Vibratory and cooling detection thresholds compared with other tests in diagnosing and staging diabetic neuropathy.

Increasingly more tests are being used to detect and characterize diabetic polyneuropathy, but their value in setting minimal criteria for the diagnosis of neuropathy and for staging severity remains inadequately studied. In 180 diabetics, we compared the percentage of patients with test abnormalities and associations among test results, evaluating neuropathic symptoms [neuropathy symptom score (NSS) and neuropathy scale of neuropathy symptom profile (NNSP)], deficits [neurologic disability score (NDS) and vibratory (VDT) and cooling (CDT) detection thresholds], or nerve dysfunction [nerve conduction (NC)]. The percentage of patients that were abnormal varied considerably depending on criteria for abnormality and the tests used. Abnormality (greater than or equal to 3 SD of 1 or more parameters) of NC of one or more of four nerves occurred in 80%, of two or more in 69%, of three or more in 46%, and of four in 21%. Similarly, for other tests, the rate of abnormality decreased with use of increasingly stringent criteria. Setting the criteria for abnormal NC at abnormality of two or more nerves, NSS at greater than or equal to 1, NDS at greater than 6, NNSP at greater than or equal to 97.5th percentile, and at greater than or equal to 95th percentile for the other tests, NC was abnormal in 69%, NSS in 54%, NDS in 48%, NNSP in 47%, VDT in 44%, and CDT in 35%. Abnormality of any two or more of the six tests evaluated occurred in 64% of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Imaging system for nerve and fiber tract morphometry: components, approaches, performance, and results.

This report describes the imaging system that was developed to recognize, count, size, and evaluate shapes of transverse myelinated fiber (MF) profiles in nerves and fiber tracts automatically and by operator interaction. Automatic analysis, without operator interaction, will either miss a variable percentage of small MFs (using thresholds that discriminate against all other tissue profiles) or include most MFs but spuriously detect other tissue profiles (using more sensitive thresholds). Systems such as this must therefore be operator-interactive. The system that was developed will, in a favorable histologic section, automatically detect and border myelin in more than 85% of MFs without inclusion of other tissue elements. The remainder of the MFs are then identified by the operator with the digitizer pen, and the myelin is automatically bordered or, in rare cases, drawn in. Very reliable, reproducible, and rapid measurements of MF number, size, and shape can be obtained with this system. From evaluation of the size and shape of MFs in semithin sections in the light microscope as compared with the same fibers in adjacent thin sections in the electron microscope, measurements by this system can be expressed as if they were obtained on thin sections. Evaluations can be analyzed statistically, with results printed out, displayed on a video screen, and graphed. Such a system will be useful in evaluating and following morphologic changes in number, size, and shape of MFs in development, aging, regeneration, neurotoxicity, and various diseases.

Effect of serum hyperosmolality on morphometry of healthy human sural nerve.

Fascicles of human sural nerve, fixed by immersion in isosmolar 2.5% glutaraldehyde solution and in isosmolar osmium tetroxide and embedded in epoxy, undergo a 10% shrinkage in area when compared with cryostal sections. By contrast, fascicles fixed in hyperosmolar solutions (whether 5.6% glutaraldehyde solution or 2.5% glutaraldehyde raised to the same level of hyperosmolality with sucrose) undergo a 43% shrinkage in area. Axis cylinders of myelinated fibers undergo a selective and severe shrinkage and assume noncircular shapes, the shapes allowing the transverse area to decrease when the perimeter remains unchanged. These studies raise the intriguing question of whether interstitial hyperosmolality in metabolic diseases, such as diabetes mellitus, or in uremia may cause osmotic axonal shrinkage, altered transverse fiber shape, and abnormality of function and structure of nerve.

Longitudinal study of neuropathic deficits and nerve conduction abnormalities in hereditary motor and sensory neuropathy type 1.

We measured neuropathic deficit (neurologic disability score [NDS]) and attributes of nerve conduction in hereditary motor and sensory neuropathy (HMSN 1) in cross-sectional evaluation of 69 patients and in longitudinal evaluation over approximately 15 years in 31 of them. Neuropathic deficit worsened by 0.6 NDS point per year in patients 5 to 14 years old at first evaluation, by 1.1 points in patients 15 to 39 years old, and by 0.9 point in patients 40 or more years old. Neuropathic deficit was greater in HMSN 1b (the disorder linked to Duffy) than in HMSN 1a (not linked to Duffy). Nerve conduction attributes changed significantly depending on attribute studied, age, and nerve. In patients evaluated serially, ulnar conduction velocity (CV) increased by a few meters per second in patients who were 5 to 14 or 15 to 39 years old at first examination, but decreased in patients who were older. In serial measurements, peroneal nerve amplitude decreased in all 3 age groups. We found an association between CV and amplitude or NDS at first and last examinations, suggesting an association between severity of the CV abnormality and neuropathic deficit. The severity of the CV abnormality in the young appears to predict later neurologic abnormality.

The syndrome of acute sensory neuropathy: clinical features and electrophysiologic and pathologic changes.

We followed 42 patients with clinically defined pure sensory neuropathy of acute or subacute onset for 2 to 35 years. The symptoms began in the upper limbs in 23 patients, in the lower limbs in 13, symmetrically in all 4 limbs in 4, and the face was 1st affected in 2. For 19 patients, the symptoms began asymmetrically. Electrophysiologic testing typically showed absence of sensory potentials. Spinal fluid was usually acellular with a normal protein level. Sural nerve biopsy in 22 patients showed loss of large myelinated fibers and axonal atrophy without inflammation. Six of the patients died: 4 of unrelated causes and 2 of subdural hemorrhages. Only 2 patients had severe functional impairment. Twenty-two had significant sensory deficit but were able to carry out most of their usual activities. In 8, the symptoms had resolved completely. The acute, often focal onset suggests an immune-mediated or vascular process at the level of the posterior root or dorsal root ganglion.

A 4, 2, and 1 stepping algorithm for quick and accurate estimation of cutaneous sensation threshold.

In quantitative sensory testing, certain methods may lead to incorrect estimates of vibratory (VDT), cool (CDT), or warm (WDT) detection thresholds. We have shown that the specific forced-choice algorithm of testing employed in our Computer-Assisted Sensory Examination (CASE IV) system, when compared with other tests of nerve dysfunction, provides accurate and reproducible estimates of these thresholds. Because this forced-choice algorithm is time consuming and performance might be made worse by drowsiness or boredom, we explored other algorithms that might provide estimates of threshold similar to those obtained with the forced-choice algorithm, but more quickly. In a trial of 25 healthy subjects and 25 patients with neuropathy, the 4, 2, and 1 stepping algorithm with null stimuli, based in part on comparative data from computer simulation and insights from patient decision making, provides an accurate estimate of threshold. On average, the time needed for forced-choice testing was 12.8 +/- 2.9 minutes (mean +/- SD). For 4, 2, and 1 stepping testing, it was 2.7 +/- 2.5 minutes--a large saving of time. Since null stimuli were employed in the 4, 2, and 1 stepping algorithm, it was possible to monitor for spurious responses and repeat the test if they occurred at an excessive rate. The algorithm appears to be sufficiently robust to be recommended for clinical use and for some controlled clinical and epidemiologic trials.

Comparison of algorithms of testing for use in automated evaluation of sensation.

Estimates of vibratory detection threshold may be used to detect, characterize, and follow the course of sensory abnormality in neurologic disease. The approach is especially useful in epidemiologic and controlled clinical trials. We studied which algorithm of testing and finding threshold should be used in automatic systems by comparing among algorithms and stimulus conditions for the index finger of healthy subjects and for the great toe of patients with mild neuropathy. Appearance thresholds obtained by linear ramps increasing at a rate less than 4.15 microns/sec provided accurate and repeatable thresholds compared with thresholds obtained by forced-choice testing. These rates would be acceptable if only sensitive sites were studied, but they were too slow for use in automatic testing of insensitive parts. Appearance thresholds obtained by fast linear rates (4.15 or 16.6 microns/sec) overestimated threshold, especially for sensitive parts. Use of the mean of appearance and disappearance thresholds, with the stimulus increasing exponentially at rates of 0.5 or 1.0 just noticeable difference (JND) units per second, and interspersion of null stimuli, Békésy with null stimuli, provided accurate, repeatable, and fast estimates of threshold for sensitive parts. Despite the good performance of Békésy testing, we prefer forced choice for evaluation of the sensation of patients with neuropathy.

The Rochester Diabetic Neuropathy Study: reassessment of tests and criteria for diagnosis and staged severity.

We evaluated the initial assessments of the 380 diabetic patients with and without polyneuropathy in the Rochester Diabetic Neuropathy Study for (1) associations among neuropathy test results, (2) usefulness of different tests for diagnosing and staging polyneuropathy, (3) appropriateness of different minimal criteria for the diagnosis of polyneuropathy, and (4) significant differences in test results with increasing stage of polyneuropathy. Nerve conduction ([NC]; abnormality in two or more nerves) and quantitative autonomic examination ([QAE]; decreased heart-beat response to deep breathing [DB] or the Valsalva maneuver [VAL]) were the most sensitive and objective and were especially suitable for detection of subclinical neuropathy. We propose the following minimal criteria for the diagnosis of diabetic polyneuropathy: greater than or equal to 2 abnormal evaluations (from among neuropathic symptoms, neuropathic deficits, NC, quantitative sensory examination [QSE], and QAE) with one of the two being abnormality of NC or QAE (DB or VAL). Neuropathy Symptom Score, Neuropathy Disability Score, QSE (vibratory or cooling detection threshold), and summated compound muscle action potential of ulnar, peroneal, and tibial nerves were best for judging severity. Inability to walk on heels provided a discrete separation of diabetic patients into those with mild and those with more severe neuropathy--a separation helpful in staging.

Cool, warm, and heat-pain detection thresholds: testing methods and inferences about anatomic distribution of receptors.

We recently found that vibratory detection threshold is greatly influenced by the algorithm of testing. Here, we study the influence of stimulus characteristics and algorithm of testing and estimating threshold on cool (CDT), warm (WDT), and heat-pain (HPDT) detection thresholds. We show that continuously decreasing (for CDT) or increasing (for WDT) thermode temperature to the point at which cooling or warming is perceived and signaled by depressing a response key ("appearance" threshold) overestimates threshold with rapid rates of thermal change. The mean of the appearance and disappearance thresholds also does not perform well for insensitive sites and patients. Pyramidal (or flat-topped pyramidal) stimuli ranging in magnitude, in 25 steps, from near skin temperature to 9 degrees C for 10 seconds (for CDT), from near skin temperature to 45 degrees C for 10 seconds (for WDT), and from near skin temperature to 49 degrees C for 10 seconds (for HPDT) provide ideal stimuli for use in several algorithms of testing and estimating threshold. Near threshold, only the initial direction of thermal change from skin temperature is perceived, and not its return to baseline. Use of steps of stimulus intensity allows the subject or patient to take the needed time to decide whether the stimulus was felt or not (in 4, 2, and 1 stepping algorithms), or whether it occurred in stimulus interval 1 or 2 (in two-alternative forced-choice testing). Thermal thresholds were generally significantly lower with a large (10 cm2) than with a small (2.7 cm2) thermode.(ABSTRACT TRUNCATED AT 250 WORDS)

The Rochester Diabetic Neuropathy Study: design, criteria for types of neuropathy, selection bias, and reproducibility of neuropathic tests.

A cross-sectional survey and subsequent longitudinal study among diabetic residents of Rochester, MN--The Rochester Diabetic Neuropathy Study (RDNS)--is population-based and uses quantitative, validated, and unique end points to detect, classify, and stage neuropathy. Nondiabetic persons, drawn from the same population, serve as controls. For patients 10 to 70 years old, the RDNS cohort is representative of diabetics living in Rochester, MN. We assessed reproducibility of tests used to characterize and quantitate severity of neuropathy in 20 diabetic subjects without neuropathy and with varying severities of neuropathy. Using intraclass correlation coefficient (rI) as a measure of test reproducibility, we found high rI (usually 0.9 or better) with small confidence intervals for the Neurologic Disability Score (NDS); weakness subset of NDS (W-NDS); vibratory and cooling detection thresholds (using computer-assisted sensory examination [CASE] IV); compound muscle action potentials; sensory nerve action potentials; and motor nerve conduction velocities. There was good agreement among three trained observers for NDS and the W-NDS.

The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study.

The magnitude of the health problem from diabetic neuropathies remains inadequately estimated due to the lack of prospective population-based studies employing standardized and validated assessments of the type and stage of neuropathy as compared with background frequency. All Rochester, Minnesota, residents with diabetes mellitus on January 1, 1986, were invited to participate in a cross-sectional and longitudinal study of diabetic neuropathies (and also of other microvascular and macrovascular complications). Of 64,573 inhabitants on January 1, 1986 in Rochester, 870 (1.3%) had clinically recognized diabetes mellitus (National Diabetes Data Group criteria), of whom 380 were enrolled in the Rochester Diabetic Neuropathy Study. Of these, 102 (26.8%) had insulin-dependent diabetes mellitus (IDDM), and 278 (73.2%) had non-insulin-dependent diabetes mellitus (NIDDM). Approximately 10% of diabetic patients had neurologic deficits attributable to nondiabetic causes. Sixty-six percent of IDDM patients had some form of neuropathy; the frequencies of individual types were as follows: polyneuropathy, 54%; carpal tunnel syndrome, asymptomatic, 22%, and symptomatic, 11%; visceral autonomic neuropathy, 7%, and other varieties, 3%. Among NIDDM patients, 59% had various neuropathies; the individual percentages were 45%, 29%, 6%, 5%, and 3%. Symptomatic degrees of polyneuropathy occurred in only 15% of IDDM and 13% of NIDDM patients. The more severe stage of polyneuropathy, to the point that patients were unable to walk on their heels and also had distal sensory and autonomic deficits (stage 2b) occurred even less frequently--6% of IDDM and 1% of NIDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Minimal pathologic expression of a mutant gene for hereditary motor and sensory neuropathy.

Transverse sections of the sural nerve of a 46-year-old woman without neuropathic symptoms or abnormalities on nerve conduction, electromyography, or computer-assisted sensory examination contained minute regions with large onion bulbs intermingled with normal-appearing myelinated fibers and surrounded by fields of normal myelinated fibers. This woman's 19-year-old daughter had long-standing hypertrophic neuropathy with diffusely distributed large onion bulbs. Computer-imaging reconstruction of myelinated fibers and teased myelinated fiber studies of fascicles containing focal regions with onion bulbs of the mother's nerve provided evidence that onion bulbs surrounded atrophic axons with short internodes and demyelination. This is the least expression for inherited neuropathy which has been reported. These findings therefore suggest that an inherited neuropathy may be minimally expressed by a pathologic alteration of only selected neurons (axons).

Non-response bias in studies of diabetic complications: the Rochester Diabetic Neuropathy Study.

Non-response can bias studies of disease conditions but its influence has rarely been evaluated due to limitations of available data on the non-respondents. Because of a detailed medical record review for eligibility, we were able to compare clinical as well as demographic characteristics of respondents and non-respondents in a population-based study of diabetic complications among Rochester, Minnesota residents. Non-respondents were older, less well educated, more likely to be widowed and more often retired. They were much more likely to have cardiovascular disease at baseline, but the prevalence of retinopathy, nephropathy and diabetic neuropathy was similar for respondents and non-respondents, who were also comparable with regard to type of diabetes and diabetic therapy. While these findings indicate that data from the Rochester Diabetic Neuropathy Study can probably be generalized to diabetic residents generally, they reemphasize the potential for non-response bias in epidemiologic studies of clinical conditions, especially cardiovascular disease.

Sural nerve myelinated fiber density differences associated with meaningful changes in clinical and electrophysiologic measurements.

New forms of therapy for diabetic and other neuropathies may prevent, stabilize, or ameliorate loss of nerve fibers. Clinically meaningful changes in mean Neurological Disability Score (NDS), and the associated mean change of electrophysiologic attributes have been described in diabetic polyneuropathy. It is unknown what magnitude of myelinated fiber (MF) density change is associated with these meaningful changes of clinical and electrophysiologic alterations. In 18 diabetics and 5 normal controls associations between the mean NDS, summated (ulnar, peroneal and tibial) compound muscle action potential (sigma CMAP), summated (ulnar and sural) sensory nerve action potential (sigma SNAP), sural SNAP, and MF density in the sural nerve, were assessed using linear regression analyses. Values were corrected for age and sex. For a decrease of: 2 points in the mean NDS (minimum clinically detectable change), MF density decreased by approximately 200 fibers/mm2 (p < 0.001) 1 mV in the mean sigma CMAP (sum of the ulnar, peroneal and tibial CMAP amplitudes), MF density decreased by 160 fibers/mm2 (p < 0.01) 1 microV in the mean sigma SNAP (sum of ulnar and sural SNAP amplitudes), MF density decreased by approximately 70 fibers/mm2 (p < 0.001) 1 microV in the mean sural SNAP, MF density decreased by approximately 150 fibers/mm2 (p < 0.01). Changes in sensory detection thresholds were also associated with a measurable change in the MF density. A quantifiable association exists between the magnitude of change in density of MF, and a meaningful alteration in mean NDS and various electrophysiologic parameters. Knowledge of this is needed to assess the statistical power of a clinical trial in which density of myelinated fibers is an outcome measurement.

A standard test of heat-pain responses using CASE IV.

Heat-pain threshold and stimulus response characteristics can be evaluated with graduated heating pulses from a radiant heat source or a contact thermode. Results may be used to: (1) evaluate differences in sensation among anatomical sites, sides of the body, and with development and aging; and (2) provide an end-point for the study of the efficacy of drugs; or to follow the course of sensory alteration in disease (medical practice, epidemiologic studies, and controlled clinical trials). Because there is great variability in how tests of this kind are performed and scored, comparisons of results among medical centers are difficult. To meet this need, we have developed, and here describe, a standardized and validated test of heat-pain. We use both pyramidal and trapezoid-shaped stimuli. The range of stimulus magnitudes we recommend is sufficient to test heat-pain at a sensitive region (the face) of young people and an insensitive region (the foot) of healthy old people. From tests on healthy subjects and patients, we find that neither our previously published forced-choice or 4, 2, and 1 stepping algorithms are suitable for testing heat-pain sensation. We, therefore, introduce the Non-Repeating Ascending with Null Stimuli (NRA-NS) algorithm which performs satisfactorily. The graphed data points of responses to increasingly stronger heat pulses were made up of two components-the no pain (0) response line and the heat-pain response line (> or = 1 numerical scaling of the pain responses graded from 1 [least] to 10 [greatest]). For the pain responses, we found that usually a curve could be fit using a quadratic equation. Using this equation, or interpolation where necessary, it is possible to compute the heat-pain detection threshold (HPDT or HP:0.5), an intermediate heat-pain response (HP:5.0), and the difference between the two (HP:5.0-0.5). Our studies show that a certain time is needed between successive stimuli and tests to minimize changing basal skin temperature or threshold. We also demonstrated that low or high baseline skin temperatures can affect heat-pain responses, therefore, we advocate specific testing conditions. Based on a study of 25 healthy subjects, the reproducibility of the test falls within +/-1 stimulus steps 88% of the time for HP:5.0 and 76% of the time for HP:0.5. The precise approaches employed to make the test standard and reproducible are described. We illustrate that the algorithm and testing system is able to document altered pain threshold with skin abrasion, with intradermal injection of nerve growth factor, and with diabetic polyneuropathy.

Effects of low voltage pulsed current on edema formation in frog hind limbs following impact injury.

The purpose of this study was to test the effect of low voltage pulsed current (LVPC) on posttraumatic edema formation in frog hind limbs. Feet of 26 anesthetized bullfrogs were systematically injured by weight drop. One hind limb of each animal was randomly selected to receive continuous 100-pps LVPC at 90% of motor threshold; the opposite hind limb served as a control. A series of four 30-minute treatments (interrupted by 30-minute rests) was begun minutes after injury. Changes from pretrauma limb volumes were determined before and after each treatment and at 8, 17, 20, and 24 hours posttrauma. Analysis of variance revealed no significant treatment effect. Similar studies utilizing high voltage pulsed current (HVPC) at 90% of motor threshold revealed significant curbing of edema formation in frogs. Waveform (LVPC versus HVPC) seems to influence the efficacy of electrotherapy for edema control.

High voltage pulsed current using surface electrodes: effect on acute edema formation after hyperflexion injury in frogs.

We have repeatedly demonstrated that high voltage pulsed current (HVPC) applied via immersion technique at 120 pps and 90% of visible motor threshold curbs posttraumatic edema formation in nonhuman vertebrates. Clinically, however, HVPC is frequently applied to patients via surface electrodes. The purpose of this study was to determine whether use of HVPC with surface electrodes would also result in curbing of edema formation in nonhuman vertebrates. Ankles of 20 anesthetized frogs were sprained bilaterally. One randomly selected limb of each frog received HVPC for 30 minutes immediately after trauma, while the other limb served as a control. Limb volumes were measured before and after trauma, after treatment, and at 1-hour intervals for 4 hours. Unlike three previous experiments with cathodal HVPC, a single 30-min HVPC treatment delivered via surface electrodes did not curb edema formation. These results suggest that electrode type or position or both may be critical factors in the efficacy of HVPC in the treatment of edema in frogs. J Orthop Sports Phys Ther 1992;16(3):140-144.

Spatial distribution of capillaries in rat nerves: correlation to ischemic damage.

Computerized imaging was used to assess the spatial distribution of capillaries (number, density, and intercapillary distance) in normal rat sciatic nerve and its branches, to be able to make inferences about their distribution to central fascicular degeneration typical of ischemic nerve injury. Capillary density was significantly less in the central regions of fascicles than in outer contour areas in sciatic and proximal tibial nerves, the difference being greater in large fascicles. The mean of the minimum intercapillary distance was significantly greater in the central fascicular region of fascicles of the sciatic but not of the tibial and peroneal nerves. These anatomic characteristics may be a factor in ischemic-induced central fascicular degeneration. A decrease in the number of capillaries in a region might lead to impaired oxygen diffusion when blood flow to the region is compromised.

Thin axons relative to myelin spiral length in hereditary motor and sensory neuropathy, type I.

The relationship of axonal to myelin area in semithin transverse sections of myelinated fibers obtained from sural nerves at the ankle level was morphometrically assessed using computer imaging. Ten patients with hereditary motor and sensory neuropathy, type I and 41 control subjects were examined. In large- and intermediate-diameter myelinated fibers of diseased nerves, axons were significantly attenuated relative to the amount of myelin. Using electron micrographs, a similar finding was obtained when axon area was regressed on myelin spiral length. The altered relationship was found to be greater with more severe fiber loss. These data, plus other evidence, indicate that in this disorder there is a progressive atrophy of axons, usually most severe in distal aspects of lumbosacral neurons and associated with secondary segmental demyelination and remyelination and hypertrophic neuropathy, preceding distal axonal loss. Because the process may begin in utero or in infancy, not only atrophy but also maldevelopment of axons may be involved.

Fiber loss is primary and multifocal in sural nerves in diabetic polyneuropathy.

Pathological, morphometric, and teased fiber studies of sural nerve from 36 diabetic patients with (n = 32) and without (n = 4) neuropathy and from 47 healthy subjects provide evidence that in diabetic polyneuropathy: (1) fiber loss is primary; (2) demyelination and remyelination with or without onion bulb formation are secondary; (3) remaining fibers, on average, have the same ratio of small to large fibers as in healthy individuals, but with a greatly increased variability; and (4) the spatial distribution of fiber loss is both diffuse and multifocal. Criteria developed during the study of experimental models of ischemic neuropathy were employed to assess whether ischemic nerve damage had occurred in diabetic polyneuropathy. We conclude that there is increasing evidence that microvascular pathological abnormality and ischemia may be involved in the pathogenesis of human diabetic polyneuropathy. Cases with selective loss of small or large afferent fibers are probably extremes of a normal distribution and not different disorders.