Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes. Despite its relationship to an increased risk of cardiovascular mortality and its association with multiple symptoms and impairments, the significance of DAN has not been fully appreciated. The reported prevalence of DAN varies widely depending on the cohort studied and the methods of assessment. In randomly selected cohorts of asymptomatic individuals with diabetes, 20% had abnormal cardiovascular autonomic function. DAN frequently coexists with other peripheral neuropathies and other diabetic complications, but DAN may be isolated, frequently preceding the detection of other complications. Major clinical manifestations of DAN include resting tachycardia, exercise intolerance, orthostatic hypotension, constipation, gastro- paresis, erectile dysfunction, sudomotor dysfunction, impaired neurovascular function, "brit- tle diabetes," and hypoglycemic autonomic failure. DAN may affect many organ systems throughout the body (e.g., gastrointestinal (GI), genitourinary, and cardiovascular). GI distur- bances (e.g., esophageal enteropathy, gastroparesis, constipation, diarrhea, and fecal inconti- nence) are common, and any section of the GI tract may be affected. Gastroparesis should be suspected in individuals with erratic glucose control. Upper-GI symptoms should lead to con- sideration of all possible causes, including autonomic dysfunction. Whereas a radiographic gastric emptying study can definitively establish the diagnosis of gastroparesis, a reasonable approach is to exclude autonomic dysfunction and other known causes of these upper-GI symptoms. Constipation is the most common lower-GI symptom but can alternate with episodes of diarrhea. Diagnostic approaches should rule out autonomic dysfunction and the well-known causes such as neoplasia. Occasionally, anorectal manometry and other specialized tests typically performed by the gastroenterologist may be helpful. DAN is also associated with genitourinary tract disturbances including bladder and/or sexual dysfunction. Evaluation of bladder dysfunc- tion should be performed for individuals with diabetes who have recurrent urinary tract infec- tions, pyelonephritis, incontinence, or a palpable bladder. Specialized assessment of bladder dysfunction will typically be performed by a urologist. In men, DAN may cause loss of penile erection and/or retrograde ejaculation. A complete workup for erectile dysfunction in men should include history (medical and sexual); psychological evaluation; hormone levels; mea- surement of nocturnal penile tumescence; tests to assess penile, pelvic, and spinal nerve func- tion; cardiovascular autonomic function tests; and measurement of penile and brachial blood pressure. Neurovascular dysfunction resulting from DAN contributes to a wide spectrum of clinical disorders including erectile dysfunction, loss of skin integrity, and abnormal vascular reflexes. Disruption of microvascular skin blood flow and sudomotor function may be among the earliest manifestations of DAN and lead to dry skin, loss of sweating, and the development of fissures and cracks that allow microorganisms to enter. These changes ultimately contribute to the development of ulcers, gangrene, and limb loss. Various aspects of neurovascular function can be evaluated with specialized tests, but generally these have not been well standardized and have limited clinical utility. Cardiovascular autonomic neuropathy (CAN) is the most studied and clinically important form of DAN. Meta-analyses of published data demonstrate that reduced cardiovascular autonomic function as measured by heart rate variability (HRV) is strongly (i.e., relative risk is doubled) associated with an in- creased risk of silent myocardial ischemia and mortality. The determination of the presence of CAN is usually based on a battery of auto- nomic function tests rather than just on one test. Proceedings from a consensus conference in 1992 recommended that three tests (R-R variation, Valsalva maneuver, and postural blood pressure testing) be used for longitudi- nal testing of the cardiovascular autonomic system. Other forms of autonomic neuropathy can be evaluated with specialized tests, but these are less standardized and less available than commonly used tests of cardiovascular autonomic function, which quantify loss of HRV. Interpretability of serial HRV testing re- quires accurate, precise, and reproducible procedures that use established physiological maneuvers. The battery of three recom- mended tests for assessing CAN is readily per- formed in the average clinic, hospital, or diagnostic center with the use of available technology. Measurement of HRV at the time of diagnosis of type 2 diabetes and within 5 years after diagnosis of type 1 diabetes (unless an individual has symptoms suggestive of au- tonomic dysfunction earlier) serves to estab- lish a baseline, with which 1-year interval tests can be compared. Regular HRV testing pro- vides early detection and thereby promotes timely diagnostic and therapeutic interven- tions. HRV testing may also facilitate differen- tial diagnosis and the attribution of symptoms (e.g., erectile dysfunction, dyspepsia, and diz- ziness) to autonomic dysfunction. Finally, knowledge of early autonomic dysfunction can encourage patient and physician to im- prove metabolic control and to use therapies such as ACE inhibitors and -blockers, proven to be effective for patients with CAN. Diabetes Care 26:1553-1579, 2003

/pdf/diabetic-autonomic-neuropathy-4kabtayo3d.pdf

Diabetic Autonomic Neuropathy

Diabetic autonomic neuropathy is the most common and troublesome complication of diabetes mellitus. Although involvement of the autonomic nervous system is generally diffuse, symptoms may be confined to a single target organ or organ system. Complications of diabetic autonomic neuropathy contribute greatly to the morbidity, mortality, and reduced quality of life of the person with diabetes and are the major source of increased costs of caring for the diabetic patient. Factors in the pathogenesis of these complications are altered metabolism, vascular insufficiency, loss of growth factor trophism, and autoimmune destruction of nerves in a visceral and cutaneous distribution. The clinical manifestations and the complications of diabetic autonomic neuropathy are reviewed. Future therapeutic strategies that are developed from a better understanding of the pathogenetic processes underlying this disorder can be directed at the cause rather than the manifestations. There are studies in progress that suggest that autonomic nerves can be induced to regenerate, and the future for patients with diabetic autonomic neuropathy is brighter.

Diabetic autonomic neuropathy.

CONTEXT. Fabry disease is an X-linked multisystem disorder. Enzyme-replacement therapy in adults has limited efficacy in treating major sequelae of advanced Fabry disease, such as kidney failure or stroke. This prompted a study of the safety and efficacy of enzyme replacement at an earlier stage of Fabry disease. OBJECTIVES. Our purpose with this work was to evaluate safety and to explore efficacy of enzyme treatment with agalsidase alfa in pediatric patients with Fabry disease. METHODS. We conducted a 6-month open-label study at 3 tertiary care centers with 24 children (19 boys and 5 girls) with a mean age of 11.8 (range: 6.5–18) years, to examine safety parameters, including infusion reactions and antiagalsidase alfa antibodies. RESULTS. Agalsidase alfa was well tolerated, and all of the patients completed the study. Six boys and 1 girl had mild-to-moderate infusion reactions. One boy developed transient immunoglobulin G antibodies against agalsidase alfa. The boys showed a significant reduction in plasma globotriaosylceramide on treatment. Mean estimated glomerular filtration rate, cardiac structure, and function were normal and did not change over 26 weeks. Heart rate variability, as determined by 2-hour ambulatory monitoring, was decreased in the boys compared with the girls at baseline. All indices of heart rate variability improved significantly in the boys. Three patients with anhidrosis, as determined by quantitative sudomotor axon reflex testing, developed sweating. Six of 11 patients could reduce or cease their use of antineuropathic analgesics. CONCLUSIONS. Enzyme replacement with agalsidase alfa was safe in this study. The exploratory efficacy analysis documented increased clearance of globotriaosylceramide and improvement of autonomic function. Prospective long-term studies are needed to assess whether enzyme replacement initiated early in patients with Fabry disease is able to prevent major organ failure in adulthood.

Enzyme-replacement therapy with agalsidase alfa in children with Fabry disease.

Autonomic neuropathy, once considered to be the Cinderella of diabetes complications, has come of age. The autonomic nervous system innervates the entire human body, and is involved in the regulation of every single organ in the body. Thus, perturbations in autonomic function account for everything from abnormalities in pupillary function to gastroparesis, intestinal dysmotility, diabetic diarrhea, genitourinary dysfunction, amongst others. "Know autonomic function and one knows the whole of medicine!" It is now becoming apparent that before the advent of severe pathological damage to the autonomic nervous system there may be an imbalance between the two major arms, namely the sympathetic and parasympathetic nerve fibers that innervate the heart and blood vessels, resulting in abnormalities in heart rate control and vascular dynamics. Cardiac autonomic neuropathy (CAN) has been linked to resting tachycardia, postural hypotension, orthostatic bradycardia and orthostatic tachycardia (POTTS), exercise intolerance, decreased hypoxia-induced respiratory drive, loss of baroreceptor sensitivity, enhanced intraoperative or perioperative cardiovascular lability, increased incidence of asymptomatic ischemia, myocardial infarction, and decreased rate of survival after myocardial infarction and congestive heart failure. Autonomic dysfunction can affect daily activities of individuals with diabetes and may invoke potentially life-threatening outcomes. Intensification of glycemic control in the presence of autonomic dysfunction (more so if combined with peripheral neuropathy) increases the likelihood of sudden death and is a caveat for aggressive glycemic control. Advances in technology, built on decades of research and clinical testing, now make it possible to objectively identify early stages of CAN with the use of careful measurement of time and frequency domain analyses of autonomic function. Fifteen studies using different end points report prevalence rates of 1% to 90%. CAN may be present at diagnosis, and prevalence increases with age, duration of diabetes, obesity, smoking, and poor glycemic control. CAN also cosegregates with distal symmetric polyneuropathy, microangiopathy, and macroangiopathy. It now appears that autonomic imbalance may precede the development of the inflammatory cascade in type 2 diabetes and there is a role for central loss of dopaminergic restraint on sympathetic overactivity. Restoration of dopaminergic tone suppresses the sympathetic dominance and reduces cardiovascular events and mortality by close to 50%. Cinderella's slipper can now be worn!

Diabetic autonomic neuropathy (DAN) represents a major complication of diabetes mellitus but there is considerable uncertainty about its incidence, prevalence, pathogenesis, diagnosis, and prognosis. There are conflicting opinions about the pathogenesis of DAN: the 'classical hypothesis' has been supplemented by some new insights. Clinical symptoms of autonomic neuropathy do not generally occur until long after the onset of diabetes. DAN seems to be detectable even in asymptomatic children and adolescents with diabetes and is associated with the most serious consequences, such as cardiovascular dysfunction. Because of its association with a variety of adverse outcomes, including cardiovascular deaths, cardiovascular autonomic neuropathy is the most clinically important and well-studied form of DAN. No form of therapy in DAN has been identified that provides unequivocal, safe, and effective stabilization or reversal of the condition, just a near normal control of blood glucose in the early years after the onset of diabetes that may delay the development of clinically significant nerve impairment. This article reviews recent developments in knowledge of epidemiology, pathogenesis, clinical symptoms, diagnosis, and therapy of DAN.

/pdf/new-insights-in-diabetic-autonomic-neuropathy-in-children-4n7mk9fuwe.pdf

New insights in diabetic autonomic neuropathy in children and adolescents.

OBJECTIVE: Adults with type 1 diabetes may have abnormal alterations in heart rate variability (HRV) due to cardiac autonomic neuropathy. This prospective study was performed to determine whether HRV can be used to detect subclinical autonomic neuropathy in diabetic children. RESEARCH DESIGN AND METHODS: We examined five time domain and three frequency domain HRV indices determined from 24-h Holter recordings in 73 diabetic children and adolescents aged 3-18 years (mean 12.1 years) with a mean duration of diabetes of 55 months. The measures were compared with normal ranges. Z scores were established for each parameter and were compared with classic risk factors of other diabetic complications. RESULTS: Most HRV indices were significantly depressed in children aged > or = 11 years, and the levels of HRV abnormalities were significantly correlated with long-term metabolic control (mean GHb for 4 years) in that age-group. In younger patients, HRV indices were within the normal range and were not correlated with the level of metabolic control. Illness duration and microalbuminuria but not short-term metabolic control (most recent GHb) were also independently predictive of HRV abnormalities. CONCLUSIONS: These results suggest that early puberty is a critical period for the development of diabetic cardiac autonomic dysfunction. Therefore, all type 1 diabetic patients should be screened for this complication by HRV analysis beginning at the first stage of puberty regardless of illness duration, microalbuminuria, and level of metabolic control.

Cardiac autonomic dysfunction in diabetic children.

The aim of this study was to assess heart rate variability, a noninvasive parameter for studying the neurohumoral control of heart rate, in children with atrial septal defect. We examined five time-domain and three frequency-domain indices of heart rate variability determined from 24-hour Holter recordings in 20 children, aged 3-14 years, with secundum atrial septal defect who were about to undergo operation. The measures were compared to normal ranges and to the hemodynamic data of the preoperative cardiac catheterization. Most indices of heart rate variability were moderately depressed in children with atrial septal defect. Our data revealed negative correlations between indices and the mean right atrial pressure and the enddiastolic right ventricular pressure, respectively. The study demonstrates the importance of the right ventricular filling pressures for the autonomic control of the heart in children with atrial septal defect.

Heart Rate Behavior in Children with Atrial Septal Defect

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Cardiac autonomic dysfunction in diabetic children.

Heart Rate Behavior in Children with Atrial Septal Defect