Manifestations Of Autonomic Neuropathy Research Articles

Diabetic Charcot neuroarthropathy: A threat to both limb and life.

Diabetic Charcot neuroarthropathy (DCN), first described in 1936, occurs in less than 1% of diabetic patients, but in those diabetic subjects with distal symmetrical polyneuropathy, the overall incidence increases to 30% and the risk is even greater in those with type 1 diabetes. Factors that precipitate DCN are trauma, ischaemia due to arterio-venous shunting, increased osteoclastic activity and inflammation. DCN usually presents with a painless swollen foot and/or ankle which is 'hot to the touch'. These clinical findings are soon followed by characteristic magnetic resonance imaging (MRI) abnormalities and later X-ray changes. The joints that are most typically involved in chronological order are the tarsometatarsals followed by the naviculocuniform, sub-tarsal, talonavicular and metatarsal and tarsophalangeal. The cornerstone of therapy is prolonged (3-12 months) offloading with immobilization. Bisphosphonates may possibly accelerate recovery, whereas other unproven possible therapies include rhPTH, 1-34, calcitonin and methylprednisolone, which are not only ineffective but in some cases may also prolong the time to healing. Denosumab is potentially an efficacious, if unproven, therapy to accelerate healing. The risk of amputation is high and increases in the presence of a foot ulcer. DCN is associated with manifestations of autonomic neuropathy, including cardiac denervation, so that the risks of a cardiac event and heart failure are increased with DCN. Mortality is also increased with DCN, especially in the presence of a foot ulcer. To avoid the recurrence of DCN and especially to lower the risk of the recurrence of a foot ulcer recurrence reconstructive, surgery may be needed.

Autonomic neuropathy in dialysis patients – investigations with a new symptom score (COMPASS 31)

BackgroundSymptoms of autonomic neuropathy (AN) are common in patients with diabetes and advanced renal disease. As yet different domains of autonomic neuropathy cannot be detected by a singular laboratory or invasive test. COMPASS 31, a new self-assessment test, has shown reliable results not only in cardiac autonomic neuropathy but also in different sub-domains when judging manifestation of AN by scores.MethodsOne hundred eighty-three patients with or without diabetes were enrolled, one hundred nineteen of them were treated with permanent dialysis therapy (HD), sixty-four patients served as controls (eGFR > 60 ml/min.) Using COMPASS 31 different symptoms of AN were assessed (orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, pupillomotor changes) and transferred into AN-scores.ResultsAN was more pronounced in dialysis patients compared with controls (AN-score 27,5 vs. 10,0; p < 0,01). These differences were present also in every sub-domain of AN (orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, pupillomotor changes; p < 0,05 for all sub-domains). In diabetic patients there was a strong correlation between symptoms of AN and diabetes duration (correlation coefficient r = 0,45, p < 0,001). Current glycemic control (HbA1c), body mass index (BMI), sex, and height had no influence on AN when comparing dialysis patients and controls. C-reactive protein (CRP) showed a positive linear correlation with AN-scores (correlation coefficient r = 0,21; p < 0,05).ConclusionSymptoms of AN are more pronounced in dialysis patients not only in total but also in all different domains of neuropathic changes. Longlasting diabetic disease promotes development of AN, as duration of diabetes was positively correlated with AN. Future longitudinal studies might help to identify the high cardiovascular and mortality risk in dialysis patients by the easy-to-use COMPASS 31 without need of invasive and time-spending methods for diagnosing AN.

Hyporeninemic hypoaldosteronism as a manifestation of autonomic neuropathy in a patient with type 2 diabetes mellitus against the background of coronavirus disease. A clinical case

Coronavirus disease (COVID-19) is often associated with endocrine complications. The article describes a clinical case of the patient with type 2 diabetes mellitus and COVID-19 after which, for the first time, there was a need for basal-bolus insulin therapy, and secondly, a significant arterial hypotension occurred. The mechanism of damage to β-cells of the pancreas in the patient is debatable. After analyzing the features of diabetes course, we found an acute onset of the disease at the age of 44 years with pronounced hyperglycemia and ketosis, which required insulin therapy. Then for a long time there was no need in insulin therapy, and the patient took metformin, having overweight, no antibodies to β-cell antigens. It is also impossible to exclude the effect of SARS-CoV-2 on the secretory function of β-cells of the pancreas. Accordingly, clinical cases are interesting, as their analysis helps to understand not only the mechanism of development and progression of this infection, but also the diagnosis and treatment of its complications. We have described a rare clinical case of the hyporeninemic hypoaldosteronism in the patient with type 2 diabetes mellitus after COVID-19 infection. Afeature of the hyporeninemic hypoaldosteronism course was the absence of electrolyte disorders in the patient, with severe arterial hypotension, suppression of renin and aldosterone. We believe that the hyporeninemic hypoaldosteronism has been associated with the progression of chronic diabetes complications, mainly autonomic neuropathy against the background of COVID-19. To improve the identified disorders, replacement therapy with mineralocorticoids was prescribed. The blood pressure, symptoms of fluid retention and electrolyte levels were monitored when selecting the dose of fludrocortisone. The patient has been under observation for 14 months, the need for fludrocortisone replacement therapy persists to this day. Practicing doctors need to pay attention to the diagnosis of autonomic disorders, which reduce the patients’ quality of life and are an independent risk factor for cardiovascular mortality.

426-P: Sudomotor Dysfunction Is Associated with Decreased Cardiac Diastolic Function in Patients with Type 2 Diabetes

Diabetic autonomic neuropathy has been proved to be associated with onset of heart failure in patients with diabetes. However, relationship between sudomotor dysfunction, the early manifestation of autonomic neuropathy, and cardiac diastolic function has not yet been investigated. This study aimed to explore the association between sudomotor function and cardiac diastolic function in patients with type 2 diabetes mellitus (T2DM). A total of 63 patients (65% male, 50±13 years old) with T2DM were enrolled and divided into two groups according to mean feet electrochemical skin conductance (ESC) assessed by sudoscan device: sudomotor dysfunction group(SDF group: ESC≤60 μS) and normal sudomotor function group (NSF group: ESC&amp;gt;60 μS). Impaired cardiac diastolic function detected by tissue Doppler imaging echocardiography manifested as elevations of late atrial (A) transmitral peak flow velocity (LgA) and the early (E) transmitral peak flow velocity/early diastolic velocity (e’) (E/e’ratio). The prevalence of sudomotor dysfunction was 30.2%. In SDF group, LgA and E/e’ ratio were significantly higher than those in NSF group (-0.2±0.2 m/s vs. -0.4±0.3 m/s, P=0.011 and 11.0±3.8 vs. 8.8±2.7, P=0.013, respectively). Pearson correlation analysis revealed that LgA was negatively correlated with mean feet ESC(r=-0.3, P=0.017). In logistic regression analyse, LgA (OR=0.05, 95%CI 0.004-0.585, P=0.017) and E/e‘ ratio (OR=0.79, 95%CI 0.641-0.970, P=0.025) were found to be independently associated with presence of sudomotor dysfunction. Cardiac diastolic function significantly decreased in type 2 diabetic patients with sudomotor dysfunction. Disclosure X. Chen: None. X. Yang: None. W. Xu: None. H. Deng: None. J. Wu: None. J. Yan: None. B. Yao: None. Funding Natural Science Foundation of Guangdong Province (2018A030313915); Medical Scientific Research Foundation of Guangdong Province (A2018286)

Spontaneous or Deliberate: Effects of Acute Variations in Glycemia on Gastric Emptying in Type 1 Diabetes.

During the last 30 years, there has been a paradigm shift in knowledge relating to gastric emptying in diabetes, reflecting the application of novel investigative techniques. Scintigraphy, which utilizes radiolabeled solid and/or liquid meals and a γ-camera, remains the gold standard for quantifying gastric emptying (1,2). More recently, stable isotope breath tests, involving measurement of 13CO2 in breath samples after ingestion of a 13C-labeled meal, have been validated against scintigraphy with inherent advantages of simplicity, point-of-care sampling, and avoidance of radiation exposure (1). Key insights in diabetes include the recognition that solids and liquids empty from the stomach differentially and that interindividual variation—already substantial in health (1–4 kcal/min) (2)—is increased in diabetes because emptying is delayed in ∼30–40% of complicated, suboptimally controlled patients attending tertiary centers (2–4), while often modestly accelerated in well-controlled patients with type 1 or type 2 diabetes (2). Upper gastrointestinal symptoms, such as nausea and fullness, occur frequently and impact quality of life adversely, but their relationship to gastric emptying is weak (1–3). Rather than simply being a manifestation of autonomic neuropathy, the pathogenesis of gastroparesis is heterogeneous, involving loss of interstitial cells of Cajal (“pacemaker” cells), an immune infiltrate, and muscle atrophy in addition to changes in intrinsic and extrinsic (vagal) innervation (1). There is a relatively weak relationship between gastroparesis and autonomic dysfunction, as assessed by standardized cardiovascular reflexes (3). Finally, and perhaps most importantly, gastric emptying influences postprandial glycemic excursions, the dominant determinant of HbA1c when the latter is less than ∼64 mmol/mol (8.0%) (5), and emptying can be modulated by dietary or pharmacological approaches (e.g., short-acting glucagon-like peptide 1 receptor agonists or pramlintide) for therapeutic gain (2). Accordingly, gastric emptying is central to the pathogenesis and personalized management of diabetes (6). …

Diabetic autonomic neuropathy as a risk factor for emergencies

Diabetic autonomic neuropathy includes damage of various organ systems. The manifestations of autonomic neuropathy usually occur in setting of distal sensory motor polyneuropathy but autonomic disorders may be presented disproportionately compared to sensory and motor disorders. Diabetic autonomic neuropathy increases the risk of cardiac arrhythmias and sudden death, significantly reduces the patients’ quality of life, and exacerbates other vascular complications of diabetes mellitus. There are cardiovascular, gastrointestinal and urogenital forms of diabetic autonomic neuropathy and damaged function of autonomic nerve fibers involving respiratory system, pupils, sudoriferous glands, thermoregulatory and endocrine system. Cardiovascular autonomic neuropathy is the most studied, clinically meaningful and prognostically pejorative form of autonomic neuropathy. Autonomous diabetic neuropathy can cause frequent emergency admissions of patients with this pathology, increased mortality in patients with diabetes, which requires informing of general practitioners, endocrinologists, and intensivists about the features of the clinical manifestations and course of this disease.

New symptoms in a patient with diagnosed porphyria – untypical clinical course or another disease? Extended differential diagnosis of multiple sclerosis

Acute liver porphyrias are caused by mutations of genes encoding the heme biosynthesis enzymes. A lack of any of these enzymes leads to a decrease in the heme level, which in each case is manifested by identical clinical symptoms. Nervous tissue is particularly susceptible to a depletion of heme levels. Three classical symptoms of a porphyria attack include: abdominal pain (as a manifestation of autonomic neuropathy), peripheral neuropathy, and psychic disturbances. Apart from the main symptoms, porphyria attacks may be manifested as various neurological disturbances, such as: bulbar palsy, epileptic seizures, psychic disturbances and focal symptoms of CNS damage. The intensity of individual symptoms can vary. Although neurological symptoms usually disappear after the attack, they may cause permanent deficits. Through involving CNS, porphyria can mimic other neurological disorders. Damage to the nervous system can be confirmed by additional examinations. Thus far, disseminated focal changes during the attack, which disappear after the regression of clinical symptoms, have been described in magnetic resonance imaging (MRI) scans of the brain. Spinal cord abnormalities in MRI scans have not been described yet, despite the fact that damage to the anterior horn associated with porphyria has been confirmed in literature. While examining cerebrospinal fluid during the attack, an elevated protein level has been noticed, so far without the presence of oligoclonal bands. This paper aimed to demonstrate that porphyria should be considered in differential diagnosis of clinically isolated syndrome (CIS) and multiple sclerosis (MS). This paper is based on the case of a symptomatic patient who carried a mutation in one of the genes for porphyria, and who developed a clinical manifestation of focal damage to CNS. A differential diagnosis of porphyria and CIS, with a subsequent conversion to a clinically defined MS, was carried out. The results of additional examinations performed routinely in both disorders, the clinical picture and data from medical literature have been used in the analysis of this case. The authors present the case of a patient with confirmed genetic porphyria, who was hospitalized for purposes of establishing a diagnosis due to weakened lower extremities. The patient manifested spastic lower extremity paresis, sensation disorders and urinary incontinence, which indicated spinal cord damages. An MRI scan of the thoracic spine revealed disseminated foci with contrast enhancement. A high level of proteins and oligoclonal bands were detected in the cerebrospinal fluid. On the basis of a new clinical picture (differing from the previous attack symptoms), prolonged symptoms, spinal cord lesions in MRI, and the presence of oligoclonal bands, CIS was diagnosed. Quick and complete recovery was obtained due to the administering of a steroid therapy. After several months, the patient reported a similar, passing episode, which, according to the authors, confirmed the diagnosis and an expected conversion to a clinically defined MS. Taking into consideration the clinical manifestation of spinal cord involvement untypical of porphyria, the detection of spinal lesions in an MRI scan, the presence of oligoclonal bands in the cerebrospinal fluid and the positive effect of steroid therapy, the authors believe that this described patient, who was a symptomatic carrier of a mutation in a gene for porphyria, developed CIS. This reported case, supported by data from medical literature, shows that porphyria should be taken into consideration in any differential diagnosis of CIS and MS.

Case Study: Recurrent Diabetic Ketoacidosis Resulting From Spurious Hypoglycemia: A Deleterious Consequence of Inadequate Detection of Partial Strip Filling by a Glucose Monitoring System

E.K., a 28-year-old woman with poorly controlled type 1 diabetes of 10 years' duration, presented with mild nausea, occasional vomiting, dizziness, and recurrent, asymptomatic severe hypoglycemia. In phone consultations with the physician's office in the preceding week, she had reduced her insulin in half because of recurrent, very low (usually asymptomatic) glucose readings but sporadic low glucose levels continued to be problematic. She also had episodic, marked hyperglycemia complicating her dosing decisions. Her patterns of high and low glucose appeared discordant with food intake and insulin dosing. Her history was remarkable for diabetes and recurrent, intermittent nausea, vomiting, and diarrhea presumed to be manifestations of autonomic neuropathy. She had known hypoglycemia unawareness but had not had problems with unconscious hypoglycemia or seizures. She had no other known autoimmune disorders and no retinopathy or renal dysfunction. She often missed office appointments and, until recently, had been erratic in her glucose monitoring. At the time of her presentation, she was on 10 units of NPH insulin in the morning and 5 units at night, with small doses of lispro only taken to compensate for very high glucose readings. Her exam was remarkable for dry mucous membranes and orthostatic hypotension, with a sitting blood pressure of 98/74 mmHg and pulse of 102 bpm and a standing blood pressure of 72/40 mmHg and pulse of 120 bpm. Otherwise, she had normal skin pigmentation and no lipohypertrophy or lipoatrophy, and her neck, heart, lung, abdomen, and extremities were all unremarkable. Because of the frequent low glucose levels, her insulin was further decreased, down to 7 units in the morning and 2 units at night, and she was provided new bottles of her insulins and test strips. She was instructed to aggressively hydrate and closely monitor her blood glucose and urine ketone levels. Fasting laboratory tests …

Delayed Radionucleotide Gastric Emptying Studies Predict Morbidity in Diabetics with Symptoms of Gastroparesis

Purpose: Gastroparesis is a serious complication of diabetes mellitus (DM). However, little is known regarding the health implications of gastroparesis in diabetics. The specific aims of this study were to test the hypotheses that diabetic patients with proven gastroparesis differ from those with normal gastric emptying: 1: In the number of days spent in hospital per 1000 patient days, 2: In the prevalence of other manifestations of autonomic neuropathy and microvacular disease and 3: In blood glucose control. Methods: This was a parallel cohort study with 3 separate groups of DM patients (both Type 1 and Type 2) treated between 2000 and 2008. Group A: Gastroparesis diagnosed by both classic symptoms and a delay in gastric emptying on a radionucleotide gastric emptying study. Group B: Classic symptoms of gastroparesis but with a normal gastric emptying study. Group C: Patients without symptoms of gastroparesis (no gastric emptying study performed). We gathered data on subsequent health outcomes and resource utilization including: number of days hospitalized, number of office visits, number of ED visits, number of hospitalization and deaths in this eight-year period. We also collected data on HbA1C levels, medication use, medical history and complications of DM. Results: There were 94 subjects in each group. By univariate analysis Group A had significantly more Hospital Days per 1000 patient days than Group B. (See Table 1). Group A also had significantly more hospitalizations, office visits and ED visits. There was a trend toward more deaths per 1000 patient days in Group A compared to Group B. Compared to Group C, Group A again had significantly more days in hospital, hospitalizations, office visits and ED visits. None of these measures differed significantly between Group B and Group C with the exception of more office visits for Group B. HbA1Cs were similar in the 3 groups. Group A patients were more likely to have vascular disease (CAD, HTN, retinopathy) but not more likely to have neuropathy. On multivariate analysis, Group A maintained a significant difference vs. B and C and the differences between Groups B and C disappeared.Table 1Conclusion: In this study, a positive radionucleotide gastric emptying study for gastroparesis in diabetics was predictive of greater healthcare utilization in terms of number of hospitalizations, number of office visits, number of ED visits and number of days in hospital. Risk of death was also increased but did not reach statistical significance. We also identified a correlation between diabetic gastroparesis and CAD and HTN which has not previously been reported. These data suggest that a positive radionucleotide gastric emptying study is of clinical and prognostic significance.

Unawareness of hypoglycaemia and inadequate hypoglycaemic counterregulation: no causal relation with diabetic autonomic neuropathy.

To examine the traditional view that unawareness of hypoglycaemia and inadequate hypoglycaemic counterregulation in insulin dependent diabetes mellitus are manifestations of autonomic neuropathy. Perspective assessment of unawareness of hypoglycaemia and detailed assessment of autonomic neuropathy in patients with insulin dependent diabetes according to the adequacy of their hypoglycaemic counterregulation. One routine diabetic unit in a university teaching hospital. 23 Patients aged 21-52 with insulin dependent diabetes mellitus (seven with symptoms suggesting autonomic neuropathy, nine with a serious clinical problem with hypoglycaemia, and seven without symptoms of autonomic neuropathy and without problems with hypoglycaemia) and 10 controls with a similar age distribution, without a personal or family history of diabetes. Presence of autonomic neuropathy as assessed with a test of the longest sympathetic fibres (acetylcholine sweatspot test), a pupil test, and a battery of seven cardiovascular autonomic function tests; adequacy of hypoglycaemic glucose counterregulation during a 40 mU/kg/h insulin infusion test; history of unawareness of hypoglycaemia; and response of plasma pancreatic polypeptide during hypoglycaemia, which depends on an intact and responding autonomic innervation of the pancreas. There was little evidence of autonomic neuropathy in either the 12 diabetic patients with a history of unawareness of hypoglycaemia or the seven patients with inadequate hypoglycaemic counterregulation. By contrast, in all seven patients with clear evidence of autonomic neuropathy there was no history of unawareness of hypoglycaemia and in six out of seven there was adequate hypoglycaemic counterregulation. Unawareness of hypoglycaemia and inadequate hypoglycaemic counterregulation were significantly associated (p less than 0.01). The response of plasma pancreatic polypeptide in the diabetic patients with adequate counterregulation but without autonomic neuropathy was not significantly different from that of the controls (change in plasma pancreatic polypeptide 226.8 v 414 pmol/l). The patients with autonomic neuropathy had a negligible plasma pancreatic polypeptide response (3.7 pmol/l), but this response was also blunted in the patients with inadequate hypoglycaemic counterregulation (72.4 pmol/l) compared with that of the controls (p less than 0.05). Unawareness of hypoglycaemia and inadequate glucose counterregulation during hypoglycaemia are related to each other but are not due to autonomic neuropathy. The blunted plasma pancreatic polypeptide responses of the patients with inadequate hypoglycaemic counterregulation may reflect diminished autonomic activity consequent upon reduced responsiveness of a central glucoregulatory centre, rather than classical autonomic neuropathy.

PROTEIN-BOUND IODINE LEVELS IN PREGNANCY.

OBJECTIVE--To examine the traditional view that unawareness of hypoglycaemia and inadequate hypoglycaemic counterregulation in insulin dependent diabetes mellitus are manifestations of autonomic neuropathy. DESIGN--Perspective assessment of unawareness of hypoglycaemia and detailed assessment of autonomic neuropathy in patients with insulin dependent diabetes according to the adequacy of their hypoglycaemic counterregulation. SETTING--One routine diabetic unit in a university teaching hospital. PATIENTS--23 Patients aged 21-52 with insulin dependent diabetes mellitus (seven with symptoms suggesting autonomic neuropathy, nine with a serious clinical problem with hypoglycaemia, and seven without symptoms of autonomic neuropathy and without problems with hypoglycaemia) and 10 controls with a similar age distribution, without a personal or family history of diabetes. MAIN OUTCOME MEASURES--Presence of autonomic neuropathy as assessed with a test of the longest sympathetic fibres (acetylcholine sweatspot test), a pupil test, and a battery of seven cardiovascular autonomic function tests; adequacy of hypoglycaemic glucose counterregulation during a 40 mU/kg/h insulin infusion test; history of unawareness of hypoglycaemia; and response of plasma pancreatic polypeptide during hypoglycaemia, which depends on an intact and responding autonomic innervation of the pancreas. RESULTS--There was little evidence of autonomic neuropathy in either the 12 diabetic patients with a history of unawareness of hypoglycaemia or the seven patients with inadequate hypoglycaemic counterregulation. By contrast, in all seven patients with clear evidence of autonomic neuropathy there was no history of unawareness of hypoglycaemia and in six out of seven there was adequate hypoglycaemic counterregulation. Unawareness of hypoglycaemia and inadequate hypoglycaemic counterregulation were significantly associated (p less than 0.01). The response of plasma pancreatic polypeptide in the diabetic patients with adequate counterregulation but without autonomic neuropathy was not significantly different from that of the controls (change in plasma pancreatic polypeptide 226.8 v 414 pmol/l). The patients with autonomic neuropathy had a negligible plasma pancreatic polypeptide response (3.7 pmol/l), but this response was also blunted in the patients with inadequate hypoglycaemic counterregulation (72.4 pmol/l) compared with that of the controls (p less than 0.05). CONCLUSIONS--Unawareness of hypoglycaemia and inadequate glucose counterregulation during hypoglycaemia are related to each other but are not due to autonomic neuropathy. The blunted plasma pancreatic polypeptide responses of the patients with inadequate hypoglycaemic counterregulation may reflect diminished autonomic activity consequent upon reduced responsiveness of a central glucoregulatory centre, rather than classical autonomic neuropathy.