Background & Aims
Caspr2 autoantibody-positive patients are rare, and the clinical phenotypes vary (1). Caspr2 is widely expressed in the central (CNS) and peripheral nervous system (PNS). Therefore, patients suffer from CNS-focused symptoms, like limbic encephalitis, seizures, insomnia, and cerebellar dysfunction, but also PNS-related symptoms like neuromyotonia and neuropathic pain occur quite frequently (2). The C-fibers and A?-fibers of the dorsal root ganglion (DRG) transmit pain from the periphery to the central nervous system (CNS). In the membrane of DRG neurons, Caspr2 is part of the voltage-gated potassium channel (VGKC) complex (3). The VGKC complex drives the repolarization of the depolarized axonal membrane. Caspr2 autoantibodies may conflict with this process and cause hyperexcitability. We asked whether the pain phenotype is reflected by a specific IgG subclass and if Caspr2 autoantibodies affect the function of associated potassium channels and thus alter neuronal excitability.
Methods
The presence and phenotype of pain of a cohort of anti-Caspr2-positive patients from the German Network for Research on Autoimmune Encephalitis (GENERATE) was analyzed. In addition, we tested 40 sera of the cohort in immunocytochemical stainings of Caspr2 transfected HEK293 cells for the presence of IgG subclasses IgG1, 2, 3, or 4. Since IgG4 differs in its properties from IgG1-3, the patient sera were classified into four groups according to the presence of IgG4 only or IgG4+IgG1-3 and depending on the presence of pain. Four pools of sera and a healthy control pool were used for electrophysiological recordings on DRG neurons preincubated with sera pools of defined time windows. The analysis of neuronal functionality concentrated on potassium channels of the Kv subtypes.
Results
Our analysis revealed 37 patients with chronic pain and 65 without pain. 20 out of 37 patients suffered from pain as their major symptom and two patients showed pain as their only symptom. A cluster analysis provided two groups of phenotypic similarity: One group showed predominantly distal burning pain and another one displayed widespread pain, myalgia, arthralgia, and cramps as core symptoms (4). We identified the composition of IgG subclasses in 40 patient sera. IgG4 was the predominant subclass of anti-Caspr2 autoantibodies and present in all patients except for three. 19 out of 40 patients displayed pain and 21 patients did not. Four patients with pain and six patients without pain had only IgG4. Independent of the pain phenotype, the potassium currents were reduced in DRG neurons treated with Caspr2-autoantibodies. The observed decreased potassium channel activity was more pronounced for patient sera containing only IgG4 in comparison to sera with IgG4+IgG1-3.
Conclusions
Our data show pain as a relevant symptom in Caspr2-autoantibody-positive patients. The painful states differ in their intensity and localization. The large number of patients in our cohort supports the existence of two groups of manifestations of pain such as distal burning pain and widespread pain. A distinct association of the IgG subclass distribution with the pain phenotype was not identified. The observed decrease in the potassium channel activity argues for an enhanced excitability of DRG neurons. Moreover, the reduced potassium current amplitudes also suggest that targeting of Caspr2 by autoantibodies most likely alters the VGKC as a secondary effect and hence the functionality of the associated potassium channels.
References
1.Ellwardt E, Geber C, Lotz J, Birklein F. Heterogeneous presentation of caspr2 antibody-associated peripheral neuropathy – A case series. Eur J Pain. 2020 Aug;24(7):1411-1418. doi: 10.1002/ejp.1572. Epub 2020 Apr 30. PMID: 32279412.
2.van Sonderen A, Ariño H, Petit-Pedrol M, Leypoldt F, Körtvelyessy P, Wandinger KP, Lancaster E, Wirtz PW, Schreurs MW, Sillevis Smitt PA, Graus F, Dalmau J, Titulaer MJ. The clinical spectrum of Caspr2 antibody-associated disease. Neurology. 2016 Aug 2;87(5):521-8. doi: 10.1212/WNL.0000000000002917. Epub 2016 Jul 1. PMID: 27371488; PMCID: PMC4970662.
3.Binks SNM, Klein CJ, Waters P, Pittock SJ, Irani SR. LGI1, CASPR2 and related antibodies: a molecular evolution of the phenotypes. J Neurol Neurosurg Psychiatry. 2018 May;89(5):526-534. doi: 10.1136/jnnp-2017-315720. Epub 2017 Oct 21. PMID: 29055902; PMCID: PMC5909759.
4.Greguletz P, Plötz M, Baade-Büttner C, Bien CG, Eisenhut K, Geis C, Handreka R, Klausewitz J, Körtvelyessy P, Kovac S, Kraft A, Lewerenz J, Malter M, Nagel M, von Podewils F, Prüß H, Rada A, Rau J, Rauer S, Rößling R, Seifert-Held T, Siebenbrodt K, Sühs K-W, Tauber SC, Thaler F, Wagner J, Wickel J, Leypoldt F, Rittner HL, Sommer C, Villmann C, Doppler K and the GENERATE study group, Different pain phenotypes are associated with anti-Caspr2 autoantibodies, Journal of Neurology, accepted
Presenting Author
Patrik Greguletz
Poster Authors
Patrik Greguletz
MSc
Universitätsklinikum Würzburg
Lead Author
Margarita Habib MSc
Lead Author
Anna-Lena Wießler PhD
Lead Author
Maria Plötz
Lead Author
Carolin Baade-Büttner MD
Lead Author
Christian G. Bien Prof.
Lead Author
Katharina Eisenhut MD
Lead Author
Christian Geis Prof.
Lead Author
Robert Handreka MD
Lead Author
Jaqueline Klausewitz MD
Lead Author
Peter Körtvelyessy MD
Lead Author
Stjepana Kovac Prof.
Lead Author
Andrea Kraft MD
Lead Author
Jan Lewerenz Prof.
Lead Author
Michael Malter MD
Lead Author
Michael Nagel MD
Lead Author
Felix von Podewils Prof.
Lead Author
Harald Prüß Prof.
Lead Author
Anna Rada MD
Lead Author
Johanna Rau MD
Lead Author
Sebastian Rauer Prof.
Lead Author
Rosa Rößling MD
Lead Author
Thomas Seifert-Held MD
Lead Author
Kai Siebenbrodt MD
Lead Author
Kurt-Wolfram Sühs Prof.
Lead Author
Simone C. Tauber Prof.
Lead Author
Franziska Thaler MD
Lead Author
Judith Wagner MD
Lead Author
Jonathan Wickel MD
Lead Author
Frank Leypoldt MD
Lead Author
Heike Rittner
University Hospital Wuerzburg
Lead Author
Claudia Sommer
University of Wuerzburg
Lead Author
Carmen Villmann Prof.
Lead Author
Kathrin Doppler MD
Lead Author
Topics
- Specific Pain Conditions/Pain in Specific Populations: Neuropathic Pain - Peripheral