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PubMed1996

Peripheral neuropathy in the spontaneously diabetic WBN/Kob rat.

We report that the morphological characteristics of the peripheral neuropathy in WBN/Kob rat, a diabetic animal model that develops persistent diabetes, were primary segmental demyelination and secondary axonal degeneration. These findings are similar to those in human patients with diabetes mellitus and unlike those in rodents with streptozotosin-induced diabetes. However, these changes were also indistinguishable from those of age-dependent neuropathy. In the spontaneous peripheral motor neuropathy of rats, pressure neuropathy from housing in wire-mesh cages has also been reported to be indistinguishable from the peripheral neuropathy in plantar nerve or tibial nerve. Therefore, we examined phrenic nerves that were free from the pressure of body weight in rats and described the changes with light and electron microscopy. The morphological changes of the nerve fibers consisted of myelin blebbing or distention, and early remyelination. The changes were seen with age. On morphometric analysis, a marked reduction of fiber occupancy was observed in WBN/Kob rats over 23 months old. The present study demonstrated that the peripheral neuropathy of WBN/Kob rats is myelinopathy. Since the phrenic nerve was not affected by pressure neuropathy anatomically, this study indicates that the peripheral neuropathy of WBN/Kob rats is not pressure neuropathy.

Animals↗
PubMed2000

Plasma epinephrine and norepinephrine response to stimuli in autonomic neuropathy of type 2 diabetes mellitus.

The objective of this study was to examine epinephrine and norepinephrine plasma levels in patients with clinical type 2 diabetes mellitus, at different stages of autonomic neuropathy. Eighteen patients were classified in groups without (n = 6) and with early (n = 6), definite (n = 3) and severe (n = 3) neuropathy. Blood catecholamine levels were measured after the Valsalva maneuver, cold exposure and orthostatic tests. The norepinephrine basal levels were lower in patients with severe neuropathy (0.4 +/- 0.2 nmol/l), compared with the group with no neuropathy (1.3 +/- 0.5 nm/l, p = 0.034), or with early neuropathy (1.3 +/- 0.7 nm/l, p = 0.035). After the Valsalva maneuver, no increase was found in the group with severe alteration. In patients without neuropathy, cold exposure induced a peak of norepinephrine at 5 min (delta = 1.9 +/- 1.6 nmol/l). The increase was lower in groups with definite and severe damage. In patients with definite or moderate neuropathy, the orthostatic test induced minimal or no response. The epinephrine response to the maneuvers was not significant, and no differences were found among the groups. Norepinephrine basal levels and cold responses are diminished in patients with definite and severe autonomic neuropathy. This provides further evidence on their impaired response to stress. The comparable epinephrine levels in patients with or without autonomic neuropathy indicates that adrenal medullar function is not significantly altered.

Autonomic Nervous System Diseases↗
PubMed1999

Management of diabetic neuropathy.

The only strategy shown to be consistently beneficial in the treatment of diabetic neuropathy is meticulous control of blood glucose. The largest study of the effects of glycemic control on progression of neuropathy was the Diabetes Control and Complications Trial, which enrolled 1,500 patients. Meticulous control of blood glucose by multiple injections or continuous subcutaneous infusion both delayed the onset of neuropathy and slowed its progression. A weakness of this and other studies of the effect of glycemic control is that they used surrogate measures of improvement (or slowing of progression) of neurologic function. Most used sensory and motor nerve conduction studies and some used vibration perception thresholds. Whether such measures correlate reliably with neuropathy symptom scores, neurologic examination, quality-of-life measures, neuropathic complications (foot ulcers and amputation), and mortality remains controversial. Also, most studies of tight glycemic control do not address the complications of more intensive therapy, among them severe hypoglycemia. Severe hypoglycemia can precipitate acute painful neuropathy, and it markedly increases axonal degeneration in experimental diabetic neuropathy. Finally, all studies have been confined to patients with mild neuropathy; some patients had no clinical evidence of neuropathy. Whether benefit can accrue to patients with more advanced neuropathy is not known. The most physiologic means of achieving glycemic control is through pancreas transplantation; this can result in significant improvement in clinical and electrophysiologic measures of motor and sensory function and slightly improve autonomic function. Strategies to reduce the metabolic consequences of hyperglycemia on nerves and to enhance axonal regeneration are needed to supplement careful glycemic control. Aldose reductase inhibitors hold promise for reducing metabolic nerve injury, but further study is needed.

Aldehyde Reductase↗
PubMed1999

Features of amiodarone-induced optic neuropathy.

PURPOSE: To report clinical features of amiodarone-induced optic neuropathy and outline the differentiation of amiodarone optic neuropathy from nonarteritic anterior ischemic optic neuropathy. METHOD: We reviewed data from 73 patients reported to have developed an optic neuropathy while taking amiodarone. RESULTS: Amiodarone optic neuropathy is characterized by an insidious onset, slow progression, bilateral visual loss, and protracted disk swelling that tends to stabilize within several months of discontinuing the medication. Nonarteritic ischemic optic neuropathy is characterized by acute, unilateral visual loss that is usually complete at onset, with resolution of disk edema over several weeks. CONCLUSION: Unique clinical features of amiodarone-induced optic neuropathy may help clinicians diagnose and distinguish between amiodarone-induced optic neuropathy and nonarteritic anterior ischemic optic neuropathy.

Amiodarone↗
PubMed1998

Diabetic neuropathy in Mauritius: prevalence and risk factors.

The study of diabetic neuropathy has been primarily in Europids, despite the high prevalence of diabetes in other populations. We set out to ascertain the prevalence of diabetic neuropathy and its risk factors in the island nation of Mauritius. Population surveys were carried out in 1987 and 1992 in Mauritius to establish the prevalence of Type 2 diabetes. In the second survey, vibration perception threshold (VPT) was also measured at the great toe in 847 subjects with diabetes, 204 subjects with impaired glucose tolerance and 127 subjects with normal glucose tolerance. Neuropathy was defined as levels of VPT exceeding the mean plus 2 standard deviations defined separately for three age groups of Mauritian non-diabetic subjects. Risk factors for neuropathy were identified cross sectionally from the 1992 data, and longitudinally from the 1987 data. Neuropathy was detected in 8.3% of the 847 diabetic subjects (12.7%) of those with known diabetes, and 3.6% of those with newly diagnosed diabetes). Logistic regression identified diabetes duration (odds ratio [95% CI]; 1.08 [1.04-1.13] per year, P=0.0002), treatment with insulin or oral hypoglycaemic agents (2.63 [1.36-5.09], P=0.004) and greater height (1.36 [1.19-1.57] per 5 cm, P < 0.001) as risk factors for neuropathy, in the cross sectional analysis. In the longitudinal analysis, diabetes duration (1.11 [1.05-1.18] per year, P=0.001), fasting glucose (1.12 [1.03-1.22] per mmol/l, P=0.01) and height (1.23 [1.03-1.45] per 5 cm, P=0.02) were associated with neuropathy. A lower 2-h plasma insulin was also associated with neuropathy in the longitudinal analysis. The prevalence of diabetic neuropathy in Mauritius is the lowest reported for any population, but the risk factors associated with it are similar to those previously found.

Adult↗
PubMed2001

Mild diabetic neuropathy affects ankle motor function.

OBJECTIVE: To evaluate the effect of age and diabetic neuropathy on ankle motor function in the frontal plane in terms of rate of torque development and capability for balance recovery. DESIGN: Case control study. Six older women with diabetic neuropathy compared to six women without neuropathy, matched for age and presence of diabetes mellitus; and nine healthy young women. BACKGROUND: Neuropathy causes a distal impairment in lower extremity sensory function which increases fall risk. Impairments in ankle inversion/eversion proprioceptive thresholds have been identified, but the effect of neuropathy on ankle motor strength in the frontal plane is unknown. METHODS: Subjects' abilities to recover from a lateral lean (with center of gravity offset as percentage of foot width) while standing on one foot, and to rapidly generate inversion torque about the ankle, were quantified. RESULTS: All nine of the young, but only one of six older, control subjects recovered from a 10% lean (P=0.0052). Three of six older controls, but no neuropathy subject, recovered from a 5% lean (P=0.083). Neuropathy subjects demonstrated half the ankle rate of torque development [78.2 (50.8) N m/s; P=0.016] of the young and older controls [162.0 (54.6) and 152.7 (22.2) N m/s, respectively]. CONCLUSIONS: Diabetic neuropathy leads to a decrease in rapidly available ankle strength which impairs balance recovery among older women. Younger women demonstrate similar ankle strength but superior balance recovery compared to older women without neuropathy.

Adult↗
PubMed1995

Flow motion in peripheral diabetic neuropathy.

1. Flow motion is the cyclical variation in blood flow owing to the rhythmical opening and closing of arterioles. Previous studies have suggested that cutaneous flow motion may be altered in diabetic neuropathy but have not been consistent in their findings. 2. In order to assess the effect of diabetic peripheral neuropathy on flow motion, we have examined the frequency and amplitude of flow motion in 12 patients with diabetic peripheral neuropathy, 10 age-matched diabetic patients without peripheral neuropathy and 10 age-matched non-diabetic controls. 3. Peripheral neuropathy was diagnosed by a history of foot ulceration or chronic painful neuropathy, clinical examination and abnormal peroneal nerve conduction velocities. Blood flow, using laser Doppler flowmetry, was measured at four sites on the dorsum of both hands and feet. Flow motion was analysed using fast Fourier transform analysis, between 0.05 and 0.2 Hz, and displayed on a power spectral density graph. Predominant frequency and relative amplitude of flow motion were calculated. 4. Relative amplitude and frequency of flow motion were similar in the hands of all three groups, as was the frequency in the feet of the three groups. Relative amplitude was significantly smaller in the feet of diabetic patients with neuropathy (median 7.2%, 95% confidence interval 4.9-9.4%) than in diabetic patients without neuropathy (median 13.5%, 95% confidence interval 6.3-21.5%, P < 0.02) or in non-diabetic control subjects (median 10.3%, 95% confidence interval 6.9-27.4%, P < 0.02). 5. Flow motion amplitude is reduced in diabetic peripheral neuropathy. The control of flow motion amplitude appears to be at least partly under neurological control.

Diabetes Mellitus↗
PubMed2002

Autonomic neuropathy is associated with increased cardiovascular risk factors: the EURODIAB IDDM Complications Study.

AIMS: To assess the prevalence of and risk factors for autonomic neuropathy in the EURODIAB IDDM Complications Study. METHODS: The study involved the examination of randomly selected Type I (insulin-dependent) diabetic patients from 31 centres in 16 European countries. Neuropathic symptoms and two tests of autonomic function (changes in heart rate and blood pressure from lying to standing) were assessed and data from 3007 patients were available for the present analysis. Autonomic neuropathy was defined as an abnormality of at least one of the tests. RESULTS: The prevalence of autonomic neuropathy was 36% with no sex differences. The frequency of one and two abnormal reflex tests was 30% and 6%, respectively. The R-R ratio was abnormal in 24% of patients while 18% had orthostatic hypotension defined as a fall in systolic blood pressure > 20 mmHg on standing. Significant correlations were observed between autonomic neuropathy and age (P < 0.01), duration of diabetes (P < 0.0001), HbA1c (P < 0.0001), diastolic blood pressure (P < 0.05), lower HDL-cholesterol (P < 0.01), the presence of retinopathy (P < 0.0001) and albuminuria (P < 0.0001). New associations have been identified from the study: the strong relationship of autonomic neuropathy to cigarette smoking (P < 0.01), total cholesterol/HDL-cholesterol ratio (P < 0.05) and fasting triglyceride (P < 0.0001). As a key finding, autonomic neuropathy was related to the presence of cardiovascular disease (P < 0.0001). All analyses were adjusted for age, duration of diabetes and HbA1c. However, data have been only partly confirmed by logistic regression analyses. Frequency of dizziness on standing up was 18%, while only 4% of patients had nocturnal diarrhoea and 5% had problems with bladder control. CONCLUSION: Cardiovascular reflex tests, even in the form of the two tests applied, rather than a questionnaire, seem to be appropriate for the diagnosis of autonomic neuropathy. The study has identified previously known and new potential risk factors for the development of autonomic neuropathy, which may be important for the development of risk reduction strategies. Our results may support the role of vascular factors in the pathogenesis of autonomic neuropathy.

Adolescent↗
PubMed1987

Metabolic and cardiovascular responses to epinephrine in diabetic autonomic neuropathy.

Norepinephrine-induced vasoconstriction, which is mediated by alpha-adrenergic receptors, is accentuated in patients with autonomic neuropathy. In contrast, responses mediated by beta-adrenergic receptors, including vasodilatation and metabolic changes, have not been evaluated in these patients. To study these responses, we administered epinephrine in a graded intravenous infusion (0.5 to 5 micrograms per minute) to seven diabetic patients without neuropathy, seven diabetic patients with autonomic neuropathy, and seven normal subjects. Mean arterial pressure decreased significantly in the patients with autonomic neuropathy (P less than 0.01) but was unchanged in the other groups. Since cardiac output increased to a similar extent in the three groups, the decrease in blood pressure was due to a significantly larger decrease (P less than 0.01) in total peripheral vascular resistance in the patients with autonomic neuropathy. The heart rate increased significantly more during the infusions in the patients with neuropathy than in those without neuropathy. Epinephrine produced a greater increase in blood glucose, the glucose-appearance rate, lactate, glycerol, and free fatty acids in the patients with autonomic neuropathy than in the other groups (P less than 0.05). These findings indicate that several beta-receptor-mediated responses to epinephrine are enhanced in patients with diabetic autonomic neuropathy. The underlying mechanism remains to be elucidated.

Adult↗
PubMed2004

Diabetic neuropathy: an intensive review.

PURPOSE: The epidemiology, classification, pathology, and treatment of diabetic neuropathy are reviewed. SUMMARY: Diabetic peripheral neuropathy is a common complication of diabetes that can cause significant morbidity and mortality. Some 30% of hospitalized and 20% of community-dwelling diabetes patients have peripheral neuropathy; the annual incidence rate is approximately 2%. The primary risk factor is hyperglycemia. Sensorimotor neuropathy is marked by pain, paresthesia, and sensory loss. Cardiac autonomic neuropathy (CAN) may contribute to myocardial infarction, malignant arrhythmia, and sudden death. Gastroparesis is the most debilitating complication of gastrointestinal autonomic neuropathy. Genitourinary autonomic neuropathy can cause sexual dysfunction and neurogenic bladder. The pathology of diabetic neuropathy involves oxidative stress, advanced glycation end products, polyol pathway flux, and protein kinase C activation; all contribute to microvascular disease and nerve dysfunction. For symptom management current evidence from clinical trials supports the use of desipramine, amitriptyline, capsaicin, tramadol, gabapentin, bupropion, and venlafaxine as preferred medications. Citalopram, nonsteroidal antiinflammatory drugs, and opioid analgesics may be used as adjuvant agents. Lamotrigine, oxcarbazepine, paroxetine, levodopa, and alpha-lipoic acid are alternative considerations. Evidence supporting the use of zonisamide, fluoxetine, mexiletine, dextromethorphan, and phenytoin is considered equivocal. Complementary therapies have also shown efficacy. The symptoms of CAN may be ameliorated with fludrocortisone, clonidine, midodrine, dihydroergotamine or caffeine, octreotide, and beta-blockers. Gastroparesis may be treated with metoclopramide or erythromycin. The most promising disease-modifying therapy is ruboxistaurin, which is in Phase III trials. Glycemic control remains the foundation of prevention and the prerequisite of adequate treatment. CONCLUSION: Diabetic neuropathy is a many-faceted complication of diabetes that can be managed symptomatically with an array of drugs.

Analgesics, Opioid↗
PubMed1984

Endoneurial blood flow and oxygen tension in the sciatic nerves of rats with experimental diabetic neuropathy.

Endoneurial hypoxia has been postulated to be important in the pathogenesis of diabetic peripheral neuropathy and may be due to reduced nerve blood flow. Neither blood flow nor oxygen tension have previously been measured in peripheral nerve in diabetic neuropathy. We have therefore measured both nerve blood flow and endoneurial oxygen tension in the sciatic nerves of 8 rats with streptozotocin-induced diabetes for four months, and in 8 age-matched controls. In 7 of the diabetic animals mean nerve blood flow was 8.7 +/- 1.3 ml X min-1 X 100 g-1 which is significantly less than mean nerve blood flow in the controls (13.08 +/- 0.8 ml X min-1 X 100 g-1; P less than 0.01). In one diabetic animal, nerve blood flow was too low to be accurately measured. The reduction in nerve blood flow in diabetic neuropathy is due to an increase in resistance to flow which may be due to microangiopathy and to blood hyperviscosity. Endoneurial oxygen tension was also significantly reduced in experimental diabetic neuropathy in which 60 per cent of the oxygen measurements were less than 25 mmHg, compared with 19 per cent in the controls. Nerve blood flow was also measured in rats with experimental galactose neuropathy in which there is more marked sugar-alcohol accumulation, endoneurial oedema and elevation of endoneurial fluid pressure than in experimental diabetic neuropathy. The results obtained in this neuropathy suggest that the reduction in nerve blood flow which occurs in experimental diabetic neuropathy is due largely to factors other than sugar-alcohol accumulation in nerve. We postulate that endoneurial hypoxia may produce many of the observed morphological and biochemical changes in experimental diabetic neuropathy.

Animals↗
PubMed1991

Sural nerve morphometry in diabetic autonomic and painful sensory neuropathy. A clinicopathological study.

Observations have been made on a selected series of insulin-dependent patients with neuropathy, subdivided into three groups: (1) severe autonomic neuropathy with an accompanying painless sensory neuropathy; (2) severe autonomic neuropathy with a chronic painful sensory neuropathy; and (3) chronic or acute painful sensory neuropathy with no autonomic neuropathy. All three groups showed a loss of large and small myelinated nerve fibres in sural nerve biopsy specimens which was greater in Groups 1 and 2. Regenerative activity was prominent in all three groups, but least in Group 3. Teased fibre studies showed evidence both of axonal regeneration and remyelination. Active fibre degeneration was rare. Measurements of g ratio (axon diameter:total fibre diameter) gave no indication of axonal atrophy. The density of unmyelinated axons was reduced in all three groups, as was their median diameter. Vibration sense threshold was positively correlated with the total number of myelinated fibres and thermal sensory threshold with median unmyelinated axon diameter but not with total unmyelinated axon numbers. No correlation between the occurrence of pain and active degeneration of myelinated fibres or with regenerative activity either in myelinated or unmyelinated axons was detectable. Assessment of differential loss of large or small myelinated nerve fibres was difficult because of the presence of large numbers of small regenerating myelinated axons. The results are discussed in relation to the concept of 'diabetic small fibre neuropathy' and the causation of pain in diabetic neuropathy.

Adult↗
PubMed2003

An update on electrophysiological studies in neuropathy.

PURPOSE OF REVIEW: The review concentrates on the use of clinical neurophysiology in peripheral nerve disorders covered in the present issue. It is pertinent to distinguish different types of involvement of fibers in diabetic neuropathy, including the involvement of small and large fibers, to outline the diagnostic criteria of inflammatory neuropathies, and to describe the spectrum of peripheral nerve pathophysiology in inherited neuropathies. Painful neuropathies represent a particular challenge to clinical neurophysiology since it is mainly small fibers, which are difficult to study, that are affected. RECENT FINDINGS: Electrodiagnostic studies have relevance in distinguishing neuropathies with different etiologies in diabetes mellitus, and different strategies and methods are necessary to study patients with autonomic and small-fiber involvement. The involvement of motor or sensory fibers, or both, and primary axonal or demyelinative pathology are important questions relating to immune-mediated neuropathies studied in the context of the specificity of antibodies against various neuronal and Schwann-cell structures. In hereditary neuropathy, electrophysiological studies are also used to distinguish axonal neuropathies from demyelinating neuropathies, though overlap and 'intermediate' patterns have become well recognized. In pain syndromes, conventional electrophysiological studies may give normal results if large fibers are not involved, and the use of autonomic measures in these situations has particular relevance. SUMMARY: The usefulness of electrodiagnostic measures depends on the clinical, diagnostic, or pathophysiological question involved, and the strategy employed should reflect the advantages and limitations of these methods. If adequate consideration is paid to these properties, then such studies have a central role in the diagnosis and adequate treatment of patients with neuromuscular disorders.

Diabetic Neuropathies↗
PubMed1999

Inherited neuropathies: from gene to disease.

Inherited disorders of peripheral nerves represent a common group of neurologic diseases. Charcot-Marie-Tooth neuropathy type 1 (CMT1) is a genetically heterogeneous group of chronic demyelinating polyneuropathies with loci mapping to chromosome 17 (CMT1A), chromosome 1 (CMT1B) and to another unknown autosome (CMT1C). CMT1A is most often associated with a tandem 1.5-megabase (Mb) duplication in chromosome 17p11.2-12, or in rare patients may result from a point mutation in the peripheral myelin protein-22 (PMP22) gene. CMT1B is associated with point mutations in the myelin protein zero (P0 or MPZ) gene. The molecular defect in CMT1C is unknown. X-linked Charcot-Marie-Tooth neuropathy (CMTX), which has clinical features similar to CMT1, is associated with mutations in the connexin32 gene. Charcot-Marie-Tooth neuropathy type 2 (CMT2) is an axonal neuropathy, also of undetermined cause. One form of CMT2 maps to chromosome 1p36 (CMT2A), another to chromosome 3p (CMT2B) and another to 7p (CMT2D). Dejerine-Sottas disease (DSD), also called hereditary motor and sensory neuropathy type III (HMSNIII), is a severe, infantile-onset demyelinating polyneuropathy syndrome that may be associated with point mutations in either the PMP22 gene or the P0 gene and shares considerable clinical and pathological features with CMT1. Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder that results in a recurrent, episodic demyelinating neuropathy. HNPP is associated with a 1.5-Mb deletion in chromosome 17p11.2-12 and results from reduced expression of the PMP22 gene. CMT1A and HNPP are reciprocal duplication/deletion syndromes originating from unequal crossover during germ cell meiosis. Other rare forms of demyelinating peripheral neuropathies map to chromosome 8q, 10q and 11q. Hereditary neuralgic amyotrophy (familial brachial plexus neuropathy) is an autosomal dominant disorder causing painful, recurrent brachial plexopathies and maps to chromosome 17q25.

Animals↗
PubMed1998

Susceptibility to diabetic neuropathy in patients with insulin dependent diabetes mellitus is associated with a polymorphism at the 5' end of the aldose reductase gene.

OBJECTIVES: There is evidence that the polyol pathway is involved in the pathogenesis of diabetic neuropathy. Aldose reductase (ALR2) is the first and rate limiting enzyme of this pathway and recent studies have suggested that polymorphisms in and around the gene are associated with the development of diabetic microvascular disease. The aim was to examine the role of ALR2 in the susceptibility to diabetic neuropathy in patients with insulin dependent diabetes mellitus (IDDM). METHODS: One hundred and fifty nine British white patients with IDDM and 102 normal healthy controls were studied using the polymerase chain reaction to test for a highly polymorphic microsatellite marker 2.1 kilobase (kb) upstream of the initiation site of the ALR2 gene. RESULTS: Seven alleles were detected (Z-6, Z-4, Z-2, Z, Z+2, Z+4, and Z+6). There was a highly significant decrease in the frequency of the Z+2 allele in those patients with overt neuropathy compared with those with no neuropathy after 20 years duration of diabetes (14.1% v 38.2%, chi2 =17.3, p<0.00001). A similar difference was also found between the neuropathy group and those patients who have had diabetes for < five years with no overt neuropathy (14.1% v 30.2%, chi2=9.0, p<0.0025). The neuropathy group also had a significant decrease in the frequency of the Z/Z+2 genotype compared with those patients who have no neuropathy after 20 years duration of diabetes (14.0% v 44.7%, chi2=13.0, p<0.0005). CONCLUSION: These results suggest that the aldose reductase gene is intimately involved in the pathogenesis of diabetic neuropathy.

Adult↗
PubMed1986

Decreased alpha 2-adrenergic receptors on platelet membranes from diabetic patients with autonomic neuropathy and orthostatic hypotension.

Platelet adrenergic receptors were studied in normal subjects and diabetic patients with autonomic neuropathy to determine the relationship between adrenoreceptor status and orthostatic hypotension. The binding of [3H]clonidine and [3H]yohimbine to platelet membranes was measured in diabetic patients with autonomic neuropathy and orthostatic hypotension (n = 12) and without orthostatic hypotension (n = 11), diabetic patients without autonomic neuropathy (n = 12), and normal subjects (n = 9). Mean basal and standing plasma norepinephrine levels were not different in the four groups, and there was no relationship between orthostasis and norepinephrine responses. The diabetic patients with orthostatic hypotension had a significantly greater fall in mean blood pressure [31 +/- 2.8 (+/- SE) mm Hg] than any of the other three groups. Diabetic patients with diabetic autonomic neuropathy and orthostatic hypotension had a 30-40% decrease in number of platelet alpha 2-adrenergic receptors, as demonstrated by [3H]clonidine and [3H]yohimbine binding. The maximum number of binding sites for clonidine was 34 +/- 2.8 (+/- SE) fmol/mg protein in normal subjects, 27.4 +/- 3.4 in diabetic patients with neuropathy, 26 +/- 2.5 in diabetic patients with autonomic neuropathy without orthostatic hypotension, and 20.4 +/- 3.8 fmol/mg protein in diabetic patients with autonomic neuropathy with orthostatic hypotension (P less than 0.001). The maximum number of binding sites for yohimbine was 112 +/- 12.6 in normal subjects, 127 +/- 10 in diabetic patients without orthostatic hypotension, and 87 +/- 12.4 fmol/mg protein in patients with diabetic autonomic neuropathy with orthostatic hypotension (P less than 0.001). Reduced platelet alpha 2-receptors are associated with postural hypotension in diabetic autonomic neuropathy. If applicable to the postjunctional alpha 2-adrenergic receptor on sympathetic neurons, reduced vascular responses to changes in posture would be expected despite normal or enhanced norepinephrine secretion.

Adult↗
PubMed1999

Total neuropathy score: validation and reliability study.

OBJECTIVE: To determine the validity and reliability of the total neuropathy score (TNS) in normal subjects and in subjects with diabetic polyneuropathy. BACKGROUND: Clinical research in peripheral neuropathy requires validated outcome measures. Multiple outcome measures have been used in clinical trials, including symptom measures, functional scales, quantitative clinical examinations, nerve conduction studies, computerized sensory examinations, and nerve biopsy. Each of these measures has its strengths and weaknesses. In two previous studies of toxic neuropathy from chemotherapeutic agents, the authors used the TNS as the outcome measure. The TNS combines information obtained from grading of symptoms, signs, nerve conduction studies, and quantitative sensory tests, and provides a single measure to quantify neuropathy. METHODS: The authors measured the inter- and intrarater reliability of the TNS and preformed a cross-sectional validation study of the TNS and its subscales with the Mayo Clinic measures of neuropathy, neuropathy symptom score (NSS), and the neurologic impairment score (NIS) in five healthy control subjects and 30 individuals with varying severities of diabetic polyneuropathy. RESULTS: Inter- and intrarater reliability of the TNS was excellent (0.966 and 0.986 respectively). The cross-sectional validation study showed excellent correlations among all measures of neuropathy. CONCLUSIONS: The total neuropathy score is a validated measure of peripheral nerve function and could be used as an end point for clinical trials of peripheral neuropathy.

Adolescent↗
PubMed2004

Hereditary sensory neuropathies.

Hereditary sensory neuropathies (HSNs) are a group of genetically determined peripheral neuropathies with prominent disturbance of the peripheral sensory neurons. They are characterized by sensory loss, insensitivity to pain, a variable degree of muscle weakness and wasting, as well as autonomic features. Frequent complications are foot ulcerations and infections that may lead to osteomyelitis, followed by necrosis and amputations. Consequently, the hereditary sensory neuropathies have also been termed ulceromutilating neuropathies. On the other hand, in the presence of additional motor weakness, they have been subclassified among the group of Charcot-Marie-Tooth (CMT) disorders. Sporadic and familial cases with different modes of inheritance are known to affect both children and adults. The most prevalent forms of the autosomal dominantly inherited hereditary sensory neuropathies are HSN I and CMT 2b. HSN I is associated with mutations in the SPTLC1 gene, whereas mutations in the RAB7 gene have been identified in CMT 2b. However, at least one more hitherto unknown gene responsible for autosomal-dominant hereditary sensory neuropathies must exist. Autosomal-recessive hereditary sensory neuropathies types III and IV, and probably also type V, result from mutations in the IKBKAP and NTRK1 genes. Very recently, the gene in HSN II (HSN2) has been identified. A spontaneous autosomal-recessive mutation in the Cct4 gene has been reported in the Sprague-Dawley rat strain with early onset sensory neuropathy. Although no curative treatment is available so far, and current therapy is limited to symptom relief, these molecular genetic advances in knowledge about the hereditary sensory neuropathies can be translated into clinical practice by improving diagnosis and genetic counseling. They will also be the basis for functional studies in the future.

Animals↗