Contactin-1 autoimmunity: Serologic, neurologic, and pathologic correlates

Abstract

Objective: To determine serologic characteristics, frequency, phenotype, paraneoplastic associations, and electrodiagnostic and histopathologic features accompanying contactin-1 autoimmunity.

Methods: Archived sera known to produce synaptic tissue-based immunofluorescence patterns were reevaluated, and contactin-1 specificity was confirmed by recombinant protein assays. Screening of 233 chronic/relapsing demyelinating neuropathies for additional cases was performed.

Results: We identified 10 contactin-1 IgG seropositive cases. Frequency of contactin-1 immunoglobulin (Ig) G among tested Mayo Clinic chronic/relapsing demyelinating neuropathies was 2%. Sensory predominant presentations (n = 9, 90%), neuropathic pain (n = 6, 60%), and subacute progression (n = 5, 50%) were commonly encountered among contactin-1 neuropathies. Two patients had chronic immune sensory polyradiculopathy-like phenotype at presentation. Electrodiagnostic studies were consistent with demyelination (slowed conduction velocities and/or prolonged distal latencies) without conduction block. Markedly elevated CSF protein (median 222 mg/dL, range 69-960 mg/dL), thickening/gadolinium enhancement of nerve roots (4/5), and subperineural edema on nerve biopsy (4/4) were other characteristic features. Three cases were diagnosed with paraneoplastic demyelinating neuropathies (thymoma, n = 1; breast cancer, n = 1; plasmacytoma, n = 1). Four of the 9 patients treated with IV immunoglobulin demonstrated initial clinical improvement, but the favorable response was sustained in only 1 case (median follow-up, 60 months). Sustained clinical stabilization or improvement was observed among 3 of the 6 cases in whom second-line therapies (rituximab, cyclophosphamide, and azathioprine) were used.

Conclusion: Contactin-1 IgG has a distinct sensory predominant presentation commonly associated with neuropathic pain, with demyelinating changes on electrophysiologic studies. A paraneoplastic cause should be considered. Testing of contactin-1 IgG among cases with similar presentations may guide immunotherapy selection, especially second-line immunotherapy consideration.

Figure 1. Somatosensory evoked potentials (A and B) and MRIs (C–F) of 2 contactin-1 IgG patients demonstrating favorable response to immunotherapy

Right median somatosensory evoked potential demonstrating prolongation of N9 (arrow) to N13 (arrowhead) interval consistent with cervical sensory root involvement (A), which improves after treatment with IV immunoglobulin (B). Enhancement of the cauda equina on (C) sagittal and (D) axial postgadolinium T1 sequences, which resolves postimmunotherapy (E and F). IVIG = IV immunoglobulin; IVMP = intravenous methylprednisolone; MMF = mycophenolate mofetil.

Figure 2. Nerve pathology of contactin-1 IgG neuropathy is distinct from classic-CIDP

Three example patients with contactin-1 autoimmunity are shown (A–F). Closely approximated osmium-fixed teased nerve fibers from a fascicular biopsy demonstrate widened nodes of Ranvier with demyelination (A) compared with 2 sural nerve biopsies (C and F) where axonal injury is prominent including with early (asterisk) and late (arrowhead) degenerative stages including with empty nerve fibers (arrow) (E). Semithin sections stained with toluidine blue in all patients had distinct prominent subperineural edema (asterisk) without onion bulb formation as is typical in CIDP. Axonal degeneration was most prominently seen in (D, F-arrowheads). CIDP = chronic inflammatory demyelinating polyradiculoneuropathy.