Neuropathy Complications Research Articles

Improving Microvascular Outcomes in Patients with Diabetes through Management of Hypertension

Diabetes mellitus is an independent risk factor for cardiovascular disease (CVD) and current opinion holds that hyperglycemia directly damages smaller blood vessels, resulting in microvascular complications of nephropathy, retinopathy, and neuropathy. In a patient with diabetes, hypertension compounds and greatly increases the risk of microvascular complications, and thus the risk of end-stage kidney disease, vision loss, and nontraumatic limb amputations. Hypertension and hyperglycemia directly damage the microvasculature, leading to small vessel dysfunction that manifests as the clinical disease states of diabetic retinopathy and nephropathy. Early recognition and treatment of both hyperglycemia and hypertension may prevent vision loss and chronic kidney disease, the devastating outcomes of these microvascular complications. One of the pathogenic mechanisms for microvascular dysfunction is upregulation of the angiotensin II type 1 receptor, the most physiologically common receptor for the vasoconstrictor properties of angiotensin II. In patients with diabetic retinopathy and nephropathy, tight control of blood pressure (BP) (< 130/80 mm Hg) delays the progression of retinopathy and nephropathy in addition to reducing cardiovascular morbidity and mortality. Aggressive treatment with 2 or more antihypertensive agents, selected from different drug classes, is often needed to reach the optimal BP target level. A PubMed search was conducted to identify randomized controlled trials that evaluated hypertension control and microvascular outcomes in patients with diabetes. Several clinical trials have yielded promising data with renin-angiotensin-aldosterone system (RAAS) inhibitors (the direct renin inhibitor aliskiren, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers). Attainment of BP control with RAAS inhibitors reduces the risk for CVD, nephropathy, and retinopathy. In addition, RAAS inhibitors have demonstrated renoprotective effectiveness independent of the BP reduction achieved. This review will examine the results of clinical trials in the context of BP control, diabetes, and the microvascular complications of retinopathy and nephropathy.

International collaborative research on Charcot's disease

On Sept 17–18, the US National Institute of Diabetes, Digestive and Kidney Diseases and the Office of Rare Diseases of the National Institutes of Health hosted an international symposium on Charcot's disease of the foot (neuroarthropathy) in diabetes, in Bethesda, MD, USA. The intention was to bring together experts from different countries with the aim of promoting international collaboration to investigate the causes and best treatment of this uncommon, but potentially devastating, complication of diabetic neuropathy. Research has hitherto been hampered by the rarity of the condition, its protean manifestations, and the lack of any specific diagnostic marker. Indeed, it is a disease without even a formal definition, though it is one that is often easily recognisable by those with a high index of suspicion.

Charcot neuroarthropathy triggered by osteomyelitis and/or surgery

Charcot neuroarthropathy (CN) is a rare but devastating complication of diabetic neuropathy. Osteomyelitis is also a complication of the diabetic foot and it may be difficult to differentiate from CN. A patient with Type 1 diabetes and peripheral neuropathy developed a foot ulcer complicated by osteomyelitis of the first proximal phalanx. He was successfully treated with antibiotics and surgical excision of the infected bone. Six months later, he developed a hot, swollen, red foot and X-ray showed destruction of the second and third metatarsal heads. At the second presentation, it was difficult to determine whether this was a recurrence of osteomyelitis or a new onset of CN. Thus, to obtain a definitive diagnosis, recourse was made to more sophisticated imaging techniques. 99mTc methylenediphosphonate (MDP) bone scans and magnetic resonance imaging proved inconclusive to differentiate between osteomyelitis and CN. Subsequently, an indium-labelled white cell scan confirmed the absence of osteomyelitis and the patient was successfully treated for CN. Infection and/or surgery may be predisposing factors in the development of diabetic CN but the combination of the two could accelerate the onset of the Charcot process in people with diabetes and neuropathy.

The charcot foot: Medical and surgical therapy

Charcot neuro-osteoarthropathy (CN) is among the most devastating complications of neuropathy and now most commonly occurs in the feet of diabetic patients. Because it is relatively rare and because most patients and practitioners do not expect major bone pathology in the absence of significant pain, CN is often misdiagnosed as cellulitis, deep venous thrombosis, or gout. Also, radiographs early in the process are often relatively unremarkable. Although MRI findings are characteristic, treatment should not wait for the MRI result. The hot swollen erythematous neuropathic foot suspected to be CN should be emergently mechanically protected, usually in an irremovable total contact cast. Mechanical protection is the mainstay of conservative therapy, but surgical reconstruction of a deformed foot can usually also be successful. Unless diagnosed very early, significant decrements in quality of life result. Controlled studies are urgently needed to identify best practices.

Charcot osteo-arthropathy

Summary Charcot osteo-arthropathy is a potentially catastrophic complication of neuropathy. It can occur in any joint and has been associated with many of the causes of sensory deprivation; however it most commonly presents in the foot and ankle in the diabetic population. This article stresses early recognition and prevention of deformity. The key topics are: Pathophysiology: unrecognised microtrauma versus osseous hyperaemia as likely aetiologies, leading to fragmentation of the affected joint or bone. Assessment: diagnosis of neuropathy, x-ray changes, alternative imaging and its limitations and investigation to rule out other causes. Classification and staging: current staging of Charcot osteo-arthropathy and anatomical classification of foot and ankle Charcot osteo-arthropathy. Treatment: Current recommended treatment modalities including conservative, operative and pharmacological.

Cytoprotective effects of phenolic acids on methylglyoxal‐induced apoptosis in Neuro‐2A cells

In the process of glycation, methylglyoxal is a reactive dicarbonyl compound physiologically generated as an intermediate of glycolysis, and is found in high levels in blood or tissue of diabetic models. Biological glycation has been commonly implicated in the development of diabetic microvascular complications of neuropathy. Increasing evidence suggests that neuronal cell cycle regulatory failure followed by apoptosis is an important mechanism in the development of diabetic neuropathy complication. Naturally occurring antioxidants, especially phenolic acids have been recommended as the major bioactive compounds to prevent chronic diseases and promote health benefits. The objective of this study was to investigate the inhibitory abilities of phenolic acids (chlorogenic acid, syringic acid and vanillic acid) on methylglyoxal-induced mouse Neuro-2A neuroblastoma (Neuro-2A) cell apoptosis in the progression of diabetic neuropathy. The data indicated that methylglyoxal induced mouse Neuro-2A neuroblastoma (Neuro-2A) cell apoptosis via alternation of mitochondria membrane potential and Bax/Bcl-2 ratio, activation of caspase-3, and cleavage of poly (ADP-ribose) polymerase. Furthermore, the results demonstrated that activation of mitogen-activated protein kinase signal pathways (JNK and p38) participated in the methylglyoxal-induced Neuro-2A cell apoptosis process. Treatment of Neuro-2A cells with phenolic acids markedly suppresses cell apoptosis induced by methylglyoxal, suggesting that phenolic acids possess cytoprotective ability in the prevention of diabetic neuropathy complication.

Inhibitory effect of vanillic acid on methylglyoxal-mediated glycation in apoptotic Neuro-2A cells

Methylglyoxal is a reactive dicarbonyl compound generated as an intermediate of glycolysis during the physical glycation in the diabetic condition. It is considered to be a potent precursor of advanced glycation end products (AGEs) formation. Methylglyoxal itself and methylglyoxal-derived AGEs have been commonly implicated in the development of diabetic neuropathy. Our previous study indicated that vanillic acid showed an inhibitory effect against methylglyoxal-mediated Neuro-2A cell apoptosis, suggesting that vanillic acid might possess cytoprotective properties in the prevention of diabetic neuropathy complication. In this study, the effects of vanillic acid on the methylglyoxal-mediated glycation system involved in the progression of Neuro-2A cell apoptosis were further investigated. Our findings indicated that methylglyoxal-induced Neuro-2A cell apoptosis was mediated through the possible glycation mechanism of oxidative stress, activation of the MAPK signaling pathway (p38 and JNK) and oxidation-sensitive protein expression (PKC and p47 phox) and methylglyoxal-derived N-ɛ-(carboxymethyl)lysine (CML) formation. Vanillic acid, however, suppressed methylglyoxal-induced Neuro-2A cell apoptosis via inhibition of glycation mechanisms including ROS, p38 and JNK, PKC and p47 phox, and methylglyoxal-derived CML formation. In the present study, we established the first evidence that vanillic acid might contribute to the prevention of the development of diabetic neuropathy by blocking the methylglyoxal-mediated intracellular glycation system.

Decompressive surgery of lower limbs for symmetrical diabetic peripheral neuropathy.

Symmetrical peripheral neuropathy is a common complication of diabetic neuropathy. No treatments are known to be effective for progressive pain and sensory loss associated with diabetic neuropathy. Alternative effective treatment strategies have been sought. To systematically review the evidence from randomized controlled trials concerning the role of decompressive surgery of lower limbs for symmetrical diabetic peripheral neuropathy. We searched the Cochrane Neuromuscular Disease Trials Register (May 2006), CENTRAL (The Cochrane Library, Issue 2 2006), MEDLINE from (January 1966 to August 2006), EMBASE (from January 1980 to August 2006), LILACS (from January 1982 to August 2006), and CINAHL (from January 1982 to August 2006). We included all randomized or quasi-randomized controlled human trials in which any form of decompressive surgery of the lower limbs nerves had been used to treat diabetic symmetrical distal polyneuropathy (DSDP) compared with no treatment or medical therapy. Patients with DSDP were included if they had decompression (with or without neurolysis) of at least two of the following nerves in both lower limbs, for the treatment of DSDP: the posterior tibial nerve (including calcaneal, medial and lateral plantar nerves), deep peroneal nerve at the ankle, common peroneal nerve at the knee, lateral femoral cutaneous nerve and sural nerves in the posterior calf region. The primary outcome measure was the change in pain measured by the visual analogue scale (VAS) between the baseline and a follow-up period of greater than three months. We identified 142 publications from the above search strategies. The three authors of this manuscript reviewed abstracts of all papers independently. Only eight of these were considered relevant to the question at hand. The data from these 8 studies were entered onto standardized data extraction forms. We planned to use Review Manager to pool the results from appropriate studies comparing the same treatments; dichotomous outcomes to obtain pooled relative risks (RR); measured outcomes to obtain pooled weighted mean differences; and a fixed-effect analysis unless there was evidence of serious heterogeneity between studies sufficient to justify the use of random-effects analysis. This review failed to identify a single randomized controlled trial or any other well designed prospective study controlling for the non-operated limb that showed improvements in pre defined end points after decompressive surgery. The results of this review suggest that the role of decompressive surgery for diabetic symmetric distal neuropathy is unproven.

Mentoring Junior Faculty in Geriatric Oncology: Report From the Cancer and Aging Research Group

Mentoring Junior Faculty in Geriatric Oncology: Report From the Cancer and Aging Research Group

Neurological complications of coeliac disease: what is the evidence?

Coeliac disease is a chronic immune-mediated disorder that primarily affects the gastrointestinal tract. There is an inflammatory response in the intestine to the ingestion of gluten which improves with a...

Advanced glycation end products and diabetic foot disease

Diabetic foot disease is an important complication of diabetes. The development and outcome of foot ulcers are related to the interplay between numerous diabetes-related factors such as nerve dysfunction, impaired wound healing and microvascular and/or macrovascular disease.The formation of advanced glycation end products (AGEs) has been recognized as an important pathophysiological mechanism in the development of diabetic complications. Several mechanisms have been proposed by which AGEs lead to diabetic complications such as the accumulation of AGEs in the extracellular matrix causing aberrant cross-linking, the binding of circulating AGEs to the receptor of AGEs (RAGE) on different cell types and activation of key cell signalling pathways with subsequent modulation of gene expression, and intracellular AGE formation leading to quenching of nitric oxide and impaired function of growth factors. In the last decade, many experimental studies have shown that these effects of AGE formation may play a role in the pathogenesis of micro- and macrovascular complications of diabetes, diabetic neuropathy and impaired wound healing. In recent years also, several clinical studies have shown that glycation is an important pathway in the pathophysiology of those complications that predispose to the development of foot ulcers. Currently, there are a number of ways to prevent or decrease glycation and glycation-induced tissue damage. Although not in the area of neuropathy or wound healing, recent clinical studies have shown that the AGE-breakers may be able to decrease adverse vascular effects of glycation with few side effects.

Interactions between microvascular and macrovascular disease in diabetes: pathophysiology and therapeutic implications

Convention partitions the complications of diabetes into two main subtypes. First are the diabetes-specific microvascular complications of retinopathy, nephropathy and neuropathy; second are the atherothrombotic macrovascular complications that account for the majority of premature deaths. Pathological interactions between microvascular and macrovascular complications, for example, nephropathy and macrovascular disease, are common. Similar mechanisms and shared risk factors drive the development and progression of both small and large vessel disease. This concept has therapeutic implications. Mounting evidence points to the need for multifactorial strategies to prevent vascular complications in subjects with diabetes and/or the metabolic syndrome. We advocate a combined therapeutic approach that addresses small and large vessel disease. Preferential use should be made of drug regimens that (i) maximize vascular protection, (ii) reduce the risk of iatrogenic vascular damage and (iii) minimize the increasing problem of polypharmacy.

Nitrofurantoin Neuropathy

Nitrofurantoin is a widely prescribed antibiotic used to treat uncomplicated lower urinary tract infections. Unknown in the obstetric and gynecologic literature is the complication of peripheral neuropathy as an adverse effect. We describe a patient who developed a severe sensory neuropathy after taking nitrofurantoin intermittently and then continuously over a 7-year period. She recovered almost completely after its discontinuation. Peripheral neuropathy is a rare and potentially reversible adverse effect, unreported in the obstetric and gynecologic literature, and commonly unrecognized by physicians who prescribe it.

A multicenter survey on the diabetic foot and its neuropathy in China

To investigate the characteristics of diabetic foot with neuropathy and its related factors. 530 out- and in-patients in 14 grade A class 3 comprehensive hospitals in China with foot problems were surveyed. 337 of the 500 patients (63.58%) suffered from neuropathy, 172 (32.45%) with diabetic foot with simple neuropathy and 165 (31.13%) with simple neuropathy combined with peripheral artery disease (PAD). 193 of the 500 patients (36.42%) suffered from peripheral artery disease (PAD). 77.7% of ulcer were caused by physical factors. Questionnaire survey was conducted to collect the demographic data, present and past history, history of the hyperglycemia and lipid disorders, classification and phases of the foot ulcers based on Wagner' system and Texas system, characteristics of neuropathy and other diabetic complications, and relative risk factors. Detailed physical examination was performed, including 10 g nylon filament sensation examination. The duration of diabetic foot of the patients with simple neuropathy was 3 (1, 60) months, significantly shorter than that of the diabetic foot patients with PAD [5 (1, 96) months, P < 0.001]. The Wagner degree of ulcer was related to the duration of diabetes, economic income, foot deformity, nerve reflection, diapason vibration sensation of foot, sensation point of 10 g nylon filament, ankle/brachial index (ABI), foot artery pulse, fasting blood sugar (FBS) and glycated hemoglobin (HbA1c). Stepwise regression analysis revealed that ABI of left posterior tibial artery, vibration detection threshold and economic income were the most significant influencing factors of the degree of ulcer. Neuropathy ulcer is common in diabetic foot patients. The prognosis of healing in diabetic foot with neuropathy is prior to that of diabetic foot with PAD. The neuropathy and PAD of foot influence each other and aggravate the condition of diabetic foot. The examinations of diapason vibration sensation of foot, sensation point of 10 g nylon filament, and Achilles tendon reflex are simple and practical, and are worth recommending.

Treatment of Diabetic Foot Ulcer: An Overview Strategies for Clinical Approach

Diabetic foot disease is a major health problem, which concerns 15% of the 200 million patients with diabetes worldwide. Major amputation, above or below the knee, is a feared complication of diabetes. More than 60% of non-traumatic amputations in the western world are performed in the diabetic population. Many patients who undergo an amputation, have a history of ulceration. Major amputations increase morbility and mortality and reduce the patient's quality of life. Treatment of foot complications is one of the main items in the absorption of economic and health resources addressed to the diabetic population. It is clear that effective treatment can bring about a reduction in the number of major amputations. Over recent years, we have seen a significant increase in knowledge about the physiopathological pathways of this complication, together with improvements in diagnostic techniques, but above all a standardized conservative therapeutic approach, which allows limb salvage in a high percentage of cases. This target has been achieved in specialized centers. An important prelude to diabetic foot treatment is the differing diagnosis of neuropathic and neuroischemic foot. This differentiation is essential for effective treatment. Ulceration in neuropathic foot is due to biomechanical stress and high pressure, which involves the plantar surface of toes and metatarsal heads. Treatment of a neuropathic plantar ulcer must correct pathological plantar pressures through weight bearing relief. Surgical treatment of deformities, with or without ulcerations, is effective therapy. A neuropathic ulcer that is not adequately treated can become a chronic ulcer that does not heal. An ulcer that does not heal for many months has a high probability of leading to osteomyelitis, for which treatment with antibiotics is not useful and which usually requires a surgical procedure. Charcot neuroarthropathy is a particular complication of neuropathy which may lead to fragmentation or destruction of joints and bones. A well-timed diagnosis of Charcot neuroartropathy is essential to avoid deformities of chronic evolution. In the diabetic population peripheral vascular disease (PVD) is the main risk factor for amputation. If peripheral vascular disease is ignored, surgical treatment of the lesion cannot be successful. In diabetic patients, PVD is especially distal, but often fully involves the femoral, popliteal and tibial vessels. It can be successfully treated with either open surgical or endovascular procedures. Infection is a serious complication of diabetic foot, especially when neuroischemic: phlegmon or necrotizing fascitis are not only limb-threatening problems, but also life-threatening ones. In this case, emergency surgery is needed. Primary and secondary prevention of foot ulceration is the main target. Prevention programs must be carried out to highlight risk factors, lowering amputation incidence.

Oral Antimicrobial Therapy for Diabetic Foot Osteomyelitis

Osteomyelitis in the foot of a diabetic individual is a common complication of peripheral neuropathy, peripheral vascular disease, and infection. Operative facilities and home intravenous antibiotic therapy programs may not be available in remote or rural communities. Limited data are available regarding the treatment results of oral antimicrobial therapy, with or without limited office debridement for diabetic foot osteomyelitis. This retrospective medical record review of 325 consecutive diabetic patients who were evaluated at a multidisciplinary foot clinic identified 94 (29%) patients with 117 episodes of osteomyelitis. The most common group of organisms isolated were aerobic gram-positive cocci, and the single most frequent organism was Staphylococcus aureus. A mean of 1.6 +/- 0.8 (range 1 to 4) pathogens were recovered per episode of osteomyelitis. Therapy was guided by culture results. There were 93 episodes of osteomyelitis (79 patients) that were treated with a mean of 3 +/- 1 oral antimicrobial agents (with or without an initial short course of intravenous antimicrobial agents) and had adequate followup to evaluate outcome of treatment; office treatment included bone debridement in 26 (28%) and toe amputation in nine (10%) of the 93 episodes (79 patients). Of the 93 episodes treated with oral antimicrobial agents (with or without an initial short course of intravenous antimicrobial agents), 75 (80.5%) episodes were put into remission. Mean duration of oral antimicrobial therapy was 40 +/- 30 weeks. Mean relapse-free followup duration was 50 +/- 50 weeks. Diabetic foot osteomyelitis was effectively managed with oral antimicrobial therapy with or without limited office debridement in most patients. This regimen may be especially useful in communities where infectious disease specialists and operative resources are limited.

Spontaneous Avulsion Fracture Of The Calcaneus In A Non-Diabetic Patient

Doctors working in Emergency Medicine are well aware of the common mechanism of injury causing and the clinical appearances of fractures of the calcaneus. We report a rare case of an avulsion fracture of the calcaneus. Although avulsion fractures are a well-recognised complication of diabetic neuropathy they can occasionally occur in non-diabetic patients. The pathology and management of these fractures is further discussed.

Compartment Syndrome, Fasciotomy, and Neuropathy After a Rattlesnake Envenomation: Aspects of Monitoring and Diagnosis

Compartment syndrome resulting from pitviper envenomation is uncommon in North America; however, when it does occur, early diagnosis, optimal antivenom therapy, and possible surgical decompression are the primary means of preventing the complication of neuropathy. Here, we report a case of a rattlesnake envenomation in the anterior compartment of the lower leg that required high doses of morphine to control pain. Although compartment syndrome was considered a possible outcome, subfascial pressures were not monitored and antivenom was discontinued at 24 hours. At 36 hours, the patient developed dorsal foot numbness and foot drop, and 15 hours later pressures within the anterior compartment were >68 mm Hg. Emergency fasciotomy was performed 59 hours postenvenomation. Peroneal neuropathy was evident after surgery and only partially recovered postoperatively. Earlier monitoring of subfascial pressures and using those pressures as a guide for decisions about time and dose of CroFab antivenom treatment may have permitted earlier surgical treatment after onset of compartment syndrome or even prevented the onset of this condition.

Acculturation and Diabetes among Hispanics: Evidence from the 1999–2002 National Health and Nutrition Examination Survey

Hispanic individuals in the United States have a greater prevalence of diabetes mellitus than non-Hispanic white individuals; however, it is unclear whether Hispanics' risk of diabetes differs based on their level of acculturation. The purpose of our research was to examine acculturation among Hispanic Americans with respect to prevalence and control of diabetes. We conducted an analysis of the National Health and Nutrition Examination Survey (NHANES), 1999-2002, a nationally representative sample of the noninstitutionalized U.S. population. We evaluated data on Hispanic adults (> or = 18 years of age, unweighted n=2,696), analyzing diagnosed diabetes, glycemic blood pressure and lipid control, and diabetes complications according to acculturation as measured by language and birth outside the United States. Hispanics with low acculturation were more likely to be without a routine place for health care, have no health insurance, and have low levels of education. In adjusted analyses, individuals with low acculturation, measured by language, were more likely to have diabetes (odds ratio [OR] 1.90, 95% confidence interval [CI] 1.02, 3.54). Among individuals with diagnosed diabetes, no significant association was yielded between acculturation and diabetes control. However, individuals with low language acculturation were more likely to have the diabetes complication of peripheral neuropathy (OR 4.01, 95% CI 1.40, 11.48). Acculturation as measured through language is associated with diabetes and complications among Hispanics even after controlling for a variety of demographic characteristics including health insurance and education. The findings suggest that even within a "single" minority ethnic group, there are differences in disease prevalence and complications and access to health care.

Recent advances in the diagnosis and management of diabetic neuropathy

The World Health Organisation estimated that in the year 2000, 150 million people had diabetes mellitus, and it is predicted that this number will rise to 366 million by the year 2030.[1][1] Neuropathy is a common complication of diabetes and is characterised by a progressive loss of peripheral