Power spectral analysis of heart rate variation in diabetic patients with neuropathic foot ulceration

OBJECTIVE: To evaluate the relationship between diabetic autonomic neuropathy and diabetic neuropathic foot ulceration, we used power spectral analysis (PSA) of heart rate variation, which provides the accurate simultaneous quantification of parasympathetic and sympathetic activities, to assess autonomic function in diabetic patients. RESEARCH DESIGN AND METHODS: We studied 55 NIDDM patients including 10 diabetic patients without neuropathy, 23 diabetic patients with neuropathy and no history of foot ulceration, and 22 diabetic patients with neuropathic foot ulceration. We performed PSA of 100 R-R intervals at rest and analyzed the results by fast Fourier transformation. RESULTS: The low frequency (LF) power, which reflects sympathetic activity, and the high frequency (HF) power, which reflects parasympathetic (vagal) activity, were inversely correlated with the duration of diabetes and the fasting plasma glucose (FPG) levels. By multiple regression analysis, the FPG remained with significant influence on both LF and HF powers. The LF and HF powers were positively correlated with motor nerve conduction velocity (MCV) and sensory nerve conduction velocity (SCV) in the upper and lower limbs and the coefficient of variation of R-R intervals. The LF and HF powers were significantly reduced in patients with neuropathy and patients with foot ulceration compared with patients without neuropathy. Although the median MCV and SCV were similar between diabetic patients with neuropathy and patients with foot ulceration, both the LF and HF powers were significantly decreased in patients with foot ulceration compared with patients with neuropathy. There was no difference in the value of the LF:HF ratio, an index of sympathovagal balance, among three subgroups. We observed a positive correlation between LF and HF power in all subjects; however, the LF and HF powers were not correlated in the subgroups of patients with foot ulceration. CONCLUSIONS: These results showed that diabetic patients with neuropathic foot ulceration have a greater impairment in spectral indexes of autonomic activity obtained by PSA than patients with neuropathy and no history of foot ulceration, whereas no difference was present in nerve conduction velocities.     

Conduction block in vasculitic neuropathy

Vasculitis involving peripheral nerves usually presents as an acute asymmetrical axonal neuropathy. We report a 67-year-old man with a symmetrical subacute neuropathy in which nerve conduction studies showed prominent conduction block, a finding indicative of demyelination. Sural nerve biopsy showed a vasculitic neuropathy with invasion of blood vessel walls by inflammatory cells and a mixture of nerve fiber loss and demyelination. The demyelination in this case was presumably a consequence of subinfarctive nerve ischemia.     

Isolated triceps weakness in exercise-induced radial neuropathy

OBJECTIVE: We report a case of isolated triceps weakness resulting from radial neuropathy. PATIENT: A middle-aged healthy man, a keen athlete, developed acute weakness of the triceps brachii muscle due to radial neuropathy. No other radial nerve innervated muscles were involved. Triceps function completely recovered in six weeks clinically and electrophysiologically suggesting focal conduction block secondary to demyelination. DISCUSSION: Acute radial neuropathy after strenuous arm exercise resulting from a compression lesion with acute conduction block, has been previously described. However, all reported cases involved severe weakness of radial nerve innervated distal muscles with wrist drop, while isolated weakness of the triceps brachii muscle in radial neuropathy has never been previously described. CONCLUSIONS: We suggest that selective weakness in the triceps could be the sole manifestation of an exercise-related radial neuropathy. This particular type of radial neuropathy could be a variant of neuralgic amyotrophy.     

Diabetic neuropathy: clinical aspects

The importance of diabetic neuropathy derives from its remarkable frequency and its clinical impact. In view of the varying underlying pathogenetic mechanisms and the resulting diversity of clinical representations, it becomes apparent that there are diabetic neuropathies, rather than a single entity of diabetic neuropathy. The scope of involvement is widespread with virtually every system at risk. Although peripheral neuropathy is by far the most common expression, visceral neuropathy is also highly significant. It may affect every part of the gastrointestinal tract, the genitourinary tract, and sexual function, as well as direct autonomic nerve pathology. Clearly, neuropathy in diabetes offers a specific and important diagnostic challenge to the clinician and plays a definitive role in differential diagnosis. The problem is heightened by the fact that any and all of the diabetic neuropathic syndromes may be the initial clinical manifestation of diabetes in the absence of covert manifestations of carbohydrate metabolic disorder. It is to be stressed that the diagnosis is more than an academic exercise, since each diabetic neuropathic syndrome carries with it some beneficial therapeutic modality to aid the patient.     

Ambulatory blood pressure measurement in type-II diabetic patients with autonomic neuropathy

The aim of our study was to access the 24-hr ambulatory blood pressure (BP) in diabetic patients with autonomic neuropathy (AN). Twenty-two NIDDM patients without hypertension, being treated with sulfonylureas, were studied. The 24-hr ambulatory blood pressure recordings were performed using portable non-invasive automatic system. Autonomic neuropathy was assessed by standard cardiovascular reflex tests. There were ten patients with and 12 without AN, matched for age, body mass index, duration of diabetes and glycemic control. Mean BP increased at night in four of the subjects with AN and decreased in the remaining 18 patients. The group of subjects with nocturnal increases in BP had more severe autonomic nerve dysfunction compared with those with decreases in nocturnal BP. No significant difference between clinical and ambulatory day-time measurements was found. In three patients with AN after 5 weeks intensified therapy. 24-hr BP did not show any significant difference.     

Insulin-like growth factor-I prevents development of a vincristine neuropathy in mice

Vincristine is a commonly used antitumor agent whose major dose-limiting side-effect is a mixed sensorimotor neuropathy. To assess whether insulin-like growth factor-I (IGF-I), a neurotrophic agent that supports the survival of motoneurons and enhances regeneration of motor and sensory neurons, could prevent the peripheral neuropathy produced by vincristine, mice were treated with both vincristine (1.7 mg/kg, i.p., 2 x /week) and/or IGF-I (0.3 or 1 mg/kg, s.c. daily) for 10 weeks. In mice treated with vincristine alone, there was evidence of a mixed sensorimotor neuropathy as indicated by changes in behavior, nerve conduction and histology. Caudal nerve conduction velocity was significantly slower in mice treated with vincristine alone as compared with vehicle-treated mice. Vincristine treatment alone also significantly increased hot-plate latencies and reduced gait support and stride length, but not toe spread distances. The effects of vincristine were accompanied by degeneration of sciatic nerve fibers and demyelination, indicating a peripheral neuropathy. IGF-I (1 mg/kg, s.c.) administered to vincristine-treated mice prevented the neurotoxic effects of vincristine as measured by nerve conduction, gait, response to noxious stimuli and nerve histology. At a lower dose of 0.3 mg/kg administered s.c., IGF-I partially ameliorated the neuropathy induced by vincristine as this dose only prevented the change in nerve conduction and hot-plate latencies. IGF-I administered alone had no effect on any of these parameters. These results suggest that IGF-I prevents both motor and sensory components of vincristine neuropathy and may be useful clinically in preventing the neuropathy induced by vincristine treatment.     

Late onset dysthyroid optic neuropathy

We report three rare occurrences of late onset dysthyroid optic neuropathy. We reviewed each case in detail and found that these middle-aged patients developed onset of optic neuropathy 7 to 12 years following stabilization of clinically significant, stable ophthalmopathy. There was no corresponding reactivation of orbital inflammatory symptoms or signs. Characteristic of a Graves' ophthalmopathy, the vision was responsive to either corticosteroid or surgical decompression, or to a combination thereof. None of the patients had diabetes, hypertensive, or cardiovascular disease. We hypothesize that in these unique cases possible mechanical vascular factors may have induced decompensation of optic nerve function in otherwise stable disease.     

Clinical characteristics of Cuban epidemic neuropathy

INTRODUCTION: At the beginning of 1992 an epidemic neuropathy was seen in Cuba. MATERIAL AND METHODS: To determine the clinical characteristics we studied the clinical and neurological features, cerebrospinal fluid, and did neurophysiological investigations and sural nerve biopsies. RESULTS: Sixty patients were studied. Of these, 42 (70%) had polyneuropathy which was predominantly peripheral and 18 (30%) had combined forms. Most patients had asthenia and weight loss. The polyneuropathic effects were mainly in the legs. In 33.3% of the patients there were distal autonomic effects and sphincter disorders. Only 7 patients had hypoacusia. However, subclinical neurosensorial hypoacusia was seen in 33.3%. Optic neuropathy affected central vision bilaterally and symmetrically with temporal pallor of the papilla in half the cases. In 3 patients there was loss of ganglionar nerve fibres of the papillo-macula bundle. The contrast sensitivity visual test was abnormal in some patients with peripheral polyneuropathy, showing subclinical optic neuropathy in these cases. Sensory neuroconduction suggested axonal neuropathy in 30 patients, demyelinating neuropathy in 5 patients, while the remainder were normal. Motor neuroconduction was normal in most patients. Sural nerve biopsy of 27 patients showed axon damage in 96.2% of cases. CONCLUSIONS: The clinical picture is similar to that seen in nutritional deficiencies and toxic processes.     

Small fiber neuropathy and vasculitis

Vasculitis-associated neuropathy usually presents as multiple mononeuropathies or sensorimotor polyneuropathies that affect large nerve fibers; painful small fiber sensory neuropathy has not previously been described in association with vasculitis. This report describes 2 patients with small fiber neuropathy in whom vasculitis was found to be present. Patients with small fiber neuropathy for which no other cause has been identified should be evaluated for the presence of vasculitis.     

Propafenone-induced peripheral neuropathy

Propafenone hydrochloride, a class IC antiarrhythmic drug, is used in the treatment of ventricular and supraventricular arrhythmias. Herein we describe a patient with episodic jabbing and crushing pain in his hands and feet, aching in his forearms, and hyperesthesias of his extremities. He had been taking propafenone for 1 year because of ventricular arrhythmias. Results of a nerve conduction velocity test were abnormal. Electron microscopic findings on a sural nerve biopsy specimen represented distal small fiber neuropathy. Findings on a thermoregulatory sweat test and on autonomic tests were abnormal, compatible with a distal small fiber neuropathy. To our knowledge, peripheral neuropathy has not previously been reported to occur with use of propafenone. In this patient, propafenone seemed to be responsible for the development of peripheral neuropathy, which resolved after use of the drug had been discontinued.     

The effect of neurolysis on the recovery of experimentally induced entrapment neuropathy

While chronic entrapment neuropathy is a common problem in orthopaedic practice, controversy remains over which is the most appropriate surgical procedures. There have been few experimental studies addressing this problem. This study was undertaken to compare the effects, as well as the risks, of various surgical procedures on experimentally induced chronic entrapment neuropathy in rat. Ninety adult male Wistar rats (250-300 g) were used as the experimental animals. The sciatic nerves were wrapped by silastic tubes each 10 mm long with an internal diameter of 1.5 mm. At eight months later, after the nerves had demonstrated changes compatible with clinical chronic entrapment neuropathy, the tubes were removed and simple decompression, external or internal neurolysis was carried out on the entrapped nerve. Nerves at 1, 2, 4 and 6 months after surgery were morphologically and functionally examined. Electrophysiological and histological changes were gradually ameliorated after simple decompression. The externally neurolysed nerve showed improvements in the normal nerve functions. Internal neurolysis on chronically entrapped nerves produced a deterioration in the nerve functions, as well as in the nerve structures. We concluded that more favorable results were achieved by the external neurolysis, whereas internal neurolysis was a very harmful procedure for chronic entrapment neuropathy.     

Peripheral neuropathy: an often-overlooked cause of falls in the elderly

Peripheral neuropathy is common in the elderly and results in impairments in distal proprioception and strength that hinder balance and predispose them to falls. The loss of heel reflexes, decreased vibratory sense that improves proximally, impaired position sense at the great toe, and inability to maintain unipedal stance for 10 seconds in three attempts all suggest functionally significant peripheral neuropathy. Physicians can help their patients with peripheral neuropathy to prevent falls by teaching them and their families about peripheral nerve dysfunction and its effects on balance and by advising patients to substitute vision for the lost somatosensory function, correctly use a cane, wear proper shoes and orthotics, and perform balance and upper extremity strengthening exercises.     

Subacute multifocal painful neuropathy with spontaneous remission

We present the cases of two patients with subacute onset of multifocal painful neuropathy with spontaneous remission and no relapse. The distribution of pain in patient 1 was hands (median > ulnar nerve region) and feet (peroneal and terminal tibial nerve regions), and in patient 2, hands (ulnar nerve region) and feet, left worse than in right. Both patients experienced facial numbness. Deep tendon reflexes were intact except for absent ankle jerks in patient 2. Motor nerve conduction studies demonstrated a marked prolongation of the distal motor latencies with normal proximal segment conduction velocities, suggesting distal demyelination. Cerebrospinal fluid protein concentration was elevated in patient 2, but no definite abnormality was found on sural nerve biopsy. A demyelinating neuropathy with a monophasic self-limited course may be consistent with Guillain-Barre syndrome (GBS). However, the multifocal painful sensory symptoms with facial numbness and the marked distal nerve conduction slowing in our cases are not consistent with GBS.     

Entrapment neuropathy of the deep peroneal nerve associated with the extensor hallucis brevis

The authors report a case of entrapment neuropathy of the deep peroneal nerve associated with the extensor hallucis brevis. This entrapment neuropathy was found distal to the inferior retinaculum that causes the anterior tarsal tunnel syndrome. Surgical decompression of the deep peroneal nerve that was entrapped by the extensor hallucis brevis relieved the symptoms. This condition, like the anterior tarsal tunnel syndrome, deserves attention.     

Cardiac autonomic nerve function and insulin sensitivity in obese subjects

OBJECTIVE: To investigate whether obesity influences cardiac autonomic nerve function. DESIGN: Comparing two groups of subjects with different degrees of obesity to normal weight controls. SUBJECTS: 19 healthy controls (mean age 33 y, BMI 21.7 +/- 0.2 kg/m2) and 17 obese non-diabetic subjects (mean age 39 y, BMI 33.7 +/- 1.8 kg/m2). MEASUREMENTS: Insulin sensitivity was calculated by an oral glucose tolerance test. Autonomic nerve function was evaluated by analysing the variation of the heart frequency at rest (coefficient variation of R-R intervals, REST 1), during deep respiration, at a Valsalva maneuver (longest/shortest R-R interval during inspiration hold) and by the Ewing test (ratio between the 30th and 15th R-R interval after reaching up-right position). RESULTS: The obese showed a lower insulin sensitivity than healthy controls (3.09 vs 4.60 mg x l2/mmol x mU x min, P < 0.001). Their variation in heart frequency was reduced (REST 1: 1.95 vs 2.9, P < 0.01, Valsalva: 1.30 vs 1.52 and Ewing test: 1.03 vs 1.14, P < 0.05). However, patients with moderate (BMI 31.7 kg/m2) or severe obesity (39.0 kg/m2) with identical insulin sensitivity had no significant difference in autonomic nerve function. Except for the Ewing test all measured parameters for the evaluation of cardiac autonomic nerve function correlated with the degree of diminished insulin sensitivity (REST 1: r = 0.475, P < 0.001). CONCLUSION: Moderate obesity with significantly decreased insulin sensitivity is associated with impaired cardiac autonomic nerve function.     

Pathophysiology and treatment of painful diabetic neuropathy of the lower extremity

BACKGROUND: Symptomatic peripheral neuropathy is the most common complication of diabetes mellitus, affecting up to 62% of Americans with diabetes. METHODS: We reviewed the literature using the National Library of Medicine's MEDLINE search service. In total, we reviewed 54 articles. RESULTS: Hyperglycemia leads to increased activity in the polyol pathway in nerve cells; this ultimately results in abnormal nerve function. Numerous pharmacologic agents have been used to treat symptomatic peripheral neuropathy, but all of these drugs can be associated with adverse side effects. Recent work has indicated that subsensory electrical stimulation may be preferred to pharmacotherapy, since it is equally effective and has a more favorable safety profile. CONCLUSION: Although the pathophysiology of diabetic neuropathy is well understood, treatment of the symptoms associated with this condition can be challenging. Additional research is needed to reveal a safe and effective treatment for this debilitating sequela of diabetes mellitus.     

Radiation optic neuropathy after stereotactic radiosurgery

PURPOSE: The purpose of the study is to report the occurrence of optic neuropathy after stereotactic radiosurgery for perichiasmal tumors. METHODS: Records of four patients with visual deterioration after stereotactic radiosurgery were reviewed, including clinical findings, neuroimaging results, and treatment methods. RESULTS: Optic neuropathy developed 7 to 30 months after gamma knife radiosurgery. All patients experienced an abrupt change in visual function. Clinical findings indicated anterior visual pathway involvement. Patterns of field loss included nerve fiber bundle and homonymous hemianopic defects. Gadolinium-enhanced magnetic resonance imaging (MRI) showed swelling and enhancement of the affected portion of the visual apparatus in three patients. Systemic corticosteroids were administered in all patients and one partially recovered. One patient also received hyperbaric oxygen without improvement. CONCLUSIONS: Although rare, optic neuropathy may follow radiosurgery to lesions near the visual pathways. Careful dose planning guided by MRI with restriction of the maximal dose to the visual pathways to less than 8 Gy will likely reduce the incidence of this complication.     

Autonomic neuropathy in diabetic children

OBJECTIVE: Evaluate the presence of cardiovascular autonomic nerve dysfunction in children and adolescents with insulin-dependent diabetes mellitus. METHODOLOGY: We studied 110 patients (54 male, 56 female) and 100 healthy sex and age-matched children. Autonomic nerve function was assessed by standard cardiovascular reflex tests: (1) Fall in systolic blood pressure in response to standing. (2) Heart rate in response to standing. (3) Beat-to-beat rate variation during deep breathing. (4) Quotient of heart rate during and after Valsalva manoeuvre. (5) Change in blood pressure response to sustained handgrip. The coefficient of variation of heart rate was determined from 150 systoles using a microcomputer-based technique. The lower limits of normal were defined according to statistical analysis taking into account the relationship between heart rate variability and age. RESULTS: Forty-seven of the 110 diabetic children and adolescents studied showed one or more abnormal tests for cardiovascular autonomic dysfunction; many patients had an abnormality in more than one test. Twenty-two patients showed early involvement, 18 patients had definite and 7 severe involvement. No correlation was found between sex, glycaemic control, duration of diabetes or presence of retinopathy and persistent microalbuminuria and the autonomic nerve function. CONCLUSIONS: In the paediatric age group also, autonomic nerve dysfunction can be present in asymptomatic diabetic patients. Heart rate variation during Valsalva manoeuvre and maximum/minimum 30:15 ratio are the most sensitive indices to detect autonomic abnormalities in children.     

Noninvasive assessment of cardiac diabetic neuropathy by carbon-11 hydroxyephedrine and positron emission tomography

OBJECTIVES: The purpose of this investigation was to evaluate the sympathetic nervous system of the heart by positron emission tomographic (PET) imaging in patients with diabetes mellitus with and without diabetic autonomic neuropathy. BACKGROUND: The clinical assessment of cardiac involvement in diabetic autonomic neuropathy has been limited to cardiovascular reflex testing. With the recent introduction of radiolabeled catecholamines such as carbon (C)-11 hydroxyephedrine, the sympathetic innervation of the heart can be specifically visualized with PET imaging. METHODS: Positron emission tomographic imaging was performed with C-11 hydroxyephedrine and rest myocardial blood flow imaging with nitrogen-13 ammonia. Three patient groups were studied, including healthy volunteers as control subjects, diabetic patients with normal autonomic function testing and diabetic patients with varying severity of autonomic neuropathy. Homogeneity of cardiac tracer retention as well as absolute tracer retention was determined by relating myocardial tracer retention to an arterial C-11 activity input function. RESULTS: Abnormal regional C-11 hydroxyephedrine retention was seen in seven of eight patients with autonomic neuropathy. Relative tracer retention was significantly reduced in apical, inferior and lateral segments. The extent of the abnormality correlated with the severity of conventional markers of autonomic dysfunction. Absolute myocardial tracer retention index measurements showed a 45 +/- 21% decrease in distal compared with proximal myocardial segments in autonomic neuropathy (0.069 +/- 0.037 min-1 vs. 0.13 +/- 0.052 min-1, p = 0.02). CONCLUSIONS: This study demonstrates a heterogeneous pattern of neuronal abnormalities in patients with diabetic cardiac neuropathy. The extent of this abnormality correlated with the severity of neuropathy assessed by conventional tests. Future studies in larger groups of patients are required to define the relative sensitivity of this imaging approach in detecting cardiac neuropathy and to determine the clinical significance of these scintigraphic findings in comparison with conventional markers of autonomic innervation.     

Nociceptor hyper-responsiveness during vincristine-induced painful peripheral neuropathy in the rat

Neuropathic pain accompanies peripheral nerve injury after a wide variety of insults including metabolic disorders, traumatic nerve injury, and neurotoxic drugs. Chemotherapy-induced neuropathic pain, caused by drugs such as vincristine and taxol, occurs in cancer patients who receive these drugs as antineoplastic agents. Although a variety of remediations have been attempted, the absence of knowledge concerning mechanisms of chemotherapy-induced neuropathic pain has hindered the development of treatment strategies. Vincristine, a widely used chemotherapeutic agent, produces painful peripheral neuropathy in humans and mechanical hyperalgesia in rats. To test the hypothesis that alterations in C-fiber nociceptor function occur during vincristine-induced painful peripheral neuropathy, we performed in vivo extracellular recordings of single neurons from the saphenous nerve of vincristine-treated rats. Forty-one percent of C-fiber nociceptors were significantly hyper-responsive to suprathreshold mechanical stimulation. As a population, these mechanically hyper-responsive nociceptors also had significantly greater responses to suprathreshold heat stimulation; however, heat hyper-responsiveness was found only in a subset of these nociceptors and was never detected in the absence of mechanical hyper-responsiveness. In addition, mean conduction velocities of A-fibers and C-fibers in vincristine-treated rats were significantly slowed. Mean heat and mechanical activation thresholds of C-fiber nociceptors, their distribution among subclasses, and the percentage of spontaneously active neurons in vincristine-treated rats were not statistically different from controls. Vincristine does not, therefore, cause generalized impairment of C-fiber nociceptor function but rather specifically interferes with mechanisms underlying responsiveness to suprathreshold stimuli. Furthermore, vincristine-induced nociceptor hyper-responsiveness may involve alterations specifically in mechanotransduction in some nociceptors and alterations in general cellular adaptation mechanisms in others.