The multiple roles of nerve biopsy in the diagnosis and prognosis of suspected immune neuropathies

Abstract

Introduction: The value of a sural nerve biopsy for the diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is controversial. Evidence-based recommendations for its implementation are lacking. We investigated factors leading to biopsy and analyzed biopsy outcomes and consequences, assessed the predictability of biopsy outcomes through clinical parameters to avoid unnecessary biopsies, and compared results with electrophysiological and clinical severity to determine their prognostic value.

Methods: 190 sural nerve biopsies were analyzed in two cohorts. One consisted of 163 biopsies and the second of 72 biopsies from the prospective Immune-mediated Neuropathies Biomaterial and Data registry (INHIBIT). Both have an intersection of 45 patients. 75 data sets from patients without biopsy were used. Analysis of nerve conduction studies, treatment, overall disability sum score (ODSS), biopsy outcomes, and diagnosis was performed.

Results: 51% of biopsied patients received the diagnosis CIDP (77% fulfilled EFNS/PNS criteria), 21% were not CIDP typical, and 27% were unspecific. Biopsied patients responded less frequently to immunotherapies at time of biopsy than non-biopsied patients (p = 0.003). Immunotherapy was initiated more frequently after biopsy (p < 0.001) and more often with intravenous immunoglobulins (p < 0.0001). 76% of all biopsied patients met the electrophysiological criteria for CIDP. Sensory nerve action potential amplitudes of 0 µV still provide 73% of histological diagnostic value. Histologic signs of degeneration predicted ODSS worsening after 1 year (p = 0.028) but disease severity did not correlate with histological damage severity.

Discussion: The main indication for nerve biopsy was the treatment of refractory cases of autoimmune neuropathies with the therapeutic consequence of treatment initiation or escalation. Sural biopsy also provided prognostic information. Even with extinguished sural SNAP, the biopsy can still have diagnostic value.

Keywords: CIDP; Histology; Nerve biopsy; Polyneuropathy.

Fig. 1

Representative histology findings. Representative histology findings. Immunoreaction against CD68 (A) shows an increased number of activated macrophages in endoneurium. Immunohistochemistry staining for CD45 (B) and CD8 (C) demonstrate infiltrating lymphocytes, in part consisting of cytotoxic T-cells. Toluidine blue stained semithin sections D–G demonstrate variation in fiber density, patchy distribution of axonal loss, endoneurial edema, attenuation and disruption of myelin sheaths, thin myelin layers as well as clusters of axonal regeneration and denuded axons, indicating chronic demyelinating and axonal damage. 100× magnification in A, B, C, D, and G. 200× magnification in E and F

Fig. 2

Data of treatment. A Treatment response of patients with and without nerve biopsy. No change in type, dose, or frequency of immunotherapy was considered a positive treatment response, while a change in treatment was considered as negative treatment response. Significant difference in positive treatment response between patients with and without biopsy (p = 0.003). B Distribution of therapeutics before and 6 month after biopsy. N = 103 patients. Before biopsy and after: T = 33/85 (p < 0.001); NT = 68/17; F + S = 9/26; SL = 10/33 (p = 0.0001); FL = 23/51; Glu = 16/19; IG = 3/23 (p = 0.0001); C = 4/6. Treatment with intravenous Immunoglobulins and second-line treatments were significantly increased after biopsy

Fig. 3

Diagnosis within the biopsy cohort (n = 163 patients). 119 biopsies were diagnostically valuable (73%). Of these, 85 (51.1%) biopsies showed histologically a CIDP and 34 (20.9%) showed other diagnosis such as vasculitis (n = 4, 2.5%), microangiopathy (n = 23, 14.1%), and others (n = 7, 4.3%)

Figure 4

EEFNS/PNS fulfillment in the biopsy cohort and distribution of histological damage pattern. Comparisons show a significant higher fulfillment of criteria in patients with mostly demyelinating damage pattern (p = 0.027)

Fig. 5

Comparison of histological outcome parameters depending on the electrophysiological measurement result of the N. suralis of 151 patients. A Distribution of histological outcomes in patients with electrophysiological suralis SNAP of 0 µV (n = 77). B Distribution of histological outcomes in patients with electrophysiological suralis SNAP > 0 µV (n = 74). Corresponding colors matching histological outcome parameters. Green = diagnostic or unspecific histology. Blue = histologically CIDP or CIDP atypical biopsy. Orange = histological burn-out nerves or not burn-out nerves. The percentages always refer to the group. There were no significant differences in histological outcome parameters. SNAP of 0 µV showed only 9% histologically burn-out pattern

Fig. 6

Comparison of ODSS (overall, arm, leg) of patients with and without histological signs of progression. (A) and regeneration (B). A A total of 92 datasets was examined for histological signs of progression at time of biopsy, 68 after a year, and 45 after 2 years. After 1 year, patients with signs of progression in histology had significantly higher overall ODSS (with progression markers: 2.77 ± 2.05; without progression markers 1.83 ± 1.57; p = 0.028). B A total of 76 datasets was examined for histological signs of regeneration at time of biopsy, 60 after a year, and 40 after 2 years