Small and large fiber neuropathy in those with type 1 and type 2 diabetes: a 5‐year follow‐up study

The purpose of this study was to evaluate progression of diabetic polyneuropathy and differences in the spectrum and evolution of large‐ and small‐fiber involvement in patients with diabetes type 1 and 2 over 5 years. Fifty‐nine patients (35 type 1 and 24 type 2) were included. Nerve conduction studies (NCS), quantitative sensory testing, skin biopsy for quantification of intraepidermal nerve fiber density (IENFD), symptom scoring and clinical evaluations were performed. Z‐scores were calculated to adjust for the physiologic effects of age and height/gender. Neuropathic symptoms were not significantly more frequent in type 2 than in type 1 diabetic patients at follow‐up (54% vs. 37%). The overall mean NCS Z‐score remained within the normal range, but there was a small significant decline after 5 years in both groups: type 1 (p = 0.004) and type 2 (p = 0.02). Mean IENFD Z‐scores changed from normal to abnormal in both groups, but only significantly in those with type 2 diabetes (reduction from 7.9 ± 4.8 to 4.3 ± 2.8 fibers/mm, p = 0.006). Cold perception threshold became more abnormal only in those with type 2 diabetes (p = 0.049). There was a minimal progression of large fiber neuropathy in both groups. Reduction of small fibers predominated and progressed more rapidly in those with type 2 diabetes.     

Porphyric neuropathies in an acute intermittent porphyria family

The objective of this study was to investigate two patients with porphyric neuropathy in a family with acute intermittent porphyria. Molecular analysis of the porphobilinogen deaminase (PBGD) gene was performed. We analyzed the clinical course of peripheral neuropathy and serial changes in nerve conduction studies (NCS) of the two patients. We also examined the pathological findings of sural nerve biopsy in one patient. Molecular analysis of the PBGD gene revealed a missense mutation (Arg26His) in exon 2 for two patients and their family members. Distal polyneuropathy was noted in the patients with chronic porphyric neuropathy. In the follow‐up NCS, recovery was relatively poor in the lower limb in one patient with severe polyneuropathy, and NCS evidence of deterioration was found following frequent hormone‐related porphyric attacks in another patient. The sural nerve biopsy showed marked loss of myelinated and unmyelinated fibers in one patient with chronic porphyric neuropathy. In contrast to radial and fibular motor nerves in acute porphyric neuropathy, the sural nerve is vulnerable to involvement in chronic porphyric neuropathy following repeated porphyric attack as seen in the NCS.     

Small-fiber involvement in spinobulbar muscular atrophy (Kennedy's disease)

We assessed the involvement of cutaneous innervation in two subjects with a molecularly confirmed diagnosis of spinobulbar muscular atrophy (SBMA) using antidromic nerve conduction studies, quantitative sensory testing, and sweat tests, as well as immunohistochemical techniques and confocal microscopy of glabrous and hairy skin biopsy. Both patients showed a marked reduction in amplitude of sensory action potentials and moderate or severe abnormalities of tactile thresholds and mechanical pain perception. A severe reduction of sweat drops on the Silastic imprint test and a widespread loss of small myelinated and unmyelinated fibers in hairy skin were also observed. Fiber loss involved either somatic or autonomic fibers and did not show any distal-proximal gradient. These results, together with loss of Meissner corpuscles and their large myelinated afferent fibers in glabrous skin, confirmed the extensive involvement of sensory neurons of large and small size and revealed an autonomic skin denervation in SBMA.     

Epidermal nerve fiber density and sural nerve morphometry in peripheral neuropathies

OBJECTIVE: To study intraepidermal nerve fiber (IENF) density in distal leg skin biopsies, sural nerve morphometry, electrophysiology, and clinical features in patients with peripheral neuropathies. METHODS: We studied 26 patients with neuropathic complaints who had undergone clinical evaluation, nerve conduction studies, distal leg skin biopsy, and sural nerve biopsy. We quantified densities of IENF and of myelinated and unmyelinated fibers in the sural nerve. Associations among skin and sural nerve morphometric measures and sensory nerve action potential (SNAP) amplitudes were examined nonparametrically. Morphometric measures were examined with respect to diagnostic category of neuropathy. RESULTS: IENF density correlated with the densities of sural nerve total myelinated (r = 0.57, p = 0.0011), small myelinated (r = 0.53, p = 0.0029), and large myelinated fibers (r = 0.49, p = 0.0054). There was a trend toward an association between IENF and sural nerve unmyelinated fiber densities (r = 0.32, p = 0.054). Sural SNAP amplitude and large myelinated fiber densities were highly correlated (r = 0.87, p < 0.0001). IENF density and sural nerve small fiber measures were concordant in 73% of patients. Reduced IENF density was the only indicator of small fiber depletion in 23% of cases. It was usually normal in acquired demyelinating neuropathies and where clinical suspicion for neuropathy was low. CONCLUSIONS: Distal leg Intraepidermal nerve (IENF) density may be more sensitive than sural nerve biopsy in identifying small fiber sensory neuropathies. Assessments of IENF density and large fiber measures on biopsy and electrophysiology are both useful for characterizing sensory and sensorimotor neuropathies.     

Nodes of Ranvier in skin biopsies of patients with diabetes mellitus

Paranodal demyelination has been discussed as a potential mechanism of nerve fiber damage in diabetic neuropathy (DNP). Studies on human tissue are limited, as nerve biopsies are invasive and only rarely performed in patients with confirmed DNP. Skin biopsy has recently been suggested as a tool to analyze paranodal and nodal changes of myelinated fibers. We analyzed the myelinated fibers of skin biopsies of 35 patients with DNP, 17 patients with diabetes mellitus (DM) without neuropathy, and 30 normal controls. Immunofluorescence of skin sections with antibodies against Caspr, neurofascin, sodium channels, and myelin basic protein was performed to assess paranodal/nodal architecture, segmental demyelination, and myelinated nerve fibers. Staining with antibodies against protein gene product 9.5 was used to quantify unmyelinated nerve fibers. There was an increase of elongated Ranvier nodes and a dispersion of neurofascin at the distal leg in patients with DM with and without neuropathy and at the finger in patients with DNP. An increased dispersion of Caspr was only found in biopsies of the finger in patients with DNP. Skin biopsy may be an appropriate tool to analyze nodes of Ranvier in patients with DM. Structural nodal changes are detectable in DNP and even in diabetic patients without neuropathy.     

Myelinated nerve endings in human skin

We used immunohistochemical techniques and confocal microscopy to study the morphometry of myelinated nerve endings in glabrous and hairy skin. A total of 30 healthy volunteers took part in this study designed to assess the possibility of obtaining reliable information on myelinated fibers using samples of hairy skin and to determine whether differences exist between myelinated terminations from different sites. We obtained consistent information on cutaneous myelinated terminations using hairy as well as glabrous skin samples. Myelinated endings from hairy and glabrous skin differ in density and distribution. However, from a comparison of our findings with data from nerve biopsy studies, we conclude that all cutaneous myelinated terminations are thinner terminal branches of large myelinated A beta fibers, whereas cutaneous terminations of small myelinated A delta fibers lose their myelin before entering the dermis and become indistinguishable from C-fiber terminations. The classic criteria, based on fiber size, used to distinguish myelinated fiber subgroups in sensory nerves are therefore not suitable for identifying myelinated terminations in the skin.     

Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy. Zenarestat Study Group.

OBJECTIVE: To determine whether the aldose reductase inhibitor (ARI) zenarestat improves nerve conduction velocity (NCV) and nerve morphology in diabetic peripheral polyneuropathy (DPN). METHODS: A 52-week, randomized, placebo-controlled, double-blinded, multiple-dose, clinical trial with the ARI zenarestat was conducted in patients with mild to moderate DPN. NCV was measured at baseline and study end. Contralateral sural nerve biopsies were obtained at 6 weeks and at the study's end for nerve sorbitol measurement and computer-assisted light morphometry to determine myelinated nerve fiber density (number of fibers/mm2 cross-sectional area) in serial bilateral sural nerve biopsies. RESULTS: Dose-dependent increments in sural nerve zenarestat level and sorbitol suppression were accompanied by significant improvement in NCV. In a secondary analysis, zenarestat doses producing >80% sorbitol suppression were associated with a significant increase in the density of small-diameter (<5 microm) sural nerve myelinated fibers. CONCLUSIONS: Aldose reductase pathway inhibition improves NCV slowing and small myelinated nerve fiber loss in DPN in humans, but >80% suppression of nerve sorbitol content is required. Thus, even low residual levels of aldose reductase activity may be neurotoxic in diabetes, and potent ARIs such as zenarestat may be required to stop or reverse progression of DPN.     

Evaluating dermal myelinated nerve fibers in skin biopsy

Although there has been extensive research on small, unmyelinated fibers in the skin, little research has investigated dermal myelinated fibers in comparison. Glabrous, nonhairy skin contains mechanoreceptors that afford a vantage point for observation of myelinated fibers that have previously been seen only with invasively obtained nerve biopsies. This review discusses current morphometric and molecular expression data of normative and pathogenic glabrous skin obtained by various processing and analysis methods for cutaneous myelinated fibers. Recent publications have shed light on the role of glabrous skin biopsy in identifying signs of peripheral neuropathy and as a potential biomarker of distal myelin and mechanoreceptor integrity. The clinical relevance of a better understanding of the role of dermal myelinated nerve terminations in peripheral neuropathy will be addressed in light of recent publications in the growing field of skin biopsy. Muscle Nerve, 2013     

Near-nerve needle sensory and medial plantar nerve conduction studies in patients with small-fiber sensory neuropathy

Background and purpose:  The aim of this prospective study was to show and compare the rate of large-fiber involvement with near-nerve needle sensory (NNNS) nerve conduction study (NCS) and with medial plantar NCS recorded with surface electrodes in a group of patients who had clinically pure small-fiber sensory neuropathy (SFSN) with reduced intra-epidermal nerve fiber density in skin biopsy and with normal routine NCS.
Methods and results:  The study included 19 patients with clinically pure SFSN with normal routine NCS results and 17 healthy volunteers. Routine NCS, skin biopsy, medial plantar NCS and NNNS NCS were performed. NNNS NCS data were evaluated both by using univariate analysis methods and by using a multivariate analysis method, principal components analysis (PCA). Eight patients (42%) had abnormal results for medial plantar NCS with surface electrodes. Seven patients (37%) had abnormal results for NNNS NCS with PCA, whilst only four patients with univariate analysis. We found a significant correlation between intra-epidermal nerve fiber densities, medial plantar NCS and PCA results of NNNS NCS.
Conclusions:  This study showed that large-nerve fibers are also involved in some patients with pure SFSN and medial plantar NCS can accurately diagnose neuropathy without a need for NNNS NCS in patients with normal routine NCS.     

A case of congenital non-progressive sensory neuropathy with tonic pupils

One case of a non-progressive congenital neuropathy is reported. Clinical findings included subtotal analgesia, and diminished temperature, vibration and proprioceptive sense in arms and legs. The sensory nerve action potentials were absent. Autonomic dysfunctions were restricted to tonic pupils. Sural nerve biopsy taken at the age of 8 1/2 showed fascicular hypoplasia, subtotal loss of myelinated nerve fibers and severe loss of unmyelinated nerve fibers with a pathological size distribution. In the skin biopsy, including several cutaneous nerves, no myelinated nerve fibers were present, the unmyelinated nerve fibers were severely reduced and the collagen density was increased. Perivascular and periglandular innervation was significantly reduced. The findings in this case are suggestive of a malformative or fetally acquired lesion and further illustrate the difficulties in classification of the hereditary sensory neuropathies.     

Intraepidermal nerve fibre density, quantitative sensory testing and nerve conduction studies in a patient material with symptoms and signs of sensory polyneuropathy

Small diameter nerve fibre (SDNF) neuropathy is an axonal sensory neuropathy affecting unmyelinated (C) and thin myelinated (A-delta) fibres. We have evaluated 75 patients with symptoms and signs suggesting SDNF dysfunction with or without symptoms and signs of co-existing large diameter nerve fibre involvement. The patients were examined clinically and underwent skin biopsy, quantitative sensory testing (QST) and nerve conduction studies (NCS). The purpose of this study was to compare the relationship between the different methods and in particular measurements of thermal thresholds and intraepidermal nerve fibre (IENF) density in the same site of the distal leg. The main subdivision of the patient material was made according to the overall NCS pattern. Patients with normal NCS (38) had 6.4 +/- 3.8 and patients with abnormal NCS (37) had 4.4 +/- 3.4 IENF per mm (P = 0.02). Limen (difference between warm and cold perception thresholds) was significantly higher (more abnormal) in those with abnormal than in those with normal NCS (22.1 +/- 9.1 vs. 13.4 +/- 5.6, P < 0.0001). Cold perception threshold was more abnormal (P < 0.0001) than warm perception threshold (P = 0.002). Correlation between IENF and QST was statistically significant only when NCS was abnormal, and thus dependent of a more severe neuropathic process in SDNFs.     

Painful sensory neuropathy: prospective evaluation using skin biopsy

OBJECTIVE: In patients presenting with painful, burning feet with minimal signs of neuropathy, the following questions were addressed: 1) How many of these patients have a peripheral neuropathy? 2) What is the role of skin biopsy in establishing a diagnosis of neuropathy? 3) What conditions are associated with the neuropathy? and 4) What laboratory studies are useful in this patient population? METHODS: A total of 117 consecutive patients referred for evaluation were prospectively studied. All underwent nerve conduction studies (NCS) and a battery of blood tests, including antinerve antibodies. If NCS were normal, a punch biopsy of the skin of the distal leg was performed to ascertain the intraepidermal nerve fiber (IENF) density. In a subset of 32 patients, the sensitivity of skin biopsy was compared to quantitative sudomotor axon test (QSART) and quantitative sensory tests (QST). Results: Three groups emerged. Group 1, with abnormal NCS (n = 60, 34 F/26 M, mean age 60 +/- 14 years), represented 51% of the cohort. The majority had neuropathies of undetermined cause, but 18 (30%) had associated conditions. Group 2, with normal NCS and reduced IENF density (n = 44, 29 F/15 M, mean age 57 +/- 14 years), represented 38% of the cohort. Three in this group had associated conditions. Group 3, with normal NCS and IENF density (n = 13, 6 F/7 M, mean age 53 +/- 13 years), represented 11% of the cohort; most had no diagnoses but two had MS. In a comparative subset analysis, skin biopsy was more sensitive than QSART or QST in diagnosing a neuropathy. CONCLUSIONS: Patients presenting with painful feet are heterogeneous, consisting of both large and small fiber sensory neuropathies. In rare cases, a central cause for pain can be found. Over one-third of patients required a skin biopsy to diagnose a small fiber sensory neuropathy. A limited battery of blood tests facilitated diagnosis, but serum antinerve antibodies were not helpful.     

Evaluation of cutaneous autonomic innervation in idiopathic sensory small-fiber neuropathy

To evaluate the loss of autonomic nerve fibers in patients with clinical pure small-fiber sensory neuropathy, we performed skin punch biopsies in 17 and 15 age- and sex-matched controls. Biopsies were taken 10 cm above the lateral malleolus, and 5-mum sections were stained with hematoxylin and eosin and the panaxonal marker protein gene product (PGP) 9.5. Positively stained fibers, represented as dots, innervating the erector pili muscles, arterioles, and sweat glands (SG) were counted. The ratios between the number of nerve fibers and nuclei of each structure were calculated. The autonomic innervation was significantly reduced in the patients' group compared with controls in all the examined autonomic-innervated structures: SG (0.27 +/- 0.15 vs. 0.66 +/- 0.37, p = 0.001), arterioles (0.38 +/- 0.32 vs. 0.86 +/- 0.45, p=0.002), and the erector pili muscle (0.58 +/- 0.27 vs. 1.23 +/- 0.87, p = 0.036). Our results suggest that autonomic involvement occurs in patients with sensory small-fiber neuropathy and that punch skin biopsy using thin sections is a simple and convenient method to detect these dermal autonomic small-fiber abnormalities.     

Comparison between nerve conduction studies and current perception threshold test in carpal tunnel syndrome.

AIM OF STUDY: Nerve conduction studies (NCS) only test large myelinated A(alpha) or A(beta) nerve fibers, whereas the current perception threshold (CPT) test has been suggested to evaluate a wide range of nerve fibers (A(beta), A(delta) and C). This study was undertaken to compare CPT and the standard NCS test by Bland's severity scale with the patient-based measurement of symptoms and functional status of the hand by Boston CTS questionnaire assessment. PATIENTS AND METHODS: We performed NCS and CPT on 31 patients (mean age 54.6+/-11.7 years; 31-79 years) with clinical diagnosis of CTS. NCS severity was classified according to Bland's scale and CPT was measured at 2000, 250 and 5 Hz and severity was graded between 0 and 12. Two-tailed Spearman's correlation analysis was performed to assess correlations between Boston questionnaire score and Bland's severity scale and CPT total score. RESULTS: The results showed that Bland's scale, based on NCS, had more significant correlations with symptoms (Spearman's rho=0.402, p=0.002) and function (rho=0.400, p=0.001) than CPT total scores (rho=0.200, p=0.135; rho=0.234, p=0.069). In CPT, only score measure at 2000 Hz showed a significant correlation with Boston CTS questionnaire scores (with symptom rho=0.308, p=0.020; with function rho=0.302, p=0.018), whereas those measured at 250 Hz and 5 Hz did not (p>0.05). CONCLUSION: Though CPT may have a supplementary role in the diagnosis of CTS, NCS better reflects patients' symptoms and functions than CPT on the patient's perspective.     

Quantitative analysis of epidermal innervation in Fabry disease

OBJECTIVE: To use skin biopsy specimens to quantitate the cutaneous innervation density of Fabry patients who had preserved renal function. BACKGROUND: The small fiber neuropathy of Fabry disease is difficult to detect and quantitate by conventional methods. Because this neuropathy is a common characteristic of Fabry disease, quantitating changes in this parameter would be helpful in demonstrating the effectiveness of enzyme or gene replacement therapy. METHODS: Patients underwent skin biopsy at the thigh and foot. Innervation density was determined by counting free nerve endings in the epidermis. These data were compared with nerve conduction studies, and in selected patients, fiber quantitation of sural nerve biopsy specimens. RESULTS: The Fabry patients had normal results of nerve conduction studies and large fiber quantitation by sural nerve biopsy. However, the involvement of small cutaneous fibers in these patients was easily demonstrable and quantifiable by skin biopsy. All patients showed severe loss of intraepidermal innervation at the ankle, but fiber loss at the distal thigh was proportionately less severe. CONCLUSIONS: The nerve damage in Fabry patients with preserved renal function involves exclusively small myelinated and unmyelinated fibers, and skin biopsy is a useful in detecting and quantitating such damage. Comparison of cutaneous innervation density with quantitation of sural nerve biopsy specimens demonstrated that skin biopsy specimens were as sensitive in detecting the presence of neuropathy as were the nerve specimens. It is speculated that analysis of cutaneous innervation may provide a useful marker of the nervous system's response to specific therapy for Fabry disease.     

Unmyelinated nerve fiber degeneration in chronic inflammatory demyelinating polyneuropathy

To determine whether unmyelinated nerve fibers escape degeneration as one might expect in an immune response exclusively directed at myelin, we performed a morphometric examination of unmyelinated axons and myelinated nerve fibers in sural nerve biopsy specimens of 14 patients with a chronic inflammatory demyelinating polyneuropathy (CIDP) and of 12 age-matched normal controls. The numbers of unmyelinated axons, myelinated nerve fibers, denervated Schwann cell units and collagen pockets were quantified and related to the clinical and electrophysiological data of the patients with CIDP. In 4 patients with a rapid onset of the neuropathy and a highly elevated CSF protein, the numbers of both unmyelinated axons and myelinated nerve fibers were decreased equally. In 8 patients we found that the unmyelinated axons were relatively spared compared with the loss of myelinated nerve fibers. In these patients, however, the presence of denervated Schwann cell units and of collagen pockets was increased. We conclude that unmyelinated nerve fibers are affected in patients with CIDP.     

Presence of crystalline inclusions in the peripheral nerve of a patient with IgA lambda monoclonal gammopathy of undetermined significance

Association of a peripheral neuropathy with an IgA monoclonal gammopathy of undetermined significance (MGUS) is not commonly observed and is sometimes considered as coincidental. We present a case in which the nerve biopsy revealed the presence of crystalline inclusions in the endoneurium, a very unusual finding. A 75‐year‐old man complained of paresthesiae in both feet and unsteady gait for 6 months. He had no weakness, but deep tendon reflexes were absent and vibratory sensation distally diminished in both legs. An IgA lambda MGUS was evidenced in his serum at 10.2 g/L with 7% plasma cells in his bone marrow and no lytic lesion at skeletal examination. A superficial peroneal nerve biopsy was performed and showed numerous crystalline inclusions in the endoneurium. These were located in the cytoplasm of macrophagic histiocytes or free in the vicinity of nerve fibers. There was also a marked loss of myelinated nerve fibers and several “onion bulb” formations surrounding either isolated remyelinating fibers or small clusters of remyelinating fibers. Such crystalline inclusions have mainly been observed in the cytoplasm of plasma cells in cases of multiple myeloma, and correspond to non‐secreted IgA or IgG immunoglobulins with a kappa or rarely lambda light chain. Such inclusions have also been reported in the cytoplasm of the epithelial cells from corneal fragments, in patients with multiple myeloma or IgG MGUS, and in the tubular cells from the kidney of patients with multiple myeloma and a nephrotic syndrome. In the literature, there is only one very briefly mentioned case of neuropathy associated with a myeloma and with crystalline inclusions present in the epineurium. Thus, in dysglobulinemic neuropathy, nerve fibers can be damaged by three kinds of interstitial deposits, easily identified by immunohistochemistry and at ultrastructural examination: the well known amyloid fibrils, granulo‐fibrillar deposits and also crystalline inclusions.     

Detection of early motor involvement in diabetic polyneuropathy using a novel MUNE method – MScanFit MUNE

ObjectiveDetection of motor involvement in diabetic polyneuropathy (DPN) by nerve conduction studies (NCS) does not occur until there is substantial loss of motor units, because collateral reinnervation maintains compound muscle action potential (CMAP) amplitude. Motor unit number estimation (MUNE) methods may therefore be more sensitive. This study was undertaken to test whether the novel method, MScanFit MUNE (MScan) can detect motor involvement in DPN despite normal NCS.MethodsFifty-two type-2 diabetic patients and 38 healthy controls were included. The median nerve was examined in all participants using standard NCS and a detailed CMAP scan, used for MScan. Additional lower extremity NCS in patients were used for DPN diagnosis.ResultsOf 52 diabetic patients, 21 had NCS-defined DPN while lower extremity NCS were normal in 31 patients. MScan motor unit number and size showed higher sensitivity and incidence of abnormality than motor NCS parameters, and a similar sensitivity to sensory NCS.ConclusionsMScan is able to detect motor axonal damage at times when collateral reinnervation limits NCS changes.SignificanceMScan is a sensitive method to detect motor involvement in DPN, which our data suggests is present as early as sensory.     

Epidermal nerve innervation in impaired glucose tolerance and diabetes-associated neuropathy.

The authors describe skin biopsy findings in patients with peripheral neuropathy associated with diabetes and impaired glucose tolerance (IGT). Six patients with IGT, eight with early diabetes-associated neuropathy, and five controls were recruited. Most subjects underwent nerve conduction studies (NCS) and quantitative sensory tests (QST). Skin biopsy was abnormal in all neuropathy subjects and correlated poorly with NCS. Neuropathy associated with IGT primarily affects small fibers and is similar to early diabetes-associated neuropathy.     

Myelinated Nerve Fibers In Glabrous Digital Skin

In the last decade, applying multiple immunolabeling with highly specific antibodies and confocal microscopy to skin biopsies, it has been possible to study extensively cutaneous innervation. This technique has proved to be reliable and even more sensitive than sural nerve biopsy to investigate mild dying back neuropathies with only a very distal involvement of nerve fibers. So far it has been used mainly on hairy skin to evaluate small fiber anomalies in congenital, acquired and idiopathic sensory neuropathies. Compared to hairy skin, glabrous skin has a peculiar characteristic: it is rich in mechanoreceptors and myelinated A_β fibers. To study these structures we selected a group of healthy volunteers and recruited a group of patients affected by hereditary or acquired sensory neuropathies. Skin biopsy was performed using a three mm disposable punch in all subjects on fingertip. We stained the cutaneous samples with a panel of antibodies identifying different neural structures such as the axon, the myelin sheath, the Schwann cell, and the Meissner corpuscle capsula. Three-D digitized images were acquired using a confocal microscope. We studied Meissner and intrapapillar myelinated nerve fiber density and using a dedicated software we measured in normal and neuropathic subjects area and density of innervation of Meissner corpuscles and thickness, internodal and Ranvier node length of the sensory fibers approaching the mechanoreceptors.