Symptoms Of Autonomic Neuropathy Research Articles

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.

Autonomic Stimulation Action of EAT (Epipharyngeal Abrasive Therapy) on Chronic Epipharyngitis.

This study investigated the pathogenesis and pathophysiology of chronic epipharyngitis, which presents a variety of symptoms, with a focus on autonomic neuropathy symptoms, and also investigated the literature for information on EAT, which is useful as a treatment method. The mechanism of action of EAT has recently been clarified in terms of its immune system-stimulating and endocrine system-stimulating effects. However, the autonomic nerve-stimulating effects of EAT are still largely unexplained. This study was conducted to collect and integrate previous studies and papers focusing on the autonomic nerve-stimulating effects of EATand to provide insight into the still not fully elucidated autonomic nerve-stimulating effects of EAT on chronic epipharyngitis. The local stimulating effects of zinc chloride and the bleeding and pain effects of EAT are also summarized, suggesting that EAT exerts its therapeutic effects through the interaction of the immune system, the endocrine system, and the autonomic nervous system. It is important to determine which mechanism is predominantly involved in each case of chronic epipharyngitis and to utilize it in treatment. Elucidating the effects of EAT on the autonomic nervous system will be an important guideline in determining the treatment strategy for chronic epipharyngitis.

Bortezomib Induced Peripheral and Severe Autonomic Neuropathy Characterized By Dizziness, Orthostatic Hypotension and Weight Loss

Background It is well known that Bortezomib (B), a proteasome inhibitor used in the treatment of Multiple Myeloma (MM) causes peripheral neuropathy in an estimated 75% of patients and compromises their quality of life. There are reports of dizziness, muscle weakness and other unusual neurologic complications caused by B. Among patients that received B based induction, we observed peripheral neuropathy as expected. In addition, in a small subset we observed profound weight loss, dizziness, orthostatic hypotension (OH) and diarrhea. Some patients with weight loss required appetite stimulants and patients with OH/dizziness required medication for symptom control. The conglomeration of symptoms frequently impairs patients' performance status requiring interruption of therapy. B was given in combination with lenalidomide and dexamethasone (VRD) but we feel the neuropathic symptoms are more due to B since the combination of just lenalidomide and dexamethasone is not known to cause such complications. There are few publications on autonomic neuropathy (AN) caused by B but we believe it is under recognized and under diagnosed. Herein we report a series of patients managed at our center that presented with significant weight loss and dizziness suggestive of AN, prompting us to explore further and bring awareness to this problem. Methods From January 2018 to July 2023, patients with MM treated in our own practice and patients induced by our referring practices and sent to our center for transplant were evaluated. We identified patients who complained of significant weight loss and dizziness and reviewed medical records, looked at the characteristics they exhibited, and identified a pattern of symptoms and clinical course. Statistics are descriptive and this retrospective study was approved by our Institutional review board. Results Sixteen patients were noted to have symptoms suggestive of AN. 13 of 16 received VRD and 3 received Daratumumab, B and dexamethasone-based induction. B was administered subcutaneously and given twice weekly. The median age was 62.5 years (range 51-76). Ten were African American and 6 White; 6 female, 4 had diabetes but no neuropathy, 10 had bone disease, 5 renal failure at presentation. The interval between initiation of therapy and AN symptoms was a median of 117 days (range 50-219) and the median B dose was 20.8 mg/M 2 (range 11.7-40.3 mg/M 2). All 16 patients had weight loss and was the most recognizable symptom. The median weight loss and percentage weight loss (compared to baseline weight) were 18.2 Kgs (range 6.7-39.14 Kgs) and 19% (range 6-41%) respectively. 10 of 16 patients had loss of appetite and 9 had diarrhea. Further treatment was held due to decline in performance status in 14 patients. Nine patients received appetite stimulants; 2 megestrol and 7 dronabinol. OH and an increase in heart rate in the standing position was seen in all 16 patients. 11 of the 16 patients had dizziness; 3 patients received fludrocortisone and one received midodrine. 14 of 16 patients also had peripheral neuropathy of whom 13 required medications for neuropathic pain and 14 required narcotic analgesics. Conclusion 14 of 16 patients received a transplant and 2 declined. Transplant was delayed by 6 months (range 2-11) to enable recovery and the end-point was weight gain, resolution of OH and clinical improvement. Post-transplant 4 patients had persistent diarrhea and 1 had persistent dizziness. One patient developed severe mucositis, dysphagia, poor appetite and required hyperalimentation, nasogastric feeding and a feeding gastrostomy tube. 9 of 14 patients had persistent peripheral neuropathy and are using medications. Two of the 16 patients progressed and received salvage treatment one of the two is now deceased. With a median follow up of 26.35 (range 8.47-53.6) months, the median survival since diagnosis is 28.72 months. Severe AN characterized by weight loss, dizziness, OH in association with loss of appetite, diarrhea and painful neuropathy is an under recognized complication of Bortezomib. This generally results in interruption of disease directed therapy and delays autologous transplantation. Transplantation without resolution of symptoms could possibly worsen the morbidity and delay post-transplant recovery. To the best of our knowledge, we are the first group to report a series of patients with this symptom complex and strongly feel it requires further study in a larger cohort.

The Effect of Epipharyngeal Abrasive Therapy (EAT) on the Baroreceptor Reflex (BR).

Introduction Epipharyngeal Abrasive Therapy (EAT) has been used as a treatment for chronic epipharyngitis, and although autonomic nerve stimulation has been pointed out as one of the mechanisms by which EAT produces therapeutic effects, there have been few reports examining this mechanism of action. This study investigated the effects of repeated EAT on autonomic nervous system activity in chronic epipharyngitis patients over time, using heart rate variability analysis. In addition, we conducted a loading test using the active standing test (AS test) to examine the effects of EAT on the baroreceptor reflex (BR). Subjects and methods A retrospective study was conducted on 39 patients who visited our clinic between July 2017 and November 2019 and underwent autonomic function tests with a diagnosis of chronic nasopharyngeal inflammation. The subjects were divided into two groups: the improvement group and the invariant group for comparison.Electrocardiographic recordings and blood pressure measurements were made under the stress of the AS test. Heart rate, high-frequency (HF) component, low-frequency (LF) component, and Coefficient of Variation on R-R interval were evaluated as indices of autonomic function.Component coefficient of variance high frequency was used as an index of parasympathetic function. ccvLF/ccvHF ratio was calculated by dividing the component coefficient of variance low frequency by ccvHF. The AS test was conducted in phase 1 in the initial resting sitting position, in phase 2 in the standing position, in phase 3 in the standing and holding the standing position, and in phase 4 in the seated and holding the sitting position. Systolic blood pressure, mean arterial pressure, and diastolic blood pressure were obtained in each phase.A paired t-test was used to compare the improved and invariant groups before and after treatment. The post-treatment comparison between the improved group and the invariant group was performed by unpaired t-test. Variation of the evaluation index over time was evaluated by repeated measures ANOVA. Multiple comparisons were corrected by the Bonferroni method. Results The EAT showed that parasympathetic activity was significantly suppressed in the improvement group, while the AS test showed significant fluctuations over time for the improvement and invariant groups. The interaction between the time course and the two factors in the improvement and invariant groups was not statistically evident. Although no significant difference was found, the improvement group showed a tendency to suppress parasympathetic activity and a tendency to stimulate sympathetic activity compared to the invariant group. Blood pressure in the improvement group showed a tendency to decrease. Conclusions EAT was found to suppress parasympathetic activity over time, and the AS test did not reveal an interaction effect of EAT on BR. However, there was a trend toward suppression of parasympathetic activity and stimulation of sympathetic activity in the improved group compared to the invariant group. Blood pressure in the improved group tended to decrease. It is possible that EAT may have a positive effect on autonomic neuropathy symptoms such as orthostatic dysregulation (OD), postural orthostatic tachycardia syndrome (POTS), etc. by stimulating the BRs. It is thought that the autonomic nervous system stimulating action and the immune system stimulating action act synergistically to express the therapeutic effect of EAT.

Autonomic Neuropathy in Ambulatory Type 2 Diabetes Mellitus Patients: A Single-arm Prospective, Observational Study

Abstract Introduction: Diabetic autonomic neuropathy (DAN), a serious complication of diabetes, is a significant contributor to increased morbidity and mortality. Although DAN often coexists with different peripheral neuropathies and other complications, it may also present in isolation. The present study aimed to understand the DAN status of a cohort of ambulatory type 2 diabetics in a tertiary care setting. Methods: A single-arm prospective observational study was carried out, where enrolled patients were interviewed for basic demographics and comorbidities, screened for symptoms of autonomic dysregulation, and other risk factors such as smoking and alcoholism. Based on the presence of overt symptoms, they were divided into two groups with or without any overt symptoms of autonomic neuropathy. Both groups were subjected to a battery of autonomic neuropathy tests, and their DAN status was characterized based on the observed scores. Results: The overall prevalence of DAN, as observed in our study, was 36%. Of 108 patients, 97 presented with one or more symptoms of autonomic dysregulation, whereas the rest, 10.1%, were without any symptoms. Among heart rate-based tests, a significant (P &lt; 0.001) decrease followed by an increase in the Valsalva ratio was observed in 6 months and 12 months, respectively. A significant decrease (P &lt; 0.001) in deep breathing test (E: I) values was observed in the 12th month. Most of the DAN patients presented with moderate autonomic dysfunction, followed by mild and severe, respectively. However, no significant change in DAN severity was noted with time. Conclusion: Using simple cardiovascular tests, DAN can be detected during the asymptomatic phase of the disease.

Bortezomib Induced Peripheral and Severe Autonomic Neuropathy Characterized By Dizziness, Orthostatic Hypotension, and Weight Loss

INTRODUCTION: It is well known that Bortezomib (B), a proteasome inhibitor used in the treatment of Multiple Myeloma (MM) causes peripheral neuropathy in an estimated 75% of patients and compromises their quality of life. There are reports of dizziness, muscle weakness and other unusual neurologic complications caused by B. Among patients that received B based induction, we observed peripheral neuropathy as expected. In addition, in a small subset we observed profound weight loss, dizziness, orthostatic hypotension (OH) and diarrhea. Some patients with weight loss required appetite stimulants and patients with OH/dizziness required medication for symptom control. The conglomeration of symptoms frequently impairs patients' performance status requiring interruption of therapy. B was given in combination with lenalidomide and dexamethasone (VRD) but we feel the neuropathic symptoms are more due to B since the combination of just lenalidomide and dexamethasone is not known to cause such complications. There are few publications on autonomic neuropathy (AN) caused by B but we believe it is under recognized and under diagnosed. Herein we report a series of patients managed at our center that presented with significant weight loss and dizziness suggestive of AN, prompting us to explore further and bring awareness to this problem. METHODS: From January 2018 to July 2022, patients with MM treated in our own practice and patients induced by our referring practices and sent to our center for transplant were evaluated. We identified patients who complained of significant weight loss and dizziness and reviewed medical records, looked at the characteristics they exhibited, and identified a pattern of symptoms and clinical course. Statistics are descriptive and this retrospective study was approved by our Institutional Review Board. RESULTS: Twelve patients were noted to have symptoms suggestive of AN. 11 of 12 received VRD and one received Daratumumab, B and dexamethasone based induction. B was administered subcutaneously and given twice weekly. The median age was 62.5 years (range 51-76). Eight were African American and 4 White; 8 female, 3 had diabetes but no neuropathy, 8 had bone disease, 2 renal failure at presentation. The interval between initiation of therapy and AN symptoms was a median of 107 days (range 50-219) and the median B dose was 20.8 mg/m2 (range 9-31 mg/m2). All 12 patients had weight loss and was the most recognizable symptom. The median weight loss and percentage weight loss (compared to baseline weight) were 19.5 Kgs (range 7-37 Kgs) and 21% (range 7-41) respectively. 7 of 12 patients had loss of appetite and 8 had diarrhea. Further treatment was held due to decline in performance status in all 12 patients. Six patients received appetite stimulants; 2 megestrol and 4 dronabinol. OH and an increase in heart rate in the standing position was seen in all 12 patients. 10 of the 12 patients had dizziness; 3 patients received fludrocortisone and one received midodrine. 11 of 12 patients also had peripheral neuropathy of whom 10 required medications for neuropathic pain and 10 required narcotic analgesics. 10 of 12 patients received a transplant and 2 declined. Transplant was delayed by 6 months (range 2-11) to enable recovery and the end-point was weight gain, resolution of OH and clinical improvement. Post-transplant 4 patients had persistent diarrhea and 1 had persistent dizziness. One patient developed severe mucositis, dysphagia, poor appetite and required hyperalimentation, nasogastric feeding and a feeding gastrostomy tube. 10 of 12 patients had persistent peripheral neuropathy and are using medications. Two of the 12 patients progressed and are receiving salvage treatment but there are no deaths. With a median follow up of 23 months (range 8-42), the median survival since diagnosis is 27 months. CONCLUSIONS: Severe AN characterized by weight loss, dizziness, OH in association with loss of appetite, diarrhea and painful neuropathy is an under recognized complication of Bortezomib. This generally results in interruption of disease directed therapy and delays autologous transplantation. Transplantation without resolution of symptoms could possibly worsen the morbidity and delay post-transplant recovery. To the best of our knowledge, we are the first group to report a series of patients with this symptom complex and strongly feel it requires to be studied further in a larger cohort of patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Accuracy of autonomic symptoms in detection of severe cardiac autonomic neuropathy

Autonomic neuropathy is a troublesome complication of diabetes mellitus often is not addressed by the physicians. The aim was to see the accuracy of autonomic symptoms in the detection of severe cardiac autonomic neuropathy (CAN). This study was done in BIRDEM in 62 adult patients with type 2 diabetes mellitus and cardiac autonomic neuropathy. Cardiac autonomic neuropathy was detected clinically by heart rate and blood pressure change to maneuvers such as deep breathing, valsalva and standing. Eight symptoms of autonomic neuropathy, namely exercise intolerance, dizziness, dysphagia, abdominal bloating, constipa- tion, diarrhea, gustatory sweating and impotence were tested. In this study, impotence was the most common symptom (58%). There was no difference in the frequency of autonomic symptoms between severe and non-severe cardiac autonomic neuropathy. Taking clinical tests as gold standard, gustatory sweating had the highest specificity (96%) and constipation had the highest sensitivity (54.05%) in detection of severe cardiac autonomic neuropathy. Sensitivity increased to 78.37 when a constellation of symptoms were tested. Autonomic symptoms are common in patients with type 2 diabetes and cardiac autonomic neuropathy. Collection of symptoms was associated with a high sensitivity for detection of severe cardiac autonomic neuropathy. BSMMU J 2022; 15(1): 11-15

異なるマグネシウム管理を行った破傷風の2例(Two cases of tetanus managed with different intravenous doses of magnesium)

要旨 硫酸マグネシウム（以下Mg）静注療法は，破傷風の筋痙攣・強直や自律神経障害への有効性が報告されている。しかし，その投与量の調整方法は確立されていない。本邦で破傷風患者は稀であるが，我々は異なる指標で硫酸Mgの投与量を調整した2名の破傷風患者を経験した。患者1では臨床所見にもとづいて調整したところ，筋痙攣・強直や自律神経障害のコントロールは良好であったものの重篤な高Mg血症を生じ，経過中にQT延長と気管内出血の合併症を来した。患者2では血清Mg濃度で投与量を調整したところ，患者1よりも血圧変動が目立ったものの，有害事象を生じることなく良好な転帰を得ることができた。破傷風に対して硫酸Mg静注を行う際には，ある程度の自律神経障害が残存したとしても，重篤な高Mg血症を来さないように血中濃度をもとに投与量を調整するほうが好ましい可能性が示唆された。

Patient-reported burden of hereditary transthyretin amyloidosis on functioning and well-being

BackgroundHereditary transthyretin (hATTR) amyloidosis is a rare, systemic, progressive, and life-threatening disease in which transthyretin proteins misfold and aggregate as insoluble amyloid deposits, disrupting nervous, cardiac, gastrointestinal, and other organ tissues. There are limited available data about the experience of patients living with hATTR amyloidosis. This study used a qualitative, non-interventional design to explore the humanistic burden of hATTR amyloidosis from the patient’s perspective.ResultsFourteen adults with hATTR amyloidosis, recruited from a patient advocacy group or an academic clinical center, participated in individual semi-structured interviews either in person or by telephone. Patients were asked to describe their experiences living with the condition, including symptoms and disease-related impacts on functioning and well-being, work, and activities of daily living (ADLs). Interviews were transcribed verbatim and analyzed for key concepts using a grounded theory approach.Patients described many symptoms of hATTR amyloidosis, particularly those associated with peripheral neuropathy such as pain, numbness, weakness, and paresthesia. Symptoms of autonomic neuropathy, such as gastrointestinal dysfunction, and symptoms related to cardiac dysfunction were also common. Worsening symptoms, especially those impacting patients’ ability to walk or use their hands, often led to a loss of autonomy and an inability to work or perform ADLs. Disease-related disability also interfered with patients’ participation in social activities, and contributed to feelings of fear, frustration, or sadness.ConclusionsThe impacts of hATTR amyloidosis were profound for the patients interviewed for this study. They described a sense of loss as their condition progressed and impacted them physically, emotionally, and socially. Patients’ reports of symptoms and impacts of hATTR amyloidosis illustrate the complex and varied manifestations of this disease. The progression of symptoms and increasing impacts of hATTR amyloidosis also highlight the need for an earlier diagnosis and effective clinical intervention to preserve patients’ functioning and well-being.

Epigenetic mechanism in search for the pathomechanism of diabetic neuropathy development in diabetes mellitus type 1 (T1DM).

The aim of this study was to check the hypothesis concerning the crucial role of DNA methylation (one of the epigenetic mechanisms) within selected genes related to the destruction and regeneration of neural cells and its input in the pathogenesis of diabetic neuropathy, using a model of the DNA in peripheral blood cells. A cross-sectional, case-control study was conducted, consisting of 24 adult Type 1 Diabetes Melitus (T1DM) patients with autonomic neuropathy (CAN), 25 T1DM patients without neuropathy and 25 matched, healthy adults acting as a control (Ctrl). The Ewing's tests, using the ProSciCard apparatus (Mewicon CATEEM-Tec GmbH), was employed to assess the severity of the patients' symptoms of autonomic neuropathy. For DNA methylation analysis, DNA material of each sample DNA after bisulfite conversion was used for the hybridization of BeadChips (Infinium Methylation EPIC Kit, Illumina), and imaged on the Illumina HiScan. The changes in the expression of selected genes were examined using real-time PCR. Probes were labeled using fluorescein amidite, FAM (Thermo Fisher Scientific). Amplification was performed using the continuous fluorescence detection 7900 HT Fast Real-Time PCR system (Thermo Fisher Scientific). The expression ratio of the target mRNA was normalized to the level of 18s RNA and compared with the control. Statistical analysis was performed using Statistica version 13.1. The statistically significant results were recognized, with a value of p < 0.05. Clinical analysis of the investigated groups revealed a significantly higher percentage of personal insulin pump users in the group without neuropathy. The glucose metabolic control, based on the HbA1c level analysis, was also significantly better in T1DM patients without CAN. The Bumphunter method for DNA methylation analysis showed statistically significant regions related to the genes involved in nerve regeneration ninjurin 2 (NINJ2) and functionality (BR serine/threonine kinase 2 BRSK2, claudin 4 CLDN4). When compared with T1DM patients without neuropathy, T1DM patients with neuropathy showed significantly increased methylation in the first NINJ2 axon, and a lower level of DNA methylation in the region of the first intron of BRSK2, as well as the CLDN4 5'UTR regions. The qRT-PCR results confirmed the decreased expression of NINJ2 and CLDN4 genes in patients with T1DM with CAN. The different DNA methylation profiles, correlating with the expression of genes related to nervous tissue development and regeneration in patients with T1DM with autonomic neuropathy provide evidence for the role of epigenetic mechanisms promoting the development of CAN, a chronic complication of T1DM.

Screening for autonomic neuropathy using validated non-invasive scale among diabetes patients treated in the selected primary health centres of Puducherry, India: an operational research

Background: Diabetes autonomic neuropathy (DAN) is a complication of diabetes which has direct implications on the mortality of diabetes patients. American Diabetes Association (ADA-2017) guidelines recommend early recognition and treatment of DAN. In this regard, we conducted a study among diabetic patients treated in the selected PHCs of Puducherry to determine the proportion with DAN and to assess the factors associated with DAN.Methods: A cross-sectional analytical study was conducted among diabetics and information on socio-demographic details, morbidity and behavioural risk factors were elicited using semi-structured interview schedule. The COMPASS-31 questionnaire was administered to assess the autonomic neuropathy symptoms. The data was captured using EpiCollect mobile app and analysed using Stata 12.0 software. The proportion of DAN was expressed as percentage with 95% confidence interval. The association between independent factors and DAN was assessed using multivariate generalized linear models. The prevalence ratio with 95% CI was used to express the strength of association.Results: Of the total 303 individuals with diabetes, 32 {10.6% (95% CI: 7.3%-14.6%)} were screened positive for autonomic neuropathy using COMPASS-31 scale. The number of individuals with diabetes who needed to be screened (NNS) for finding one with autonomic neuropathy was 10 (303/32).Conclusions: One in ten individuals with diabetes was screened positive for autonomic neuropathy. With good yield, there is need for including autonomic neuropathy screening as a component in the comprehensive care provided to diabetes patients in the primary health centres.

1583P - Autonomic neuropathy in geriatric patients with gynecologic cancer receiving taxanes and platinum chemotherapy

Background: The standard of care for ovarian cancer in elderly is using paclitaxel and carboplatin, an effective and efficient combination, but has serious toxicities. Peripheral neurotoxicity is one of the commonest toxicities which are seen occurring in 60% to 90% of patients. It is debilitating and vexing. Unfortunately, there is very little or no data regarding autonomic neuropathy in this setting. This study is an attempt to highlight this problem. Methods: Single center cohort study of patients for the period 2013-2015. All patients were above the age of 65 years. 88 patients were tested for. All patients were screened for neuropathy using standard forms and methods including positional sense and stereognostic sense for neuropathy. NCI scales of grading peripheral neuropathy were followed. Autonomic neuropathy assessments were done by cardio vascular autonomic reflex test and gastro-intestinal autonomic neuropathy by using gastric phase emptying test. Genito-urinary autonomic neuropathy was tested for erectile dysfunction and bladder dysfunction. The tests were administered at baseline after 2nd, 4th and 6th cycle or if the patient complained of suggestive symptoms. Results: 37% of patients developed grade 3/4 peripheral neuropathy. 59% of patients developed symptomatic autonomic neuropathy. Cardio vascular autonomic neuropathy occurred in 30% while gastric neuropathy was seen in 19%. Combined was seen in 10%. Constipation, diarrhoea and reeling of head were the most common complaints. Autonomic neuropathy was more common in diabetics 60% vs 48% (p > 0.05). Attempts to intervene using pharmacotherapy methods and non-pharmacotherapy methods were attempted. Conclusions: Autonomic neuropathy seems to be common in geriatric population treated by this drug combination although there is not much mention either in real life or in clinical trials or if available as data attributed to other causes. Caution must be exerted in patients in diabetics and proper screening should be done in this patient population for autonomic neuropathy and peripheral neuropathy. Legal entity responsible for the study: G S Bhattacharyya Funding: None Disclosure: All authors have declared no conflicts of interest.

Validation of the Composite Autonomic Symptom Score 31 (COMPASS 31) for the assessment of symptoms of autonomic neuropathy in people with diabetes.

To validate the Composite Autonomic Symptom Score (COMPASS) 31, in its Italian version, for the diagnosis of diabetic cardiovascular autonomic neuropathy in a clinic-based, single-centre study. A total of 73 participants with diabetes (age 55 ± 14 years) completed the COMPASS 31 questionnaire before undergoing cardiovascular autonomic neuropathy and diabetic polyneuropathy assessment according to cardiovascular reflex tests, neuropathic symptoms and signs, and vibration and thermal thresholds. The COMPASS 31 total weighted score differed between participants with and without cardiovascular autonomic neuropathy (29.9 ± 19.5 vs 16.1 ± 14.7; P = 0.003) and with and without diabetic polyneuropathy (28.9 ± 19.1 vs 12.7 ± 11.3; P < 0.0001). It was related to cardiovascular reflex tests score (rho = 0.38, P = 0.0013) as well as diabetic polyneuropathy symptoms (rho=0.61, P < 0.0001) and signs scores (rho = 0.49, P < 0.0001). Receiver-operating curve analysis showed a fair diagnostic accuracy of total score for cardiovascular autonomic neuropathy (area under the curve 0.748 ± 0.068, 95% CI 0.599-0.861) and diabetic polyneuropathy (area under the curve 0.742 ± 0.061, 95% CI 0.611-0.845). The best score thresholds were 16 for early cardiovascular autonomic neuropathy (sensitivity 75.0%, specificity 64.9%, positive predictive value 37.5% and negative predictive value 90.2%), and 17 for both confirmed cardiovascular autonomic neuropathy and diabetic polyneuropathy (sensitivity 70.0% and 65.5%, respectively; specificity 66.7% and 79.5%, respectively; positive predictive value 25.0% and 67.9%, respectively; and negative predictive value 93.0% and 77.8%, respectively). COMPASS 31 had a good internal consistency according to Cronbach's α coefficient of 0.73. COMPASS 31 can represent a valid, easy-to-use, quantitative assessment tool for autonomic symptoms in diabetic neuropathy, with a fair diagnostic accuracy for both cardiovascular autonomic neuropathy and diabetic polyneuropathy.

Lenalidomide/Melphalan / Dexamethasone Chemotherapy In 50 Patients With Newly Diagnosed Amyloid Light Chain Amyloidosis: First Results Of a Prospective Single Center Phase 2 Study (Leomex)

IntroductionAmyloid light chain (AL) amyloidosis is a rare and life-threatening protein-misfolding disorder that is causedin most cases by a monoclonal plasma cell disorder. The goal of chemotherapy is to normalize the involved free light chain in serum which leads to an improvement or at least stabilization of organ function in most of these patients. A major challenge is the high treatment-related mortalityand toxicity in patients with advanced cardiac amyloidosis. Study designWe performed a prospective single centerphase 2 trial with50 patients not eligible for high-dose treatment.Main inclusion criteria were: newly diagnosed and biopsy proven AL amyloidosis, significant organ involvement, age < 75 yrs and creatinine clearance > 40 ml/min. Treatment schedule was 6 cycles of an oral treatment with lenalidomide 10 mg day 1-21, melphalan 0.15 mg/kg day 1-4 and dexamethasone 20 mg day 1-4 every 4 weeks (L-M-dex). Primary endpoint was the rate of complete remissions (CR) of the underlying plasma cell disorder after 6 treatment cycles. Patients who received at least 3 cycles were eligible for hematologic remission (HR=CR+PR) analysis (At the time of study initiation “very good partial remission”in AL amyloidosis was not yet defined). The study was financially supported by Celgene. Patients and MethodsFiftypatients were included between 2009 and 2012. The median age was 67 years. 74% of patients had cardiac involvement. Outcome was compared with a historical group of 53 AL patients who received M-dex between 2004 and 2009 and fulfilled the same in- and exclusion criteria (patient characteristics see table). ResultsForty-five patients (90%) completed 3 cycles and 35 patients (70%) completed 6 treatment cycles; overall 253 cycles could be administered. Reasons of discontinuation were toxicity in 6 patients (including one treatment-related death in the first cycle) or AL progression (9 patients). Ninety adverse events (AE) ≥ CTC grade 3 were recorded including 16 severe AEs. Seventeen hematologic AEs were observed (neutropenia 76%, CTC grade 4 in 2 patients). Most common non-hematologic AE was worsening of cardiac function or symptoms of autonomic neuropathy (14 patients). Furthermore 8 patients suffered from an infection, one patient developed acute renal failure and one patient a deep vein thrombosis.HR was achieved in 78% of patients: CR in 9 (20%)and PR in 26 (58%) of45 evaluable patients, respectively. Organ response was observed in 5 patients at the end of the study (6 months after the end of treatment). In the historical M-dex group HR rate was lower (58%, p=0.06): CR in 6 (15%)andPR in 17(43%) of 40 evaluable patients. OS was significantly improved using L-M-dex (see figure 1, median OS not reached vs. 26 mo., p=0.03). There was also a trend for a better EFS in the L-M-dex group (see figure 2, median EFS 23 vs. 16 mo., p=0.06). Of note, 3 L-M-dex patients (6%) died within 3 months after start of chemotherapy compared to 10 patients (19%) in the M-dex-group. [Display omitted] [Display omitted] ConclusionThis is the largest phase II trial usinglenalidomide, melphalan and dexamethason in newly diagnosed AL amyloidosis patients. Treatment was effective and feasible in this cohort of mostly elderlypatients. 78% of evaluable patients achieved a hematologic remission. The early death rate was low with 6% despite of inclusion of a high number of patients with advanced cardiac amyloidosis. Overall, toxicity was manageable in most patients. Further improvement of these results might be achieved by prolongation of therapy in patients who have responded to and tolerate this combination therapy well.TableL-M-dexHistorical M-dex grouppNumber of patients5053-Time of inclusion2009-20122004-2009-Median age (range, yrs)67 (47-75)65 (45-74)0.04Median dFLC (mg/l)159 (0-3508)206 (0-1037)0.51Median NT-BNP (ng/l)2416 (54 -14609)3878 (0-27624)0.20Median number of organs (range)2 (1-6)2 (1-7)0.58Cardiac involvement (no. of pts / %)37 / 74%45 / 85%0.22 Disclosures:Schonland:Celgene: Honoraria; Janssen: Honoraria. Off Label Use: lenalidomide in amyloidosis. Hegenbart:Janssen: Honoraria.

Autonomic Neuropathy in HIV is Unrecognized and Associated with Medical Morbidity

Autonomic dysfunction is common in HIV. However, its clinical impact is not well understood and its protean symptoms make it difficult to diagnose. We sought to determine: (1) whether autonomic neuropathy is associated with morbidity and predicted mortality in HIV as measured by the Veterans Aging Cohort Study (VACS) index; and (2) if healthcare providers recognize the diagnosis of autonomic neuropathy. Data were obtained from 102 HIV-infected adults enrolled in a prevalence study of autonomic dysfunction from 2011-2012. Participants were predominantly minority with nearly equal numbers of men and women. Most were receiving an antiretroviral regimen with a nucleoside reverse transcriptase inhibitor backbone and a base of a non-nucleoside reverse transcriptase inhibitor, protease inhibitor, or integrase inhibitor. Autonomic neuropathy was defined using a laboratory-based autonomic assessment, the Composite Autonomic Severity Score (CASS). Medical records were reviewed for the year prior to the autonomic assessment. We found that the autonomic neuropathy score (CASS) was associated with the VACS index. We also found that among 53 participants with symptomatic autonomic neuropathy, the diagnosis had been considered for only one. The majority of the symptoms were either unexplained or attributed to medication side effects. This study demonstrates that autonomic neuropathy in HIV is associated with serious co-morbid illnesses known to increase mortality risk, and that HIV healthcare providers rarely consider autonomic neuropathy in their differential diagnoses. Future studies are needed to determine if autonomic neuropathy is an independent risk factor for mortality in HIV, and to raise awareness of its signs and symptoms.

Formen autonomer Nervenkrankheiten

Autonomic neuropathies are a heterogeneous group of diseases that involve damage of small peripheral autonomic Aδ- and C-fibers. Causes of autonomic nerve fiber damage are disorders such as diabetes mellitus and HIV-infection. Predominant symptoms of autonomic neuropathy are orthostatic hypotension, gastro-intestinal problems, urogenital dysfunction, and cardiac arrhythmia, which can severely impair the quality of life in affected patients. Furthermore, autonomic neuropathies can be induced by autoimmune diseases such as acute inflammatory demyelinating polyneuropathy, hereditary disorders such as the lysosomal storage disorder Fabry disease and hereditary sensory and autonomic neuropathies, as well as certain toxins and drugs.

Autonomic Neuropathy in HIV: A Case Report and Review of Potential Symptoms in an Advanced-Stage, HIV Cohort

A woman with a seventeen-year history of HIV infection on effective antiretroviral therapy presented with signs and symptoms of distal symmetric polyneuropathy (DSP). She developed significant side effects (dizziness, nausea, edema) with medications for pain management. Chart review revealed a history of similar intolerance to multiple antiretrovirals, which was not explained by known cardiac or gastrointestinal disease or psychological factors. Specialized testing revealed the presence of an autonomic neuropathy, which provided an explanation for her medication intolerance. The patient was educated on the symptoms of autonomic neuropathy and its relationship to DSP and subsequent symptomatic medications were initiated at the lowest possible doses. Although symptom management remained challenging, the patient exhibited lower frustration and greater acceptance of medication trials. Review of 168 advanced stage HIV infected individuals demonstrated that 81% experienced at least one, and 33% three or more, symptoms potentially attributable to autonomic neuropathy. Potentially autonomic symptoms were significantly associated with the presence of symptomatic DSP. Autonomic neuropathy is difficult to diagnose without specialized testing, as its symptoms are non-specific and overlap with a large number of somatic disorders. The high prevalence of autonomic-type symptoms in chronic HIV, and their association with peripheral neuropathy, may warrant further investigation of the potential for autonomic dysfunction in individuals with HIV-related symptomatic DSP.

Effect of Ginkgo leaf extract and dipyridamole injection combined with methylcobalamin treatment to heart rate variability of patients with diabetic cardiac autonomic neuropathy

Objective To evaluate the effect of Ginkgo leaf extract and dipyridamole injection combined with methylcobalamin treatment to heart rate variability of patients with diabetic cardiac autonomic neuropathy. Methods 66 patients of diabetic cardiac autonomic neuropathy were randomly divided into treatment group and control group, 33 cases of each group, the treatment group were treated with normal saline 250 ml plus Ginkgo leaf extract and dipyridamole injection 20 ml intravenous infusion,and normal saline 10 ml plus methylcobalarnmin 0.5 mg intravenousry once a day,with a total course of treatment for3 weeks. Control group was injected with vitamin B1 and vitamin B12, once a day. 24-hour ambulatory ECG testing was used to collect heart rate variability index of all patients before and after treatment, changes in these indicators were also observed and analyzed. Results After treatment, the heart rate variability index was significantly increased compared with before treatment, and autonomic neuropathy symptoms improved, compared with the control group, the differences was statically significant (P＜0.05). Conclusion Ginkgo leaf extract and dipyridamole injection combined with methylcobalamin treatment of diabetic cardiac autonomic neuropathy has significant effect and can improve heart rate variability. Key words: Ginkgo leaf extract and dipyridamole; Methylcobalamin; Diabetes; Cardiac autonomic neuropathy; Heart rate variability

Natural history of paclitaxel-associated acute pain syndrome: prospective cohort study NCCTG N08C1.

The characteristics and natural history of the paclitaxel-acute pain syndrome (P-APS) and paclitaxel's more chronic neuropathy have not been well delineated. Patients receiving weekly paclitaxel (70 to 90 mg/m(2)) completed daily questionnaires and weekly European Organisation for Research and Treatment of Cancer (EORTC) Chemotherapy-Induced Peripheral Neuropathy (CIPN) -20 instruments during the entire course of therapy. P-APS symptoms peaked 3 days after chemotherapy. Twenty percent of patients had pain scores of 5 to 10 of 10 with the first dose of paclitaxel. Sensory neuropathy symptoms were more prominent than were motor or autonomic neuropathy symptoms. Of the sensory neuropathy symptoms, numbness and tingling were more prominent than was shooting or burning pain. Patients with higher P-APS pain scores with the first dose of paclitaxel appeared to have more chronic neuropathy. These data support that the P-APS is related to nerve pathology as opposed to being arthralgias and/or myalgias. Numbness and tingling are more prominent chronic neuropathic symptoms than is shooting or burning pain.

The Association between Symptoms of Autonomic Neuropathy and the Heart Rate Variability in Diabetics

BackgroundThere are few tools to detect the diabetic autonomic neuropathy at an earlier stage. This study was conducted to investigate the association between symptoms of autonomic neuropathy and the heart rate variability (HRV) in diabetics.MethodsStudy subjects consisted of 50 diabetic patients and 30 outpatient hospital control patients at a university family medicine department. The patients completed a Korean version of composite autonomic symptom scale (COMPASS). Electrocardiography was recorded in the supine position, on standing, and during deep breathing, for 5 minutes each. HRV of frequency domain was calculated by power spectral analysis.ResultsThe COMPASS score was higher in female diabetic patients compared with that in controls. Among 50 diabetic patients, the total COMPASS score correlated positively with normalized low frequency (LF) score (normalized units, n.u.) (r = 0.62, P < 0 .001) and low frequency/high frequency (LF/HF) (r = 0.77, P < 0.001), negatively with normalized HF score (n.u.) (r = -0.59, P < 0.001) and RMSSD (square root of the mean of the sum of the square of differences between adjacent NN interval; r = -0.33, P = 0.031). The decrease in LF (n.u) and the increase in HF (n.u) by deep breathing from the supine position were higher in diabetic patients compared with those in controls. The increase in LF (n.u) and the decrease in HF (n.u) by standing from the supine position were lower in diabetic patients compared with those in controls.ConclusionThe COMPASS score correlated with some component score of the HRV in diabetics. The HRV may be used as a tool to detect diabetic autonomic neuropathy by augmentation with position change.