Painful sensory neuropathy

Methods.

This was a prospective study of consecutive patients referred to The Peripheral Neuropathy Center at The Ohio State University Hospital with the complaint of painful extremities. To be included in the study, patients had to meet the following clinical criteria: 1) painful feet as the major symptom; 2) normal strength (Medical Research Council [MRC] 5) assessed by manual muscle testing according to a previously established scale13; and 3) no diagnosis at the time of referral accounting for neuropathic pain. In addition, all patients had to undergo the following evaluation: 1) in patients with only lower extremity symptoms, unilateral sural sensory (orthodromic, normal amplitude ≥10 μV, conduction velocity ≥40 m/sec) and peroneal motor (normal amplitude ≥2 mV, conduction velocity ≥40.0 m/sec) nerve conduction studies (NCS) were performed. If either was abnormal, the same nerves were studied on the opposite leg. Upper extremity nerves were studied when symptoms involved the hands or arms, or when any lower extremity NCS was abnormal. The upper extremity NCS included median and ulnar sensory (normal amplitude ≥10 μV, conduction velocity ≥50 m/sEC) and median and ulnar motor (normal amplitude ≥4 μV, conduction velocity ≥50 m/sec); 2) punch biopsy of the skin was performed in those with normal electrodiagnostic studies; and 3) a common battery of blood tests was obtained on all study patients to search for systemic disorders, vitamin deficient states, endocrine abnormalities, autoimmune disorders (including antibodies to various nerve antigens), and paraneoplastic conditions. These included: complete blood count, blood urea nitrogen, creatinine, electrolytes, liver function tests (bilirubin, alanine transaminase, aspartate transaminase, gamma glutamyl transpeptidase, alkaline phosphatase), thyroid function tests (thyroid stimulating hormone and thyroxine), serum vitamin B12 and methlymalonic acid and homocysteine levels in patients with B12 levels <250 mg/dL, serum vitamin E, fluorescent treponemal assay (FTA), HIV, cholesterol, triglycerides, sedimentation rate, antinuclear antibodies (ANA), rheumatoid factor, extractable nuclear antigens, serum immunofixation, and quantitative immunoglobulins. A random glucose level was obtained and considered abnormal if ≥200 mg/dL as recommended by the report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.14 If abnormal, a repeat fasting value was obtained and a diagnosis of diabetes mellitus was established if the value exceeded 126 mg/dL or if 2-hour plasma glucose was ≥200 mg/dL during an oral glucose tolerance test. Blood tests also included a search for antinerve antibodies, including anti-Hu, anti-myelin associated glycoprotein (MAG), anti-sulfoglucuronyl paragloboside (SGPG), and anti-sulfatide antibodies.

Sural nerve biopsies were performed selectively on patients demonstrating one of three abnormalities during the evaluation: monoclonal gammopathy, multiple mononeuropathy by electrodiagnostic examination, or orthostatic hypotension on physical examination (a 3-minute sustained blood pressure fall of 20/10 mm Hg).

Results.

A total of 117 patients (69 women and 48 men) met entry criteria and underwent evaluation. Electrodiagnostic studies served as the primary discriminator, and were abnormal in 60 patients. Fifty-six patients had normal NCS and underwent subsequent punch biopsy of the skin. Three groups of patients emerged from this analysis (table 1). Group 1 consisted of 60 patients (34 women and 26 men, mean age 60 ± 14 years) representing 51% of the cohort with reduced or absent sural sensory nerve action potentials. Pain was the predominant clinical symptom in these patients; by definition, muscle strength was normal. Other clinical features (table 2) included depressed muscle stretch reflexes at the ankles in 26 (43%), sensory loss at the toes for vibration in 50 (83%), and proprioception loss in 28 (47%). Diminished pinprick sensation typically involved the toes and feet. In about one half of the patients the loss extended to the lower legs, but not above the knees. In 10 (20%), the diminished pinprick was found on the fingertips. Six patients (10%) had abnormal pinprick sensation as the exclusive sensory abnormality. The majority of patients in Group 1 had neuropathies of undetermined cause, but in 18 patients (30%), a condition known to be associated with peripheral nerve disease was identified (table 1). Five in this group underwent sural nerve biopsy according to the indications already cited. Two of these patients had monoclonal gammopathy of undetermined significance (MGUS), and in both, nerve biopsy showed a nonspecific axonal neuropathy; two had postural hypotension (one with monoclonal gammopathy found to have primary amyloidosis with light chain deposits in the nerve and the other had a transthyretin-related amyloidosis); and another patient had a multiple mononeuropathy by electrophysiology and was found to have nonsystemic necrotizing vasculitis on nerve biopsy.22,23 The heterogeneity of this group is emphasized by other unexpected disorders revealed by the evaluation. One patient developed Creutzfeldt-Jakob disease despite initial presentation with sensory symptoms in the extremities. In five patients there was a family history of neuropathy. Two of these patients had pes cavus and two others had pes planus. None met demyelinating criteria by NCS.24,25

Group 2 consisted of 44 patients (29 women and 15 men, mean age 57 ± 14 years) representing 38% of the cohort with NCS and reduced or absent IENF nerve fibers by skin biopsy. The skin biopsy findings included a mean IENF density of 9.62 ± 6.25/mm_EL, (age-matched controls, 33.06; 5th percentile cut-off value 20.06 for patients below age 60 years). In the patients older than age 60 years, the mean IENF density was 5.22 ± 3.82/mm_EL (age-matched controls, 20.16; 5th percentile cut-off value 11.08). In many patients, there was a complete or nearly total loss of IENFs, which was very apparent when compared to controls (figure, A versus B). The pathologic changes of the nerves, apart from reduced counts, included a range of findings. Some nerve fibers did not reach the epidermis, ending abruptly just below the basal lamina, similar to descriptions in diabetic neuropathy.17 Other fibers showed enlarged, “swollen” appearing terminal nerve endings similar to those described by Holland and colleagues and thought to reflect Wallerian-like degeneration.10,11

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Figure. Laser scanning confocal mi-croscopic images. Magnification is in-dicated by calibration bar in μm. (A) Skin biopsy from a normal control shows abundant nerve fibers within the epidermis, often demonstrating a candelabra-like pattern after piercing the continuous (green-stained) collagen band of basal lamina at the dermal–epidermal border; (B) only a single nerve (arrow) is seen piercing the basal lamina in a patient with a small fiber painful sensory neuropathy from Group 2. The nerve fibers are demonstrated using antibody to protein gene prod-uct 9.5 and the basal lamina at the dermal-epidermal border by antibody to collagen IV.

In Group 2, pain was the predominant clinical symptom and all patients had normal strength, just as in Group 1. However, fewer objective abnormalities were found on neurologic examination (see table 2). Only five Group 2 patients (11%) had depressed (i.e., with reinforcement only) or lost ankle muscle stretch reflexes, and 20 (45%) had pinprick loss (typically a poorly defined level on the toes and feet) as the only clinical sensory disturbance in distal lower extremities. Loss of vibration sensation was seen in 19 or 43% and fewer than 14% showed proprioceptive impairment. Both the electrophysiology and the clinical features favored a small fiber painful sensory neuropathy. In Group 2, three patients (7%) had conditions that are known be associated with peripheral neuropathy: one with monoclonal gammopathy, one with a family history of neuropathy, and one with proximal myotonic myopathy (PROMM) diagnosed on the basis of electromyographic presence of myotonia and absent CTG repeats on DNA testing. This patient complained of painful feet and the examination showed distal sensory loss with normal nerve conduction studies.26

Group 3 consisted of 13 patients (six women and seven men, mean age 53 ± 13 years) representing 11% of the cohort, with normal NCS and normal skin biopsies. In 11 of these patients, no diagnosis could be established. In two cases, however, a central cause for pain was found. These patients had hyperreflexia and MRI of the brain demonstrated high signal intensity lesions typical of MS.

One of the goals of this study was to compare the relative sensitivity of IENF density to QST and QSART in neuropathy detection. A subset of 32 patients undergoing all three tests allowed for comparisons (table 3). In 19 patients (59%), QSART was found to be abnormal at one or more of the four sites studied. When considered by region, QSART abnormalities were found on the forearm in six patients (19%), proximal lower leg in 14 patients (44%), distal lower leg in nine patients (28%), and on the dorsum of the foot in nine patients (28%). In these patients with abnormal findings, QSART volume was increased on the forearm and reduced on the lower leg or foot. QSART volumes at the four sites were compared on a log scale using an ANOVA method that accounted for the correlations between the observations on the same subject. QSART on the forearm was different compared to proximal lower leg (p < 0.001), distal leg (p < 0.001), and the foot (p < 0.002), but was not different between any of the sites on the leg. Quantitative sensory testing was abnormal (i.e., >95th percentile for either cold-detection or vibration-detection thresholds) in 23 of the subset of 32 patients (72%). There were slightly more patients with cold-detection abnormalities (foot, n = 14, 44%; hand, n = 20, 63%) compared to vibration (foot, n = 10, 31%; hand, n = 11, 34%), although this did not reach statistical significance. In this subset of 32 patients, 28 (87.5%) demonstrated reduced IENF density. There was no concordance among findings on skin biopsies, QSART, and QST (Fisher’s exact test). An abnormality in one of the tests did not predict an abnormality in either of the other methods of neuropathy detection.

The battery of blood tests failed to reveal any patient with a systemic disorder (renal, liver, HIV), a vitamin deficient state (cobalamin or vitamin E deficiency), or endocrine abnormality (thyroid disease or diabetes mellitus). Antinerve antibodies were negative (anti-Hu, anti-MAG, and anti-SPGP) with the exception of one patient from the small fiber group who demonstrated a positive anti-sulfatide antibody with an ELISA titer of 2637. The skin biopsy of this patient was immunostained to detect immunoglobulin G (IgG) antibodies on nerve fibers or other structures of the skin; no antibody deposits were detected. Hypertriglyceridemia (≥250 mg/dL) and hypercholesterolemia (≥200 mg/dL) were the most common laboratory abnormalities seen in the cohort of 117 patients enrolled in the study (34% and 28%, respectively). These findings, however, were seen equally in both Group 1 and Group 2 patients. Serum protein immunofixation made it possible to detect monoclonal gammopathy in four patients. MGUS was found in three (IgGκ) patients, two in the large fiber group and one in the small fiber group, and the other had primary amyloidosis (IgGλ). Extractable nuclear antigens made it possible to diagnose Sjögren’s syndrome in two patients (positive for SS-A and SS-B), and mixed connective tissue (extractable nuclear antigen-positive RNP) in one other. However, a positive ANA ≥1:160 with otherwise negative connective tissue disease markers (extractable nuclear antigens, double-stranded DNA, rheumatoid factor) was more difficult to interpret; this pattern was found in 10 patients (17%) in Group 1 and 5 patients (11%) in Group 2.

Discussion.

This was a prospective study of a large cohort of patients undergoing evaluation for painful feet, a commonly encountered malady facing the neurologist in everyday practice. By the time these patients are referred for neurologic evaluation, most causes for foot pain have been eliminated by the primary care doctor, orthopedist, or podiatrist. Many have seen a rheumatologist. These patients often have few neurologic abnormalities that can be unequivocally attributed to peripheral neuropathy. In the cohort under evaluation, all had normal strength, a criterion for admission. In the Group 2 patients, those with small fiber painful sensory neuropathy, the vast majority had preserved muscle stretch reflexes and minimal sensory loss. In this group, the practicing physician is easily drawn to an erroneous conclusion because of the mismatch of complaints versus objective findings.

The study was designed to address several questions in an unselected population of patients with painful feet and normal muscle strength. The first issue to be considered was how many of these patients have a neuropathy as a cause of their pain. We established a neuropathy diagnosis in 89% of this cohort. In slightly more than half, the electrodiagnostic studies were abnormal. The second major question of our study concerned the role of skin biopsies in diagnosing these patients. In 38% (44 of 117), the skin biopsy findings of reduced IENF density provided unequivocal evidence of a small fiber painful sensory neuropathy. In fact, the value of skin biopsy is reinforced by considering the patients with normal electrodiagnostic studies (n = 57); slightly more than three-fourths were found to have reduced IENF density. The findings are in agreement with a series of previous reports demonstrating the value of skin biopsy in various groups of patients with sensory neuropathies.10-12 Furthermore, the demonstration by Herrmann et al that loss of IENF correlates with loss of unmyelinated and small myelinated nerve fibers in the sural nerve27 emphasizes the importance of skin biopsy in the assessment of painful sensory neuropathy with normal electrophysiology.

In the evaluation of patients with painful sensory neuropathies, other modalities of testing have been employed, particularly QST and QSART. The value of each has been demonstrated in various populations.28-30 Our study directly compares loss of IENF density with abnormalities in QST and QSART in a subset of 32 patients. Skin biopsy was more sensitive in identifying neuropathy than either QST or QSART. There was a lack of concordance between tests, indicating that each may have independent importance. Take for example the three patients we identified with QSART abnormalities and normal skin biopsies. The selective findings of abnormal postganglionic sudomotor fibers may suggest a different disease process. Only a longitudinal, prospective natural history study will determine if these patients have an inherited or acquired, predominantly autonomic neuropathy. QST is also of interest in the same regard considering three patients of the subset with QST abnormalities and normal skin biopsies. The natural history of these patients also awaits future study.

The third major question of our study addressed the possible conditions associated with an unselected population of patients with painful feet. In the overall cohort of 117 patients there is considerable heterogeneity. This is particularly true of the large fiber painful sensory neuropathy group where 18 (30%) patients emerged with conditions known to be associated with neuropathy. The significance of MGUS in this small group of patients is indeterminate, but the association with neuropathy is well established.31-33 In this relatively small group of older patients, the significance of a small number of patients with MGUS and neuropathy must be interpreted cautiously. The patient with Creutzfeldt-Jakob disease may have had incidental neuropathy, although others with this condition have been reported to have a neuropathy at the time of presentation.34,35 A more direct relationship to painful sensory neuropathy is illustrated by others in Group 1 (nonsystemic vasculitis,22,23,36 amyloidosis, taxol,37,38 Sjögren’s syndrome, mixed connective tissue disease, primary amyloidosis, transthyretin amyloidosis; see table 1). These particular patients exhibited more widespread loss or reduction of sensory nerve action potential amplitudes compared to others in Group 1 (data not shown) suggesting that this finding in a patient presenting with burning feet should alert the clinician to a possible identifiable underlying disorder. Those with familial neuropathies could not be further characterized, except to say that none had a demyelinating neuropathy by conventional criteria.24,25 More information is being sought on this group but nothing further can be stated at present. The patients in Group 2 also demonstrated heterogeneity, but to a lesser degree. One patient had a familial neuropathy, and most likely had hereditary sensory and autonomic neuropathy type 1.1,39 The association with MGUS in this group remains indeterminate as in Group 1. A neuropathy has also been reported with PROMM but its relationship to the underlying disease is unclear.26 We also know from follow-up that at least some patients evolve from a strictly small fiber painful sensory neuropathy to a large fiber sensory neuropathy. We have identified one patient in this cohort of 117 who followed this pattern of evolution, and we expect others will proceed along the same course but only our ongoing longitudinal study will determine the number. The evolution from small fiber to large fiber involvement is well-established to occur in diabetes mellitus, but no patient in our study fulfilled criteria for diabetes according to currently established standards.14 The majority of the Group 2 patients with small fiber sensory neuropathy had a similar clinical picture (normal strength; normal muscle stretch reflexes and distal sensory loss for pinprick and light touch; some had decreased vibratory sensation with sparing of position sense) and normal electrodiagnostic studies (see table 2). We suspect that many of these patients have a selective small fiber neuropathy that will not progress to later involve larger nerve fibers, but this also can only be established in a longitudinal natural history study.

The final issue addressed in this study was the question of which blood tests should be obtained in this population of patients with painful feet. Findings in Group 1 patients support assessment for serologic markers of connective tissue disease, especially for Sjögren’s syndrome and serum protein analysis for monoclonal gammopathy. There were no patients with organ system failure or vitamin deficiency presenting with painful neuropathy, suggesting that a panel of blood tests for renal or liver disease, cobalamin, and vitamin E may not be necessary in the absence of corroborative findings indicative of any of these conditions. None had thyroid disease or diabetes mellitus, according to guidelines established by the report from the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. No patients harbored anti-Hu antibody, and based on findings from Dalmau et al, it is unlikely that patients with the “anti-Hu” syndrome will present with painful feet as the exclusive finding.40 The anti-MAG syndrome also has distinguishing clinical and electrophysiologic findings suggesting that anti-MAG antibody should only be ordered when these features are present or when an IgM monoclonal protein is found.41-43 The strongest statement can be made with regard to anti-sulfatide antibody; our study demonstrates that it is of little value in detection of a painful sensory neuropathy.