Nephrotic Syndrome in CASPR2 Antibody Syndromes: Two Cases with Neuro-Renal Manifestations

Introduction

Contactin-associated protein-like 2 (CASPR2) is a paranodal protein that clusters voltage-gated potassium channels. Autoantibodies against CASPR2 cause a spectrum of neurologic disorders ranging from acquired neuromyotonia (Isaac’s syndrome) to encephalopathy with autonomic dysfunction (Morvan syndrome).^1,2 While traditionally considered neurological, emerging data suggest systemic involvement, including renal disease. Membranous nephropathy (MN) is the most frequently described renal lesion, likely reflecting autoimmune podocyte injury analogous to contactin-1-associated MN in patients with chronic inflammatory demyelinating polyneuropathy (CIDP).^3,4

We report two patients with CASPR2 autoimmunity who developed biopsy-proven MN and nephrotic syndrome. These cases demonstrate contrasting clinical presentations yet shared response to antibody removal, highlighting the importance of recognizing neuro-renal overlap in Voltage gated potassium channel-complex autoimmunity.

Case 1: Morvan Syndrome with Chronic MN

A 58-year-old male with diabetes presented with subacute encephalopathy, hallucinations, dysarthria, and dysautonomia. Serology confirmed CASPR2 and LGI1 antibodies. He also had edema, with 24-hour proteinuria (4.1 g/day), hypoalbuminemia (2.6 g/dL), and hypercholesterolemia. Renal biopsy revealed MN with >50% interstitial fibrosis/tubular atrophy and focal segmental sclerosis. Phospholipase-2 (PLA2R) and Neural Epidermal Growth Factor Like 1 Protein (NELL-1) were negative [Figure 1a].

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Figure 1:

(a) Light microscopy of the kidney biopsy (Jones methenamine silver stain, ´400) showing a glomerulus with diffuse uniform thickening of the glomerular basement membranes. Multiple spikes and pinholes are evident along the capillary loops (black arrow), representing projections of basement membrane material between subepithelial immune deposits characteristic of membranous nephropathy. No significant mesangial proliferation is noted, and capillary lumina remain patent. (b) Kidney biopsy (hematoxylin and eosin stain, ´400) demonstrating a glomerulus with diffuse thickening of the glomerular capillary walls (black arrow), without mesangial or endocapillary proliferation. The capillary lumina remain patent, and no sclerosing or crescentic lesions are seen.

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He received steroids and rituximab with minimal response. Five sessions of plasmapheresis resulted in marked neurological improvement and proteinuria reduction to 1.2 g/day, with serum albumin rising to 3.5 g/dL. He remains on tapering steroids with repeat rituximab planned.

Discussion

CASPR2 antibody syndromes are IgG4-mediated and clinically heterogeneous.^1,2 Renal involvement, though rare, is increasingly recognized. Both of our patients had MN without PLA2R/NELL-1 positivity, suggesting secondary autoimmunity. A mechanistic link may involve paranodal-podocyte antigenic overlap, as described in contactin-1-related MN.^3,4

Previous reports include CASPR2 encephalitis with MN, occasionally triggered by environmental exposures such as mercury.^5,6 Potential mechanisms include molecular mimicry, epitope spreading, or systemic dysregulation.^7,8 Importantly, both of our cases showed resistance to steroids and rituximab but responded to plasmapheresis, strongly implicating circulating antibodies as pathogenic mediators.

The parallel neurological and renal responses underscore a common autoimmune basis rather than coincidental coexistence. For clinicians, edema or proteinuria in CASPR2-positive patients should prompt early nephrology evaluation and kidney biopsy. Therapeutic strategies should prioritize antibody removal or modulation, plasmapheresis being particularly effective in resistant cases.

These cases broaden the clinical spectrum of CASPR2 autoimmunity to include MN, complicating both Morvan’s and Isaac’s syndromes. Kidney involvement should be actively screened in CASPR2 syndromes, particularly in the presence of edema or proteinuria. Early biopsy and antibody-targeted therapy may be crucial to achieving remission. Larger series are required to define mechanisms and optimize management.