Enhancement of heart rate variability by cholinergic stimulation with pyridostigmine in healthy subjects

The purpose of this study was to determine the effect of the oral administration of pyridostigmine bromide on indices of heart rate variability (HRV) in healthy young volunteers. Seventeen healthy participants (11 men, 6 women; aged 27 +/- 8 y) submitted to a randomized, crossover, double-blind protocol, in which they received 30 mg pyridostigmine bromide (PYR) or placebo orally at 8-hour intervals for 24 hours, on two separate days. Venous blood samples were collected 2 and 24 hours after the first dose for determination of serum cholinesterase activity. Holter tapes were recorded during the 24-hour period and analyzed using a semiautomatic technique to evaluate time- and frequency-domain indices of HRV and to build three-dimensional return maps for later quantification. Symptoms were mild and occurred similarly during administration of PYR and placebo (p = 0.140). Serum cholinesterase activity was reduced by 15% at 2 hours (p = 0.013) and by 14% at 24 hours (p = 0.010) after the first dose of PYR, but not after administration of placebo. Pyridostigmine administration caused a significant increase in the mean 24-hour R-R interval (placebo: 814 +/- 20 msec; PYR: 844 +/- 18 msec; p = 0.003) and in time-domain indices of HRV, such as the standard deviation of all R-R intervals (SDNN; placebo: 151 +/- 9 msec; PYR: 164 +/- 9 msec; p = 0.017), and the percentage of pairs of adjacent R-R intervals differing by more than 50 msec (pNN50; placebo: 12.8 +/- 1.8%; PYR: 13.9 +/- 1.5%; p = 0.029). Pyridostigmine had no significant effect on frequency-domain indices of HRV, but resulted in significant increase in P2, a parasympathetic index derived from the three-dimensional return map (placebo: 93 +/- 13 msec; PYR: 98 +/- 13 ms; p = 0.029). In conclusion, low-dose pyridostigmine reduced mean heart rate and increased HRV during a 24-hour period in healthy young subjects.     

Protection of human muscle acetylcholinesterase from soman by pyridostigmine bromide

Introduction: Pretreatment with pyridostigmine bromide (PB) of human intercostal muscle fibers exposed to the irreversible acetylcholinesterase (AChE) inhibitor soman was investigated. Methods: Muscles were pretreated with 3 × 10^?6 M PB or saline for 20 minutes, then exposed to 10^?7 M soman for 10 minutes. Results: AChE of muscles treated with soman alone was inhibited >95%. In contrast, PB pretreatment of soman‐exposed bundles protected 20% of AChE activity. AChE of bundles exposed to PB alone recovered after 4 hours, but bundles exposed to both PB and soman did not. Soman‐induced reduction of resting membrane potentials and increment of amplitudes and decay times of miniature endplate potentials (MEPPs) were partially corrected by PB pretreatment. Conclusions: In vitro pretreatment of human muscles with PB protected up to 20% of muscle AChE and ameliorated some deleterious effects on endplate physiology induced by soman. Muscle Nerve 43: 591–595, 2011     

Gastrointestinal transit abnormalities are frequently detected in patients with unexplained GI symptoms at a tertiary centre.

The aim of this prospective study was to analyse the yield and utility of a gastrointestinal (GI) transit measurement procedure in clinical practice. Patients referred by gastroenterologists to a tertiary centre for detailed transit measurements were prospectively included. All together 243 patients were enrolled. Body mass index was recorded. The patients were categorized according to the predominant symptom into five groups: diarrhoea, constipation, nausea, vomiting and abdominal pain. The patients recorded their bowel movements and GI symptoms daily during the week before the transit measurement. Percentiles 5 and 95 of the transit values in 83 healthy subjects served as reference values. Widespread abnormalities were found in the five patient groups and 63% of the patients had at least one transit abnormality. The abnormalities were more frequent in men compared with women. Patients with underweight had more motility disturbances compared with other patients. In male and female patients with vomiting a significant delay of transit in the ascending colon was observed compared with healthy subjects. Large-scale transit measurements frequently detect transit abnormalities in clinical practice and may elucidate the relationship between some GI symptoms and abnormal motility.     

Cardiovascular autonomic neuropathy in patients with type 2 diabetes with and without sensorimotor polyneuropathy

Background and Aims

Cardiovascular autonomic neuropathy (CAN) in patients with diabetes is associated with poor prognosis. We aimed to assess signs of CAN and autonomic symptoms and to investigate the impact of sensorimotor neuropathy on CAN by examining type 2 diabetes patients with (DPN [distal sensorimotor polyneuropathy]) and without distal sensorimotor polyneuropathy (noDPN) and healthy controls (HC). Secondarily, we aimed to describe the characteristics of patients with CAN.

Methods

A population of 374 subjects from a previously described cohort of the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) were included. Subjects were examined with the Vagus™ device for the diagnosis of CAN, where two or more abnormal cardiovascular autonomic reflex tests indicate definite CAN. Autonomic symptoms were assessed with Composite Autonomic Symptom Score 31 (COMPASS 31) questionnaire. DPN was defined according to the Toronto consensus panel definition.

Results

Definite CAN was present in 22% with DPN, 7% without DPN and 3% of HC, and 91% of patients with definite CAN had DPN. Patients with DPN and definite CAN reported higher COMPASS 31 scores compared to patients with noDPN (20.0 vs. 8.3, p < 0.001) and no CAN (22.1 vs. 12.3, p = 0.01). CAN was associated with HbA1c and age in a multivariate logistic regression analysis but was not associated with IEFND or triglycerides.

Interpretation

One in five patients with DPN have CAN and specific CAN characteristics may help identify patients at risk for developing this severe diabetic complication. Autonomic symptoms were strongly associated with having both DPN and CAN, but too unspecific for diagnosing CAN.     

糖尿病自主神经病变临床分析

目的探讨糖尿病自主神经病变与脑血管病变、血糖、糖尿病肾病病变关系。方法测定65例糖尿病患者的心率变异性,据此将患者分为自主神经病变组20例和无自主神经病变组45例,2组患者均接受经颅多谱勒检查,并检验糖化血红蛋白、高敏CRP和尿微量白蛋白。结果自主神经病变组脑血管顺应性下降,脑血流减慢,血糖、尿微量白蛋白及高敏CRP升高。结论糖尿病自主神经病变与血糖控制有关,与炎症和糖尿病肾病相关,可能是促进糖尿病脑血管病变的危险因素之一。     

Relief from episodic weakness with pyridostigmine in paramyotonia congenita: A family study

Pyridostigmine relieved episodic weakness in a family with paramyotonia congenita resulting from the R1448C mutation in the sodium channel gene. The transmission was autosomal dominant and the patients had paradoxical myotonia and exercise‐induced weakness. On electrophysiological studies there were myotonic potentials, and there was progressive reduction of compound muscle action potential (CMAP) amplitudes after short exercise associated with clinical weakness. Pyridostigmine in doses of 60 mg three times daily abolished the drop in the postexercise CMAP amplitude and reduced the amplitude decrement to slow rate repetitive stimulation, but there continued to be a drop in amplitude on exposure to cold. The decline of the CMAP amplitude on exposure to cold was controlled by treatment with phenytoin. The clinical and electrophysiological features are discussed in relation to therapy with pyridostigmine and phenytoin. Muscle Nerve, 2010     

Risks for sensorimotor peripheral neuropathy and autonomic neuropathy in non-insulin-dependent diabetes mellitus (NIDDM)

Identification of risk factors for development of diabetic sensorimotor peripheral neuropathy (DSPN) and diabetic autonomic neuropathy (DNA) may help to prevent or modify these complications. The ABCD Trial, a prospective study of diabetic complications, has identified risk factors of the presence and staging of peripheral neuropathy based on neurological symptom scores, neurological disability scores, autonomic function testing and quantitative sensory examination. DSPN is independently associated with diabetes duration [odds ratio (OR) = 1.5 per 10 years], body weight (OR = 1.1 per 5 kg), age (OR = 1.8 per 10 years), retinopathy (OR = 2.3), overt albuminuria (OR = 2.5), height (OR = 1.2 per 10 cm), duration of hypertension (OR = 1.1 per 10 years), insulin use (OR = 1.4), and race/ethnicity [African American vs. non-Hispanic white (OR = 0.4) and Hispanic vs. non-Hispanic white (OR = 0.8)]. DAN is independently associated with diabetes duration (OR = 1.2 per 10 years), body weight (OR = 1.1 per 5 kg), glycosylated hemoglobin (OR = 1.1 per 2.5%), overt albuminuria (OR = 1.6), and retinopathy (OR = 1.8). © 1998 John Wiley & Sons, Inc. Muscle Nerve, 21: 72–80, 1998.     

Helicobacter pylori infection and gastric function in primary autonomic neuropathy

Helicobacter pylori (Hp) infection in diabetic patients has been related to impaired gastric clearance of bacteria due to autonomic neuropathy. Gastrointestinal dysfunction has been described in primary autonomic failure (AF). The aim of the study was to evaluate, for the first time, the presence of Hp infection and gastric function in patients with primary AF. Twelve patients with primary AF (aged 58–78), 31 healthy controls (aged 48–75) and 31 patients affected by type 2 diabetes (aged 46–75) were studied. A ¹³C-urea breath test was performed to assess the presence of Hp infection. To evaluate gastric function, AF patients underwent two non-invasive tests: 1) ¹³C-octanoic acid breath test (OBT) to evaluate gastric emptying, and 2) electrogastrogram (EGG) to evaluate gastric electrical activity. Hp infection was found in 100 % of AF patients, in 48 % of controls and in 71 % of diabetic patients (p = 0.02 between groups). Electrical or mechanical gastric function was altered in 50 % of AF patients. In particular, 1) after OBT, half-time gastric emptying was delayed in 6 out of 12 patients, and 2) EGG showed the presence of gastric dysrhythmias in 6 out of 12 patients. In conclusion, Hp infection was detected in all AF patients studied; as previously demonstrated in diabetes, such a finding might be related to autonomic neuropathy causing mechanical or electrical gastric dysfunction. Hp detection might be important for the gastrointestinal and extradigestive complications of such infection. Received: 4 August 2001, Accepted: 11 March 2002     

A comparison of autonomic function in patients with inflammatory bowel disease and in healthy controls

We evaluated autonomic function, symptoms and psychological parameters in patients with ulcerative colitis (UC), Crohn's disease (CD) and matched controls to assess whether UC patients have greater basal sympathetic autonomic activity. Outpatients with UC (n = 15), CD (n = 13) and healthy controls (n = 28) underwent spectral analysis of heart rate variability to assess cardiac autonomic function, a methacholine challenge to assess cholinergic pulmonary responsiveness, and questionnaires assessing disease severity, anxiety and depression. UC but not CD patients had greater sympathetic activity than controls with increased absolute (6600 vs 5884; P = 0.04) and relative (62.8%vs 54.8%; P = 0.02) low frequency areas. This was not because of increased overall autonomic nervous system (ANS) activation and was independent of disease activity. In UC patients, trait (personality-related) anxiety correlated strongly with disease symptoms (R = 0.84; P < 0.001) and quality of life (R = -0.81; P < 0.001) while situational (state) anxiety did not. In CD patients, ANS measures were similar to controls and disease activity was unrelated to psychological measures. Cholinergic pulmonary responsiveness was normal in both UC and CD patients. UC patients have an increased sympathetic ANS activity which is independent of symptom severity. In these patients symptom severity is strongly associated with measures of personality related (but not current) anxiety.     

Electrophysiological tests of autonomic function in patients with idiopathic autonomic failure syndromes

Three electrophysiological tests of autonomic function were performed in patients with autonomic nervous system dysfunction to define test sensitivities and specificities. The skin sympathetic response, Valsalva ratio, and heart rate variation with deep breathing were studied in 10 patients with multiple system atrophy (MSA) and in 7 patients with pure (also called progressive or primary) autonomic failure (PAF); control subjects were 17 normal individuals of similar age. Thirteen patients had abnormal skin sympathetic responses, and 16 had abnormal Valsalva ratios. Fourteen patients had an abnormal variation of the heart rate with deep breathing. Taking the three tests together, binary logistic regression for distinguishing between patients and normal subjects correctly classified 91% of the 33 individuals for whom there were complete data with sensitivity of 88% and specificity of 94%. However, only 69% of the patients could be correctly classified by a logistic regression for discriminating between MSA and PAF. Electromyography (EMG) studies showed that 7 of 8 patients with MSA but only 2 of 7 patients with PAF (both multiparous women) had denervation of the rectal sphincter muscle. The EMG study is, therefore, valuable in men, but has a high false positive rate in women, probably because of pudendal nerve injury from parturition. © 1996 John Wiley & Sons, Inc.     

Incidence of nonamyloidogenic mutations in the transthyretin gene in patients with autonomic and small fiber neuropathy

Introduction: Mutations of the transthyretin (TTR) gene have been associated with polyneuropathy; the protein product has a tendency to form amyloid deposits in the peripheral nervous system. Methods: Patients with small fiber neuropathy (SFN) with or without autonomic symptoms were given skin biopsies to assess nerve fiber density. Any patient with autonomic symptoms was assessed for autonomic neuropathy (AN). If testing revealed no clear cause of neuropathy, the TTR gene was sequenced. Results: Thirty‐six percent of patients were found to harbor at least 1 mutation in the TTR gene sequence (variants of unknown significance [VUS]). Of 24 patients diagnosed with SFN, 8% of patients had a point mutation (c76G>A). Of those patients who were diagnosed with both SFN and AN, 68% of patients had a VUS within the TTR gene (c76G>A, c337‐18G>C). Conclusions: The results suggest an association between presumed nonamyloidogenic mutations in the TTR gene and the development of AN and SFN. Muscle Nerve 57 : 140–142, 2017     

交感皮肤反应对糖尿病自主神经病变的诊断价值

目的探讨交感皮肤反应（sympathetic skin response,SSR）在糖尿病自主神经病变诊断中的价值。方法对186例糖尿病周围神经病（Diabetic peripheral neuropathy,DPN）患者和203例糖尿病非DPN患者进行SSR检测,同时对102例健康人进行SSR检测。结果SSR起始潜伏期异常率高于波幅异常率,下肢的异常率高于上肢异常率。DPN患者中,174例（93.5%）SSR异常,其中32例未引出SSR,142例起始潜伏期延长,109例波幅下降。203例DM非DPN患者中,46例（22.7%）SSR起始潜伏期延长和/或波幅下降,其中19例有出汗异常,4例在检查后数月出现出汗异常。结论SSR是早期诊断糖尿病自主神经病变的敏感手段,可发现亚临床神经病,并与病情进展相吻合。     

Pyridostigmine in autonomic failure: can we treat postural hypotension and bladder dysfunction with one drug?

In a 66-year-old man with autonomic failure, pyridostigmine (180 mg/day orally) improved both postural hypotension and underactive detrusor bladder dysfunction. Acetylcholinesterase inhibition may be useful in the management of orthostatic hypotension and bladder dysfunction in autonomic failure patients.     

Urinary dysfunction and autonomic control in amyloid neuropathy

Abstract Uro-neurological assessment was performed in four patients with small-fiber neuropathy due to amyloidosis (2 transthyretin-type/2 immunoglobulin light-chain-type). Voiding difficulties were due to detrusor weakness and impaired bladder sensation. In two patients cholinesterase inhibition treatment caused urge incontinence, indicating detrusor denervation supersensitivity. The underlying mechanisms of urinary dysfunction seem to involve postganglionic cholinergic and afferent somatic nerves.