Diabetic Neuropathy

Adler AI, Boyko EJ, Ahroni JH, Stensel V, Forsberg RC and Smith DG:Risk factors for diabetic peripheral sensory neuropathy. Diabetes Care 20: 1162-1167, 1997. Authors' abstract: Objective - To identify risk factors for diabetic lower-extremity peripheral sensory neuropathy prospectively in a cohort of U.S. veterans with diabetes. Research Design and Methods - General medicine clinic outpatients were followed prospectively for the development of insensitivity to the 5.07 monofilament on the foot. Results - Of 775 subjects, 388 (50%) had neuropathy at baseline. Of the 387 subjects without neuropathy at baseline, 288 were followed up, and of these, 58 (20%) developed neuropathy. Multivariate logistic regression modeling of prevalent neuropathy controlling for sex and race revealed independent and significant associations with age, duration of diabetes, glycohemoglobin level, height, history of lower extremity ulceration, callus and edema; an independent and inverse correlation was noted with ankle-arm index. Risk factors for incident neuropathy in multivariate logistic regression included age, baseline glycohemoglobin level, height, history of ulcer, and CAGE screening instrument alcohol score; current smoking and albumin level were inversely associated with risk. Conclusions - Poorer glycemic control increases the risk of neuropathy and is amenable to intervention. Height and age directly increase the risk of neuropathy and may help identify patients at risk. A proportion of neuropathy in diabetic veterans is probably due to or worsened by alcohol ingestion. Neuropathy was less common in current smokers than subjects not currently smoking. Comments: "CAGE" is the acronym for cut down, annoyed by criticism, guilty about drinking and eye-opener drinks (Ewing JA: Detecting alcoholism: the CAGE questionnaire. JAMA 252: 1905-1907, 1984). The authors hypothesized that more healthy smokers continued smoking while the less healthy stopped. While the glycohemoglobin levels differed significantly between the neuropathy (11.6%) and non-neuropathy group (10.9%), both were high. One wonders if these patients would have fared better if they were followed in a diabetes specialty clinic rather than a general medical clinic.
Adriaensen H, Plaghki L, Mathieu C, Joffroy A, Vissers K: Critical review of oral drug treatments for diabetic neuropathic pain-clinical outcomes based on efficacy and safety data from placebo-controlled and direct comparative studies. Diabetes Metab Res Rev. 21:231-40, 2005. The present review aims to evaluate the efficacy and safety of a selection of oral treatments for the management of painful diabetic neuropathy. A literature review was conducted retrieving placebo-controlled and direct comparative studies with a selection of oral treatments for painful diabetic neuropathy. All studies were analyzed with regard to efficacy and tolerability. Efficacy was evaluated as the percentage improvement in pain intensity between baseline and endpoint. Tolerability was evaluated by means of study discontinuations due to adverse events and by incidence of drug-related adverse events.The analyzed trials enrolled different patient populations with mostly small numbers of patients. The great variability in dosages and dose titration schemes, cross-over designs with variable wash-out periods, and other design schemes made comparison between the different studies difficult. Gabapentin, lamotrigine, tramadol, oxycodone, mexiletine, and acetyl-L-carnitine were the only treatments studied in large (at least 100 patients), placebo-controlled parallel group trials.It is concluded that standardization in design and reporting for comparison of treatments is needed. Validated questionnaires for evaluation of the efficacy and safety should be further developed. Based on the reviewed randomised controlled trials, gabapentin shows good efficacy, a favourable side-effect profile with lack of drug interactions and therefore it may be a first choice treatment in painful diabetic neuropathy, especially in the elderly. However, head to head trials of current treatments are lacking and therefore randomized controlled trials are required to address this issue.
Ambrosch A, Dierkes J, Lobmann R et al: Relation between homocysteinaemia and diabetic neuropathy in patients with Type 2 diabetes mellitus. Diabet Med 18: 185-92, 2001. AIMS: Limited data are available on determinants of diabetic neuropathy as its pathogenesis is multifactorial. Since homocysteine exhibits toxic effects on vascular endothelial cells, the association between homocysteine and the prevalence of neuropathy in Type 2 diabetes mellitus was investigated. METHODS: A total of 65 Type 2 diabetic patients were consecutively enrolled into the study. Neuropathy was diagnosed according to clinical symptoms, clinical examination, electrophysiological sensory testing and autonomic function testing. With regard to homocysteine-related parameters, plasma homocysteine, folate, vitamin B12, vitamin B6 and renal function (creatinine, ceratinine clearance, cystatin C) were measured, and the C677T polymorphism of the methylenetetrahydrofolate reductase gene was determined. RESULTS: Forty-three of the Type 2 diabetic patients were classified as suffering from neuropathy. Both patient groups were comparable with regard to demographic data, blood pressure, glucose metabolism, renal function and homocysteine-related vitamins. In contrast, homocysteine levels (P = 0.04) and the frequency of hyperhomocysteinemia (>or= 15 micromol/l) (P = 0.01) were significantly increased in neuropathic patients. In a logistic regression model with neuropathy as dependent variable, homocysteine (adjusted for creatinine, homocysteine-related vitamins, HbA1c and duration of diabetes) was the only significant variable associated with the prevalence of neuropathy (odds ratio for homocysteine per 5 micromol/l increase: 2.60 (95% confidence interval 1.07-6.33)). CONCLUSION: The data indicate that homocysteine is independently associated with the prevalence of diabetic neuropathy in a collective of Type 2 diabetic patients. A larger, prospective study would be desirable to clarify the role of homocysteine in the pathogenesis of diabetic neuropathy.
Armstrong DG, Lavery LA, Vazquez JR, Short B, Kimbriel HR, Nixon BP, Boulton AJ: Clinical efficacy of the first metatarsophalangeal joint arthroplasty as a curative procedure for hallux interphalangeal joint wounds in patients with diabetes. Diabetes Care 26:3284-7, 2003. OBJECTIVE: To evaluate the safety and efficacy of first metatarsophalangeal joint arthroplasty compared with standard, nonsurgical management of wounds at the plantar hallux interphalangeal joint in patients with diabetes. RESEARCH DESIGN AND METHODS: We evaluated 41 patients with ulcers classified as University of Texas Grade 1A or 2A at the plantar aspect of the first metatarsophalangeal joint using a case-control model. Case subjects were patients treated with resectional arthroplasty and control subjects received standard nonsurgical care. Both groups received standard off-loading and wound care. Outcomes included time to healing, reulceration, infection, and amputation. RESULTS: The surgery group healed significantly faster than patients in the standard therapy group (standard 67.1 +/- 17.1 versus surgery 24.2 +/- 9.9 days, P = 0.0001), and they had fewer recurrent ulcers (standard 35.0 versus surgery 4.8%, P = 0.02, odds ratio 7.6, 95% CI 1.1-261.7) Both groups had similar rates of infection (standard 38.1 versus surgery 40.0%, P = 0.9) and amputation (standard 10.0 versus surgery 4.8%, P = 0.5). CONCLUSIONS: Results suggest that resectional arthroplasty is a safe and effective procedure to treat wounds of the plantar hallux compared with nonsurgical therapy. Comments: One always worries about healing, infection and long term benefit after surgery on a diabetic foot, especially one with neuropathy. This was a retrospective case record study in patients without significant vascular disease or infection. The control and surgery patients were quite similar except for slightly better glycemic control in the surgical group (GHb% 7.9+/-1.4 vs 8.4+/-1.2). Such patients generally heal their ulcers with offloading and time. Surgical patients, of course, commonly enjoy a few days in the hospital off their feet and tend to restrict ambulation after their surgery more than nonsurgical patients. The surgeons doing the procedures do not tell us why they chose some patients to operate on and not others. Obviously, a prospective study with a sham-surgery control group would be desirable.
Arnal JF, Dinh-Xuan AT, Pueyo M, Darblade B, Rami J: Endothelium-derived nitric oxide and vascular physiology and pathology. Cell Mol Life Sci 55:1078-87, 1999. In 1980, Furchgott and Zawadzki demonstrated that the relaxation of vascular smooth muscle cells in response to acetylcholine is dependent on the anatomical integrity of the endothelium. Endothelium-derived relaxing factor was identified 7 years later as the free radical gas nitric oxide (NO). In endothelium, the amino acid L-arginine is converted to L-citrulline and NO by one of the three NO synthases, the endothelial isoform (eNOS). Shear stress and cell proliferation appear to be, quantitatively, the two major regulatory factors of eNOS gene expression. However, eNOS seems to be mainly regulated by modulation of its activity. Stimulation of specific receptors to various agonists (e.g., bradykinin, serotonin, adenosine, ADP/ATP, histamine, thrombin) increases eNOS enzymatic activity at least in part through an increase in intracellular free Ca2+. However, the mechanical stimulus shear stress appears again to be the major stimulus of eNOS activity, although the precise mechanisms activating the enzyme remain to be elucidated. Phosphorylation and subcellular translocation (from plasmalemmal caveolae to the cytoskeleton or cytosol) are probably involved in these regulations. Although eNOS plays a major vasodilatory role in the control of vasomotion, it has not so far been demonstrated that a defect in endothelial NO production could be responsible for high blood pressure in humans. In contrast, a defect in endothelium-dependent vasodilation is known to be promoted by several risk factors (e.g., smoking, diabetes, hypercholesterolemia) and is also the consequence of atheroma (fatty streak infiltration of the neointima). Several mechanisms probably contribute to this decrease in NO bioavailability. Finally, a defect in NO generation contributes to the pathophysiology of pulmonary hypertension. Elucidation of the mechanisms of eNOS enzyme activity and NO bioavailability will contribute to our understanding the physiology of vasomotion and the pathophysiology of endothelial dysfunction, and could provide insights for new therapies, particularly in hypertension and atherosclerosis. Comments: This article summarizes the relationship of acetylcholine to nitric oxide and vasomotion. Mechanical shear stress is said to be a major stimulus of eNOS activity. Does treatment with the Circulator Boot produce such shear stress? Many investigators are busy in this field and bring us new insights. Both acute and chronic hyperglycemia and not oxidation of LDL is associated with a defect in endothelium-dependent vasodilation ( Makimattila S et al, Atherosclerosis 147:115-122, 1999)(Akbari CM et al: J Vasc Surg 28:687-94, 1998). The ACE inhibitor enalapril has been shown to improve stimulated and basal NO-dependent endothelial function (O'Driscoll G et al . J Am Coll Cardiol 33:1506-11, 1999). Iontophoresis is commonly used to introduce acetylcholine into the tissues in many studies. It is commonly assumed that an effective concentration of acetylchline is produced and that it is maintained. Various factors can obviously affect such studies, however (thickness of the skin, degradation of the acetylcholine or uptake of the acetylcholine by nerve endings). Arora et al found the vasodilatory response, which is related to the C nociceptive fiber action, is reduced at the foot level during iontophoresis of acetylcholine in the neuropathic patients. In healthy subjects, they found the endothelial-dependent and endothelial-independent vasodilatation was lower at the foot level when compared to the forearm, and thought that a generalized impairment of the microcirculation in diabetic patients with neuropathy preserved this forearm-foot gradient. They suggest that these changes may be a contributing factor for the early involvement of the foot with neuropathy when compared to the forearm (Arora S et al: Diabetes Care 21:1339-44, 1998). In diabetic rats, Terata et al report a cyclic pathological relationship: endoneural blood flow and acetylcholine-induced dilation are reduced... the reductions being associated with neural dysfunction which, in turn, might further reduce endothelial-dependent vasodilatation (Br J Pharmacol 128:837-843. 1999). Kinlay et al found that plasma alpha-tocopherol was significantly correlated with the acetylcholine response (r=0.49, P<0.05) in preserving endothelial vasomotor function in patients with coronary atherosclerosis, perhaps due primarily to the action of alpha-tocopherol in the vascular wall (Circulation 100:219-21, 1999). While much of the recent data makes sense to this reviewer, the paper of Forst T et al is somewhat confusing in that they differentiate between total, subpapillary and nutritive capillary blood flow in their studies with subcutaneous acetylcholine. They found an impaired neurovascular response in neuropathic diabetics that they attributed to a diminished total and subpapillary blood flow and not to a diminished nutritive capillary flow (Clin Sci (Colch) 94: 255-61, 1998).
Aronstan BR and Carrier GO: Insulin prevention of altered muscarinic receptor-G protein coupling in diabetic rat atria. Diabetes 38:1611-16, 1989. Insulin therapy normalizes the supersensitivity to negative chronotropic effects of muscarinic agonist and decreases the number of muscarinic receptors and the acetycholinesterase activity found in diabetic rats.
Aszmann OC, Dellon AL: Relationship between cutaneous pressure threshold and two-point discrimination. J Reconstr Microsurg 14(6):417-21, 1998. The amount of pressure that should be applied when doing the two-point discrimination test has always been a matter of controversy. The Pressure-specified Sensory Devices permits recording the pressure at which two-point discrimination (2 PD) occurs. The purpose of this study was to investigate the relationship between the cutaneous pressure threshold and 2PD in people with normal and abnormal peripheral nerve functions. The Pressure-specified Sensory Devices was used to quantify the cutaneous pressure threshold in the index-finger pulp in each individual, between the range of 2 mm and 8 mm of static 2 PD, using 1-mm intervals. Twenty normal controls were examined; ten patients were less than 45 years of age; and ten patients were greater than 45 years of age. This relationship of pressure to 2PD was also tested in eight patients with abnormal peripheral nerve function (four patients with carpal tunnel syndrome, and four patients with diabetic neuropathy). A curvilinear relationship was identified in which, for the same skin surface in the same individual, regardless of age or presence of nerve compression or neuropathy, the cutaneous pressure threshold was inversely related to static 2PD. This curve shifted upward and to the right with the increasing age of the normal population and with neurologic impairment. The awareness of this neurophysiologic relationship between 2PD and pressure threshold permits the design of strategies for sensibility testing and provides a basis for the interpretation of sensory test results.
Aszmann OC, Kress KM, Dellon AL: Results of decompression of peripheral nerves in diabetics: a prospective, blinded study. Plast Reconstr Surg 106(4):816-22, 2000.Diabetic neuropathy traditionally is considered progressive and irreversible and will result in lower extremity ulceration and amputation in a segment of the diabetic population, despite the best efforts to control serum glucose levels. Restoration of sensation to the diabetic may prevent these complications of neuropathy. The present study was designed to evaluate whether decompression of a peripheral nerve at a known site of anatomic narrowing can restore sensibility to that nerve in the diabetic. Twenty diabetic patients ( 14 type I, 6 type II, with a mean duration of diabetes of 14.8 years) had surgical decompression of a median nerve at the wrist and an ulnar nerve at the elbow, or a decompression of the posterior tibial nerve at the ankle (total of 31 nerves). A therapist, in a manner blind to the operative site, evaluated two-point discrimination in the pulp of the appropriate digit. The postoperative sensibility was compared with that of the nontreated, contralateral extremity. At a mean of 23.3 months, 69 percent of the lower-extremity nerves and 88 percent of the upper-extremity nerves (79 percent overall) had improvement in sensibility. In comparison, 32 percent of the control (not decompressed) contralateral nerves had measurable progression of neuropathy. The hypothesis that decompression of a peripheral nerve in the diabetic will improve sensibility was confirmed at the p < 0.001 level. Comments: Could entrapment be part of the diabetic syndrome? Obesity certainly is and obesity promotes joint and ligamentous deformities. Further tendons and ligaments do become glycosylated with chronic hyperglycemia, thus increasing their volume and the possibility of crowding in narrow tight areas.
Barber MA, Conolley J, Spaulding CM, Dellon AL: Evaluation of pressure threshold prior to foot ulceration: one-versus two-point static touch. J Am Podiatr Med Assoc 91(10):508-14, 2001. A prospective study of 29 patients with diabetic neuropathy and 47 nondiabetic patients with tarsal tunnel syndrome were evaluated with computer-assisted neurosensory testing at three sites on the foot. The sensitivity and specificity of one-point static touch thresholds for identifying the presence of large fiber axonal loss was done using the calculated thresholds for monofilaments derived from their markings. The sensitivity for one-point static touch in identifying axonal loss was 33% for the 5.07, 38% for the 4.93, 50% for the 4.17, and 60% for the 4.08 monofilament-equivalent, with a specificity of 100% at each level. Therefore, one-point static touch testing, even using monofilaments thinner than 5.07, has a high percentage of false-negative results in identifying patients
Bril V, Buchanan RA: Long-term effects of ranirestat (AS-3201) on peripheral nerve function in patients with diabetic sensorimotor polyneuropathy. Diabetes Care 29:68-72, 2006. OBJECTIVES: We aimed to determine whether ranirestat, an aldose reductase inhibitor, maintains the improved nerve function observed in patients with diabetic sensorimotor polyneuropathy (DSP) after completing a 12-week nerve biopsy study. RESEARCH DESIGN AND METHODS: Patients with mild to moderate DSP, as determined by the presence of sural nerve responses, were enrolled in a double-blind, placebo-controlled biopsy trial and randomized to placebo or 5 or 20 mg/day ranirestat for 12 weeks. Patients completing this biopsy study were offered a 48-week extension at the same ranirestat dose or at 5 mg/day ranirestat if they were originally treated with placebo. Electrophysiological tests, the Toronto Clinical Neuropathy Score, and vibration perception thresholds (VPTs) were performed at entry and at 12 (end of the biopsy study) and 60 (end of the 48-week extension) weeks. RESULTS: Peroneal motor nerve conduction velocity (NCV) improved in the 20-mg/day group following 60 weeks of treatment. Sural and median sensory NCV improved after both 12 and 60 weeks of treatment with 20 mg/day. VPT improved after 60 weeks of treatment with 20 mg/day. Ranirestat was well tolerated with no difference in adverse events between the 5- and 20-mg/day groups. CONCLUSIONS: Twenty milligrams ranirestat per day improves NCV and VPT following 60 weeks of administration. The improved sensory nerve function observed after 12 weeks of therapy was maintained at 60 weeks, and improved motor nerve function was observed at 60 weeks.
Bus SA, Yang QX, Wang JH, Smith MB, Wunderlich R, Cavanagh PR: Intrinsic muscle atrophy and toe deformity in the diabetic neuropathic foot: a magnetic resonance imaging study. Diabetes Care 25:1444-50, 2002. OBJECTIVE: The objectives of this study were to compare intrinsic foot muscle cross-sectional area (CSA) in patients with diabetic polyneuropathy and nondiabetic control subjects and to examine the association between intrinsic muscle CSA and clawing/hammering of the toes in neuropathic feet. RESEARCH DESIGN AND METHODS: High-resolution T2-weighted fast spin-echo images and parametric T2 multiple spin-echo images were acquired using multiple spin-echo magnetic resonance imaging (MRI) of frontal plane sections of the metatarsal region of the foot in a sample of eight individuals with diabetic polyneuropathy and eight age- and sex-matched nonneuropathic nondiabetic control subjects. The configuration of joints of the second toe was obtained using a three-dimensional contact digitizer. RESULTS: Remarkable atrophy was found in all the intrinsic muscles of neuropathic subjects as compared with nondiabetic control subjects. Quantitative T2 analysis showed a 73% decrease in muscle tissue CSA distally in the neuropathic subjects. Muscle comprised only 8.3 +/- 2.9% (means +/- SD) of total foot CSA compared with 30.8 +/- 3.9% in control subjects. No significant differences were found between the groups in the metatarso-phalangeal and proximal and distal interphalangeal joint angles of the second ray. Moreover, clawing/hammering of the toes was found in only two of eight neuropathic subjects. CONCLUSIONS: Although sensory neuropathy is often emphasized in considerations of diabetic foot pathology, our results show that the consequences of motor neuropathy in the feet are profound in people with diabetes. This has implications for foot function and may play a significant role in postural instability. However, intrinsic muscle atrophy does not necessarily appear to imply toe deformity.
Bus SA, Maas M, Cavanagh PR, Michels RP, Levi M: Plantar fat-pad displacement in neuropathic diabetic patients with toe deformity: a magnetic resonance imaging study. Diabetes Care 27:2376-81, 2004. OBJECTIVE: The aim of this study was to quantify the association between claw/hammer toe deformity and changes in submetatarsal head (sub-MTH) fat-pad geometry in diabetic neuropathic feet. RESEARCH DESIGN AND METHODS: Thirteen neuropathic diabetic subjects (mean age 56.2 years) with toe deformity, 13 age- and sex-matched neuropathic diabetic control subjects without deformity, and 13 age- and sex-matched healthy control subjects without deformity were examined. From high-resolution sagittal plane magnetic resonance images of the second and third ray of the foot, toe angle (a measure of deformity), sub-MTH fat-pad thickness, and subphalangeal fat-pad thickness were measured. The ratio of these thicknesses was used to indicate fat-pad displacement. RESULTS: Sub-MTH fat pads were significantly thinner (2.5 +/- 1.3 vs. 6.0 +/- 1.4 mm, P < 0.001) and subphalangeal fat pads significantly thicker (9.1 +/- 1.9 vs. 7.6 +/- 1.2 mm, P < 0.005) in the neuropathic group with deformity compared with neuropathic control subjects. As a result, thickness ratio was substantially smaller in the deformity group: 0.28 +/- 0.14 vs. 0.79 +/- 0.14 in neuropathic control subjects (P < 0.001). A significant correlation of 0.85 was present between toe angle and thickness ratio (P < 0.001). No significant differences were found between neuropathic and healthy control subjects. CONCLUSIONS: This study shows a distal displacement and subsequent thinning of the sub-MTH fat pads in neuropathic diabetic patients with toe deformity and suggests that, as a result, the capacity of the tissue in this region to reduce focal plantar pressure is severely compromised. This condition is likely to increase the risk of plantar ulceration in these patients. Comments: Here marked dorsiflexion of the neuropathic toes is shown to be associated with thinning of the fat pad under the MP joints. Forcibly dorsiflexing normal toes will pull the plantar fat pad against the MP joint likewise seeming to thin it. Ulcers under such joints may be hard to heal. We have found that tenotomy (cutting the dorsal tendons to the toes) may allow the toes to fall to a normal position, restore tissue mass under the MP joint and allow recalcitrant ulcers to heal with our boot therapy. See case 87.
Cameron NE, Eaton SE, Cotter MA, Tesfaye S: Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy. Diabetologia 2001 Nov;44(11):1973-88, 2001. Diabetes mellitus is a major cause of peripheral neuropathy, commonly manifested as distal symmetrical polyneuropathy. This review examines evidence for the importance of vascular factors and their metabolic substrate from human and animal studies. Diabetic neuropathy is associated with risk factors for macrovascular disease and with other microvascular complications such as poor metabolic control, dyslipidaemia, body mass index, smoking, microalbuminuria and retinopathy. Studies in human and animal models have shown reduced nerve perfusion and endoneurial hypoxia. Investigations on biopsy material from patients with mild to severe neuropathy show graded structural changes in nerve microvasculature including basement membrane thickening, pericyte degeneration and endothelial cell hyperplasia. Arterio-venous shunting also contributes to reduced endoneurial perfusion. These vascular changes strongly correlate with clinical defects and nerve pathology. Vasodilator treatment in patients and animals improves nerve function. Early vasa nervorum functional changes are caused by the metabolic insults of diabetes, the balance between vasodilation and vasoconstriction is altered. Vascular endothelium is particularly vulnerable, with deficits in the major endothelial vasodilators, nitric oxide, endothelium-derived hyperpolarising factor and prostacyclin. Hyperglycaemia and dyslipidaemia driven oxidative stress is a major contributor, enhanced by advanced glycation end product formation and polyol pathway activation. These are coupled to protein kinase C activation and omega-6 essential fatty acid dysmetabolism. Together, this complex of interacting metabolic factors accounts for endothelial dysfunction, reduced nerve perfusion and function. Thus, the evidence emphasises the importance of vascular dysfunction, driven by metabolic change, as a cause of diabetic neuropathy, and highlights potential therapeutic approaches.
Carrington AL, Shaw JE, Van Schie CH, Abbott CA, Vileikyte L, Boulton AJ: Can motor nerve conduction velocity predict foot problems in diabetic subjects over a 6-year outcome period? Diabetes Care 25:2010-5, 2002. OBJECTIVE: This study examined motor nerve conduction velocity (MNCV) and other peripheral nerve and vascular tests as predictors for foot ulceration, amputation, and mortality in diabetes over a 6-year follow-up period. RESEARCH DESIGN AND METHODS: We recruited 169 diabetic subjects (without significant peripheral vascular disease with an ankle brachial pressure index [ABPI] >/=0.75) for the study and separated them into groups (to ensure diversity of nerve function). The control group consisted of 22 nondiabetic people. At baseline, all subjects underwent assessment of MNCV; vibration, pressure, and temperature perception thresholds; peripheral vascular function; and other diabetes assessments. RESULTS: Over the 6-year outcome period, 37.3% of the diabetic subjects developed at least one new ulcer, 11.2% had a lower-limb amputation (LLA) (minor or major), and 18.3% died. Using multivariate Cox's regression analysis (RR [95% CI] and removing previous ulcers as a confounding variable, MNCV was found to be the best predictor of new ulceration (0.90 [0.84-0.96], P = 0.001) and the best predictors of amputation were pressure perception threshold (PPT) (5.18 [1.96-13.68], P = 0.001) and medial arterial calcification (2.88 [1.13-7.35], P = 0.027). Creatinine (1.01 [1.00-1.01], P < 0.001), MNCV (0.84 [0.73-0.97], P = 0.016), and skin oxygen levels (14.32 [3.04-67.52], P = 0.001) were the best predictors of mortality. CONCLUSIONS: This study shows that MNCV, which is often assessed in clinical trials of neuropathy, can predict foot ulceration and death in diabetes. In addition, tests of PPT and medial arterial calcification can be used in the clinic to predict LLA in diabetic subjects.
Chew J T-H, Tan S-B, Sivathasan C, Pavanni R and Tan S-K: Vascular assessment in the neuropathic diabetic foot. Clin Orthopaedics and Related Research. Number 320:95-100, 1995. 12 age 36.1+/-1.975 years type 1 diabetics with peripheral neuropathy and history of surgery for foot infections studied. Doppler velocities from popliteal to big toes same as controls but triphasic flow lost and replaced by monophasic flow with prolonged diastolic flow at level of dorsalis pedis and posterior tibial arteries and distally. Pulsatile index (peak to peak height/mean velocity) reduced from 9.85 +/-4.2 (normals) to 3.14+/-0.81. Toe pressures reduced from 98.23+/-10.12 to 64.17+/-20.87. Linear correlation between degree of neuropathy and decrease in toe pressure (r=0.7). Popliteal arterial velocity same in diabetics and controls (0.742+/-0.124 M/s vs 0.63+/-0.112). At level of the hallus velocity 0.2+/-0.017 vs 0.19+/-0.01).
Coppey LJ, Davidson EP, Dunlap JA, Lund DD, Yorek MA: Slowing of motor nerve conduction velocity in streptozotocin-induced diabetic rats is preceded by impaired vasodilation in arterioles that overlie the sciatic nerve. Int J Exp Diabetes Res 1(2):131-43, 2000. Diabetes mellitus produces marked abnormalities in motor nerve conduction, but the mechanism is not clear. In the present study we hypothesized that in the streptozotocin (STZ)-induced diabetic rat impaired vasodilator function in arterioles that provide circulation to the region of the sciatic nerve is associated with reduced endoneural blood flow (EBF) and that these defects precede slowing of motor nerve conduction velocity, and thereby may contribute to nerve dysfunction. As early as three days after the induction of diabetes endoneural blood flow was reduced in the STZ-induced diabetic rat. Furthermore, after 1 week of diabetes acetylcholine-induced vasodilation was found to be impaired. This was accompanied by an increase in the superoxide level in arterioles that provide circulation to the region of the sciatic nerve as well as changes in the level of other markers of oxidative stress including an increase in serum levels of thiobarbituric acid reactive substances and a decrease in lens glutathione level. In contrast to the vascular related changes that occur within 1 week of diabetes, motor nerve conduction velocity and sciatic nerve Na+/K+ ATPase activity were significantly reduced following 2 and 4 weeks of diabetes, respectively. These studies demonstrate that changes in vascular function in the STZ-induced diabetic rat precede the slowing of motor nerve conduction velocity (MNCV) and are accompanied by an increase in superoxide levels in arterioles that provide circulation to the region of the sciatic nerve.
D'Ambrogi E, Giurato L, D'Agostino MA, Giacomozzi C, Macellari V, Caselli A, Uccioli L: Contribution of plantar fascia to the increased forefoot pressures in diabetic patients. Diabetes Care 26:1525-9, 2003. OBJECTIVES: Secondary to peripheral neuropathy, plantar hyperpressure is a proven risk factor for foot ulceration. But limited joint mobility (LJM) and soft tissue abnormalities may also contribute. The aim of this study was to evaluate the relationships among thickness of plantar fascia, mobility of the metatarso-phalangeal joint, and forces expressed under the metatarsal heads. RESEARCH DESIGN AND METHODS: We evaluated 61 diabetic patients: 27 without neuropathy (D group), 19 with neuropathy (DN group), and 15 with previous neuropathic foot ulceration (DNPU group). We also examined 21 control subjects (C). Ultrasound evaluation was performed with a high resolution 8- to 10-MHz linear array (Toshiba Tosbee SSA 240). The foot loading pattern was evaluated with a piezo-dynamometric platform. First metatarso-phalangeal joint mobility was assessed with a mechanic goniometer. RESULTS: Diabetic patients presented increased thickness of plantar fascia (D 2.9 +/- 1.2 mm, DN 3.0 +/- 0.8 mm, DNPU 3.1 +/- 1.0 mm, and C 2.0 +/- 0.5.mm; P < 0.05), and significantly reduced motion range at the metatarso-phalangeal joint (D 54.0 +/- 29.4 degrees, DN 54.9 +/- 17.2 degrees, DNPU 46.8 +/- 20.7 degrees, and C 100.0 +/- 10.0 degrees; P < 0.05). The evaluation of foot-floor interaction under the metatarsal heads showed increased vertical forces in DN and DNPU and increased medio-lateral forces in DNPU. An inverse correlation was found between the thickness of plantar fascia and metatarso-phalangeal joint mobility (r = -0.53). The thickness of plantar fascia was directly correlated with vertical forces under the metatarsal heads (r = 0.52). CONCLUSIONS: In diabetic patients, soft tissue involvement may contribute to the increase of vertical forces under the metatarsal heads. Changes in the structure of plantar fascia may also influence the mobility of the first metatarso-phalangeal joint. Comments: Here the plantar fascia and below the Achilles tendon (Grant et al)
Davis MT and Greene NM: Polarographic studies of skin oxygen tension following sympathetic denervation. J Appl Physiol 14:961-965, 1959. Sympathectomy decreases skin PO2 levels as AV shunts open...Comment: Hardly a desirable effect and good reason to avoid the procedure.

Dillon RS: Role of cholinergic nervous system in healing neuropathic lesions: preliminary studies and prospective, double-blinded placebo-controlled studies. Angiology 42: 767-778, 1991. (Also presented at the American Diabetes Association Meetings: Diabetes 40(suppl 1):388A, 1991.) Angiology abstract: The amplitudes of photo-electric-plethysmography (PPG) tracings were significantly increased by subcutaneous injections of methacholine (MC) and diminished by injections of atropine (AT) as compared with placebo injections of multi-electrolyte solution (MES) both in 8 normal subjects and 11 patients with diabetic peripheral neuropathy. AT-containing lotion delayed healing compared with placebo in the forearms of 6 normal subjects. MC-containing lotion sped healing compared with placebo in the forearms of 6 subjects with diabetic neuropathy. Thigh incisions in 6 neuropathic patients were shown to heal faster if soaked in MES rather than saline. Healing with the MES solution was shown to be further increased by the addition of MC to the solution and to be decreased by the addition of AT. The addition of MC produced erythema and an increase in the amplitude of PPG tracings. AT solutions produced blanching and a decrease in the PPG amplitude. It was concluded that (1) the slow healing characteristic of neuropathic ulcers is associated with a loss of cholinergic nerve function; (2) cholinergic stimulation will increase capillary blood flow and promote healing while cholinergic blockade has opposite effects; (3) secondary ischemia makes the ulcers susceptible to the deleterious effects of therapeutic agents such as saline; (4) the ischemic tissue will heal faster with a balanced MES than with saline; and (5) the benefits of MES on healing are augmented in patients with diabetic neuropathy by the addition of cholinergic agents to the solution. Comments: This paper explains Dr. Dillon's explanation as to why neuropathic lesions are slow to heal even with appropriate rest and protection. The ideas are best summarized in the following drawings:

In the normal foot, regulators of cutaneous blood flow include both the sympathetic and cholinergic nervous systems. Normal sympathetic tone minimizes flow through A-V shunts while decreased sympathetic tone as occurs with overheating, sympatholytic drugs or sympathectomy opens the shunt delivering arterial blood to the venous side and bypassing the nutrient vessels. Postganglionic cholinergic fibers may release acetylcholine resulting in a release of nitric oxide and an increase in flow in the nutrient vessels thus delivering leukocytes, platelets, antibiotics and growth factors.

In the diabetic neuropathic foot, decreased sympathetic tone results in an open A-V shunt and occasionally a warm pink foot. Increased flow rates are perhaps causally related to the commonly associated medial calcinosis of the arteries; kinks in the calcified vessel occasionally results in obstruction and decreased flow. A loss of cholinergic tone results in a decrease in sweating, dry skin and a decrease in flow through the nutrient vessels; in the presence of injury or infection, blood flow does not appropriately increase, and leukocytes, platelets, growth factors, antibiotics etc. are deficient. Essentially, the body behaves as if it did not know the lesion was there.

The legs of Patient "RM" are illustrative of the findings in the study. When this study was over, cup #1 was found to have had saline; #2, Sea Soaks and atropine; #3, Sea Soaks and methacholine; and #4, Sea Soaks alone. Here at 24 hours, healing was fastest in #3 and #4. Perhaps seen here and below, as in most patients, the skin color with Sea Soaks (left top) remained unchanged, with metahcholine (right top) became pink, with atropine (bottom left) became pale and with saline (right bottom) became inflamed.

After ten days, all of the lesions were healed. PPG arterial flow curves are shown above and below each lesion. #1 (saline) had healed last and remained red and inflamed; a reactive hyperemia was seen. #2 (atropine) was the third to heal and had regained its color and baseline PPG flow. #3 (methacholine) was second healed in this study. Its rubor had largely faded now but the PPG flow remained increased. The skin around the cup with Sea Soaks (left top) had some pigment from tape, but the lesion was close to invisible and the skin within the cup remained the color of the skin a few inches away from the taped area and, finally, the PPG flow was back to or below baseline.

Comments: As seen in the section on vascular hormones, there are other factors that also regulate skin blood flow. There we learn that pumping on the leg may increase nitrous oxide and prostacyclin, both increasing tissue blood flow. In Dr. Dillon's Angiology paper, one learns that perhaps because of the vasodilating effect of cholinergic agents, their application may increase the rate of wound healing. Hence, they may be added to the multi-electrolyte solutions used in the Mini-Boot systems. A beneficial effect of cholinergic agents on wound healing has also been documented in work done at Dr. Cooke's laboratory at Stanford. At the June 2002 Meetings of the Society for Vascular Medicine and Biology in Boston, their group reported an endogenous cholinergic pathway for angiogenesis mediated by endothelial nicotinic cholinergic receptors and found that stimulation of the receptor accelerated wound healing in diabetic mice. Other references relating to the importance of the cholinergic system in blood flow include: Zhu BQ, Heeschen C, Sievers RE, Karliner JS, Parmley WW, Glantz SA, Cooke JP: Second hand smoke stimulates tumor angiogenesis and growth. Cancer Cell 4(3):191-6, 2003; Rodriguez-Manas L, Lopez-Doriga P, Petidier R, et al: Effect of glycaemic control on the vascular nitric oxide system in patients with type 1 diabetes. J Hypertens. 21:1137-43, 2003; Mahajan H, Richards SM, Rattigan S, Clark MG: Local methacholine but not bradykinin potentiates insulin-mediated glucose uptake in muscle in vivo by augmenting capillary recruitment. Diabetologia. 47:2226-34, 2004.) and Thengchaisri N, Rivers RJ: Remote arteriolar dilations caused by methacholine: a role for CGRP sensory nerves? Am J Physiol Heart Circ Physiol. 289:H608-13, 2005.

Ellenberg M: Diabetic neuropathic ulcer. J Mt Sinai Hosp NY 3:585-594, 1968.. Neuropathic ulcers not unique to diabetes; patients with myelodysplasia, old spinal cord injuries, syringomyelia, tabes, leprosy and hereditary sensory syndromes develop such ulcers.
Finegold D et al: Polyol pathway activity and myo-inositol metabolism: a suggested relationship in the pathogenesis of diabetic neuropathy. Diabetes 32:988, 1983.
Freeman R.: Autonomic peripheral neuropathy. Lancet 365(9466):1259-70, 2005. The autonomic neuropathies are a group of disorders in which the small, lightly myelinated and unmyelinated autonomic nerve fibres are selectively targeted. Autonomic features, which involve the cardiovascular, gastrointestinal, urogenital, sudomotor, and pupillomotor systems, occur in varying combination in these disorders. Diabetes is the most common cause of autonomic neuropathy in more developed countries. Autonomic neuropathies can also occur as a result of amyloid deposition, after acute infection, as part of a paraneoplastic syndrome, and after exposure to neurotoxins including therapeutic drugs. Certain antibodies (eg, anti-Hu and those directed against neuronal nicotinic acetylcholine receptor) are associated with autonomic signs and symptoms. There are several familial autonomic neuropathies with autosomal dominant, autosomal recessive, or X-linked patterns of inheritance. Autonomic dysfunction can occur in association with specific infections. The availability of sensitive and reproducible measures of autonomic function has improved physicians' ability to diagnose these disorders. This article is included to remind the clinician that in the diabetic with autonomic neuropathy and well-controlled diabetes, there are other causes of the neuropathy besides the diabetes.
Gaylarde PM et al: Transcutneous oxygen tension in legs and feet of diabetic patients. Diabetes 37:714-716, 1988. With an oxygen electrode at 37 degrees, the PO2 was increased in the legs and feet of neuropathic patients. Normal subjects, unlike neuropathic patients, had higher PO2's in the legs than the feet. With the electrode at 45 degrees, patients dilated less. Authors conclude that an inability to vasodilate, here with the stress of heat, may contribute to the formation of neuropathic ulcers.
Gilmore JE, Allen JA and Hayes JR: Autonomic function in neuropathic diabetic patients with foot ulceration. Diabetes Care 16:61-67, 1963. Vasoconstrictor response to deep breathing in diabetic ulcer patients significantly smaller than in normal diabetic patients (15.3+/-2.7 vs 38+/14%). Response to body cooling likewise significantly smaller 6.27+/-3.1 vs 20.8+/-3.5%. Tests of cardiac autonomic function and measurements of motor and sensor nerve conduction were similar in both groups. Patients with PVD excluded if ABI 0.9.
Grant WP, Sullivan R, Sonenshine DE, Adam M, Slusser JH, Carson KA, Vinik AI: Electron microscopic investigation of the effects of diabetes mellitus on the Achilles tendon. J Foot Ankle Surg 1997 Jul-Aug;36(4):272-8. Fine structural changes in the Achilles tendons of patients with long-term diabetes mellitus were investigated. All patients had clinical and electrophysiological evidence of diabetic neuropathy and had ulceration and/or Charcot neuroarthropathy. Several differences between tendons of diabetic (n = 12) and nondiabetic (n = 5) individuals were observed by electron microscopy. In diabetics, these differences included increased packing density of collagen fibrils, decreases in fibrillar diameter, and abnormal fibril morphology. In one diabetic patient, individual collagen fibrils were tightly apposed so that many areas of tendon appeared as a single mass of closely adhering fibrillae. In addition, foci in which collagen fibrils appeared twisted, curved, overlapping and otherwise highly disorganized were common in specimens from most patients (11 of 12). These morphologic abnormalities in the Achilles tendons of diabetics appear to reflect a poorly known process of structural reorganization that may be the result of nonenzymatic glycation expressed over many years. Such structural changes could contribute to the tightening of the Achilles tendor a phenomenon consistent with clinical observations of extreme shortening of the Achilles tendon-gastrocnemius-soleus complex common in advanced diabetic neuropaths. In patients with diabetic neuropathy, tendon shortening causes severe equinus that may precipitate serious ulceration, stress fractures, and Charcot collapse of the foot. However, in nondiabetics, the fine structure of the Achilles tendon appears normal, consistent with the finding that the ultrastructural changes result from diabetes rather than neuropathy. Comments: We think of neuropathic feet as having pathology in nerve and vascular tissue. Here we see that tissue structure itself may be altered by hyperglycemia. We have benefited some of these patients with shortened Achilles tendons by cutting them (e.g. patient #186).
Gregory R, Tattersall RB and Allison SP: Peripheral neuropathy as a presenting feature of type 2 diabetes: a case-controlled study. Diabetic Medicine 11:407-409, 1993. 68 newly diagnosed diabetics with neuropathy contrasted with matched controls without neuropathy. 35% of the neuropathic patients had PVD vs 9% of controls (P less than 0.0021). 30% of the neuropathic patients had retinopathy at diagnosis vs no controls. 10% neuropathic patients presented with foot ulcers vs no controls.... Likely that macrovascular disease either exacerbates or causes neuropathy in this group of patients. Femoral, popliteal, dorsalis pedis and posterior tibial pulses graded as normal (0), diminished (1), or absent (2). A sum over 4 defined as PVD.
Hamdy O, Abou-Elenin K, LoGerfo FW, Horton ES, Veves A: Contribution of nerve-axon reflex-related vasodilation to the total skin vasodilation in diabetic patients with and without neuropathy. Diabetes Care 24(2):344-9, 2001. OBJECTIVE: To examine the contribution of nerve-axon reflex-related vasodilation to total acetylcholine-induced vasodilation in the skin of normal and diabetic subjects. RESEARCH DESIGN AND METHODS: The skin microcirculation was evaluated at the forearm level in 69 healthy subjects and 42 nonneuropathic diabetic patients and at the foot level in 27 healthy subjects and 101 diabetic patients (33 with neuropathy, 23 with Charcot arthropathy, 32 with peripheral vascular disease and neuropathy, and 13 without complications). Two single-point laser probes were used to measure total and neurovascular vasodilation response to the iontophoresis of 1% acetylcholine, 1% sodium nitroprusside, and deionized water. RESULTS: The neurovascular response to acetylcholine was significantly higher than the response to sodium nitroprusside and deionized water (P < 0.01). At the forearm level, the contribution of neurovascular response to the total response to acetylcholine was 35% in diabetic patients and 31% in control subjects. At the foot level, the contribution was 29% in diabetic patients without neuropathy and 36% in control subjects, while it was significantly diminished in the three neuropathic groups. A significantly lower nonspecific nerve-axon-related vasodilation was observed during the iontophoresis of sodium nitroprusside, which does not specifically stimulate the C nociceptive fibers. CONCLUSIONS: Neurovascular vasodilation accounts for approximately one-third of the total acetylcholine-induced vasodilation at both the forearm and foot levels. The presence of diabetic neuropathy results in reduction of both the total vasodilatory response to acetylcholine and the percentage contribution of neurovascular vasodilation to the total response. Acetylcholine and sodium nitroprusside cause vasodilation in the skin microcirculation through different pathways.
Hollis Caffee H: Treatment of diabetic neuropathy by decompression of the posterior tibial nerve. Plast Reconstr Surg 106(4):813-5, 2000. A series of 58 operations on 36 patients were performed for decompression of the posterior tibial nerve for the treatment of diabetic neuropathy. Preoperative symptoms included lack of sensation, pain, or both. Eleven of the 36 patients had neurotrophic ulcers, which were treated simultaneously. The operation was found to be effective for relief of pain in 24 of the 28 patients with that complaint (86 percent). Restoration of sensation was less consistent with improvement noted in 18 of the 36 patients (50 percent). The follow-up period ranged from 12 to 84 months (mean, 32 months) and five patients had some degree of recurrent symptoms. No patient has developed a new ulcer after nerve decompression. Wound complications were minimal (12 percent), even though ulcers were treated simultaneously. No patient required surgical treatment for the decompression incision, although one did require hospital admission for treatment of a wound infection. In general, the procedure seemed to be a worthwhile treatment, which should be considered ill selected diabetics with symptomatic neuropathy.
Khaodhiar L, Niemi JB, Earnest R, Lima C, Harry JD, Veves A: Enhancing sensation in diabetic neuropathic foot with mechanical noise. Diabetes Care 26:3280-3, 2003. OBJECTIVE: Localized low-level mechanical or electrical noise can significantly enhance tactile sensitivity in healthy young subjects and older adults. This phenomenon is termed stochastic resonance (SR). In this study, we examined the effect of SR on vibratory and tactile sensation in patients with moderate to severe diabetic peripheral neuropathy. RESEARCH DESIGN AND METHODS: A total of 20 subjects were included in the study. The vibration perception threshold (VPT) test and the Semmes-Weinstein filament (SWF) threshold at the plantar surface of the left foot and the big toe were determined under two mechanical noise stimulus conditions: null (no noise) condition and at 10% lower than each subject's mechanical noise threshold of perception. RESULTS: The baseline values (mean +/- SD) were as follows: Neuropathy Symptom Score (NSS) 5.2 +/- 2.5, Neuropathy Disability Score (NDS) 5.0 +/- 2.1, VPT 24 +/- 11 V, and SWF threshold 5.6 +/- 0.8 at the plantar surface of the foot and 5.3 +/- 0.9 at the big toe. The VPT improved significantly from 24 +/- 11 under null condition to 19 +/- 10 V with mechanical noise (P < 0.0001). Mechanical noise also significantly increased the number of detections of the SWF at the plantar surface of the foot (detection rate 66 +/- 11 vs. 59 +/- 15%, P < 0.02) but not at the big toe (63 +/- 10 vs. 61 +/- 16%, P = NS). CONCLUSIONS: Mechanical noise stimulation improves vibration and tactile perception in diabetic patients with moderate to severe neuropathy. Additional studies are required to examine the effect of long-term noise stimulation on parameters of nerve function. Comments: Sound improving neuopathy? We know boot therapy does. See cases #8, 143 and 152.
Kochman AB, Carnegie DH, Burke TJ: Symptomatic reversal of peripheral neuropathy in patients with diabetes. J Am Podiatr Med Assoc 92:125-30, 2002. Forty-nine consecutive subjects with established diabetic peripheral neuropathy were treated with monochromatic near-infrared photo energy (MIRE) to determine if there was an improvement of sensation. Loss of protective sensation characterized by Semmes-Weinstein monofilament values of 4.56 and above was present in 100% of subjects (range, 4.56 to 6.45), and 42 subjects (86%) had Semmes-Weinstein values of 5.07 or higher. The ability to discriminate between hot and cold sensation was absent (54%) or impaired (46%) in both groups prior to the initiation of MIRE treatment. On the basis of Semmes-Weinstein monofilament values, 48 subjects (98%) exhibited improved sensation after 6 treatments, and all subjects had improved sensation after 12 treatments. Therefore, MIRE may be a safe, drug-free, noninvasive treatment for the consistent and predictable improvement of sensation in diabetic patients with peripheral neuropathy of the feet. Comments: Here we have improvement in local sensation associated with 12 local treatments. Such claims, if substantiated, lend insight into the pathogenesis of diabetic neuropathy. The entire neuroaxis from brain to the toes is exposed to the noxious effects of hyperglycemia. Symptoms in the feet have been thought to be most prominent simply because the feet are at the end of the line: any lesion(s) in the proximal nerve tissue may alter nerve function in the feet. Presumably, the 890 nanometer photoenergy can penetrate deeply into the tissue and release nitric oxide from red cells. The nitric oxide, in turn, causes local smooth muscle relaxation and vasodilation improving blood flow and tissue oxygenation. Nitric oxide generally is thought to have local effect and not last long enough to have systemic benefits. As local anoxia itself is a very potent vasodilator, one might wonder how the local generation of nitric oxide would benefit blood flow especially if proximal vascular lesions are not ameliorated in some fashion. Further, there is the possibility that local heating, which increases the oxygen requirements of local tissues, in the absence of an improvement in arterial inflow, might do harm. Finally, the results of this study are subject to error due to patient training. Patient subjective responses were recorded, not some objective findings like motor nerve velocities. And patients responses can improve without treatment due to practice and awareness of the expectations of the investigators.
Kumar D and Marshall HJ: Diabetic peripheral neuropathy: Amelioration of pain with transcutaneous electrostimulation. Diabetes Care 20: 1702-1705, 1997. Results: In the sham-treated group (n=13), the neuropathic symptoms improved in 5 (38%) patients, and the pain score declined from 2.92 ± 0.13 to 2.38 ± 0.26 (P<0.04), suggesting a procedure-related placebo effect. In the electrotherapy group (n=18), symptomatic improvement was seen in 15 (83%) cases, 3 of which were completely asymptomatic; the pain score declined from 3.17 ± 0.12 to 1.44 ± 0.25 (P<0.01) and the posttreatment pain scores were considerably lower (P<0.03), indicating a substantial treatment effect over and above any placebo influence. Patients in the electrotherapy group reported greater reduction in symptoms (52 ± 7% vs 27 ± 10% in the control subjects, P< 0.05 on an analog scale. Moreover, the electrotherapy decreased pain scores (from 3.0 ± 0.62 to 1.56 ± 0.32, P<0.02) in nine patients who had received sham treatment earlier. Comments: Such studies baffle those not enthusiastic about electrostimulation. Proper stimulation may produce "nonfatiguing" muscular contractions. Patients were instructed to adjust treatment intensity depending on individual comfort levels. It would seem that the "sham" group, who had no muscular contractions and no discomfort due to the treatment and had a procedure-related placebo effect, might have suspected that they were indeed untreated. Patients receiving a bang from their treatment are more likely to have a placebo effect. Again, the electrodes in this study were placed at spots just above and below the knee, a good distance from the feet where patients with peripheral neuritis most commonly suffer. One wonders just what the treatment does to thrombotic lesions in the vaso-nervorum etc.
Krishnan ST, Rayman G: The LDIflare: a novel test of C-fiber function demonstrates early neuropathy in type 2 diabetes. Diabetes Care 27(12):2930-5, 2004. OBJECTIVE: The aim of this study was to evaluate a novel method for assessing the axon reflex and to determine its value in detecting neuropathy in type 2 diabetes. RESEARCH DESIGN AND METHODS: The neurogenic flare response to nociceptive stimuli is mediated by an axon reflex involving small unmyelinated C-fibers. We developed a method to assess this reflex involving skin heating to 44 degrees C to evoke the flare followed by scanning the site using a laser Doppler imager (LDI) to measure the area; we termed this method LDIflare. To confirm its neurogenic nature, we examined the LDIflare in eight healthy subjects before and after topical administration of anesthesia. We used this technique to detect C-fiber neuropathy in people with type 2 diabetes. A total of 36 subjects were studied: 12 subjects with neuropathy (group DN), 12 subjects without neuropathy (group DC), and 12 age- and sex-matched control subjects (group NC). For comparison, small-fiber function was also assessed using the Computer Aided Sensory Evaluator-IV (CASE IV) (WR Medical Electronics, Stillwater, MN). RESULTS: In the eight healthy control subjects, LDIflare was markedly reduced after topical administration of anesthesia (1.62 [1.45-1.72] vs. 5.2 cm2 [3.9-5.9], P <0.0001), confirming its neurogenic nature. Similarly, in neuropathic subjects, LDIflare was significantly smaller compared with normal and diabetic control subjects (LDIflare area: DN 1.3 cm2 [0.9-1.8], NC 5.5 cm2 [3.9-5.8], and DC 2.8 cm2 [2.5-3.8]; P <0.0001 and P=0.01, respectively). The group without neuropathy (DC) also demonstrated a reduced flare compared with the NC group (P=0.01). In contrast, C-fiber function assessed by evaluating the quantitative thermal thresholds (CASE IV) did not detect a difference between the latter two groups. CONCLUSIONS: This study confirms the neurogenic nature of the LDIflare and clearly demonstrates loss of C-fiber function in neuropathic subjects with type 2 diabetes. Moreover, it demonstrates C-fiber dysfunction before its detection by other currently available methods, including CASE IV. The LDIflare seems to be a simple objective method to detect early neuropathy and may be of value in assessing therapeutic interventions aimed at preventing or reversing C-fiber dysfunction. Comments: This technique offers a quantitative, noninvasive and non-painful means to follow one form of neuropathy. Hopefully, soon we may see the effects of boot therapy on nerve function as determined by this test.
Lithner F, Bergenheim T and Borssen B: Extensor digitorium brevis in diabetic neuropathy: a controlled evaluation in diabetic patients aged 15-50 years. J Internal Med 230:449-453, 1991. Muscle bulk graded as normal, reduced or absent. 375 diabetics and 100 healthy controls. Reduced or absent mass more common in type 1 (44%) and type 2 (48%) diabetics than controls (12%). In type 1 abnormal mass associated with age, duration of DM, smoking dry feet and foot ulcers. Sensory thresholds for vibration, perception and pain all significantly elevated in type 1 patients with abnormal mass vs type 1 patients with normal mass. Low mass in controls correlated only with smoking. Dorsiflexion of the toes against resistance used to test the function of the muscle.
Lundberg TCM, Eriksson SV and Malm M: Electrical nerve stimulation improves healing of diabetic ulcers. Ann Plast Surg 29:328-331, 1992. A controlled study of the effects of electrical nerve stimulation (ENS) was performed in 62 diabetic patients producing significant differences in ulcer areas and healing ulcers in the ENS patients. Comments: As the patients were said to have diabetic LEG ulcers due to VENOUS STASIS and were excluded from the study if they had osteomyelitis, abscess or an ankle blood pressure under 75mm Hg, the study might have been better titled "ENS in venous stasis disease among diabetics". Their equipment produced alternating constant current square-wave pulses of 1 msec at an intensity-evoking paresthesias and was administered for 20 minutes twice daily.
Maser RE et al: Epidemiological correlates of diabetic neuropathy. Report from Pittsburgh epidemiology of diabetes complications study. Diabetes 38:1456-61, 1989. Analysis of baseline risk factors for 400 subjects. Neuropathy said to be present if abnormal sensory or motor signs, symptoms, or decreased deep tendon reflexes. 34% had neuropathy (18% of those 18-29 years old and 58% of those >=30). Duration, elevations in glycohemoglobin, smoking, and low HDL cholesterol associated with neuropathy. Univariate associations were found with macrovascular disease, nephropathy, and retinopathy.
Mueller MJ, Sinacore DR, Hastings MK, Lott DJ, Strube MJ, Johnson JE: Impact of achilles tendon lengthening on functional limitations and perceived disability in people with a neuropathic plantar ulcer. Diabetes Care 27:1559-64, 2004. OBJECTIVE-An Achilles tendon-lengthening (ATL) procedure is effective at reducing ulcer recurrence in patients with diabetes, peripheral neuropathy, and a plantar ulcer, but its effects on functional limitations and perceived disability are unknown. The purpose of this study is to report the effects of an ATL and total contact casting (TCC) on the functional limitations and perceived disability of patients with neuropathic plantar ulcers. RESEARCH DESIGN AND METHODS-Twenty-eight subjects with a mean age of 55 +/- 10 years and a BMI of 33 +/- 6 kg/m(2) participated. All subjects had a history of diabetes, loss of protective sensation, limited ankle motion, and a recurrent forefoot ulcer. Subjects were randomized into two groups: an ATL group (n = 14), who received treatment of ATL, and TCC and a TCC group (n = 14), who received TCC only. Subjects completed a modified physical performance test (PPT) and the SF-36 Health Survey before treatment, after primary treatment and healing of the plantar forefoot ulcer, and 8 months after initial ulcer healing. RESULTS-There were no significant changes in functional limitations as measured by the PPT between groups or over time. The physical summary score of the SF-36 decreased slightly from before treatment to 8 months after initial ulcer healing in the ATL group (35 +/- 7 to 31 +/- 6), whereas the TCC group score increased during this time (34 +/- 8 to 39 +/- 11; P < 0.05). CONCLUSIONS-The ATL resulted in no measurable change in functional limitations, but patients receiving an ATL and TCC reported lower physical functioning at 8 months after initial ulcer healing than subjects receiving TCC alone and may require additional physical therapy to address this perceived disability. Comments: We and others have successfully used lengthening of the Achilles tendon to heal and avoid ulcer recurrences in patients with difficult plantar neuropathic ulcers (see patient #186 in our case history section). These authors in a simultaneous publication showed that lengthening the Achilles tendon reduces the forces in the distal foot by reducing the force of plantar flexion rather than affecting the degree of motion of the ankle joint (J Biomech. 37:897-906, 2004). In this publication we learn that the patients may be aware of this decrease in power.
Naruse K, Hamada Y, Nakashima E, et al: Therapeutic neovascularization using cord blood-derived endothelial progenitor cells for diabetic neuropathy. Diabetes 54:1823-8, 2005. Diabetic neuropathy is based on the impairment of nerve blood flow and the metabolic disorder. Although the vasodilating agents and anticoagulants improve nerve function and symptoms in diabetic neuropathy, more effective treatments are needed. Because endothelial progenitor cells (EPCs) have been identified in adult human peripheral blood, many studies have shown that transplantation of EPCs improves circulation to ischemic tissues. In this study, we have demonstrated that therapeutic neovascularization using human umbilical cord blood-derived EPCs reversed diabetic neuropathy. EPCs were isolated and expanded on day 7 of culture from cord blood mononuclear cells. Unilateral intramuscular injection of EPCs into hindlimb skeletal muscles significantly ameliorated impaired sciatic motor nerve conduction velocity and sciatic nerve blood flow in the EPC-injected side of streptozotocin-induced diabetic nude rats compared with the saline-injected side of diabetic nude rats. Histological study revealed an increased number of microvessels in hindlimb skeletal muscles in the EPC-injected side of diabetic rats. These findings suggest that transplantation of EPCs from cord blood may be a useful treatment for diabetic neuropathy. Ischemia as a prime cause for peripheral neuropathy is not commonly considered by the clinical neurologist or endocrinologist. Potter et al below, however, found a surprisingly high incidence of peripheral neuropathy in the remaining leg of nondiabetic persons having a leg amputation for ischemia. In our case histories, we show many cases with peripheral ischemia whose neuropathy markedly improves along with their circulation with boot therapy (for examples see cases 8 and 152). In this study, neuropathy and circulation are improved with the infusion of cord blood-derived endothelial progenitor cells.
Newrick PG, Cochrane T, Ward JD and Boulton AJM: Reduced hyperemic response under the diabetic neuropathic foot. Diabetic Medicine 5:570-573, 1988.
Pfutzner A, Forst T, Engelbach M, Margin T, Goitom K, Lobig M, Beyer J, Kunt T: The influence of isolated small nerve fibre dysfunction on microvascular control in patients with diabetes mellitus. Diabet Med 18(6):489-94, 2001. AIM: The aim of the study was to investigate the influence of isolated small nerve fibre dysfunction on microvascular skin blood flow and transcutaneous oxygen tension in patients with diabetes mellitus. METHODS: Small nerve fibre dysfunction was assessed by the measurement of thermal and pain perception thresholds. Patients with evidence of large fibre disturbances as evaluated by means of vibration perception threshold were excluded from the study. Microvascular blood flow was investigated with laser-Doppler-fluxmetry (LDF) following stimulation with acetylcholine and mild thermal injury. RESULTS: Diabetic patients with small nerve fibre injury showed a significantly reduced increase in the laser-Doppler-flux signal following the application of acetylcholine compared with patients without neuropathy or healthy control subjects (2.8 arbitrary units (AU) (1.3-5.5) vs. 7.2 AU (4.1-25.5); P = 0.007 and vs. 8.5 AU (3.0-17.0), P = 0.02, respectively). The increase in LDF following thermal injury was also diminished in patients with small nerve fibre dysfunction compared with patients without neuropathy or the control group (29.8 AU (17.2-46.5) vs. 51.2 AU (29.5-93.5); P = 0.02 and vs. 54.6 AU (39.7-97.7); P = 0.004, respectively). In addition, they showed a significantly reduced transcutaneous oxygen tension compared with the other groups (42.9 mmHg (41.6-55.5) vs. 56.1 mmHg (49.2-60.8); P = 0.04 and vs. 59.0 mmHg (54.6-80.3), P = 0.03, respectively). CONCLUSIONS: Our study confirms an association between small nerve fibre injury and skin microvascular dysfunction. It further underlines the concept of neurovascular disturbances in the pathogenesis of neurotrophic foot ulceration.
Piaggesi A, Viacava P, Rizzo L, Naccarato G, Baccetti F, Romanelli M, Zampa V, Del Prato S: Semiquantitative analysis of the histopathological features of the neuropathic foot ulcer: effects of pressure relief. Diabetes Care 26:3123-8, 2003. OBJECTIVE: This study was designed to evaluate the histopathology of neuropathic ulcers and whether pressure relief could change such histological patterns. RESEARCH DESIGN AND METHODS: We compared neuropathic plantar ulcers tissue excised from 10 diabetic patients (group A) with those taken from 10 patients with comparable lesions and glycemic control after 20 days in a total contact cast (group B). Tissue specimens were blindly examined by two independent pathologists for hyperkeratosis, fibrosis, cutaneous annexes, capillaries, inflammation, cellular debris, and granulating tissue. For each parameter, quantification was obtained according to an arbitrary score: 0, absent; 1, present in <33%; 2, present in 34-66%; and 3, present in >67% of the lesion. RESULTS: Patients in group B showed a marked reduction in ulcer size after 20 days of casting (P < 0.01). The histopathological features of the two groups markedly differed. Group A patients showed a predominance of inflammatory elements as well as matrix alterations, vessel disruptions, inflammation, and debris. Group B ulcers showed a shift toward a reparative pattern with prevalence of neoformed capillaries and fibroblasts. Semiquantitative analysis confirmed the prevalence of hyperkeratosis, fibrosis, inflammation, and cellular debris in group A patients (P < 0.05), whereas cutaneous annexes, capillaries, and granulating tissue were more prevalent in group B lesions (P < 0.01). CONCLUSIONS: These results indicate that pressure relief with a total contact cast is associated with changes in the histology of neuropathic foot ulcers, indicating reduction of inflammatory and reactive components and acceleration of reparative processes.
Potter PJ, Maryniak O, Yaworski R, Jones IC and BMath MA: Incidence of Peripheral Neuropathy in the Contralateral Limb of Persons with Unilateral Amputation Due to Diabetes. Journal of Rehabilitation Research and Development 35:335-339, 1998. Abstract--Eighty persons with first-time, nontraumatic amputation, mean age 66.7 yrs ± 12.6 (1 SD) were examined to determine the extent of peripheral neuropathy (PN) present in the intact limb. Thirty-eight (47.5%) of the subjects had confirmed diabetes mellitus (DM); in those subjects, vibration sense (73.3%), temperature sense (42.1%), and nociception (71.1%) were decreased or absent in the intact limb. The prevalence of sensory impairment was significantly less in nondiabetic subjects in whom vibration sense 46.5% (p<0.02), temperature sense 16.3% (p<0.01), and nociception 32.6% (p<0.02) were decreased or absent. Using a scale that stages the severity of PN, a significant difference (p<0.001) in the distribution was found between these two groups. Only one person with known DM had no evidence of PN. Twenty-eight out of 42 nondiabetic subjects had evidence of PN. Eighty percent of all subjects had PN. This study confirms the significant potential for PN in persons with DM and presents new evidence of a significant incidence of neuropathy in nondiabetic individuals with amputation. The finding of unexpected peripheral nerve compromise is an important consideration in the treatment of patients with peripheral vascular disease who are at risk for amputation and for persons with amputation who depend on the intact limb for stability and ambulation. Comments: The surprisingly high incidence of peripheral neuropathy in the nondiabetic subjects is worth noting. Why did they have neuropathy? Was their neuropathy due to ischemia? How much diabetic neuropathy is due to ischemia?
Reddy GK, Stehno-Bittel L, Enwemeka CS: Glycation-induced matrix stability in the rabbit achilles tendon. Arch Biochem Biophys 2002 Mar 15;399(2):174-80, 2002. Connective tissue susceptibility to nonenzymatic glycation was examined following 0, 2, 4, 6, 8, and 10 weeks of incubating the rabbit Achilles tendon in phosphate-buffered saline containing ribose (glycated). The biomechanical integrity of the glycated tendons was then compared to control tendons incubated in phosphate-buffered saline (non-glycated) at each time interval, while the biochemical stability of both groups of tendons was determined by examining collagen extractability and the formation of pentosidine at 8 weeks. Whereas there were no significant biomechanical differences between control and glycated tendons at 0- and 2-week intervals (P > 0.05), moderately significant increases in maximum load, energy to yield, and toughness of glycated tendons were observed at 4 weeks. Beyond 4 weeks of incubation, the differences between glycated and non-glycated tendons became highly significant, as glycated tendons withstood more load and tensile stress (P < 0.01 for each variable), attained significantly higher modulus of elasticity (P < 0.01), absorbed more energy (P < 0.01), and became tougher (P < 0.01) than controls. These differences in the biomechanical indices of the effects of glycation were stable between the 6th and 10th week of glycation. The maximum increases in the biomechanical measurements as a result of glycation were 29% for maximum load, 125% for stress, 19% for strain, 106% for Young's modulus of elasticity, 14% for energy to yield, and 57% for toughness. Biochemical analysis showed a 61% reduction in the extractability of neutral salt-soluble collagen, a 48% decrease in acid-soluble collagen, and a 29% decline in pepsin-soluble collagen in glycated tendons (P < 0.01). In contrast, there was a 28% increase in the amount of insoluble collagen and significantly higher amounts of pentosidine (P < 0.01) in glycated tendons. Collectively, these biomechanical and biochemical results suggest that nonenzymatic glycation may explain the altered stability of connective tissue matrix induced by the processes of diabetes and aging. Comments: So poor diabetes control does alter the biochemistry of tendinous structures. Grant et al, above, noted the electron microscopic changes in the Achilles tendon associated with diabetes. Lormeau B et al (The "short Achilles tendon" syndrome: a new entity of the diabetic foot. Diabetes Metab 23(5):443-7, 1997) and Hastings MK et al (Effects of a tendo-Achilles lengthening procedure on muscle function and gait characteristics in a patient with diabetes mellitus. J Orthop Sports Phys Ther 30(2):85-90, 2000.) report cases in which clear benefit was appreciated in lengthening the Achilles tendon. It would seem likely that the entrapment syndromes and the benefit their relief may afford on diabetic neuropathy have an explanation also in glycosylation processes which lead to structure and volume changes in tendon and ligamentous structures. Are these changes reversible over time with tight control of the diabetes? Is the improvement in sensation commonly experienced by boot patients related to a reduction in swelling or stretching of these structures?
Richter RW, Portenoy R, Sharma U,et al: Relief of painful diabetic peripheral neuropathy with pregabalin: a randomized, placebo-controlled trial. J Pain 6:253-60, 2005. This was a 6-week, randomized, double-blind, multicenter study evaluating the efficacy of pregabalin in the treatment of painful diabetic neuropathy. Two hundred forty-six men and women with painful diabetic neuropathy received pregabalin (150 or 600 mg/day by mouth) or placebo. The primary efficacy variable was mean pain score at the end of treatment. Efficacy results indicate that pregabalin 600 mg/day significantly decreased mean pain score to 4.3 (vs 5.6 for placebo, P = .0002) and increased the proportion of patients who had a > or =50% decrease from baseline pain (39% vs 15% for placebo, P = .002). Pregabalin also significantly reduced sleep interference, past week and present pain intensity, sensory and affective pain scores, and bodily pain and decreased by > or =50% the number of patients describing their pain as gnawing, sickening, fearful, and punishing-cruel. More patients receiving pregabalin 600 mg/day than placebo showed improvement, as rated on the Clinical and Patient Global Impression of Change scales, 73% vs 45% and 85% vs 47%, respectively. Pregabalin 150 mg/day was essentially no different from placebo. Dizziness was the most common side effect. These study results show pregabalin 600 mg/day to be safe and effective in reducing the pain and other associated symptoms of painful diabetic neuropathy. PERSPECTIVE: Painful diabetic peripheral neuropathy is a challenging neuropathic pain syndrome. This randomized controlled trial demonstrates that pregabalin, a new drug that interacts with the alpha2-delta protein subunit of the voltage-gated calcium channel, is an efficacious and safe treatment for the pain of this condition.
Ryder REJ, Kennedy RL, Newrick PG, Wilson RM, Ward JD and Hardisty CA: Autonomic denervation may be a prerequisite of diabetic neuropathic foot ulceration. Diabetic Medicine 7:726-730, 1990. Comment: Used a "sweat spot test" dependent on intradermal acetylcholine causing secretion by innervated sweat glands... results detected by starch/iodine discoloration. All patients with neuropathic ulcers had peripheral autonomic denervation. The loss of sweating promotes dryness possibly leading callus to fissure etc. Creams possibly might be prescribed to prevent such dryness.
Scott AR et al: Abnormal thermoregulation in diabetic autonomic neuropathy. Diabetes 37:961-68, 1988. On exposure to cold, the core body temperature of neuropathic patients did not rise like controls.
Stansberry KB, Peppard HR, Babyak LM, Popp G, McNitt PM, Vinik AI: Primary nociceptive afferents mediate the blood flow dysfunction in non-glabrous (hairy) skin of type 2 diabetes: a new model for the pathogenesis of microvascular dysfunction. Diabetes Care 22:1549-54, 1999. OBJECTIVE: To test the independent contributions of vascular endothelium, sympathetic activation and inhibition, vessel distensibility, and nociceptor-mediated vasodilation in both glabrous and hairy skin circulations. RESEARCH DESIGN AND METHODS: We measured blood flow using laser Doppler techniques in 10 people with type 2 diabetes and 10 age- and BMI-matched healthy control subjects at the pulp of the index finger (glabrous skin) and the dorsum of the hand (hairy skin). A 5-min ischemic block of the arm was used to test vascular endothelium. Warming of the probe site to 45 degrees C tested neurogenic vasodilation in hairy skin only. Vessel distensibility was tested by gravitational pressure. RESULTS: Basal blood flow and reactive hyperemia did not differ between groups at either skin site. The vasodilative response to local warming (P < 0.01) and limb lowering (P < 0.05) were significantly different between groups in hairy skin but not in glabrous skin in the absence of objective measured neuropathy. Nociceptor-mediated flow correlated significantly with the warm thermal threshold (r = -0.50, P < 0.05). Endothelial-mediated blood flow correlated with systolic blood pressure (r = -0.76, P < 0.01), LDL cholesterol (r = -0.62, P < 0.001), C-peptide (r = 0.65, P < 0.05), and triglycerides (r = 0.47, P < 0.05). CONCLUSIONS: These data suggest that neurogenic nociceptor-mediated vasodilation is impaired in subjects with type 2 diabetes when endothelial and sympathetic function are relatively intact. Heat-induced vasodilation may be a specific test of small heat-sensitive C-fiber peripheral neurons and may be an integral part of the metabolic syndrome. Comments: These investigators have earlier publications showing changes in Doppler flow in diabetes. They have found that blood flow in younger diabetic subjects resembled that of older control subjects. They interpreted their data as showing that diabetes has effects on precapillaries, that may be direct or mediated via autonomic nerves, which result in a deficit that resembles premature aging (Stansberry KB et al in Diabetes Care 20:1711-6, 1997). Again, with the use of laser Doppler microvascular measurements, they found diabetic subjects to have impaired low-frequency oscillation vasomotion in 75% of age-matched patients (15 of 20 patients), with mean amplitudes of 24.9 +/- 6.4 vs. 129.0 +/- 33.2 (P < 0.0039). Of six somatic and autonomic neuropathy variables, only the warm thermal sensory threshold correlated significantly with the mean amplitude of vasomotion (r = -0.75, P < 0.0009)( Stansberry KB et al. Diabetes Care 19:715-21, 1996). Their findings in patients with Charcot feet were surprising. While Doppler flowmetry patterns of peripheral vasomotion and blood flow were clearly disordered in diabetic neuropathy, they were intact in patients with a Charcot osteoarthropathy, despite a more severe sensory nerve impairment. They suggested that the loss of peripheral blood flow and vasomotion often seen in diabetic neuropathy may actually be protective against Charcot arthropathy by preventing bone resorption. (Shapiro SA et al in J Diabetes Complications 12:147-53, 1998).Their figure (Diabetes Care 22:1550) illustrates their view of the microcirculation in diabetes:

CGRP (calcitonin gene-related peptide), ACh (acetylcholine) and VIP (vasoactive intestinal polypeptide) may not be familar to the reader in this context.
Tesfaye S, Malik R, Harris N, Jakubowski JJ, Mody C, Rennie IG, Ward JD: Arterio-venous shunting and proliferating new vessels in acute painful neuropathy of rapid glycaemic control (insulin neuritis). Diabetologia 39(3):329-35, 1996. Insulin neuritis, or painful neuropathy following rapid improvement in glycaemic control, is well recognised but its aetiology is unclear. An understanding of the processes involved in the genesis of acute painful neuropathy of rapid glycaemic control may give an insight into the early pathogenetic factors leading to diabetic nerve damage in general. We have identified five subjects with insulin neuritis including one who developed severe autonomic neuropathy following treatment with insulin. Subjects underwent: 1) assessment of neuropathic symptom and deficit scores; 2) quantitative sensory and electrophysiological studies and 3) sural nerve epineurial vessel photography and fluorescein angiography in vivo. The sural nerve photographs were independently graded by an ophthalmologist. All subjects with insulin neuritis presented with severe sensory symptoms but clinical examination and electrophysiological tests were normal except in the subject with the severe autonomic neuropathy in whom all the tests were abnormal. On nerve photography, there was an abundance of epineurial nutrient vessels although these showed severe abnormalities including arteriolar attenuation, tortuosity and arterio-venous shunting in all subjects. Proliferating neural 'new vessels' which bear striking similarities to those found in the retina and that were more leaky to fluorescein than normal vessels, were observed in three subjects. Venous distension and/or tortuosity was also observed in three subjects and this was most marked in the subject with severe autonomic neuropathy. This study shows that epineurial nutrient vessel anatomy is abnormal in subjects with acute painful neuropathy of rapid glycaemic control, a condition previously thought to be purely metabolic in origin. The presence of epineurial arterio-venous shunting and a fine network of vessels resembling the new vessels of the retina, may lead to a 'steal' effect rendering the endoneurium ischaemic. This process may be important in the genesis of neuropathic pain, and further supports the importance of vascular factors in the pathogenesis of diabetic neuropathy. Comments: These authors find parallels between the vascular lesions of diabetic retinopathy and those of acute painful diabetic neuritis. See our case #143 in which we document both retinopathy and peripheral painful ischemia (associated with normal palpable pulses) both improved with boot therapy! Of course, we had to include the work of these authors!
Uccioli L, Mancini L, Giordano A, Solini A, Magnani P, Manto A, Cotroneo P, Greco AV and Ghirlanda G: Lower limb arterio-venous shunts, autonomic neuropathy and diabetic foot. Diabetes Research and Clin Pract 16:123-130, 1992. Three groups of diabetics studied: (A) 12 healthy nonneuropathic patients, (B) 12 neuropathic patients free of foot lesions and (C) 12 neuropathic patients with recurrent foot ulcers. Pulmonary uptake of radioactive albumen microspheres injected into femoral artery or "shunting": C 10.4%+/-2.7% > B 6.8%+/-2.3% (P < 0.01) > A 3.8%+/-1.2% (P < 0.001). All tests exploring autonomic foot were more impaired in B & C vs A, with no difference between B & C. A direct correlation was found between a-v shunting and the duration of disease (P < 0.001) and the following cardiovascular tests: postural hypotension (PH) (P < 0.02), sustained handgrip (SH) (P < 0.001), deep breathing (DB)(P < 0.005) and lying to standing (LS) (P < 0.01). Pts C had more sensory (vibratory sense) and motor (sural nerve potentials and peroneal motor conduction velocity and amplitude) neuropathy. Patients were screened to have a Doppler ankle/arm BP index > 1 in the absence of major vascular calcifications.
Vayssairat M, Le Devehat C: Diabetic angiopathy: the role of microvascular exploration in routine practice. Consequences of a new algorithm for care of the diabetic foot. J Mal Vasc 26(2):126-9, 2001. Diabetes mellitus is the chief medical cause of amputation. The risk of amputation is 15-fold higher in diabetic subjects and 5 out of 6 amputees are diabetic. There are three types of clinical presentation of diabetes-neurological, infectious and ischemic. In clinical practice, these three forms are often intertwined but the most frequent clinical sequence of events is neuropathy --> ulceration --> infection --> amputation. In this sequence, ischemia is not mentioned. The explanation is that the ischemic component of the diabetic foot is only recognized when ankle pulses are missing and when duplex scanning shows stenosis or occlusion of the main arterial trunks of the legs. This manner of diagnosing the ischemic component of diabetic foot is wrong as it fails to recognize the possibility of distal diabetic arteritis. Some experts in diabetology deny the existence of this arteritis which is obvious for those who measure systolic toe pressure. This distal arteritis is present in about 15% of all diabetic patients without trophic changes and in 35% of those with trophic changes. This foot arteritis is closely related to neuropathy. Toe pressure is not usually mentioned in text books or in consensus conferences concerning the diabetic foot. This is the main explanation for the calamitous number of amputations among diabetic patients. Nothing will change as long as physicians do not include toe pressure as a useful diagnostic tool in patients with diabetes. We present here a four-stage algorithm including toe pressure measurement for the management of the diabetic foot.
Veves A, Akbari CM, Primavera J et al: : Endothelial dysfunction and the expression of endothelial nitric oxide synthetase in diabetic neuropathy, vascular disease, and foot ulceration. Diabetes 47(3):457-63, 1998. We studied endothelial-mediated microvascular blood flow in neuropathic diabetic patients to determine the association between endothelial regulation of the microcirculation and the expression of endothelial constitutive nitric oxide synthetase (ecNOS) in the skin. Vasodilation on the dorsal foot in response to heating and iontophoresis of acetylcholine (endothelium-dependent) and sodium nitroprusside (endothelium-independent) were measured using single-point laser Doppler and laser Doppler imaging in diabetic patients with neuropathy (DN), with neuropathy and vascular disease (DI), with Charcot arthropathy (DA), and without complications (D), and in healthy control subjects (C). The response to heat was reduced in the DN (321 [21-629] percentage of increase over the baseline, median [interquartile range]) and DI (225 [122-470]) groups but was preserved in the DA (895 [359-1,229]), D (699 [466-1,029]), and C (810 [440-1,064], P < 0.0001) groups. The endothelial-mediated response to acetylcholine was reduced in the DN (17 [11-25]), DA (22 [2-34]), and DI (13 [2-30]) groups compared with the D (47 [24-58]) and C (44 [31-70], P < 0.001) groups. The non-endothelial-mediated response to sodium nitroprusside was also reduced in the DI (4 [0-18]), DN (17 [9-26]), and DA (21 [11-31]) groups compared with the D (37 [19-41]) and C (44 [26-67], P < 0.0001) groups. There was a significant reduction in vasodilation in the DI group compared with all other groups (P < 0.0001). Full thickness skin biopsies from the dorsum of the foot of 15 DN, 10 DI, and 11 C study subjects were immunostained with antiserum to human ecNOS, the functional endothelial marker GLUT1, and the anatomical endothelial marker von Willebrand factor. The staining intensity of ecNOS was reduced in both diabetic groups. No differences were found among the three groups in the staining intensity of von Willebrand factor and GLUT1. We conclude that the endothelium-dependent and endothelium-independent vasodilations are impaired in diabetic patients predisposed to foot ulceration and that neuropathy is the main factor associated with this abnormality. Reduced expression of ecNOS may be a major contributing factor for endothelial dysfunction. These data provide support for a close association of neuropathy and microcirculation in the pathogenesis of foot ulceration.

Vileikyte L, Hutchings G, Hollis S, Boulton AJM: The tactile circumferential discriminator. A new, simple screening device to identify diabetic patients at risk of foot ulceration. Diabetes Care 20:623-626, 1997. The tactile circumferential discriminator (TCT) (Tacticon Medical Enterprises Inc. West Chester, PA) is a handheld disc with eight protruding rods of increasing circumference that test large fiber nerve function essentially by two-point discrimination. The authors studied 133 diabetic patients of whom 37 had a history of neurotrophic foot ulcers. They compared the TCT (a score of 6 signifying significant neuropathy), the vibration perception threshold (a reading of 35 volts on the hallux with a neuroesthesiometer or a biothesiometer representing significant neuropathy with risk of ulceration) and the Semmes-Weinstein monofilaments (inability to feel the 5.07 filament defined as significant neuropathy). They found the TCT to be simple and reliable. The following chart summarizes their results with the data being number of patients (% patients) except for the VPT where the median voltage (interquartile range) are given:

# Patients	# Pts with history of ulcers (%)	TCD	VPT	# Pts insensate to 5.07 filament(%)
3	-	1	6(5-18)	-
11	-	2	10(5-20)	1(9.1%)
17	-	3	11(8-18)	-
16	-	4	19(11-27)	1(6.3%)
9	-	5	27(16-31)	2(22.2%)
10	3(30%)	6	27(25-36)	4(40%)
8	1(12.5%)	7	30(23-36)	4(50%)
59	33(55.9%)	>7	49(32-51)	45(76.3%)

Vinik AI, Suwanwalaikorn S, Stansberry KB, Holland MT, McNitt PM, Colen LE: Quantitative measurement of cutaneous perception in diabetic neuropathy. Muscle Nerve 18:574-84, 1995. To determine the diagnostic value of various cutaneous sensory modalities in diabetic neuropathy, we studied cutaneous perception at the dominant hallux of 113 subjects (32 normal healthy controls and 81 diabetic subjects). The cutaneous sensory perception tests included warm and cold thermal perception, vibration, touch-pressure sensation, and current perception testing (CPT). The sensitivity of each modality when specificity is held greater than 90% was as follows: warm = 78%, cold = 77%, vibration = 88%, tactile-pressure = 77%, 5-Hz CPT = 52%, 250-Hz CPT = 48%, and 2000-Hz CPT = 56%. Combination thermal and vibratory gave optimum sensitivity (92-95%) and specificity (77-86%). We conclude that vibratory and thermal testing should be the primary screening tests for diabetic peripheral neuropathy. Other modalities may be of use only in specific situations. Comments: This group has been active in studying diabetic neuropathy both in the clinic and the basic science laboratory. Elsewhere in studying the progression of autonomic neuropathy, they found that most clinical signs and symptoms of autonomic neuropathy do not progress. Thus, among the symptoms of autonomic neuropathy in 57 of 76 subjects examined after 9 years, only gastroparesis increased in prevalence (P < 0.01) and of five cardiovascular measures of autonomic neuropathy, only the R-R response to the Valsalva maneuver deteriorated (F[1,44] = 10.61, P < 0.01). (Levitt NS et al in Diabetes Care 19:751-4, 1996).
Vinik A, Mehrabyan A, Colen Let al: Focal entrapment neuropathies in diabetes. Diabetes Care 27:1783-8, 2004. Comments: This paper is recommended reading for the clinician. Below is their table 1:
Waters JH, Watson TB, Ward MG: Conus medullaris injury following both tetracaine and lidocaine spinal anesthesia. J Clin Anesth 8(8):656-8, 1996. Multiple reports of cauda equina syndrome and transient radicular nerve root irritation have suggested that lidocaine spinal anesthesia may be responsible. In this case report, a patient with a preexisting diabetic neuropathy received a partial block following a tetracaine spinal, which was followed by a lidocaine spinal. Following block resolution, a new conus medullaris syndrome was diagnosed. Because of the close proximity of the cauda equina and the conus medullaris, differentiation between these syndromes can be difficult. The preexisting diabetic neuropathy may have predisposed this patient to neurologic injury. The choice of a different local anesthetic drug with less neurotoxic potential such as bupivacaine may have prevented this injury. Comments: One almost hates to include an article like this in this litigious world of ours. First, we see the spontaneous and sudden development of diabetic mononeuropathies, which occur presumably on the basis of a vascular accident. Should these be attributed to any anticedent event (a sneeze, an allergy pill, a nightmare etc.)? Then, we do see numerous obese diabetics with spinal stenosis opting for apinal anesthesia for medical and personal reasons. Many of these have increased symptoms postoperatively perhaps related to the long periods of lying flat on a firm operating room table. Most get better... but some do not.
Wollersheim H et al: Ephedrine improves the microcirculation in the diabetic neuropathic foot. Angiology 40: 1030-1033, 1989. Ephedrine may close AV shunts thus increasing capillary perfusion pressure and subcutaneous PO2 levels.Comments: This article was added to increase the understanding of the reader about neuropathic vascular dysfunction, not to encourage the use of ephedrine. Ephedrine has the disadvantages of raising blood pressure, potentiating glaucoma, opposing the release of insulin by the pancreas and increasing arterial vasoconstriction. Indeed, susceptible patients, such as those with Raynaud's phenomenon, may develop peripheral cyanosis and ulcers with the regular use of ephedrine-containing nosedrops.
Zahir KS, Zahir FS, Thomas JG, Dudrick SJ: The double-crush phenomenon--an unusual presentation and literature review. Conn Med 63(9):535-8, 1999. The double-crush syndrome was initially described by Upton and McComas in 1973. They postulated that nonsymptomatic impairment of axoplasmic flow at more than one site along a nerve might summate to cause a symptomatic neuropathy. This was suggested by their clinical observation that the majority of their patients had a median or ulnar neuropathy associated with evidence of cervicothoracic root lesions. They also hypothesized that one of the constraints on axoplasmic flow could be a metabolic neuropathy, and this is supported by the high association of diabetes and carpal tunnel syndrome. Other researchers have since reported series of patients supporting the frequent association of a proximal and distal nerve compression syndrome, including carpal tunnel syndrome associated with cervical radiculopathy, brachial plexus compression, and diabetic neuropathy. Subsequently, MacKinnon and Dellon have expanded the description of this syndrome to include a) multiple anatomic regions along a peripheral nerve, b) multiple anatomic structures across a peripheral nerve within an anatomic region, c) superimposed on a neuropathy, and d) combinations of the above. We present an unusual case of symptomatic nerve compression caused by two nonanatomic structures within an anatomic region.
Zimny S, Dessel F, Ehren M, Pfohl M, Schatz H: Early detection of microcirculatory impairment in diabetic patients with foot at risk. Diabetes Care 24(10):1810-4, 2001. OBJECTIVE: To assess microcirculatory impairment and alterations of the skin oxygen supply in diabetic patients with foot at risk. RESEARCH DESIGN AND METHODS: This study evaluated skin blood flow in 21 type 2 diabetic patients with a foot at risk (defined as a foot with neuropathy but without ulceration or previous ulcerations), 20 type 2 diabetic patients without foot lesions or neuropathy, and 21 normal subjects as a control group. The skin blood flow was determined by measuring the transcutaneous oxygen pressure (TcPO(2)) at the dorsum of the foot in supine and sitting position. The clinical assessment included standard measures of peripheral and autonomic neuropathy, but peripheral vascular disease was excluded by Doppler ultrasound. RESULTS: In supine position, TcPO(2) was significantly reduced (means +/- SE) in diabetic patients with foot at risk (6.04 +/- 0.52 kPa) compared with diabetic (7.14 +/- 0.43 kPa, P = 0.035) and nondiabetic (8.10 +/- 0.44 kPa, P = 0.01) control subjects. The sitting/supine TcPO(2) difference was higher in diabetic subjects with foot at risk (3.13 +/- 0.27 kPa) compared with both diabetic (2.00 +/- 0.18, P = 0.004) and nondiabetic (1.77 +/- 0.15 kPa, P = 0.0003) control subjects. The mean sitting/supine ratio was 1.70 +/- 0.12 in diabetic patients with foot at risk, 1.32 +/- 0.04 in diabetic control subjects, and 1.25 +/- 0.03 in nondiabetic control subjects (P = 0.007). The sitting/supine TcPO(2) ratio was negatively correlated with the heart rate variation coefficient at rest (r = -0.32, P = 0.044) and at deep respiration (r = -0.31, P = 0.046). CONCLUSIONS: Our data indicate that skin oxygen supply is reduced in type 2 diabetic patients with foot at risk. This is probably due to an impaired neurogenic blood flow regulation and may contribute to capillary hypertension, followed by disturbed endothelial function leading to edema and skin damage of the foot. The determination of TcPO(2) appears to be a useful tool in screening type 2 diabetic patients for foot at risk.

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