Neuropathic pain in CASPR2 antibody disease spectrum: A systematic review

Background: Contactin-associated protein-like 2 (CASPR2) antibodies are mainly linked to acquired neuromyotonia, limbic encephalitis and Morvan syndrome. Nevertheless, neuropathic pain is increasingly reported, though data on its characteristics remain limited. Here, we describe a patient with isolated neuropathic pain associated with CASPR2 antibodies and we conducted a systematic review to better define this relevant presentation. Methods: Index case was reported following CARE guidelines. The systematic review was performed on MEDLINE, Embase, and Cochrane, according to the updated PRISMA statement guidelines. Results: The literature review identified 216 patients with neuropathic pain in the context CASPR2 antibody disease spectrum, with isolated pain described in only 16/216 (7.4 %) cases. Pain was typically severe and presented as distal burning pain (74/147, 50.3 %), widespread pain with myalgia and cramps (31/147, 21.1 %), or severe back pain radiating to the legs (13/147, 8.8 %). Peripheral nerve hyperexcitability was found in 50/76 (65.8 %) of patients, while small nociceptive fiber dysfunction was identified in 16/19 (84.2 %). Immunotherapy, especially second line treatments, improved pain in 85.4 % (76/89) of cases, with complete remission of symptoms in 34/89 (38.2 %), while symptomatic treatment helped 55.1 % (27/49) of patients, with complete response in 10/49 (20.4 %). Long-term therapy was often needed, and relapses occurred in 5.2 % (5/96) after discontinuation. Conclusions: Neuropathic pain appears to be a suggestive and relevant symptom in CASPR2 disease. Although rare, it can be the solely clinical feature of the disease. Testing for CASPR2 antibodies should be included in the screening of patients with neuropathic pain as in these cases rapid initiation of immunotherapy and escalation to second-line treatments can be highly effective. Registration information: The systematic review protocol was registered in the PROSPERO website [Protocol number CRD42024582950].