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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 (≥ 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 ≥ 1, NDS at > 6, NNSP at ≥ 97.5th percentile, and at ≥ 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. We estimated that at least 16% of patients without abnormal NC (<2 abnormal nerves) had other findings indicative of neuropathy. By regression analysis, results of one test were in almost all cases associated with those of another test, but the association was not close enough to be predictive. Therefore, although NC provides objective and repeatable results, symptoms and deficits must be measured independently. Assuming no differences between groups of patients, the standardized and validated test (NNSP, VDT, or CDT) should provide the same results at different medical centers. By contrast, the results of NSS or NDS tests, with less standardized approaches and based on the judgment of physicians, might not provide the same results at different medical centers. Tests such as the ones described here may be used to define minimal criteria for the diagnosis of polyneuropathy and for staging its severity.

OBJECTIVE— Because α-lipoic acid (ALA), a potent antioxidant, prevents or improves nerve conduction attributes, endoneurial blood flow, and nerve (Na(+) K(+) ATPase activity in experimental diabetes and in humans and may improve positive neuropathic sensory symptoms, in this report we further assess the safety and efficacy of ALA on the Total Symptom Score (TSS), a measure of positive neuropathic sensory symptoms. RESEARCH DESIGN AND METHODS— Metabolically stable diabetic patients with symptomatic (stage 2) diabetic sensorimotor polyneuropathy (DSPN) were randomized to a parallel, double-blind study of ALA (600 mg) (n = 60) or placebo (n = 60) infused daily intravenously for 5 days/week for 14 treatments. The primary end point was change of the sum score of daily assessments of severity and duration of TSS. Secondary end points were sum scores of neuropathy signs (NIS), symptoms (NSC), attributes of nerve conduction, quantitative sensation tests (QSTs), and an autonomic test. RESULTS— At randomization, the groups were not significantly different by the criteria of metabolic control or neuropathic end points. After 14 treatments, the TSS of the ALA group had improved from baseline by an average of 5.7 points and the placebo group by an average of 1.8 points (P < 0.001). Statistically significant improvement from baseline of the ALA, as compared with the placebo group, was also found for each item of the TSS (lancinating and burning pain, asleep numbness and prickling), NIS, one attribute of nerve conduction, and global assessment of efficacy. CONCLUSIONS— Intravenous racemic ALA, a potent antioxidant, rapidly and to a significant and meaningful degree, improved such positive neuropathic sensory symptoms as pain and several other neuropathic end points. This improvement of symptoms was attributed to improved nerve pathophysiology, not to increased nerve fiber degeneration. Because of its safety profile and its effect on positive neuropathic sensory symptoms and other neuropathic end points, this drug appears to be a useful ancillary treatment for the symptoms of diabetic polyneuropathy.

AbstractPhosphatidylcholine acyltransferase (lecithin:cholesterol acyltransferase or LCAT; EC 2.3.1.43) activity was found to be present in pig ovarian follicular fluid (POFF), in addition to pig serum (PS). The cholesterol esterification rate in both POFF and PS is linear with incubation time up to 2 hr. The mean absolute rate of POFF‐cholesterol esterification was 8.1±0.4 nmoles per ml per hr approximately one‐fourth of that in PS. However, the fractional rate (percent of labeled cholesterol esterified per hr) of POFF‐cholesterol esterification was similar to that observed in PS. There was little variation of absolute rate of cholesterol esterification in the fluid obtained from different sizes of follicles. Fatty acid or triacylglycerol did not participate in the reaction of cholesterol esterification in POFF. No appreciable change in enzymatic activity was found from storing POFF at 4 C for periods of time up to 24 hr or at −70 C up to 2 months, but activity was lost thereafter. On the other hand, PS showed a much longer period of stability (5 days at 4 C and 9 months at −70 C). A discrepancy between the fatty acid composition of cholesteryl esters formed by the LCAT reaction and the fatty acid composition at the C‐2 position of phosphatidylcholine led us to propose a two‐step mechanism for the LCAT reaction. It is concluded that the LCAT of POFF, as well as that of plasma, is specific for individual fatty acids rather than for the fatty acid composition of phosphatidylcholine. The fatty acid concentration of lysophosphatidylcholine decreased during prolonged incubation times (6 to 21 hr) suggesting that the increased lysophosphatidylcholine formed as a product of the LCAT reaction may be reused as substrate for the LCAT reaction or for hydrolysis by lysophosphatidylcholine hydrolase.

AbstractThree of six kin were identified, by high performance thin layer chromatography, capillary gas chromatography and mass spectrometry, as having phytanic acid storage disease. Phytanic acid was found in triacylglycerol and, to a lesser degree, in phosphatidylcholine and free fatty acids. An unsaturated analogue of phytanic acid was additionally identified in plasma and erythrocyte triacylglycerols. In plasma, branched chain fatty acids were primarily localized in the low density lipoprotein fraction. The concentration of plasma major fatty acids was not affected by the presence of these branched chain fatty acids. In contrast to plasma, only small amounts of phytanic acid were found in cerebrospinal fluid and biopsied sural nerve. The nerve phytanate was mainly associated with triacylglycerol in epineurial and perineurial tissues. Lack of phytanate accumulation in sural endoneurium, even in cases with severe fiber degeneration, suggests that demyelination in Refsum's disease may not be due to myelin instability resulting from the incorporation of branched chain fatty acids into peripheral nerve membrane.

OBJECTIVE—The aim of this trial was to evaluate the effects of α-lipoic acid (ALA) on positive sensory symptoms and neuropathic deficits in diabetic patients with distal symmetric polyneuropathy (DSP). RESEARCH DESIGN AND METHODS—In this multicenter, randomized, double-blind, placebo-controlled trial, 181 diabetic patients in Russia and Israel received once-daily oral doses of 600 mg (n = 45) (ALA600), 1,200 mg (n = 47) (ALA1200), and 1,800 mg (ALA1800) of ALA (n = 46) or placebo (n = 43) for 5 weeks after a 1-week placebo run-in period. The primary outcome measure was the change from baseline of the Total Symptom Score (TSS), including stabbing pain, burning pain, paresthesia, and asleep numbness of the feet. Secondary end points included individual symptoms of TSS, Neuropathy Symptoms and Change (NSC) score, Neuropathy Impairment Score (NIS), and patients’ global assessment of efficacy. RESULTS—Mean TSS did not differ significantly at baseline among the treatment groups and on average decreased by 4.9 points (51%) in ALA600, 4.5 (48%) in ALA1200, and 4.7 (52%) in ALA1800 compared with 2.9 points (32%) in the placebo group (all P < 0.05 vs. placebo). The corresponding response rates (≥50% reduction in TSS) were 62, 50, 56, and 26%, respectively. Significant improvements favoring all three ALA groups were also noted for stabbing and burning pain, the NSC score, and the patients’ global assessment of efficacy. The NIS was numerically reduced. Safety analysis showed a dose-dependent increase in nausea, vomiting, and vertigo. CONCLUSIONS—Oral treatment with ALA for 5 weeks improved neuropathic symptoms and deficits in patients with DSP. An oral dose of 600 mg once daily appears to provide the optimum risk-to-benefit ratio.

Dopamine-β-hydroxylase activity accumulated above a ligature on biopsy samples of normal human sural nerves incubated in vitro. The rate of accumulation indicated that this enzyme was transported distally at a velocity of 2 millimeters per hour. Axoplasmic transport of dopamine-β-hydroxylase was greatly reduced in sural nerves from a few patients with peripheral neuropathies.

OBJECTIVE—The degree to which chronic glycemic exposure (CGE) (fasting plasma glucose [FPG], HbA1c [A1C], duration of diabetes, age at onset of diabetes, or combinations of these) is associated with or predicts the severity of microvessel complications is unsettled. Specifically, we test whether combinations of components correlate and predict complications better than individual components. RESEARCH DESIGN AND METHODS—Correlations and predictions of CGE and complications were assessed in the Rochester Diabetic Neuropathy Study, a population-based, cross-sectional, and longitudinal epidemiologic survey of 504 patients with diabetes followed for up to 20 years. RESULTS—In multivariate analysis, A1C and duration of diabetes (and to a lesser degree age at onset of diabetes but not FPG) were the main significant CGE risk covariates for complications. A derived glycemic exposure index (GEi) correlated with and predicted complications better than did individual components. Composite or staged measures of polyneuropathy provided higher correlations and better predictions than did dichotomous measures of whether polyneuropathy was present or not. Generally, the mean GEi was significantly higher with increasing stages of severity of complications. CONCLUSIONS—A combination of A1C, duration of diabetes, and age at onset of diabetes (a mathematical index, GEi) correlates significantly with complications and predicts later complications better than single components of CGE. Serial measures of A1C improved the correlations and predictions. For polyneuropathy, continuous or staged measurements performed better than dichotomous judgments. Even with intensive assessment of CGE and complications over long times, only about one-third of the variability of the severity of complications is explained, emphasizing the role of other putative risk covariates.

Background Congenital hyposensitivity to pain or hereditary sensory and autonomic neuropathy represents a variety of disorders characterized by decreased perception of nociception, loss of other modalities of sensation, and variable expression of autonomic dysfunction. Sensory loss, especially that of pain, is associated with self-mutilations that may require frequent operations. Little is known about the safety of anesthesia for these patients. Methods The authors performed a computerized search of the Mayo Clinic medical records database between January 1996 and November 2005 for patients with congenital hyposensitivity to pain and related disorders who underwent general anesthesia. Medical records were reviewed for demographics, anesthetic techniques and agents, use of opioids, and perioperative complications. In addition, the authors conducted a comprehensive review of the literature to summarize the current knowledge regarding anesthesia for patients with congenital hyposensitivity to pain, and compared it with the patients with hyposensitivity to pain identified at the Mayo Clinic. Results The authors identified seven patients with hereditary sensory and autonomic neuropathy II, IV, or V and undefined variants of congenital pain hyposensitivity who generated 17 anesthesia records: 12 for orthopedic operations, 3 for sural nerve biopsies, and 2 for ophthalmologic procedures. In all patients, standard doses of volatile agents were used during anesthesia. Small amounts of opioids were used during the course of eight operations. Most patients experienced mild hypothermia (lowest temperature 34.7 degrees C), and none experienced hyperthermia. All patients were hemodynamically stable during otherwise uneventful anesthesia. During recovery from anesthesia, opioids were given to only one patient, a single dose of 1 mg morphine. Even after major orthopedic operations, the patient did not require additional analgesia. Conclusions The patients with profound congenital hyposensitivity to pain underwent anesthesia without any adverse events. The authors found that despite reduced pain perception, the requirements for volatile anesthetics were within the expected range for population with normal pain perception, but they did not require opioids postoperatively. Intraoperative mild hypothermia was easily managed by adjustment of environmental temperature.

Whether compression nerve injury is due to ischemia, direct mechanical injury, or both remains unsettled. To assess structural changes of nerve during compression, peroneal nerves of rats were compressed at various pressures for different times, and the structural alterations were stopped by simultaneous in situ and perfusion fixation. The structural changes observed during a few minutes of compression cannot be explained by ischemic injury because the pathologic alterations characteristic of ischemia take many hours to develop and in any case are different from the ones found here. The pressure- and time-related structural changes observed in the present study under the cuff were (i) decrease in fascicular area and increase in fiber density due to expression of endoneurial fluid; (ii) compression and expression of axoplasm, sometimes to the point of fiber transection; (iii) lengthening of internodes; and (iv) obscuration of nodes of Ranvier due to cleavage and displacement of myelin and overlapping of nodes by displaced loops of myelin. At the edges of the cuff the changes were (i) increase of fascicular area probably from expressed endoneurial fluid; (ii) widening of nodal gaps, perhaps mainly from translocated axonal fluid; and (iii) disordered structure of axoplasm. We suggest that the process of paranodal demyelination and axonal transection are linked, occur during the act of compression, and are due to shear forces. The initial event is expression of endoneurial fluid, followed by compression and expression of axoplasm and cleavage and displacement of layers of myelin. Conceivably, with prolonged cuff compression ischemic injury might be found to be superimposed on mechanical injury.