Pathophysiology of Gastroparesis Syndromes Includes Anatomic and Physiologic Abnormalities.

BACKGROUND: Factors underlying gastroparesis are not well defined. AIMS: We hypothesized that multiple systems may be involved in patients with gastroparesis symptoms and performed a comparative physiologic study. METHODS: We studied 43 consecutive eligible patients with gastroparetic symptoms categorized by GI symptoms, metabolic status, illness quantification, and gastric physiology. Patients were evaluated by two methods in each of five core areas: inflammatory, autonomic, enteric, electrophysiologic, and hormonal with abnormalities examined by correlations. RESULTS: Patients had similar GI symptoms regardless of baseline gastric emptying or diabetic/idiopathic status, and all patients demonstrated abnormalities in each of the 5 areas studied. Nearly all patients presented with elevated markers of serum TNFα (88%) and serum IL-6 (91%); elevated cutaneous electrogastrogram frequency (95%); and interstitial cells of Cajal count abnormalities (inner: 97%, outer: 100%). Measures of inflammation correlated with a number of autonomic, enteric anatomy, electrophysiologic and hormonal abnormalities. CONCLUSIONS: We conclude that patients with the symptoms of gastroparesis have multiple abnormalities, when studied by traditional, as well as newer, diagnostic assessments. Inflammation appears to be a fundamental abnormality that affects other organ systems in symptomatic patients. Future work on gastroparetic syndromes and their treatment may benefit from a focus on the diffuse nature of their illness, diverse pathophysiologic mechanisms involved, especially the possible causes of underlying inflammation and disordered hormonal status. TRAIL REGISTRY: This study is registered with Clinicaltrials.gov under study # NCT03178370 https://clinicaltrials.gov/ct2/show/NCT03178370 .

Autogenic biofeedback training improves autonomic responses in a participant with cervical motor complete spinal cord injury- case report.

STUDY DESIGN: Single-subject case design OBJECTIVE: To evaluate the Autogenic Feedback Training Exercise (AFTE) on autonomic nervous system responses. INTRODUCTION: AFTE combines specific autogenic exercises with biofeedback of multiple physiological responses. Originally developed by the National Aeronautics and Space Administration (NASA), AFTE is used to improve post-flight orthostatic intolerance and motion sickness in astronauts. Individuals with cervical or upper thoracic spinal cord injury (SCI) often present symptoms of autonomic dysfunction similar to astronauts. We hypothesize that AFTE challenges nervous system baroreflex, gastric and vascular responses often impaired after SCI. METHODS: Using a modified AFTE protocol, we trained a hypotensive female participant with cervical motor complete (C5/6-AIS A) SCI, and a male non-injured control participant (NI) and measured blood pressure (BP), heart rate (HR), gastric electrical activity, and microvascular blood volume before, during and after AFTE. The participants were instructed to complete breathing and imagery exercises to help facilitate relaxation. Subsequently, they were instructed to use stressful imagery and breathing exercises during arousal trials. RESULTS: Both participants completed 8 sessions of approximately 45 min each. Microvascular blood volume decreased 23% (SCI) and 54% (NI) from the beginning to the end of the stimulation cycles. The participant with SCI became progressively more normotensive and improved levels of gastric electrical activity, while the NI participant's changes in HR, gastric electrical activity, and BP were negligible. CONCLUSIONS: AFTE may offer a novel non-pharmacologic intervention to minimize symptoms of dysautonomia in people with SCI.

Autonomic Nervous System Profiling In Response to Liver Transplantation: Prognostic Evaluation and Preliminary Study.

BACKGROUND: Liver cirrhosis leads to autonomic dysfunction (AD). We present a pilot study and review of published literature to investigate the long-term changes in the Autonomic Nervous System (ANS) of patients who underwent liver transplant. We propose Autonomic Function Tests (AFT) can be used as a predictor of liver transplant outcome. METHODS: Twenty-eight patients (19 men and 9 women; mean age 45 years) with cirrhosis due to different etiologies underwent a noninvasive ANS evaluation test, pre- and post-liver transplant at 3 to 6 months, 8 to 12 months, and 14 to 24 months. Data were compared with 45 age-matched controls (14 men and 31 women). We investigated changes in the following 3 adrenergic measures: percentage of cutaneous vasoconstriction in the hand and foot in response to cold stress test and cutaneous blood flow adjustment ratio; and 3 cardiovagal measures: change in heart rate in relation to deep respiration, forced respiration represented as Valsalva Ratio, and head-up tilting (30/15 ratio). RESULTS: A total of 23 of 28 patients (82%) had impairment in AFT before transplant, 16 of 28 (57%) in the sympathetic adrenergic measures, and 15 of 28 (54%) in the parasympathetic cardiovagal measures. There was a gradual improvement in ANS function posttransplant, with a significant improvement in the cardiovagal measure of Valsalva Ratio (P < .05 from baseline). These data suggest some temporary decline in ANS functions within the first 6 months posttransplant. CONCLUSIONS: To optimize outcomes in liver transplant patients with autonomic dysfunction, autonomic testing perhaps combined with frailty testing can be used as objective measures of mortality in the pre-liver transplant stage.

Autonomic and enteric function profiling can predict disordered gastric emptying in diabetic gastropathy.

Gastric emptying tests (GET) are the gold standard for diagnosing gastroparesis, but many patients do not have delayed emptying. We aimed to examine the combination of autonomic nervous system testing (ANS) and the enteric measure (ENS) of electrogastrography (EGG) to predict disordered GET. Seventy-six patients (47 F, 29 M mean age 40 years) with diabetes mellitus underwent evaluation for end-organ failure including gastroparesis. ANS testing assessed autonomic function by finger capillary pulse to positional changes (PAR), vasoconstriction to cold (VC), and EKG R-R interval change (RRI) with deep breathing; the ENS measures of cutaneous EGG assessed gastric myoelectrical activity. Solid (S) GET subgroups were based on 50% emptying (TS50). Via linear regression analysis: VC, PAR, and EGG had a significant inverse correlation with GET TS50 and decreased in response to a delay in gastric emptying (p < 0.05). Via ordinal logistic regression RRI and EGG-predicted gastric emptying (p < 0.01). Patients with a higher RRI and EGG value were 0.93 and 0.14 times more likely to be diagnosed with rapid gastric emptying. The areas under the curve for receiver operator characteristics (AUROC) for all measures were 0.72 in comparison to 0.59 with EGG. Based on the results, four components (RRI, VC, PAR, and EGG) quantitatively describe gastric emptying in patients with signs of diabetic gastropathy better than EGG alone.

Gastroparesis syndromes: Response to electrical stimulation.

BACKGROUND AND AIMS: Factors underlying gastroparesis are not well defined, nor is the mechanism of action of gastric electrical stimulation (GES). We hypothesized that GES acts via several mechanisms related to underlying disordered pathophysiology. METHODS: We studied 43 consecutive eligible patients with gastroparetic symptoms, previously evaluated by two methods in each of five core areas: inflammatory, autonomic, enteric, electrophysiologic, and hormonal; and also categorized by GI symptoms, metabolic status, illness quantification, and gastric physiology. We then studied 41 patients who underwent temporary GES for 5-7 days. Thirty-six of those patients were implanted and 30 were followed up at 6 months after permanent GES. RESULTS: In previous but separately reported work, patients had similar GI symptoms regardless of baseline gastric emptying or diabetic/idiopathic status and all patients demonstrated abnormalities in each of the five areas studied. After GES, patients showed early and late effects of electrical stimulation with changes noted in multiple areas, categorized by improvement status. CONCLUSION: Patients with symptoms of gastroparesis have multiple abnormalities, including systemic inflammation and disordered hormonal status. GES affects many of these abnormalities. We conclude electrical stimulation improves symptoms and physiology with (a) an early and sustained anti-emetic effect; (b) an early and durable gastric prokinetic effect in delayed emptying patients; (c) an early anti-arrhythmic effect that continues over time; (d) a late autonomic effect; (e) a late hormonal effect; (f) an early anti-inflammatory effect that persists; and (g) an early and sustained improvement in health-related quality of life. This study is registered with Clinicaltrials.gov under study # NCT03178370 (https://clinicaltrials.gov/ct2/show/NCT03178370).

Efficacy of Gastric Electrical Stimulation for Gastroparesis: US/European Comparison.

BACKGROUND: Gastric electrical stimulation (GES) is used in both the US and Europe, but little research has investigated the demographics of gastroparesis patients receiving GES by geographic location. METHODS: We compared data from 380 patients, 296 female and 84 males, mean age 42 years, 246 idiopathic (ID), 107 diabetic (DM), and 27 post-surgical (PS). The statistical significance was calculated by Chi-square test and a P-value obtained for ID, DM, and PS. The statistical significance was calculated by Fischer exact test and a P-value obtained comparing male vs. female. RESULTS: European centers had 61 GES patients compared to 319 from the US. In Europe, 100% of patients had gastric emptying test (GET) values available; in the US, it was 75% of patients. European centers had more DM patients (59%) than the US (22%), and a smaller proportion of ID patients (25%) than the US (72%). There was a statistical difference between the causes of gastroparesis in the patients receiving GES (P-value < 0.00001). There was also significant difference in the gender of the patients receiving GES, with a greater proportion of women in the US (P value = 0.0023). CONCLUSIONS: Comparing GES in US vs. Europe demonstrated significant differences in gastroparesis demographics and percentage of patients with GET data. After analyzing the previously discussed results and reviewing recent updates in evidence-based medicine guidelines, the discrepancy and variance in patient populations in the US and Europe emphasizes the need for a database that allows better analysis and treatment of gastroparesis patients worldwide including stimulation therapies.

Gastric electrical stimulation is safe and effective: a long-term study in patients with drug-refractory gastroparesis in three regional centers.

BACKGROUND: Drug-refractory gastroparesis has previously been without acceptable alternative therapies. Although gastric electrical stimulation has been used for over a decade, no long-term multicenter data exist. METHODS: We studied 214 consecutive drug-refractory patients with the symptoms of gastroparesis (146 idiopathic, 45 diabetic, 23 after surgery) who consented to participate in a variety of clinical research and clinical protocols at three centers from January 1992 through January 2005, resulting in 156 patients implanted with a gastric electrical stimulation device and the other 58 patients serving as controls. The patients were stratified into three groups: (1) consented but never permanently implanted; (2) implanted with permanent device, and (3) consented while awaiting a permanent device. The patients were followed over time for gastrointestinal symptoms, solid gastric emptying, health-related quality of life, survival, device retention, and complications. Demographics, descriptive statistics, and t tests were used for comparison between baseline and latest follow-up. RESULTS: At latest follow-up, median 4 years for 5,568 patient months, most patients implanted (135 of 156) were alive with intact devices, significantly reduced gastrointestinal symptoms, and improved health-related quality of life, with evidence of improved gastric emptying, and 90% of the patients had a response in at least 1 of 3 main symptoms. Most patients explanted, usually for pocket infections, were later reimplanted successfully. There were no deaths directly related to the device. CONCLUSION: Based on this sample of patients, implanted with gastric electrical stimulation devices at three centers and followed for up toward a decade, gastric electrical stimulation for drug-refractory gastroparesis is both safe and effective.

Long-Term Follow-Up of Autonomic and Enteric Measures in Patients Undergoing Vertical Banded Gastroplasty for Morbid Obesity.

BACKGROUND: A multi-component model of autonomic and enteric factors may correlate with ultimate weight loss or gain after restrictive obesity surgery. This study aimed to determine relevant parameters to predict successful long-term weight loss. METHODS: Thirty-nine patients (four males and 35 females) with a mean age of 37.2 years were followed for over 15 years after vertical banded gastroplasty. Baseline adrenergic: postural adjustment ratio (PAR) and vasoconstriction (VC); cholinergic: electrocardiogram R-to-R interval (RRI) and enteric measure: electrogastrogram (EGG) were utilized by a discriminant function analysis to classify patients as a long-term loser or gainer. Using latest weight compared to baseline, patients were divided as 10 gainers and 29 losers. RESULTS: A discriminate model successfully predicted ultimate weight gain in 8/10 (80%) of patients who subsequently gained weight and weight loss in 24/29 (83%) of patients who lost weight for a total correct classification of 32/39 (82%). The same model with data at 3 months postoperatively predicted weight gain in 9/10 (90%) of patients and weight loss in 24/29 (83%) of patients, for a total correct classification of 34/39 (87%). CONCLUSIONS: A multi-component model at baseline and 3 months postoperative can predict long-term weight outcome from restrictive obesity surgery.

Autonomic Evaluation of Patients With Gastroparesis and Neurostimulation: Comparisons of Direct/Systemic and Indirect/Cardiac Measures.

BACKGROUND: Disorders of nausea, vomiting, abdominal pain, and related problems often are manifestations of gastrointestinal, neuromuscular, and/or autonomic dysfunction. Many of these patients respond to neurostimulation, either gastric electrical stimulation or electroacupuncture. Both of these therapeutic techniques appear to influence the autonomic nervous system which can be evaluated directly by traditional testing and indirectly by heart rate variability. METHODS: We studied patients undergoing gastric neuromodulation by both systemic autonomic testing (39 patients, six males and 33 females, mean age 38 years) and systemic autonomic testing and heart rate variability (35 patients, seven males and 28 females, mean age 37 years) testing before and after gastric neuromodulation. We also performed a pilot study using both systemic autonomic testing and heart rate variability in a small number of patients (five patients, all females, mean age 48.6 years) with diabetic gastroparesis at baseline to compare the two techniques at baseline. Systemic autonomic testing and heart rate variability were performed with standardized techniques and gastric electrical stimulation was performed as previously described with electrodes implanted serosally in the myenteric plexus. RESULTS: Both systemic autonomic testing and heart rate variability measures were often abnormal at baseline and showed changes after gastric neuromodulation therapy in two groups of symptomatic patients. Pilot data on a small group of similar patients with systemic automatic nervous measures and heart rate variability showed good concordance between the two techniques. CONCLUSIONS: Both traditional direct autonomic measures and indirect measures such as heart rate variability were evaluated, including a pilot study of both methods in the same patient group. Both appear to be useful in evaluation of patients at baseline and after stimulation therapies; however, a future full head-to-head comparison is warranted.

Measures of Autonomic Dysfunction in Diabetic and Idiopathic Gastroparesis.

BACKGROUND: Gastroparesis is a condition classically characterized by delayed gastric emptying and is associated with considerable morbidity. While the etiology of gastroparesis remains elusive, autonomic dysfunction may play an important role, especially as many patients with gastroparesis also have diabetes. The aim of this study was to determine whether measures of autonomic function differ between adults with diabetic gastroparesis (DG) and adults with idiopathic gastroparesis (IG). METHODS: Tests of systemic autonomic function were performed among 20 adults with GD (six men and 14 women, mean age: 42 years) and 21 adults with IG (seven men and 14 women, mean age: 37 years). Measures included vagal cholinergics by R-R interval percentage variation (RRI-PV) and sympathetic adrenergics by vasoconstriction to cold (VC) and postural adjustment ratio (PAR). The two groups were compared using Wilcoxon rank sum tests and linear regression analysis (STATA 10.0). RESULTS: In univariate analysis, the following autonomic measures differed significantly between DG and IG: VC (P = 0.004), PAR (P = 0.045), VC + PAR (P = 0.002) and RRI-PV (P < 0.001). In multivariate analysis (P = 0.002, R2 = 0.55), only RRI-PV (adjusted odds ratio (aOR): 1.02, 95% confidence interval (CI): 1.01 - 1.03) differed significantly between DG and IG patients. CONCLUSIONS: Vagal cholinergics are affected to a greater degree in DG compared to IG, suggesting that impaired vagal tone is not a universal mechanism for gastroparesis.

Serum catecholamines and dysautonomia in diabetic gastroparesis and liver cirrhosis.

BACKGROUND: Plasma catecholamine influences autonomic function and control, but there are few reports correlating them. In this study, 47 individuals (mean age, 38 years) were studied: 19 diabetes mellitus (DM) patients with gastroparesis, 16 with liver disease and 12 control subjects. METHODS: Noninvasive autonomic function was assessed for sympathetic adrenergic functions as peripheral vasoconstriction in response to cold stress test and postural adjustment ratio (PAR) and cholinergic function as Valsalva ratio, represented by change in R-R intervals. Measurements were compared by analysis of variance and Spearman's correlation, and results were reported as mean ± standard error. RESULTS: Plasma norepinephrine (1902.7 ± 263.3; P = 0.001) and epinephrine (224.5 ± 66.5; P = 0.008) levels, as well as plasma dopamine levels (861.3 ± 381.7), and total plasma catecholamine levels were highest for patients with liver disease, who also had significant negative correlation between norepinephrine level and vasoconstriction (P = 0.01; r = -0.5), PAR1 (P = 0.01; r = -0.5), sympathetic adrenergic functions (P = 0.005; r = -0.6), total autonomic index (P = 0.01-0.5) and total autonomic function (P = 0.01; r = -0.2) and also negative correlation between epinephrine plasma level and total autonomic function (P = 0.04; r = 0.4). DM patients were next highest in norepinephrine level (133.26 ± 7.43), but lowest for plasma catecholamine; a positive correlation between dopamine level and PAR1 (P = 0.008; r = 0.6) was also seen in this group. Plasma dopamine levels and spider score correlated negatively (P = 0.04; r = -0.5) and total plasma catecholamine positively with encephalopathy (P = 0.04; r = 0.5) in patients with liver disease. CONCLUSIONS: Plasma catecholamine levels correlated with adrenergic functions in control subjects and patients with DM and liver disease, with no significant correlation seen for cholinergic function.

Autonomic and Enteric Nervous System Dysfunction May Play a Role in Hyperemesis Gravidarum.

BACKGROUND: Nausea and vomiting, seen in 70-85% of all pregnancies, becomes intractable in hyperemesis gravidarum (HG). We aimed to investigate the relationship between HG and autonomic nervous system functioning and gastric electrical activity. METHODS: Twenty-seven pregnant patients, 21 with HG and six normal, were studied with sympathetic adrenergic; percent vasoconstriction (%VC) and postural adjustment ratio (PAR); parasympathetic vagal cholinergic functions by R-to-R intervals (RRIs), a total autonomic score; and enteric nervous system measured by electrogastrography (EGG). RESULTS: Significant differences were found in parasympathetic measures (RRI for HG 29.98 ± 2.95 vs. control 40.91 ± 2.38, P < 0.05); sympathetic PAR was significantly lower in patients (PAR for HG 24.5 ± 5.0 vs. 67.6 ± 11.4 for controls, P < 0.01); mean total autonomic score was significantly lower in HG (131.75 ± 9.61 vs. 196.87 ± 12.8, P < 0.05). EGG results were borderline different (normal < 3.3, HG 3.4 vs. controls 3.0, P = 0.07). CONCLUSION: Autonomic and enteric nervous system dysfunction may play a role in the pathophysiology of HG.

Charcot-Marie-Tooth disease (hereditary motor sensory neuropathies) and hereditary sensory and autonomic neuropathies.

BACKGROUND: Since the description of Charcot-Marie-Tooth disease over a century ago. it has now been recognized that these conditions are not caused by generalized metabolic defects but rather have various discrete genetic origins. These disorders can also have variable phenotypes due to dysfunction of peripheral nerve axons or their myelin due to the genetic defects that affect the formation of specific nerve proteins. REVIEW SUMMARY: This article summarizes the clinical presentation of various phenotypes of the hereditary motor sensory neuropathies and the hereditary sensory and autonomic neuropathies, genetic mutations, and their relevant protein products. Proper identification of the genetic defects provides the opportunity for better genetic counseling and hopefully therapies in the future.

Effects of 3-4 diaminopyridine (DAP) in motor neuron diseases.

OBJECTIVE: To study the safety of 3-4 diaminopyridine (DAP) in patients with motor neuron diseases and to examine its efficacy in reducing muscle fatigue and weakness and in improving objective parameters of muscle function. DESIGN: Assessments of safety included a questionnaire of symptoms, clinical examination, blood testing, and electrocardiography at each visit; efficacy was assessed by subjective scores of fatigue and weakness; an Amyotrophic Lateral Sclerosis Functional Rating Scale and functional ability scores, including timed verbal scores; manual muscle testing; grip dynamometry; pulmonary function tests; timed functional tests; and electrophysiological studies. PARTICIPANTS: Thirteen subjects with amyotrophic lateral sclerosis and seven subjects with only a lower motor neuron syndrome. MAIN OUTCOMES: Assess tolerability of DAP and determine if there was symptomatic improvement of muscle fatigue. SECONDARY OUTCOME: To determine the effects of DAP on objective parameters of muscle function. RESULTS: The drug was well tolerated with only four subjects reporting tingling of lips and fingers during the active drug period. The subjective scores for fatigue and weakness showed a mild improvement after 4 weeks on DAP compared with placebo. A significant benefit of DAP was also demonstrated in the timed verbal scores. CONCLUSION: 3-4 DAP appeared to be safe and produced subjective benefit in motor neuron diseases. The drug could be added for symptomatic treatment in these diseases. Larger studies are necessary to demonstrate efficacy.

Predictors of response to a behavioral treatment in patients with chronic gastric motility disorders.

Chronic gastric motility disorders have proven intractable to most traditional therapies. Twenty-six patients with chronic nausea and vomiting were treated with a behavioral technique, autonomic training (AT) with directed imagery (verbal instructions), to help facilitate physiological control. After treatment, gastrointestinal symptoms decreased by >30% in 58% of the treated patients. We compared those improved patients to the 43% who did not improve significantly. No significant differences existed in baseline symptoms and autonomic measures between both groups. However, baseline measures of gastric emptying and autonomic function predicted treatment outcome. Patients who improved manifested mild to moderate delay in baseline gastric emptying measures. The percent of liquid gastric emptying at 60 mins and the sympathetic adrenergic measure of percent of change in the foot cutaneous blood flow in response to cold stress test predicted improvement in AT outcome, with clinical diagnostic values of 77% and 71%, respectively. We conclude that AT treatment can be efficacious in some patients with impaired gastric emptying and adrenergic dysfunction. More work is warranted to compare biofeedback therapy with gastric motility patients and controls in population-based studies.

Gastric electrical stimulation is associated with improvement in pancreatic exocrine function in humans.

OBJECTIVE: To define the possible effects of gastric electrical stimulation (GES) for gastroparesis on pancreatic function, we performed 2 related human studies. METHODS: Fecal elastase values were compared in 2 patient groups: (1) GES devices ON and (2) GES devices OFF and (2) in 3 control groups: (1) no response (NR) to prokinetic medications, (2) positive response (RES) to medications, and (3) normal controls. Polypeptide levels in 7 of 9 GES patients with device ON and OFF, elastase results, GI symptoms (TSS), and heart rate variability (HRV) were compared by paired t tests and/or ANOVA and reported as mean +/- SE. RESULTS: Elastase was different for GES-ON and OFF (508.0 +/- 92.2 vs. GES-OFF 378.6 +/- 87.4, P < 0.05). Elastase was lower in medication NR and RES than in normal controls. Postprandial pancreatic polypeptide was greater with GES ON than OFF (P = 0.07). HRV revealed a lower percentage of change with device ON versus OFF (44.2 +/- 5.5 vs. 48.5 +/- 5.2, P = 0.08) and lower TSS with ON versus OFF (15.9 +/- 4.5 vs. 25.7 +/- 5.3, P < 0.05). CONCLUSIONS: GES improves exocrine pancreatic release, effects autonomic control, and improves GI symptoms, suggesting a possible role for GES in the treatment of pancreatic insufficiency associated with gastroparesis.