Beyond Nerve Hyperexcitability: Potential Implications of Cerebrospinal Fluid CASPR2 Antibodies for Central Pain Processing in Isaacs Syndrome: A Case-Based Systematic Review.

Authors

Rafaella Theologou, Panagiotis Zis

Published in

Pain and therapy. Sep 29, 2026. Epub Sep 29, 2026.

Abstract

Isaacs syndrome (IS), or acquired neuromyotonia, is a rare immune-mediated neuromuscular disorder characterized by increased peripheral nerve excitability. Clinically, it manifests with fasciculations, cramps, excessive sweating, and the presence of CASPR2 autoantibodies in the serum. IS can occur as a paraneoplastic condition or may remain idiopathic.
We report an adult case of IS that prompted a case-based literature review investigating the association between cerebrospinal fluid (CSF) CASPR2 antibodies and IS. A systematic literature search of PubMed and Scopus was conducted on 7 July 2026, with reference-list screening of eligible articles for additional relevant studies. Eligible studies reported original data on adults with IS and CSF CASPR2 antibody testing; reviews, editorials, abstracts, letters, pediatric studies, and studies without relevant CSF testing were excluded.
A 65-year-old man with a history of prostate cancer, treated with radiotherapy 4 years earlier, presented with a 3-year history of neuropathic pain and painful lower-limb cramps. Examination revealed fasciculations in all limbs and brisk tendon reflexes, with no Babinski sign. Neurophysiological studies demonstrated spontaneous doublet, triplet, and multiplet discharges. IS was supported by weakly positive serum VGKC-complex antibodies, low-positive LGI1 antibodies, and strongly positive CASPR2 antibodies, with strong CASPR2 positivity in cerebrospinal fluid, despite the absence of clinical features of Morvan syndrome. Our literature review identified six additional cases of IS in which CSF CASPR2 antibodies were tested. Of these, three had positive CSF CASPR2 antibody results. In two cases, IS remained idiopathic, whereas, in the third, it was associated with recurrent malignant thymoma. Including our patient, all reported cases of IS with CSF CASPR2 positivity presented with neuropathic pain.
IS should be considered in patients presenting with painful muscle cramps and electromyographic evidence of peripheral nerve hyperexcitability. The presence of CASPR2 antibodies in the CSF may be associated with neuropathic pain and could suggest involvement of pain pathway sensitization, potentially including central sensitization mechanisms.

PMID:
42809178
Bibliographic data and abstract were imported from PubMed on 30 Sep 2026.

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