Clinical and immunologic investigations in patients with stiff-person spectrum disorder

Eugenia Martinez-Hernandez, Helena Ariño, Andrew B McKeon, Takahiro Iizuka, Maarten J. Titulaer, Mateus M. Simabukuro, Eric Lancaster, Mar Petit-Pedrol, Jesú Planagumà, Yolanda Blanco, Robert J. Harvey, Albert Saiz, Francesc Graus, Josep Dalmau

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)714-720
Number of pages7
JournalJAMA Neurology
Volume73
Issue number6
DOIs
StatePublished - Jun 1 2016

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Stiff-Person Syndrome
Antibodies
Glycine Receptors
Extremities
Autoantibodies
Glycine Plasma Membrane Transport Proteins
Odds Ratio
Myoclonus
Glutamate Decarboxylase
Antibody Specificity
Encephalitis
Ataxia
Autoimmunity
Synapses
Epilepsy
Referral and Consultation
Outcome Assessment (Health Care)

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Martinez-Hernandez, E., Ariño, H., McKeon, A. B., Iizuka, T., Titulaer, M. J., Simabukuro, M. M., ... Dalmau, J. (2016). Clinical and immunologic investigations in patients with stiff-person spectrum disorder. JAMA Neurology, 73(6), 714-720. https://doi.org/10.1001/jamaneurol.2016.0133

Clinical and immunologic investigations in patients with stiff-person spectrum disorder. / Martinez-Hernandez, Eugenia; Ariño, Helena; McKeon, Andrew B; Iizuka, Takahiro; Titulaer, Maarten J.; Simabukuro, Mateus M.; Lancaster, Eric; Petit-Pedrol, Mar; Planagumà, Jesú; Blanco, Yolanda; Harvey, Robert J.; Saiz, Albert; Graus, Francesc; Dalmau, Josep.

In: JAMA Neurology, Vol. 73, No. 6, 01.06.2016, p. 714-720.

Research output: Contribution to journalArticle

Martinez-Hernandez, E, Ariño, H, McKeon, AB, Iizuka, T, Titulaer, MJ, Simabukuro, MM, Lancaster, E, Petit-Pedrol, M, Planagumà, J, Blanco, Y, Harvey, RJ, Saiz, A, Graus, F & Dalmau, J 2016, 'Clinical and immunologic investigations in patients with stiff-person spectrum disorder', JAMA Neurology, vol. 73, no. 6, pp. 714-720. https://doi.org/10.1001/jamaneurol.2016.0133
Martinez-Hernandez E, Ariño H, McKeon AB, Iizuka T, Titulaer MJ, Simabukuro MM et al. Clinical and immunologic investigations in patients with stiff-person spectrum disorder. JAMA Neurology. 2016 Jun 1;73(6):714-720. https://doi.org/10.1001/jamaneurol.2016.0133
Martinez-Hernandez, Eugenia ; Ariño, Helena ; McKeon, Andrew B ; Iizuka, Takahiro ; Titulaer, Maarten J. ; Simabukuro, Mateus M. ; Lancaster, Eric ; Petit-Pedrol, Mar ; Planagumà, Jesú ; Blanco, Yolanda ; Harvey, Robert J. ; Saiz, Albert ; Graus, Francesc ; Dalmau, Josep. / Clinical and immunologic investigations in patients with stiff-person spectrum disorder. In: JAMA Neurology. 2016 ; Vol. 73, No. 6. pp. 714-720.
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abstract = "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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TY - JOUR

T1 - Clinical and immunologic investigations in patients with stiff-person spectrum disorder

AU - Martinez-Hernandez, Eugenia

AU - Ariño, Helena

AU - McKeon, Andrew B

AU - Iizuka, Takahiro

AU - Titulaer, Maarten J.

AU - Simabukuro, Mateus M.

AU - Lancaster, Eric

AU - Petit-Pedrol, Mar

AU - Planagumà, Jesú

AU - Blanco, Yolanda

AU - Harvey, Robert J.

AU - Saiz, Albert

AU - Graus, Francesc

AU - Dalmau, Josep

PY - 2016/6/1

Y1 - 2016/6/1

N2 - 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.

AB - 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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