Multimodal Biomarkers Quantify Recovery in Autoimmune Autonomic Ganglionopathy

Shiwen Koay; Ekawat Vichayanrat; Fion Bremner; Jalesh N. Panicker; Bethan Lang; Michael P. Lunn; Laura Watson; Gordon T. Ingle; Ellen Merete Hagen; Patricia McNamara; Leslie Jacobson; Vincenzo Provitera; Maria Nolano; Angela Vincent; Christopher J. Mathias; Valeria Iodice

doi:10.1002/ana.26018

Multimodal Biomarkers Quantify Recovery in Autoimmune Autonomic Ganglionopathy

Shiwen Koay, Ekawat Vichayanrat, Fion Bremner, Jalesh N. Panicker, Bethan Lang, Michael P. Lunn, Laura Watson, Gordon T. Ingle, Ellen Merete Hagen, Patricia McNamara, Leslie Jacobson, Vincenzo Provitera, Maria Nolano, Angela Vincent, Christopher J. Mathias, Valeria Iodice^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

18 Citationer (Scopus)

Abstract

Objective: The objective of this study was to evaluate patients with ganglionic acetylcholine receptor antibody (gAChR-Ab) positive autoimmune autonomic ganglionopathy using a multimodal testing protocol to characterize their full clinical phenotype and explore biomarkers to quantify immunotherapy response. Methods: We conducted a cohort study of 13 individuals (7 women, 21–69 years of age) with autonomic failure and gAChR-Ab >100 pM identified between 2005 and 2019. From 2018, all patients were longitudinally assessed with cardiovascular, pupillary, urinary, sudomotor, lacrimal and salivary testing, and Composite Autonomic Symptom Score (COMPASS-31) autonomic symptom questionnaires. The orthostatic intolerance ratio was calculated by dividing change in systolic blood pressure over time tolerated on head-up tilt. Eleven patients received immunotherapy. Results: At first assessment, all 13 patients had cardiovascular and pupillary impairments, 7 of 8 had postganglionic sudomotor dysfunction, 9 of 11 had urinary retention and xeropthalmia, and 6 of 8 had xerostomia. After immunotherapy, there were significant improvements in orthostatic intolerance ratio (33.3 [17.8–61.3] to 5.2 [1.4–8.2], p = 0.007), heart rate response to deep breathing (1.5 [0.0–3.3] to 4.5 [3.0–6.3], p = 0.02), pupillary constriction to light (12.0 [5.5–18.0] to 19.0 [10.6–23.8]%, p = 0.02), saliva production (0.01 [0.01–0.05] to 0.08 [0.02–0.20] g/min, p = 0.03), and COMPASS-31 scores (52 to 17, p = 0.03). Orthostatic intolerance ratio correlated with autonomic symptoms at baseline (r = 0.841, p = 0.01) and following immunotherapy (r = 0.889, p = 0.02). Immunofluorescence analyses of skin samples from a patient 32 years after disease onset showed loss of nerve fibers supplying the dermal autonomic adnexa and epidermis, with clear improvements following immunotherapy. Interpretation: Patients with autoimmune autonomic ganglionopathy demonstrated objective evidence of widespread sympathetic and parasympathetic autonomic failure, with significant improvements after immunotherapy. Quantitative autonomic biomarkers should be used to define initial deficits, guide therapeutic decisions, and document treatment response. ANN NEUROL 2021;89:753–768.

Originalsprog	Engelsk
Tidsskrift	Annals of Neurology
Vol/bind	89
Nummer	4
Sider (fra-til)	753-768
Antal sider	16
ISSN	0364-5134
DOI	https://doi.org/10.1002/ana.26018
Status	Udgivet - apr. 2021

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10.1002/ana.26018

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Koay, S., Vichayanrat, E., Bremner, F., Panicker, J. N., Lang, B., Lunn, M. P., Watson, L., Ingle, G. T., Hagen, E. M., McNamara, P., Jacobson, L., Provitera, V., Nolano, M., Vincent, A., Mathias, C. J., & Iodice, V. (2021). Multimodal Biomarkers Quantify Recovery in Autoimmune Autonomic Ganglionopathy. Annals of Neurology, 89(4), 753-768. https://doi.org/10.1002/ana.26018

@article{5aae113e65fd47d18125655847afd26a,

title = "Multimodal Biomarkers Quantify Recovery in Autoimmune Autonomic Ganglionopathy",

abstract = "Objective: The objective of this study was to evaluate patients with ganglionic acetylcholine receptor antibody (gAChR-Ab) positive autoimmune autonomic ganglionopathy using a multimodal testing protocol to characterize their full clinical phenotype and explore biomarkers to quantify immunotherapy response. Methods: We conducted a cohort study of 13 individuals (7 women, 21–69 years of age) with autonomic failure and gAChR-Ab >100 pM identified between 2005 and 2019. From 2018, all patients were longitudinally assessed with cardiovascular, pupillary, urinary, sudomotor, lacrimal and salivary testing, and Composite Autonomic Symptom Score (COMPASS-31) autonomic symptom questionnaires. The orthostatic intolerance ratio was calculated by dividing change in systolic blood pressure over time tolerated on head-up tilt. Eleven patients received immunotherapy. Results: At first assessment, all 13 patients had cardiovascular and pupillary impairments, 7 of 8 had postganglionic sudomotor dysfunction, 9 of 11 had urinary retention and xeropthalmia, and 6 of 8 had xerostomia. After immunotherapy, there were significant improvements in orthostatic intolerance ratio (33.3 [17.8–61.3] to 5.2 [1.4–8.2], p = 0.007), heart rate response to deep breathing (1.5 [0.0–3.3] to 4.5 [3.0–6.3], p = 0.02), pupillary constriction to light (12.0 [5.5–18.0] to 19.0 [10.6–23.8]%, p = 0.02), saliva production (0.01 [0.01–0.05] to 0.08 [0.02–0.20] g/min, p = 0.03), and COMPASS-31 scores (52 to 17, p = 0.03). Orthostatic intolerance ratio correlated with autonomic symptoms at baseline (r = 0.841, p = 0.01) and following immunotherapy (r = 0.889, p = 0.02). Immunofluorescence analyses of skin samples from a patient 32 years after disease onset showed loss of nerve fibers supplying the dermal autonomic adnexa and epidermis, with clear improvements following immunotherapy. Interpretation: Patients with autoimmune autonomic ganglionopathy demonstrated objective evidence of widespread sympathetic and parasympathetic autonomic failure, with significant improvements after immunotherapy. Quantitative autonomic biomarkers should be used to define initial deficits, guide therapeutic decisions, and document treatment response. ANN NEUROL 2021;89:753–768.",

keywords = "Adult, Aged, Autoimmune Diseases of the Nervous System/diagnosis, Autonomic Nervous System Diseases/diagnosis, Biomarkers/analysis, Blood Pressure, Cohort Studies, Female, Ganglia, Autonomic, Humans, Immunotherapy, Longitudinal Studies, Male, Middle Aged, Nerve Fibers/pathology, Orthostatic Intolerance, Prognosis, Receptors, Cholinergic/immunology, Skin/pathology, Treatment Outcome, Young Adult",

author = "Shiwen Koay and Ekawat Vichayanrat and Fion Bremner and Panicker, {Jalesh N.} and Bethan Lang and Lunn, {Michael P.} and Laura Watson and Ingle, {Gordon T.} and Hagen, {Ellen Merete} and Patricia McNamara and Leslie Jacobson and Vincenzo Provitera and Maria Nolano and Angela Vincent and Mathias, {Christopher J.} and Valeria Iodice",

note = "Publisher Copyright: {\textcopyright} 2021 American Neurological Association",

year = "2021",

month = apr,

doi = "10.1002/ana.26018",

language = "English",

volume = "89",

pages = "753--768",

journal = "Annals of Neurology",

issn = "0364-5134",

publisher = "John Wiley & Sons Inc.",

number = "4",

}

TY - JOUR

T1 - Multimodal Biomarkers Quantify Recovery in Autoimmune Autonomic Ganglionopathy

AU - Koay, Shiwen

AU - Vichayanrat, Ekawat

AU - Bremner, Fion

AU - Panicker, Jalesh N.

AU - Lang, Bethan

AU - Lunn, Michael P.

AU - Watson, Laura

AU - Ingle, Gordon T.

AU - Hagen, Ellen Merete

AU - McNamara, Patricia

AU - Jacobson, Leslie

AU - Provitera, Vincenzo

AU - Nolano, Maria

AU - Vincent, Angela

AU - Mathias, Christopher J.

AU - Iodice, Valeria

PY - 2021/4

Y1 - 2021/4

N2 - Objective: The objective of this study was to evaluate patients with ganglionic acetylcholine receptor antibody (gAChR-Ab) positive autoimmune autonomic ganglionopathy using a multimodal testing protocol to characterize their full clinical phenotype and explore biomarkers to quantify immunotherapy response. Methods: We conducted a cohort study of 13 individuals (7 women, 21–69 years of age) with autonomic failure and gAChR-Ab >100 pM identified between 2005 and 2019. From 2018, all patients were longitudinally assessed with cardiovascular, pupillary, urinary, sudomotor, lacrimal and salivary testing, and Composite Autonomic Symptom Score (COMPASS-31) autonomic symptom questionnaires. The orthostatic intolerance ratio was calculated by dividing change in systolic blood pressure over time tolerated on head-up tilt. Eleven patients received immunotherapy. Results: At first assessment, all 13 patients had cardiovascular and pupillary impairments, 7 of 8 had postganglionic sudomotor dysfunction, 9 of 11 had urinary retention and xeropthalmia, and 6 of 8 had xerostomia. After immunotherapy, there were significant improvements in orthostatic intolerance ratio (33.3 [17.8–61.3] to 5.2 [1.4–8.2], p = 0.007), heart rate response to deep breathing (1.5 [0.0–3.3] to 4.5 [3.0–6.3], p = 0.02), pupillary constriction to light (12.0 [5.5–18.0] to 19.0 [10.6–23.8]%, p = 0.02), saliva production (0.01 [0.01–0.05] to 0.08 [0.02–0.20] g/min, p = 0.03), and COMPASS-31 scores (52 to 17, p = 0.03). Orthostatic intolerance ratio correlated with autonomic symptoms at baseline (r = 0.841, p = 0.01) and following immunotherapy (r = 0.889, p = 0.02). Immunofluorescence analyses of skin samples from a patient 32 years after disease onset showed loss of nerve fibers supplying the dermal autonomic adnexa and epidermis, with clear improvements following immunotherapy. Interpretation: Patients with autoimmune autonomic ganglionopathy demonstrated objective evidence of widespread sympathetic and parasympathetic autonomic failure, with significant improvements after immunotherapy. Quantitative autonomic biomarkers should be used to define initial deficits, guide therapeutic decisions, and document treatment response. ANN NEUROL 2021;89:753–768.

AB - Objective: The objective of this study was to evaluate patients with ganglionic acetylcholine receptor antibody (gAChR-Ab) positive autoimmune autonomic ganglionopathy using a multimodal testing protocol to characterize their full clinical phenotype and explore biomarkers to quantify immunotherapy response. Methods: We conducted a cohort study of 13 individuals (7 women, 21–69 years of age) with autonomic failure and gAChR-Ab >100 pM identified between 2005 and 2019. From 2018, all patients were longitudinally assessed with cardiovascular, pupillary, urinary, sudomotor, lacrimal and salivary testing, and Composite Autonomic Symptom Score (COMPASS-31) autonomic symptom questionnaires. The orthostatic intolerance ratio was calculated by dividing change in systolic blood pressure over time tolerated on head-up tilt. Eleven patients received immunotherapy. Results: At first assessment, all 13 patients had cardiovascular and pupillary impairments, 7 of 8 had postganglionic sudomotor dysfunction, 9 of 11 had urinary retention and xeropthalmia, and 6 of 8 had xerostomia. After immunotherapy, there were significant improvements in orthostatic intolerance ratio (33.3 [17.8–61.3] to 5.2 [1.4–8.2], p = 0.007), heart rate response to deep breathing (1.5 [0.0–3.3] to 4.5 [3.0–6.3], p = 0.02), pupillary constriction to light (12.0 [5.5–18.0] to 19.0 [10.6–23.8]%, p = 0.02), saliva production (0.01 [0.01–0.05] to 0.08 [0.02–0.20] g/min, p = 0.03), and COMPASS-31 scores (52 to 17, p = 0.03). Orthostatic intolerance ratio correlated with autonomic symptoms at baseline (r = 0.841, p = 0.01) and following immunotherapy (r = 0.889, p = 0.02). Immunofluorescence analyses of skin samples from a patient 32 years after disease onset showed loss of nerve fibers supplying the dermal autonomic adnexa and epidermis, with clear improvements following immunotherapy. Interpretation: Patients with autoimmune autonomic ganglionopathy demonstrated objective evidence of widespread sympathetic and parasympathetic autonomic failure, with significant improvements after immunotherapy. Quantitative autonomic biomarkers should be used to define initial deficits, guide therapeutic decisions, and document treatment response. ANN NEUROL 2021;89:753–768.

KW - Adult

KW - Aged

KW - Autoimmune Diseases of the Nervous System/diagnosis

KW - Autonomic Nervous System Diseases/diagnosis

KW - Biomarkers/analysis

KW - Blood Pressure

KW - Cohort Studies

KW - Female

KW - Ganglia, Autonomic

KW - Humans

KW - Immunotherapy

KW - Longitudinal Studies

KW - Male

KW - Middle Aged

KW - Nerve Fibers/pathology

KW - Orthostatic Intolerance

KW - Prognosis

KW - Receptors, Cholinergic/immunology

KW - Skin/pathology

KW - Treatment Outcome

KW - Young Adult

UR - http://www.scopus.com/inward/record.url?scp=85100265837&partnerID=8YFLogxK

U2 - 10.1002/ana.26018

DO - 10.1002/ana.26018

M3 - Journal article

C2 - 33438240

AN - SCOPUS:85100265837

SN - 0364-5134

VL - 89

SP - 753

EP - 768

JO - Annals of Neurology

JF - Annals of Neurology

IS - 4

ER -

Multimodal Biomarkers Quantify Recovery in Autoimmune Autonomic Ganglionopathy

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