Brain, Vol. 124, No. 12, 2427-2438,
December 2001
© 2001 Oxford University Press
Diagnostic value of sural nerve demyelination in chronic inflammatory demyelinating polyneuropathy
1 Departments of Neurology and 2 Clinical Neurophysiology of the Rudolf Magnus Institute for Neurosciences, University Medical Center Utrecht, The Netherlands
Correspondence to:
Leonard H. van den Berg, MD, Department of Neurology, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands E-mail: l.h.vandenberg{at}neuro.azu.nl
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Abstract |
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The objective of the study was to determine the diagnostic value of features of demyelination and inflammation in sural nerve biopsy specimens of patients with chronic inflammatory demyelinating polyneuropathy (CIDP). The features of (i) demyelination, (ii) axonal de- and regeneration and (iii) inflammation were investigated by measuring the number of onion bulbs, g ratio (axon diameter/total nerve fibre diameter), myelinated nerve fibre density, number of clusters and endoneurial area in 21 patients with CIDP, as well as in 13 patients with chronic idiopathic axonal polyneuropathy (CIAP) and six autopsy controls. In addition, teased fibres were classified and lengths of internodes measured. We found no difference in demyelinating features between patients with CIDP and CIAP, as the percentage of fibres with segmental de- and remyelination and the number of onion bulbs were similar in both polyneuropathy groups. The g ratio, expected to be higher in a demyelinating disease due to thinner myelin sheaths, was significantly lower in CIDP than CIAP. Evidence for axonal degeneration was found in both CIDP and CIAP, as both showed a decrease in myelinated nerve fibre density. There was no evidence of endoneurial oedema in CIDP, as the endoneurial area did not differ between CIDP, CIAP and the autopsy controls. Although significant differences of features of demyelination, axonal degeneration and inflammation were found in sural nerve biopsy specimens, there was a considerable overlap between abnormalities in CIDP and CIAP patients. In the majority of patients, quantitative analysis of light microscopical abnormalities in sural nerves was similar in CIDP and CIAP. Therefore, a sural nerve biopsy is of limited diagnostic value in CIDP.
chronic inflammatory demyelinating polyneuropathy; sural nerve; demyelination; axonal degeneration; pathology
CIAP = chronic idiopathic axonal polyneuropathy; CIDP = chronic inflammatory demyelinating polyneuropathy
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Introduction |
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Chronic inflammatory demyelinating polyneuropathy (CIDP) is a progressive or relapsing disorder of the peripheral nervous system (Prineas and McLeod, 1976
; McCombe et al., 1987; Barohn et al., 1989), associated with demyelination of peripheral nerves and spinal roots (Bouchard et al., 1999). Diagnostic criteria for CIDP are based mainly on clinical and electrophysiological features, but a sural nerve biopsy is often taken to establish the diagnosis of CIDP (Cornblath et al., 1991). Segmental demyelination and remyelination, frequently resulting in onion bulb formation, together with inflammatory infiltrates is considered to be the pathological hallmark of CIDP (Krendel et al., 1989; Dyck et al., 1993a; Uncini et al., 1999). De- and remyelinating features in CIDP are often accompanied by varying degrees of axonal degeneration (Dyck et al., 1993a; Nagamatsu et al., 1999). Myelinated fibre loss, and evidence of sprouting, as well as the presence of myelin ovoid formation in teased fibres, are considered as evidence of axonal degeneration (Krendel et al., 1989; Dyck et al., 1993b).
In many pathological studies, sural nerve biopsy specimens from patients with CIDP were not compared with well-defined control groups (Prineas and McLeod, 1976; Barohn et al., 1989; Matsumuro et al., 1994; Bouchard et al., 1999). We recently demonstrated that T cells were present in all sural nerve biopsy specimens from patients with CIDP, but also in non-inflammatory and autopsy controls. Moreover, in comparison with controls, most patients with CIDP did not differ with regard to numbers and distribution of T cells (Bosboom et al., 1999). The purpose of the present study was to determine the diagnostic value of the classical pathological features of de- and remyelination in CIDP.
Patients and methods
Patients and controls
We investigated sural nerve biopsy specimens taken between 1987 and 1995, from 21 consecutive patients who fulfilled established criteria for CIDP (Cornblath et al., 1991). As disease controls, we used sural nerves from 13 patients with a non-inflammatory chronic idiopathic axonal polyneuropathy (CIAP). CIAP is a slowly progressive polyneuropathy for which no cause could be found during a 5-year follow-up (Notermans et al., 1993, 1994, 1996; Teunissen et al., 1997). Patients with CIDP and CIAP were included in this study without using the biopsy findings to assign diagnoses. The clinical, laboratory and electrophysiological findings of the patients are summarized in Tables 1 and 2. As normal controls, we used sural nerves from six autopsy patients without known peripheral nerve disease, obtained within 24 h of death. Six of 21 patients with CIDP had been treated before the biopsy was taken: Patients 3 and 4 had high-dose intravenous immunoglobulins 2 months previously, Patients 2, 7 and 11 had prednisone >6 months previously, and Patient 1 had prednisone 1 month previously. The severity of the clinical picture was graded according to the modified Rankin scale (van Swieten et al., 1988): 0 = normal; 1 = signs but not symptoms of the neuropathy; 2 = mild motor or sensory symptoms (or both) with or without mild functional impairment; 3 = moderately disabled by motor and sensory symptoms including ataxia; 4 = requiring assistance in eating or dressing, or using a walking aid; and 5 = not ambulatory.
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Sural nerve biopsy specimens
Sural nerves were obtained under local anaesthesia. The sural nerve was biopsied at the ankle above the lateral malleolus. Part of the nerve tissue was fixed in 2% buffered glutaraldehyde, post-fixed in 1% buffered osmium tetroxide and dehydrated in acetone. The material was impregnated with and embedded in Epon and polymerized at 60°C for 24 h. Transverse whole sural nerve sections of 1 µm were stained with alkaline toluidine blue or 1% p-phenylenediamine. For teased fibre preparations, nerve tissue was fixed in 2% buffered glutaraldehyde, post-fixed in 1% buffered osmium tetroxide, dehydrated in acetone and impregnated with Epon, and the nerve fibres were teased in a film of Epon on a microscope slide.
Light microscopic analysis
Transverse sections of the sural nerve biopsy specimens of all patients with CIDP and CIAP, and autopsy controls were examined to investigate features of (i) de- and remyelination, (ii) axonal de- and regeneration and (iii) inflammation. Teased fibre preparations were available from 14 patients with CIDP (nos 1–14) and nine patients with CIAP (nos 22–30). All investigations were performed in a blinded fashion.
Demyelinating features
Segmental de- and remyelination. We performed a qualitative analysis of teased fibres in three different ways. First, segmental de- or remyelination was scored in all teased fibres, ignoring other demyelinating or axonal features (Fig. 1). The percentage of fibres with segmental demyelination was calculated and in these fibres the percentage of de- or remyelinated segments was determined. Secondly, the teased fibres were classified according to the classification of Dyck and colleagues listed in Table 3 (Dyck et al., 1993b). Teased fibres in category B were considered to be in an early stage of nerve damage not differentiating between a demyelinating or axonal cause. Teased fibres in categories C, D, F and G were considered to be affected by a demyelinating process, and teased fibres in categories E and H were considered to be affected by an axonal process. Category I was considered to appear in Wallerian degeneration. Thirdly, two experienced neuropathologists (F.G.I. Jennenens and G.H. Jansen) were asked to examine all teased fibre preparations in a blinded fashion and to determine whether a demyelinating or axonal cause of the neuropathy was most likely.
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Onion bulbs. Onion bulbs were quantified in the total endoneurial area by two independent observers (H.Z.F. and A.M.v.P.) using light microscopy (x40 objective) of transverse sections stained with alkaline toluidine blue (Fig. 1
). An onion bulb was defined as a myelinated nerve fibre axon surrounded by one or more concentrically orientated supernumerary Schwann cell processes (Low et al., 1978) for 100% of the circumference. The correlation coefficient for the measurements of both observers of onion bulbs was 0.86 (P < 0.01). For further analysis, the mean values of the measurements of both observers were used. g ratio and diameter histograms. For each myelinated nerve fibre, Feret-diameters (diameter of circle with the same area as measured area) of the axon and of the total nerve fibre were calculated. The g ratio was calculated (axon diameter/total nerve fibre diameter) and histograms of the total myelinated nerve fibre diameters and axon diameters were made.
Axonal de- and regeneration
Myelinated nerve fibres. Using a Zeiss Videoplan, myelinated nerve fibres were counted in 8–12 micrographs of randomly chosen areas of 1 µm transverse sections stained with alkaline toluidine blue. These micrographs (magnification x2240) covered a total endoneurial area of between 0.06 and 0.09 mm2 per biopsy. The myelinated nerve fibre density and total number of myelinated nerve fibres were calculated.
Clusters. Clusters, considered as evidence of sprouting, were quantified in the total endoneurial area by two independent observers (H.Z.F. and A.M.v.P.) using light microscopy (x40 objective) of transverse sections stained with p-phenylenediamine. A regenerative cluster was defined as three or more closely apposed myelinated nerve fibres (Llewelyn et al., 1991), which had maximal variation in myelin thickness of 50%, a maximal distance between different fibres of 2.5 times the myelin thickness of the fibres and a myelin thickness of <50% of the thickest fibre in the fascicle. The correlation coefficient for the measurements of both observers was 0.96 (P < 0.01). For further analysis, the mean values of the measurements of both observers were used.
Internode length. In the teased fibre preparations, each internode length of all fibres was measured (objective x10) and the mean internode length of all fibres calculated.
Inflammatory features
The endoneurial area. As an increase in the endoneurial area may be an indication of endoneurial oedema, the total endoneurial area was measured in 1 µm transverse sections stained with alkaline toluidine blue, by light microscopy (x10 objective) using a digitizing tablet and image analysis software (Jandel). The sub-perineural area without myelinated nerve fibres, sometimes widened in CIDP biopsy specimens, was not included in the total endoneurial area.
T cells. Data on T cells from our previous study were used, in which numbers and localization of CD3+ cells in transverse sections of sural nerve biopsy specimens were investigated. Patients 14 and 19 were not included in this study (Bosboom et al., 1999).
Statistical analysis
The Mann–Whitney U-test was used to compare clinical, electrophysiological and pathological features between patients with CIDP and control groups. This test was also used to compare the numbers of myelinated nerve fibres/axons with the same diameter between CIDP and the control groups. Spearman's rank correlation was used to calculate the inter-observer variation of measurements on onion bulbs and clusters. A Fisher's exact test was performed to determine whether each neuropathologist was able to assign the diagnoses CIDP or CIAP based on qualification of the teased fibres, and a Cohen's kappa was calculated to measure the agreement between the two neuropathologists. To adjust differences in pathological findings between CIDP and CIAP for age, time from onset of disease to moment of biopsy, and endoneurial area, a logistic regression analysis was carried out. In order to investigate which pathological feature had the most significant influence on the differentiation between the diagnosis CIDP and CIAP, we entered all variables with P < 0.20 into a multivariate model. Spearman's rank correlation was performed to correlate clinical (listed in Table 1) and pathological features within the group of patients with CIDP. P values <0.05 were considered to be significant.
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Results |
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For all features of demyelination, axonal de- or regeneration and inflammation, we investigated whether the results in patients with CIDP were significantly different from those in patients with CIAP or autopsy controls (Figs 2–6
). Subsequently we studied whether the values in individual CIDP patients were increased or decreased (i.e. higher or lower than the highest or lowest value in patients with CIAP or autopsy controls) (Table 4).
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= significantly higher than in patients with CIDP; 
= significantly lower than in patients with CIDP.
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Demyelinating features
Segmental de- and remyelination
The length of the teased fibres in preparations of patients with CIDP or CIAP was ~5 mm, and the number of fibres examined ranged from 27 to 87 (median 47).
The percentage of teased fibres with segmental de- or remyelination and the number of de- or remyelinating segments per affected fibre did not differ significantly between CIDP and CIAP (Fig. 2A), which means that the distribution of the de- or remyelinated segments along the fibres was similar in CIDP and CIAP. Three patients with CIDP had a higher, and one patient a lower percentage of fibres with segmental de- or remyelination, than any of the CIAP controls (Fig. 2A and Table 4).
When the teased fibres were classified according to Dyck and colleagues (Table 3) (Dyck et al., 1993b), the percentage of normal fibres (category A) was lower in CIDP than CIAP (Fig. 3). Categories D and E were significantly more frequent in CIDP. When the percentages of categories C, D and F, which were all considered to be a feature of demyelination, were taken together, there was no significant difference between CIDP and CIAP.
In the qualitative analysis of teased fibre preparations by two independent neuropathologists, neither neuropathologist was able to assign the diagnosis CIDP or CIAP based on qualification of the teased fibres (P < 1.00): one neuropathologist assigned the term `mainly demyelinating' to seven preparations of 14 patients with CIDP, and three preparations of nine patients with CIAP. The second neuropathologist assigned the term `mainly demyelinating' to eight preparations of the 14 patients with CIDP, and four preparations of the nine patients with CIAP. Of the nine preparations of patients with CIAP, two were labelled normal by the first neuropathologist and three by the second neuropathologist. The agreement between the two neuropathologists was moderate for CIDP (
= 0.57) and low for CIAP ( = 0.18).
Onion bulbs
There was no significant difference in the number of onion bulbs between patients with CIDP and CIAP, but in both patient groups the numbers of onion bulbs were significantly higher than in autopsy controls (Fig. 2B). Four patients with CIDP had a higher number of onion bulbs than any of the CIAP and autopsy controls (Fig. 2B and Table 4).
g ratio
In patients with CIDP, the g ratio was significantly lower than in patients with CIAP and autopsy controls (Fig. 2C). Only one patient with CIDP had a lower g ratio than any of the CIAP and autopsy controls (Fig. 2C, Table 4).
Axonal de- and regeneration
Myelinated nerve fibre density
Myelinated nerve fibre densities did not differ between patients with CIDP and CIAP, but were significantly lower than autopsy controls (Fig. 4A). Three patients with CIDP had higher and two lower myelinated nerve fibre densities than any of the CIAP or autopsy controls (Fig. 4A).
Clusters
The number of clusters was not increased in CIDP compared with autopsy controls, whereas in CIAP the number of clusters was significantly higher than in CIDP (Fig. 4B). One patient with CIDP had a lower number of clusters than any of the CIAP and autopsy controls (Fig. 4B).
Internode length
The internode length was significantly larger in patients with CIDP than in patients with CIAP (Fig. 4C). Ten patients with CIDP had larger internode lengths than CIAP controls (Fig. 4C).
Inflammation
Endoneurial area
The endoneurial area in CIDP was not significantly different from that in CIAP and autopsy controls (Fig. 5A). Five patients with CIDP showed a higher endoneurial area than any of the controls (Fig. 5A and Table 4).
T cells
Numbers of T cells in the total sural nerve area were significantly higher in CIDP than CIAP or autopsy controls. Six out of 23 patients with CIDP showed a higher number of T cells than any of the CIAP and autopsy controls [Fig. 5B, adapted from our previous study (Bosboom et al., 1999)]. In the endoneurium, the number of T cells was significantly higher than in CIAP or autopsy controls. Four patients with CIDP had an increased number of T cells compared with the CIAP and autopsy controls [Fig. 5C, adapted from our previous study (Bosboom et al., 1999)].
Histograms of myelinated nerve fibre diameters and axon diameters
The histograms of the myelinated nerve fibre diameters were unimodal in both CIDP and CIAP (Fig. 6). There were significantly more large myelinated nerve fibres in patients with CIDP than in those with CIAP. The histograms of the axon diameter of the myelinated nerve fibres were unimodal in patients with CIDP and CIAP, and in autopsy controls. In CIDP, significantly more fibres with a small diameter were found than CIAP or autopsy controls. In both CIDP and CIAP, a significant decrease in the largest axon diameters was found compared with autopsy controls.
Multivariate analyses
It was possible that age could influence the results of pathological features in the sural nerve biopsy specimens (Berthold et al., 1983; Jacobs and Love, 1985). However, when comparisons were adjusted for age, all significant results remained significant, and all non-significant results remained non-significant. The time from onset of disease until biopsy was significantly shorter in CIDP than CIAP (P < 0.02), and therefore we adjusted the comparisons of the quantitative analyses between CIDP and CIAP for time from onset of disease to biopsy: the differences in the number of clusters and internode length between CIDP and CIAP were no longer significant (P < 0.07 and P < 0.11). It was also possible that the myelinated nerve fibre density might be influenced by endoneurial oedema, but the difference in myelinated nerve fibre density remained significant after adjustment for endoneurial area.
In both the univariate and the multivariate analyses of features in the transverse sections of all sural nerve biopsy specimens, differences in g ratio between CIDP and CIAP gave the most differentiation between CIDP and CIAP. Teased fibre preparations of the sural nerve biopsy specimen were available in a subgroup of patients with CIDP and CIAP. In the multivariate regression analyses of all features, including the internode length, which could only be performed in this subgroup of patients, the internode length differentiated the most between CIDP and CIAP.
Demyelinating and inflammatory features in individual patients with CIDP
Table 4 shows the individual CIDP patients with increased or decreased values of demyelinating or inflammatory features. In 12 out of 21 patients with CIDP, one or more features had increased values (i.e. higher than the highest value in patients with CIAP and in autopsy controls).
Correlation of pathological features in patients with CIDP
In CIDP, a small axon diameter was correlated with a small g ratio (R = 0.70, P < 0.01). A higher endoneurial area was correlated with a higher T-cell number in the total sural nerve area (R = 0.50, P < 0.03) and in the endoneurium (R =0.56, P < 0.01). A higher number of clusters was correlated with a lower T-cell density (R = 0.49, P < 0.04).
Correlation of clinical and pathological features in patients with CIDP
In the CIDP patients, there was no correlation between the severity of the disease (maximal disability score) and any of the pathological features. Older age was correlated with lower myelinated nerve fibre densities (R = 0.56, P < 0.01) and smaller internode lengths (R = –0.60, P < 0.02). Patients with a higher CSF protein had a more rapid disease course (R = 0.54, P < 0.01) and a lower myelinated nerve fibre density (R = 0.54, P < 0.01). Patients with the most severe outcome had smaller axon diameters (R = 0.51, P < 0.03).
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Discussion |
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To determine whether light microscopical analysis of sural nerves provides diagnostic tools for the diagnosis of CIDP, we analysed sural nerve biopsy specimens of 21 patients with CIDP. Abnormalities were compared with sural nerve biopsy specimens of 13 patients with CIAP and six autopsy controls. Patients with CIAP were chosen as controls, as the polyneuropathy in this condition is based upon axonal degeneration and has no inflammatory signs. Although some significant differences were found in CIDP compared with controls, there was a considerable overlap, limiting the diagnostic value in individual patients. In CIDP, no correlation was found between severity of the disease and light microscopical abnormalities.
In previous studies of CIDP, segmental de- and remyelination ranged from 19 to 77% of the teased fibres in one study, and was found in 88% of the patients in another study (Matsumuro et al., 1994; Bouchard et al., 1999). However, neither study compared the extent of de- and remyelination in CIDP with other neuropathies or controls without neuropathy. Krendel and colleagues compared sural nerve biopsy specimens of CIDP patients with those in a heterogeneous control group. They found predominant demyelination and onion bulb formation in CIDP and other demyelinating neuropathies, in contrast to axonal neuropathies (Krendel et al., 1989). However, segmental de- and remyelination can also occur in axonal neuropathies (Jennekens et al., 1969; Llewelyn et al., 1991). Moreover, a recent study demonstrated that nerve biopsies did not help to differentiate between CIDP and diabetic polyneuropathy, as segmental de- and remyelination, onion bulbs and inflammatory infiltrates were present in both (Uncini et al., 1999). The onion bulbs we observed in axonal neuropathy might be pseudo onion bulbs derived from axonal degeneration and regeneration (Midroni and Bilbao, 1995). In our light microscopic study, we found no differences in the aspect of onion bulb-like structures between CIDP and CIAP. Our systematic analysis did not show significant differences in demyelinating features between patients with CIDP and CIAP. The finding of characteristic demyelinating changes, such as large onion bulbs and naked axons, described in previous studies on sural nerve biopsy specimens of patients with CIDP (Prineas, 1971; Prineas and McLeod, 1976; Rizzuto et al., 1982), may have helped to confirm the diagnosis. However, we did not find these features frequently in our patients with CIDP. Demyelinating features were only prominent in a minority of the CIDP patients.
As the g ratio is determined by the ratio of axon to fibre diameters, a higher g ratio can be expected in a demyelinating neuropathy, as remyelination leads to thinner myelin sheaths whereas the axon diameter remains the same. However, we observed lower g ratios in CIDP than in CIAP or autopsy controls. This finding can be explained by four mechanisms. (i) Shrinkage of axons in CIDP. Reduction of axon diameters has been observed to occur at an early stage of the demyelinating process before much destruction of the myelin sheath has occurred (Prineas and McLeod, 1976), and to persist for months during remyelination (Rizzuto et al., 1982; Gabreels-Festen et al., 1992). Our axon diameter histograms indicate that large fibres were lost or had shrunk in both CIDP and CIAP when compared with autopsy controls. In our total myelinated nerve fibre diameter histograms, there was only a decrease of large fibres in CIAP. This could indicate shrinkage of large axons in CIDP and loss of large fibres due to axonal degeneration in CIAP. (ii) Swelling of myelin in CIDP. Binding of antibodies or other humoral factors to myelin may result in alteration of membrane permeability with subsequent intracellular Schwann cell oedema (Sabatelli et al., 1996). Intramyelinic oedema has been described in CIDP patients, with thinning or disappearance of myelin sheaths (Sabatelli et al., 1996). (iii) The presence of regenerated fibres with a thin myelin sheath in CIAP, resulting in higher g ratios. (iv) Loss of small myelinated nerve fibres in CIDP, as small myelinated nerve fibres have higher g ratios than large myelinated nerve fibres (Friede and Beuche, 1985; Jacobs and Love, 1985). However, this hypothesis is not supported by our histograms. Although the differences in g ratios between CIDP and CIAP are interesting, only one patient with CIDP had a g ratio outside the range of the patients with CIAP. Therefore, g ratio analysis does not discriminate between CIDP and CIAP in individual patients.
Loss of myelinated nerve fibres is frequent in both axonal polyneuropathy and CIDP. In CIDP, myelinated nerve fibre loss is correlated with the extent of de- and remyelination in teased fibre analysis as well as with the duration of the disease, and the outcome (Bouchard et al., 1999; Nagamatsu et al., 1999). In addition, we demonstrated that myelinated nerve fibre loss in CIDP was correlated with higher CSF protein levels and a more rapid disease course. Although in the present study myelinated nerve fibre densities were reduced equally in CIDP and CIAP, in the latter condition regeneration of myelinated nerve fibres seems more prominent, as was demonstrated by increased numbers of clusters and shortened internode lengths. This finding can be explained partly by a longer time from onset of disease to the moment of biopsy in CIAP than in CIDP.
Inflammatory features were not prominent in most patients with CIDP. This study showed no consistent evidence of endoneurial oedema in CIDP. In our previous study, T cells were found in sural nerve biopsy specimens of all patients with CIDP and CIAP, and also in autopsy controls. In CIDP, increased numbers of sural nerve T cells were only found in a minority of patients (Bosboom et al., 1999).
At least three reasons can be given as to why features of demyelination and inflammation in sural nerve biopsy specimens did not differ between CIDP and CIAP. First, in CIDP, pathological changes are more extensive in proximal portions of the peripheral nerves. Secondly, the sural nerve is a sensory nerve, and motor signs and symptoms in CIDP are often more prominent than sensory signs (Hall et al., 1992; Dyck et al., 1993a). Thirdly, at the time of biopsy, disease-specific features may already have disappeared.
A previous retrospective clinical study showed no additional value of the sural nerve biopsy for the diagnosis of CIDP as the diagnosis did not change after examination of the sural nerve biopsy (Molenaar et al., 1998). However, a recent prospective study on the usefulness of sural nerve biopsy in various axonal and demyelinating neuropathies showed an alteration of the diagnosis in 14% of the cases after sural nerve biopsy (Gabriel et al., 2000). The present study, using systematic light microscopic analysis of sural nerves, demonstrates that features of demyelination and inflammation in the majority of patients with CIDP were not different from those in controls. Therefore, a sural nerve biopsy in CIDP is of less diagnostic value than suggested by previous studies.
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We wish to thank Professor F. G. I. Jennekens, MD, and G. H. Jansen, MD, for their expert analysis of teased fibres, Professor F. G. I. Jennekens for advice on the preparation of the manuscript, C. W. A. M. Engels for laboratory assistance, and C. J. M. Klijn for help with the statistical analyses. This work was supported by grants from the Netherlands Organization for Scientific Research, the Prinses Beatrix Fonds and the Kröger Foundation, and the research of Dr Van den Berg was supported by a fellowship from the Royal Netherlands Academy of Arts and Sciences.
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Received November 24, 2000. Accepted July 10, 2001.
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