Progression Of Peripheral Neuropathy Research Articles

Correlation Between the Peripheral Neuropathy and Levels of hs-CRP, IL-1β and IL-6 in Senile Parkinson's Disease Patients.

This study was carried out to investigate the correlation between the onset of peripheral neuropathy and levels of hypersensitive C-reactive protein (hs-CRP), interleukin 1β (IL-1β) and IL-6 in senile Parkinson's disease (PD) patients. For this purpose, a total of 60 PD patients and 60 age-matched healthy subjects were enrolled in this study and received the assessment for peripheral nerves by using the quantified method. Besides, levels of hs-CRP, IL-1β and IL-6 in serum were determined to analyze the correlation between the clinical features, including the severity of PD and cognitive decline, and the levels of hs-CRP, IL-1β and IL-6. Results showed that PD patients had more cases of peripheral neuropathy than those in the healthy control group. Levels of hs-CRP, IL-1β and IL-6 in the serum of PD patients were much higher than those in the healthy control (P<0.05). Besides, PD patients had lower scores of MMSE and MoCA but higher CNPI scores when compared to the healthy control group. As a result, we found that the severity of peripheral neuropathy was in a positive correlation with the levels of hs-CRP, IL-1β and IL-6. It was concluded that PD patients generally have peripheral neuropathy that may correlate with the increases in the levels of hs-CRP, IL-1β and IL-6, and early intervention may mitigate the development and progression of peripheral neuropathy.

A Role for Fatty Acids in Peripheral Neuropathy Associated with Type 2 Diabetes and Prediabetes.

Significance: As the global prevalence of diabetes rises, diabetic complications are also increasing at an alarming rate. Peripheral neuropathy (PN) is the most prevalent complication of diabetes and prediabetes, and is characterized by progressive sensory loss resulting from nerve damage. While hyperglycemia is the major risk factor for PN in type 1 diabetes (T1D), the metabolic syndrome (MetS) underlies the onset and progression of PN in type 2 diabetes (T2D) and prediabetes. Recent Advances: Recent reports show that dyslipidemia, a MetS component, is strongly associated with PN in T2D and prediabetes. Dyslipidemia is characterized by an abnormal plasma lipid profile with uncontrolled lipid levels, and both clinical and preclinical studies implicate a role for dietary fatty acids (FAs) in PN pathogenesis. Molecular studies further show that saturated and unsaturated FAs differentially regulate the nerve lipid profile and nerve function. Critical Issues: We first review the properties of FAs and the neuroanatomy of the peripheral nervous system (PNS). Second, we discuss clinical and preclinical studies that implicate the involvement of FAs in PN. Third, we summarize the potential effects of FAs on nerve function and lipid metabolism within the peripheral nerves, sensory neurons, and Schwann cells. Future Directions: Future directions will focus on identifying molecular pathways in T2D and prediabetes that are modulated by FAs in PN. Determining pathophysiological mechanisms that underlie the injurious effects of saturated FAs and beneficial properties of unsaturated FAs will provide mechanistic targets for developing new targeted therapies to treat PN associated with T2D and prediabetes. Antioxid. Redox Signal. 37, 560-577.

Influence of Glucose Fluctuation on Peripheral Nerve Damage in Streptozotocin-Induced Diabetic Rats.

BackgroundIt is unclear whether glycemic variability (GV) is a risk factor for diabetic peripheral neuropathy (DPN), and whether control of GV is beneficial for DPN. The purpose of this study was to investigate the effect of GV on peripheral nerve damage by inducing glucose fluctuation in streptozotocin-induced diabetic rats.MethodsRats were divided into four groups: normal (normal glucose group [NOR]), diabetes without treatment (sustained severe hyperglycemia group; diabetes mellitus [DM]), diabetes+once daily insulin glargine (stable hyperglycemia group; DM+LAN), and diabetes+once daily insulin glargine with twice daily insulin glulisine (unstable glucose fluctuation group; DM+Lantus [LAN]+Apidra [API]). We measured anti-oxidant enzyme levels and behavioral responses against tactile, thermal, and pressure stimuli in the plasma of rats. We also performed a quantitative comparison of cutaneous and sciatic nerves according to glucose fluctuation.ResultsAt week 24, intraepidermal nerve fiber density was less reduced in the insulin-administered groups compared to the DM group (P<0.05); however, a significant difference was not observed between the DM+LAN and DM+LAN+API groups irrespective of glucose fluctuation (P>0.05; 16.2±1.6, 12.4±2.0, 14.3±0.9, and 13.9±0.6 for NOR, DM, DM+LAN, and DM+LAN+API, respectively). The DM group exhibited significantly decreased glutathione levels compared to the insulin-administered groups (2.64±0.10 μmol/mL, DM+LAN; 1.93±0.0 μmol/mL, DM+LAN+API vs. 1.25±0.04 μmol/mL, DM; P<0.05).ConclusionOur study suggests that glucose control itself is more important than glucose fluctuation in the prevention of peripheral nerve damage, and intra-day glucose fluctuation has a limited effect on the progression of peripheral neuropathy in rats with diabetes.

Lipids and peripheral neuropathy.

Hyperlipidaemia is associated with the development of neuropathy. Indeed, a mechanistic link between altered lipid metabolism and peripheral nerve dysfunction has been demonstrated in a number of experimental and clinical studies. Furthermore, post hoc analyses of clinical trials of cholesterol and triglyceride-lowering pharmacotherapy have shown reduced rates of progression of diabetic neuropathy. Given, there are currently no FDA approved disease-modifying therapies for diabetic neuropathy, modulation of lipids may represent a key therapeutic target for the treatment of diabetic nerve damage. This review summarizes the current evidence base on the role of hyperlipidaemia and lipid lowering therapy on the development and progression of peripheral neuropathy. A body of literature supports a detrimental effect of dyslipidaemia on nerve fibres resulting in somatic and autonomic neuropathy. The case for an important modulating role of hypertriglyceridemia is stronger than for low-density lipoprotein cholesterol (LDL-C) in relation to peripheral neuropathy. This is reflected in the outcomes of clinical trials with the different therapeutic agents targeting hyperlipidaemia reporting beneficial or neutral effects with statins and fibrates. The potential concern with the association between proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor therapy and cognitive decline raised the possibility that extreme LDL-C lowering may result in neurodegeneration. However, studies in murine models and data from small observational studies indicate an association between increased circulating PCSK9 levels and small nerve fibre damage with a protective effect of PCSK9i therapy against small fibre neuropathy. Additionally, weight loss with bariatric surgery leads to an improvement in peripheral neuropathy and regeneration of small nerve fibres measured with corneal confocal microscopy in people with obesity with or without type 2 diabetes. These improvements correlate inversely with changes in triglyceride levels. Hyperlipidaemia, particularly hypertriglyceridemia, is associated with the development and progression of neuropathy. Lipid modifying agents may represent a potential therapeutic option for peripheral neuropathy. Post hoc analyses indicate that lipid-lowering therapies may halt the progression of neuropathy or even lead to regeneration of nerve fibres. Well designed randomized controlled trials are needed to establish if intensive targeted lipid lowering therapy as a part of holistic metabolic control leads to nerve fibre regeneration and improvement in neuropathy symptoms.

ROLE OF VITAMIN B12 SUPPLEMENTATION IN METFORMIN INDUCED DIABETIC NEUROPATHY IN INDIAN PATIENTS. CAN SUPPLEMENTATION HELP?

Metformin is one of the most commonly used oral hypoglycemic drug amongst type II diabetes mellitus patients, particularly overweight with normal kidney functions. Literature reports an average of 10-30% of patients taking metformin for longer duration (more than 4 years) have shown some signs of vitamin B12 deficiency.&#x0D; Thus the present study was planned to assess the development of peripheral neuropathy in metformin users due to Vitamin B12 deficiency and effect of its supplementation was assessed for improvement in terms of VPT (Vibration perception threshold) score assessed by Biothesiometer which is a simple, portable, reliable, non-invasive method to screen the peripheral neuropath&#x0D; Unique about this study is, evaluating the effect of B12 supplementation on Indians patients. They being primarily vegetarian are at more risk to develop Vitamin B12 deficiency, so, metformin induced Cobalamin deficiency assumes greater risk in such patients in terms of development and progression of peripheral neuropathy.

Bergapten Ameliorates Vincristine-Induced Peripheral Neuropathy by Inhibition of Inflammatory Cytokines and NFκB Signaling.

Bergapten, a furanocoumarin derivative found in a variety of medicinal plants, is documented to possess anti-inflammatory activity. However, whether bergapten is useful in alleviating the symptoms as well as the progress of peripheral neuropathy is not yet studied. The current investigation has been designed to explore the effect of bergapten on vincristine-induced neuropathic pain. Rats were grouped as normal, neuropathic control (vincristine), gabapentin, and bergapten treated groups with five animals in each group. Vincristine (100 μg/kg, i.p.) was administered for 10 days with 2 days break. Gabapentin (60 mg/kg, i.p.) and bergapten (10 mg/kg i.p.) treatments were given once daily for 14 days. The animals were assessed for hyperalgesia and allodynia. After 14 days, animals were sacrificed to detect plasma pro-inflammatory cytokines (TNF α, IL-1β), spinal cord, and sciatic nerve oxidative stress and expression of iNOS, COX-2, and NFkB in the spinal cord. There was a marked reduction in pain behaviors in the bergapten group as compared to the vincristine group. Bergapten also attenuated pro-inflammatory cytokines (TNFα and IL-1β), oxidative stress, and expression of NFkB, COX-2, and iNOS. Overall the current study concludes that bergapten could serve as a potential lead to drug development for the treatment of neuropathic pain.

Metabolomic signature of type 1 diabetes-induced sensory loss and nerve damage in diabetic neuropathy.

Diabetic-induced peripheral neuropathy (DPN) is a highly complex and frequent diabetic late complication, which is manifested by prolonged hyperglycemia. However, the molecular mechanisms underlying the pathophysiology of nerve damage and sensory loss remain largely unclear. Recently, alteration in metabolic flux has gained attention as a basis for organ damage in diabetes; however, peripheral sensory neurons have not been adequately analyzed with respect to metabolic dysfunction. In the present study, we attempted to delineate the sequence of event occurring in alteration of metabolic pathways in relation to nerve damage and sensory loss. C57Bl6/j wild-type mice were analyzed longitudinally up to 22weeks in the streptozotocin (STZ) model of type 1 diabetes. The progression of DPN was investigated by behavioral measurements of sensitivity to thermal and mechanical stimuli and quantitative morphological assessment of intraepidermal nerve fiber density. We employed a mass spectrometry-based screen to address alterations in levels of metabolites in peripheral sciatic nerve and amino acids in serum over several months post-STZ administration to elucidate metabolic dysfunction longitudinally in relation to sensory dysfunction. Although hyperglycemia and body weight changes occurred early, sensory loss and reduced intraepithelial branching of nociceptive nerves were only evident at 22weeks post-STZ. The longitudinal metabolites screen in peripheral nerves demonstrated that compared with buffer-injected age-matched control mice, mice at 12 and 22weeks post-STZ showed an early impairment the tricaoboxylic acid (TCA cycle), which is the main pathway of carbohydrate metabolism leading to energy generation. We found that levels of citric acid, ketoglutaric acid (2 KG), succinic acid, fumaric acid, and malic acid were observed to be significantly reduced in sciatic nerve at 22weeks post-STZ. In addition, we also found the increase in levels of sorbitol and L-lactate in peripheral nerve from 12weeks post-STZ injection. Amino acid screen in serum showed that the amino acids valine (Val), isoleucine (Ile), and leucine (Leu), grouped together as BCAA, increased more than twofold from 12weeks post-STZ. Similarly, the levels of tyrosine (Tyr), asparagine (Asn), serine (Ser), histidine (His), alanine (Ala), and proline (Pro) showed progressive increase with progression of diabetes. Our results indicate that the impaired TCA cycle metabolites in peripheral nerve are the primary cause of shunting metabolic substrate to compensatory pathways, which leads to sensory nerve fiber loss in skin and contribute to onset and progression of peripheral neuropathy.

Sensory Cutoff Value for Predicting Postural Instability in People with Peripheral Neuropathy Secondary to Diabetes

People with peripheral neuropathy (PN) secondary to diabetes have higher risks of falls due to loss of the somatosensation of the feet. The purpose of this study was to investigate the cutoff values of the vibration threshold and the monofilament test to predict postural instability. Ten healthy younger adults, ten healthy older adults and ten people with PN secondary to diabetes were recruited in this study. A handheld bio-thesiometer and a set of monofilaments were used to measure the vibration threshold (VT) and tactile sensitivity (TS), respectively. VT and TS were measured at six different sites on the plantar surface, including big toe, 1st metatarsus, little toe, 5th metatarsus, middle arch, and calcaneus (heel), plus the lateral and medial malleoli. Subjects also underwent a Sensory Organization Test (SOT) to identify postural instability, defined as equilibrium scores less than age matched norms. Linear regression was used to determine which site(s) was able to predict the balance test performance. Receiver operating characteristic curves were used to compute the VT and TS cutoff values associated with postural instability. A cutoff value of 10V for lateral malleolus VT was able to predict postural abnormality with 100% Sensitivity and 54.5% Specificity. A cutoff value of 3.61 for middle arch TS was able to predict postural abnormality with 100% Sensitivity and 86.4% Specificity. Postural instability appears earlier than the current recommended clinical cutoff values for peripheral neuropathy (25V for VT and 5.07 for TS). Although current cutoff values of the vibration threshold and the monofilament test are useful for detecting a propensity for neuropathic foot ulcer, they may not be adequate for detecting early postural instability. Fall prevention strategies may be needed early in the progression of PN. Disclosure N. Aung: None. S.A. Meardon: None. C. Lin: None. R.J. Tanenberg: None.

Assessment Tools for Peripheral Neuropathy in Pediatric Oncology: A Systematic Review From the Children's Oncology Group.

Peripheral neuropathy is a known side effect of several chemotherapy agents, including vinca alkaloids and platinum-based chemotherapy. Early recognition and monitoring of this side effect is an important role of the pediatric oncology nurse. There are a variety of peripheral neuropathy assessment tools currently in use, but the usefulness of these tools in identifying and grading neuropathy in children varies, and there is currently no standardized tool in place to evaluate peripheral neuropathy in pediatric oncology. A systematic review was performed to identify the peripheral neuropathy assessment tools that best evaluate the early onset and progression of peripheral neuropathy in pediatric patients receiving vincristine. Because of the limited information available in pediatric oncology, this review was extended to any pediatric patient with neuropathy. A total of 8 studies were included in the evidence synthesis. Based on available evidence, the pediatric-modified Total Neuropathy Scale (ped-m TNS) and the Total Neuropathy Score-pediatric version (TNS-PV) are recommended for the assessment of vincristine-induced peripheral neuropathy in children 6 years of age and older. In addition, several studies demonstrated that subjective symptoms alone are not adequate to assess for vincristine-induced peripheral neuropathy. Nursing assessment of peripheral neuropathy should be an integral and regular part of patient care throughout the course of chemotherapy treatment.

Astragaloside IV protects RGC-5 cells against oxidative stress.

Astragaloside IV is the main active compound of Astragalus membranaceus. Astragaloside IV has strong anti-oxidative activities and protective effects against progression of peripheral neuropathy. In this study, we determined whether astragaloside IV protects retinal ganglion cells (RGC) from oxidative stress injury using the rat RGC-5 cell line. Hydrogen peroxide (H2O2) was used to induce oxidative stress injury, with the protective effect of astragaloside IV examined. Cell Counting Kit-8 and 4',6-diamidino-2-phenylindole staining showed that astragaloside IV increased cell survival rate and decreased apoptotic cell number. Flow cytometry showed that astragaloside IV decreased H2O2-induced reactive oxygen species levels. While laser confocal microscopy showed that astragaloside IV inhibited the H2O2-induced decrease of mitochondrial membrane potential. Western blot assay showed that astragaloside IV reduced cytochrome c release induced by H2O2, inhibited Bax and caspase-3 expression, and increased Bcl-2 expression. Altogether, these results indicate that astragaloside IV has potential protective effects against H2O2-induced oxidative stress in retinal ganglion cells.

Dietary reversal of neuropathy in a murine model of prediabetes and metabolic syndrome.

ABSTRACTPatients with metabolic syndrome, which is defined as obesity, dyslipidemia, hypertension and impaired glucose tolerance (IGT), can develop the same macro- and microvascular complications as patients with type 2 diabetes, including peripheral neuropathy. In type 2 diabetes, glycemic control has little effect on the development and progression of peripheral neuropathy, suggesting that other metabolic syndrome components may contribute to the presence of neuropathy. A parallel phenomenon is observed in patients with prediabetes and metabolic syndrome, where improvement in weight and dyslipidemia more closely correlates with restoration of nerve function than improvement in glycemic status. The goal of the current study was to develop a murine model that resembles the human condition. We examined longitudinal parameters of metabolic syndrome and neuropathy development in six mouse strains/genotypes (BKS-wt, BKS-Leprdb/+, B6-wt, B6-Leprdb/+, BTBR-wt, and BTBR-Lepob/+) fed a 54% high-fat diet (HFD; from lard). All mice fed a HFD developed large-fiber neuropathy and IGT. Changes appeared early and consistently in B6-wt mice, and paralleled the onset of neuropathy. At 36 weeks, B6-wt mice displayed all components of the metabolic syndrome, including obesity, IGT, hyperinsulinemia, dyslipidemia and oxidized low density lipoproteins (oxLDLs). Dietary reversal, whereby B6-wt mice fed a HFD from 4-20 weeks of age were switched to standard chow for 4 weeks, completely normalized neuropathy, promoted weight loss, improved insulin sensitivity, and restored LDL cholesterol and oxLDL by 50% compared with levels in HFD control mice. This dietary reversal model provides the basis for mechanistic studies investigating peripheral nerve damage in the setting of metabolic syndrome, and ultimately the development of mechanism-based therapies for neuropathy.

Increased aortic stiffness predicts future development and progression of peripheral neuropathy in patients with type 2 diabetes: the Rio de Janeiro Type 2 Diabetes Cohort Study.

Diabetic peripheral neuropathy (DPN) is a chronic microvascular complication that is strongly associated with poor glycaemic control and also with a worse prognosis. We aimed to evaluate the predictors of the development and progression of DPN in a cohort of high-risk patients with type 2 diabetes. In a prospective study, 477 patients with type 2 diabetes were clinically assessed for the presence of DPN at baseline and after a median follow-up of 6.2 years (range 2-10 years). Clinical laboratory data were obtained at study entry and throughout the follow-up. Aortic stiffness was assessed by the carotid-femoral pulse wave velocity (cf-PWV) at baseline. Multivariate Poisson regression analysis was used to examine independent predictors of the development/progression of DPN. At baseline, 135 patients (28%) had DPN, and during follow-up 97 patients (20%) had either a new development or a worsening of DPN. Patients who showed a development or progression of DPN were taller and had a longer duration of diabetes, a greater prevalence of other microvascular complications and hypertension, greater aortic stiffness and poorer glycaemic control than patients who did not have new or progressive neuropathy. After adjustments for the baseline prevalence of DPN, the patient's age and sex, and the time interval between DPN assessments; an increased aortic stiffness (cf-PWV >10 m/s) were predictive of new/progressive DPN (incidence rate ratio 2.04, 95% CI 1.28, 3.23; p = 0.002). Other independent predictors were the mean first-year HbA1c level (p = 0.05), nephropathy (p = 0.006), arterial hypertension (p = 0.06) and height (p = 0.03). Increased aortic stiffness at baseline predicts the future development or progression of peripheral neuropathy, independent of diabetic metabolic control, suggesting a physiopathological link between macrovascular and microvascular abnormalities in type 2 diabetes.

Effect of diet-induced obesity or type 1 or type 2 diabetes on corneal nerves and peripheral neuropathy in C57Bl/6J mice.

We determined the impact diet-induced obesity (DIO) and types 1 and 2 diabetes have on peripheral neuropathy with emphasis on corneal nerve structural changes in C57Bl/6J mice. Endpoints examined included nerve conduction velocity, response to thermal and mechanical stimuli and innervation of the skin and cornea. DIO mice and to a greater extent type 2 diabetic mice were insulin resistant. DIO and both types 1 and 2 diabetic mice developed motor and sensory nerve conduction deficits. In the cornea of DIO and type 2 diabetic mice there was a decrease in sub-epithelial corneal nerves, innervation of the corneal epithelium, and corneal sensitivity. Type 1 diabetic mice did not present with any significant changes in corneal nerve structure until after 20 weeks of hyperglycemia. DIO and type 2 diabetic mice developed corneal structural damage more rapidly than type 1 diabetic mice although hemoglobin A1 C values were significantly higher in type 1 diabetic mice. This suggests that DIO with or without hyperglycemia contributes to development and progression of peripheral neuropathy and nerve structural damage in the cornea.

Neuropathies amyloïdes héréditaires : aspects thérapeutiques

Patients with familial amyloidpolyneuropathies (FAP) require multidisciplinary neurologic and cardiologic management, including specific treatments to control the progression of systemic amyloidogenesis, symptomatic treatment of peripheral and autonomic neuropathies, and management of severe organ involvement (heart, eyes, kidneys). The first-line specific treatment of choice for met30 TTR-FAP is liver transplantation (LT) which suppresses the main source of mutant TTR, halts the progression of neuropathy in 70% of cases, and doubles the median survival time. Dual kidney-liver or heart-liver transplantation may be appropriate for patients with severe renal or cardiac failure. Tafamidis (Vyndaqel(R), Pfizer), a novel stabilizer of tetrameric TTR, has shown short-term effectiveness in slowing the progression of peripheral neuropathy in very early stages of met30 TTR-FAP This drug should thus be proposed for stage 1 symptomatic polyneuropathy. Other innovative medicines (RNA interference, antisense oligonucleotides) have been developed to block hepatic production of both mutant and wildtype TTR (noxious in late-onset forms of NAH after age 50 years), and to remove amyloid deposits (monoclonal anti-SAP). Clinical trials should first include patients with late-onset FAP or non-met30 TTR-FAP who are less responsive to LT7 and patients in whom Vyndaqel(R) is ineffective or inappropriate. Initial and periodic cardiac assessment is necessary, as cardiac impairment is inevitable and largely responsible for mortality. Symptomatic treatment is crucial to improve these patients' quality of life. Familial screening for carriers of the TTR gene mutation and regular clinical examination are essential to detect disease onset and to start specific therapy in a timely manner.

Bilateral Hand Weakness and Numbness

HISTORY: 51year old right-handed male who had 3 months of tingling in his right hand's fingers. He rapidly developed weakness of the boht hands in the next few months. His arms felt "heavy" and he was having difficulty performing daily activities such as dressing himself, shaving, and eating. By presentation, the symptoms were equal in both hands/arms. He also endorses a 5 kg weight loss. The patient smokes about 1 PPD since age 16 and drinks alcohol socially. He worked as a materials handler at a federal mint until a few months ago, when he stopped working due to hand weakness. PHYSICAL EXAMINATION: CN II-XII were intact. There was noticeable atrophy in both hands with occasional fasciculations. Strength in the proximal arms was normal. He had diminished 2-3/5 strength in finger extension, 3-4/5 in finger abduction, 4/5 in finger flexion, and 4/5 in thumb abduction. Lower extremities had full strength. Reflexes were 2+ and symmetric. There was decreased pinprick sensation in the lower forearms and hands and decreased vibratory sensation in both hands. DIFFERENTIAL DIAGNOSIS: 1. Inflammatory/immune polyneuropathy 2. Brachial plexopathy 3. Paraneoplastic process 4. Vasculitis 5. Cervical spine disease with ulnar neuropathy TEST AND RESULTS: Blood work: B12, ESR, RF, ANA, HCV, pareneoplastic panel, and TSH are unremarkable. CSF with slightly high protein, but otherwise normal.No systemic markers of vasculitis. MRI: Moderate to severe spinal stenosis at C6/7 with bilateral neuroforaminal narrowing (symptoms do not correlate to this level) Moderate spinal stenosis at C5/6 and C7/T1 No abnormality of either brachial plexus Degenerative changes in lower c-spine with moderate canal and neuroforaminal stenosis EMG: Decreased ulnar sensory and motor function; median and radial nerves normal Severe chronic partial denervation in 1st dorsal interosseous and flexor digitorum profundus Other C7-innervated muscles showed mild chronic partial denervation FINAL/WORKING DIAGNOSIS: Lewis-Sumner Syndrome (variant of chronic inflammatory demyelinating polyneuropathy) TREATMENT AND OUTCOMES: 1. Oral prednisone. Follow-up in 4 months showed no further progression of peripheral neuropathy 2. Steroids will be continued for 3 months, if no evidence of axonal regeneration then IV gamma globulin will considered 3. Physical therapy

Serial nerve conduction studies of the tail of rhesus monkey ( Macaca mulatta ) and potential implications for interpretation of human neurophysiological studies

It is well accepted in clinical medicine that nerve conduction studies are helpful in the diagnosis of diabetic peripheral neuropathy. However, some clinicians utilize serial nerve conduction studies to make inferences regarding the progression of peripheral neuropathy. The validity of this clinical construct has not been established. In order to determine the variability in serial nerve conduction studies, sensory and motor responses were obtained from the caudal nerve of the tail of a diabetic monkey. In particular, the sensory and motor nerve conduction studies were obtained on seven separate occasions over a period of 4.5 months in a diabetic Macaca mulatta monkey. The coefficient of variation in the motor onset latency, motor amplitude, sensory onset latency and sensory amplitude was 10.7%, 56.4%, 4.2% and 23.4%, respectively. These results suggest that physicians should be cautious in making clinical inferences based on the changes in serial nerve conduction studies.

Inhibitory effects of astragaloside IV on diabetic peripheral neuropathy in rats

Astragaloside IV (AGS-IV), a new glycoside of cycloartane-type triterpene isolated from the root of Astragalus membranaceus (Fisch.) Bunge, has been used experimentally for its potent immune-stimulating, anti-inflammatory, and antioxidative actions. A recent study has shown AGS-IV to be an aldose-reductase inhibitor and a free-radical scavenger. This study examined the effects of AGS-IV on motor nerve conduction velocity (MNCV), tailflick threshold temperature, biochemical indexes, and the histology of the sural nerve after diabetes was induced in rats with 75 mg/kg streptozotocin (STZ). AGS-IV (3, 6, 12 mg/kg, twice a day) was administered by oral gavage for 12 weeks after diabetes was induced. Compared with control (nondiabetic) rats, obvious changes in physiological behaviors and a significant reduction in sciatic MNCV in diabetic rats were observed after 12 weeks of STZ administration. Morphological analysis showed that AGS-IV suppressed a decrease in myelinated fiber area, an increase in myelinated fiber density, and an increase in segmental demyelination in diabetic rats. The protective mechanism of AGS-IV involved a decrease in declining blood glucose concentration and HbA1C levels, and an increase in plasma insulin levels. AGS-IV increased the activity of glutathione peroxidase in nerves, depressed the activation of aldose reductase in erythrocytes, and decreased the accumulation of advanced glycation end products in both nerves and erythrocytes. Moreover, AGS-IV elevated Na+,K+-ATPase activity in both the nerves and erythrocytes of diabetic rats. These results indicate that AGS-IV exerts protective effects against the progression of peripheral neuropathy in STZ-induced diabetes in rats through several interrelated mechanisms.

The potential role of cell adhesion molecules in the pathogenesis of diabetic neuropathy.

Cross-sectional studies have shown plasma cell adhesion molecules (CAMs) to be increased in patients with diabetes-related complications. In the first prospective study of CAMs, we have shown that plasma CAMs may be a predictor of the development of diabetic neuropathy. We followed up 28 diabetic patients (13 neuropathic) over a 5 year period, starting from 1991. All patients had peroneal nerve conduction velocity (PNCV), vibration perception threshold and plasma CAMs measured at baseline and follow-up. We found P-selectin and intercellular adhesion molecule-1 (ICAM-1) to be increased at baseline in patients with neuropathy compared to non-neuropathic patients. P-selectin and E-selectin were also found to be significantly higher at baseline in patients who at follow-up showed deterioration in PNCV of more than 3 m/s (p<0.05; p=0.01; respectively). P-selectin and ICAM-1 strongly correlated with PNCV. Univariate and multivariate regression analyses showed a significant inverse association between increasing log P-selectin, log E-selectin and log ICAM-1 with decreasing PNCV, and remained significant even after adjustment for glycaemic control. P-selectin and E-selectin, odds ratios of 8.8 (95% CI: 1.1-68.8; p=0.038) and 12.5 (95% CI: 1.2-132.1; p=0.036), respectively, were significantly associated with the risk of deterioration of PNCV after 5 years. This study suggests that plasma cell adhesion molecules may play an important role in the development and progression of peripheral neuropathy in diabetes mellitus.

Peripheral diabetic neuropathy: current concepts in treatment.

To review pathophysiology and current concepts in the treatment of diabetic peripheral neuropathy (PN). References were identified through a MEDLINE search of the English-language literature from 1976 through 1994. Additional references were obtained from reference lists of articles identified through the search. All articles were considered for possible inclusion in the review. Clinical trials that involved an adequate number of patients and review articles were selected. Information from articles that was judged by the authors to be significant was selected for discussion. PN affects 5-50% of people with diabetes in the US and most commonly is characterized by tingling or burning sensations, particularly in the calves, ankles, and feet, with a loss of vibratory sense. Treatment of PN, for the most part, has been unsatisfactory. Therapy has been directed toward either improving nerve function or alleviating symptoms of PN, including pain and paresthesia. Glycemic control may slow the progression of PN. Hyperglycemia also is associated with decreased pain threshold in patients with diabetes mellitus. The aldose reductase inhibitors, particularly tolrestat, have been shown to improve objective and subjective neurologic function. Pain or paresthesia has been treated effectively with antidepressants, lidocaine, mexiletine, and capsaicin. The anticonvulsants phenytoin and carbamazepine may be effective, but are associated with a greater degree of adverse effects. Experimental treatments, such as gamma-linolenic acid, gangliosides, uridine, and the corticotropin4-9 analog ORG 2766, have been effective in improving neurologic function. Treatment of PN remains unsatisfactory. Therapy should be directed toward prevention with glycemic control and symptomatic treatment of existing PN.

Clinical experience with amino acid and keto acid diets

A diet containing about 18 g of mixed protein supplemented with essential amino acids or keto acids has been used as an alternative to dialysis for long-term treatment of 68 patients (mean age, 56 years) with end-stage renal failure (mean creatinine clearance, 4.8 mI/mm at the beginning of treatment). After institution of the dietary regimen, serum urea and serum urea! creatinine ratio decreased, while serum creatinine increased slowly due to progression of the underlying renal disease. Serum albumin and transferrin were unchanged and no progression of peripheral neuropathy was observed. The patients were treated for 30 to 840 days (mean, 215 days) before they were dialyzed or received a kidney transplant. Seven elderly patients (mean age, 68.9 years) who were considered not suitable for active treatment for medical reasons, died after an average of 326 days on treatment with the diet. The 3-year cumulative survival in all 68 patients was 68%, which is well at level with the survival rates of patients treated with dialysis or renal transplantation, especially considering the high mean age of our patients. The cumulative 3-year survival after exclusion of seven patients not accepted for active treatment and 17 transplanted patients was 86%. We conclude that treatment with an l8-g protein diet plus essential amino acids can considerably extend the period of conservative treatment and postpone the start of regular dialysis without endangering life expectancy of the patients. Am. J. Clin. Nutr. 33: 1654-1659, 1980.