NIH: RO1NS126227, U01NS120901). He is working as a consultant in the Mayo Clinic Neuroimmunology laboratory clinical service that offers commercial neural antibody testing, but revenue accrued does not contribute to salary, research support, or personal income for any of the authors. Dr Dalakas has consulted or served on a Scientific Advisory or Data Safety Monitoring board for Alexion, Grifols, Argenx, Sanofi, Octapharma, Takeda/Hyquvia, and the Dysimmune Diseases Foundation and has received personal compensation. He serves as an editor, associate editor, or editorial advisory board member for the AAN and Elsevier. Dr Flanagan has served on advisory boards for Alexion, Genentech, and Horizon Therapeutics. He has received speaker honoraria from Pharmacy Times. He received royalties from UpToDate. Dr Flanagan was a site primary investigator in a randomized clinical trial on Inebilizumab in neuromyelitis optical spectrum disorder run by Medimmune/Viela‐Bio/Horizon Therapeutics. Dr Flanagan has received funding from the NIH (R01NS113828). Dr Flanagan is a member of the medical advisory board of the MOG project. Dr Flanagan is an editorial board member of the Journal of the Neurologic Sciences and Neuroimmunology Reports. A patent has been submitted on DACH1‐IgG as a biomarker of paraneoplastic autoimmunity. He is working as a consultant in the Mayo Clinic Neuroimmunology laboratory clinical service that offers commercial neural antibody testing, but revenue accrued does not contribute to salary, research support, or personal income for any of the authors. Dr Bower reports research funding from Novartis and Transposon. Dr Dubey reports patents pending for the KLHL11 and LUZP4‐IgGs as markers of neurologic autoimmunity and germ cell tumor. He has served on advisory board for UCB and has been a consultant for Immunovant and Astellas. He is working as a consultant in the Mayo Clinic Neuroimmunology laboratory clinical service that offers commercial neural antibody testing, but revenue accrued does not contribute to salary, research support, or personal income for any of the authors. Dr Pittock reports grants, personal fees, and non‐financial support from Alexion Pharmaceuticals, Inc.; grants, personal fees, non‐financial support, and other support from MedImmune, Inc/Viela Bio.; personal fees for consulting from Genentech/Roche, UCB and Astellas. He has patent issued related to functional AQP4/NMO‐IgG assays, NMO‐IgG as a cancer marker and MAP1B‐IgG and GFAP‐IgG as a biomarker of Neurologic Autoimmunity. Dr Pittock also has patents pending for the following IgGs as biomarkers of autoimmune neurologic disorders (septin‐5, kelch‐like protein 11, DACH1, LUZP4). He is working as a consultant in the Mayo Clinic Neuroimmunology laboratory clinical service that offers commercial neural antibody testing, but revenue accrued does not contribute to salary, research support, or personal income for any of the authors. Dr Zekeridou has patents pending for PDE10A and DACH1‐IgG as biomarkers of neurologic autoimmunity, has received research funding from Roche/Genentech, and has consulted for Alexion pharmaceuticals but has not received personal compensation. She is working as a consultant in the Mayo Clinic Neuroimmunology laboratory clinical service that offers commercial neural antibody testing, but revenue accrued does not contribute to salary, research support, or personal income for any of the authors.

Figures

Figure 1
Figure 1
Patient population studied.
See this image and copyright information in PMC

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