Abstract
Chronic acquired neuropathies of unknown origin are classified as chronic inflammatory demyelinating polyneuropathies (CIDP) and chronic idiopathic axonal polyneuropathies (CIAP). The diagnosis can be very difficult, although it has important therapeutic implications since CIDP can be improved by immunomodulating treatment. The aim of this study was to examine the possible abnormalities of nodal and paranodal regions in these two types of neuropathies. Longitudinal sections of superficial peroneal nerves were obtained from biopsy material from 12 patients with CIDP and 10 patients with CIAP and studied by immunofluorescence and in some cases electron microscopy. Electron microscopy revealed multiple alterations in the nodal and paranodal regions which predominated in Schwann cells in CIDP and in axons in CIAP. In CIDP paranodin/Caspr immunofluorescence was more widespread than in control nerves, extending along the axon in internodes where it appeared intense. Nodal channels Nav and KCNQ2 were less altered but were also detected in the internodes. In CIAP paranodes, paranodin labeling was irregular and/or decreased. To test the consequences of acquired primary Schwann cells alteration on axonal proteins, we used a mouse model based on induced deletion of the transcription factor Krox-20 gene. In the demyelinated sciatic nerves of these mice we observed alterations similar to those found in CIDP by immunofluorescence, and immunoblotting demonstrated increased levels of paranodin. Finally we examined whether the alterations in paranodin immunoreactivity could have a diagnosis value. In a sample of 16 biopsies, the study of paranodin immunofluorescence by blind evaluators led to correct diagnosis in 70±4% of the cases. This study characterizes for the first time the abnormalities of nodes of Ranvier in CIAP and CIDP, and the altered expression and distribution of nodal and paranodal proteins. Marked differences were observed between CIDP and CIAP and the alterations in paranodin immunofluorescence may be an interesting tool for their differential diagnosis.
Highlights
Chronic polyneuropathy is a highly prevalent condition with various etiologies, including hereditary, metabolic, toxic or immune-mediated origins
Nodal and paranodal ultrastructure is differentially altered in Schwann cells and axons in chronic inflammatory demyelinating polyneuropathy (CIDP) and chronic idiopathic axonal polyneuropathy (CIAP)
To our knowledge, the nodal regions have not been explored in CIDP or CIAP, we used electron microscopy to determine how these regions were altered in chronic acquired neuropathies
Summary
Chronic polyneuropathy is a highly prevalent condition with various etiologies, including hereditary, metabolic, toxic or immune-mediated origins. For hereditary polyneuropathies, termed Charcot-Marie-Tooth (CMT) diseases, recent advances in the identification of the responsible genes allow a genetic diagnosis in a growing number of cases [1]. Acquired neuropathies are more frequent than hereditary neuropathies and their diagnosis is based on a combination of clinical, electrophysiological, biological and, when necessary, histopathological evidence. No cause is found in 10–15% of patients with chronic polyneuropathies [2]. We studied two types of chronic acquired polyneuropathies whose diagnosis can be challenging, chronic inflammatory demyelinating polyneuropathy (CIDP) and chronic idiopathic axonal polyneuropathy (CIAP). The distinction is important since specific treatment options are available for CIDP [3], whereas there is none of proven efficacy for CIAP [4]
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