Caspr1 antibodies autoimmune paranodopathy with severe tetraparesis: Potential relevance of antibody titers in monitoring treatment response

Nodopathies and paranodopathies are autoimmune neuropathies associated with antibodies to nodal–paranodal antigens (neurofascin 140/186 and 155, contactin‐1, contactin‐associated protein 1 [Caspr1]) characterized by peculiar clinical features, poor response to standard immunotherapies (e.g., intravenous immunoglobulins, IVIg). Improvement after anti‐CD20 monoclonal antibody therapy has been reported. Data on Caspr1 antibodies pathogenicity are still preliminary, and longitudinal titers have been poorly described.

supports the pathogenicity of Caspr1 antibodies, and suggest that their longitudinal evaluation might provide a potential biomarker to evaluate treatment response. and absence of macrophage-mediated demyelination at nerve biopsy.
Although anedotically, improvement after anti-CD20 monoclonal antibody (rituximab) therapy has been reported. 1,2 Antibodies to Caspr1, typically of IgG4 isotype, are associated with subacute onset, sensory ataxia, and neuropathic pain, even though these features have not been confirmed in all cohorts. 2 Cranial nerve involvement and respiratory failure, 2,3 and even severe pictures, for example, locked-in syndrome, have also been described.
We report on a young woman with cystic fibrosis who developed a disabling subacute neuropathy with antibodies to the Caspr1/ contactin-1 complex showing a dramatic improvement after rituximab therapy, mirrored by the decrease of antibody titers.

| CASE REPORT
A 26-year-old woman, with medical history significant for cystic fibrosis in regular pneumological follow-up, presented with subacute onset (July 2021) of severe back pain, muscle weakness, and distal paresthesias and numbness at lower limbs that spread within 1 week involving the upper limbs. In the following 2 weeks the patient also developed distal predominant weakness. The symptomatology progressively worsened and after 4 months from onset the patient was forced to discontinue her job. In addition, she started experiencing numbness at the level of the trunk, from the submammillary line downward, and weakness of neck and facial muscles. Low magnitude (0-4 Tesla) spinal magnetic resonance imaging (MRI) was unremarkable.
Neurophysiological studies revealed a demyelinating neuropathy, leading to a diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). The patient was treated with oral steroids (50 mg prednisone daily) with no benefit and progressive rapid wors- Despite the administration of intravenous methylprednisolone (500 mg intravenously per five consecutive days, followed by oral prednisone tapering) and physical therapy, the clinical picture progressively worsened, sensory loss spread up to chin and tongue, distal strength was further reduced, and the patient became unable to stand independently being restricted to wheelchair (inflammatory neuropathy cause and treatment disability score, four at lower limbs and four at upper limbs). Neuropathic pain was present at lower limbs and pregabalin was introduced with benefit.
F I G U R E 1 MRI with 3D Neurographic showed diffuse, symmetrical, homogenous hypertrophy and marked T2-STIR signal hyperintensity of roots and main divisions of brachial (A-C) and lumbosacral (E,F) plexi. Brain MRI was unremarkable. MRI, magnetic resonance imaging.  (Table 1).
Nerve ultrasound showed reduction of CSA of some nerve trunks, in particular of the brachial plexus bilaterally (CSA di 104 mm 2 on the left side, 106 mm 2 on the right side).
One year after rituximab therapy (January 2023), the patient pre-

| INTERPRETATION
Nodo-paranodopathies are autoimmune diseases of the peripheral nervous system recently separated from CIDP due to their different clinical phenotype, pathological findings, and response to therapy. 4 Our patient had a very severe progressive course with early disability and axonal damage, and slow recovery starting only a few months after antibody-depleting therapy, as described in other cases.
The association between autoimmune paranodopathy and cystic fibrosis, two rare diseases, has never been reported so far and may be coincidental.
As a novelty, antibody titer decrease mirrored the clinical improvement. Among paranodal antibodies, several studies support the pathogenic role of neurofascin-155 and contactin-1. Both NF155 and contactin-1 IgG4 can disrupt the paranode architecture, and neurofascin-155 serum titers correlate with serum neurofilament light chain (a marker of axonal injury) and decrease after rituximab therapy. 5 Both anti-contactin-1 and anti-neurofascin antibodies decrease after rituximab. 6,7 Conversely, data on Caspr1 antibodies pathogenicity are still preliminary, 2 and longitudinal titers have been poorly described. Our case, showing a close correlation between titer, disability, and treatment, supports the pathogenicity of Caspr1 antibodies, and suggest that their longitudinal evaluation might provide a potential biomarker to evaluate treatment response.

ACKNOWLEDGMENTS
Chiara Briani is a member of the European Reference Network for Neuromuscular Diseases.

CONFLICT OF INTEREST STATEMENT
The author report no conflict of interest in connection with this article.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.