Construction and clinical evaluation of novel methods for detecting autoinomic dysfunction

The autonomic nervous system innervates every organ in the body. Since autonomic disturbances affect patient survival, an understanding of and recognition of these disturbances are important. We adopted several new methods to evaluate autonomic function accurately for detecting the onset of small-fiber neuropathy, such as laser-Doppler flowmetry, ultrasonography, 123I-MIBG scintigraphy, electrogastrography, cystometry, glucose-tolerance test, near-infrared spectrophotoscopy, blood pressure tests, and evaluation of sweating. After these examinations, we applied potential effective treatments to improve the survival and daily activity of these patients. We also evaluated the effect of liver transplantation on autonomic dysfunction of familial amyloidotic polyneuropathy (FAP) patients using our tools. Liver transplantation not only prevents the progression of autonomic dysfunction in these patients but also improves some autonomic symptoms in the early stage after the operation. As all domino-liver transplantation-induced amyloid neuropathies, including our cases, were of the sensory type rather than with autonomic involvement, assessment of the pain threshold by preferential stimulation of A delta fibers is a particularly useful tool for diagnosing the onset of small-fiber neuropathies in these patients in addition to autonomic testing. Analyses and comparison of patients with FAP and domino-liver-transplanted patients with autonomic, sensory and motor dysfunction may give a clue to elucidate the pathogenesis and treatment of neuropathy in FAP. As autonomic disturbances play an important role in the symptomatology of small-fiber neuropathy, liver-transplanted FAP, and domino-liver-transplanted patients, further studies of autonomic dysfunction in these patients may lead to the pathogenesis of the disease.     

123I-meta-iodobenzylguanidine (MIBG) cardiac scintigraphy in α-synucleinopathies

Cardiac meta-iodobenzylguanidine (MIBG) uptake on ¹²³I-MIBG cardiac scintigraphy is reduced in patients with Lewy body disease such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and pure autonomic failure, and has been reported to be useful for differentiating PD from other parkinsonian syndromes, as well as DLB from Alzheimer disease (AD). Postmortem studies have shown that the number of tyrosine hydroxylase (TH)-immunoreactive nerve fibers of the heart was decreased in pathologically-confirmed Lewy body disease, supporting the findings of reduced cardiac MIBG uptake in Lewy body diseases. Now, reduced cardiac MIBG uptake can be a potential biomarker for the presence of Lewy bodies in the nervous system. ¹²³I-MIBG cardiac scintigraphy can allow us to determine the presence of Lewy bodies.     

Neuritis cordis due to the acute polyneuritis of the Guillain-Barré syndrome

Summary Three patients with the Guillain-Barré syndrome which followed the course of Landry's acute ascending paralysis died a sudden cardiac death. Autonomic dysfunction had appeared clinically, consisting of sphincter disturbances in one patient and fluctuating blood pressure and bradycardia in the other. In a twenty-three year old female patient cardiac function had been inconspicuous, apart from tachycardia, but the ECG showed S-T segment depression and flat T waves. Postmortem examination revealed acute inflammatory demyelinating polyradiculoneuritis involving the peripheral autonomic nervous system and especially the nerves of the heart. Immunohistochemically, the inflammatory cell infiltrations of this neuritis cordis consisted of macrophages (MAC 387 positive) and T lymphocytes (UCHL1 positive). No indication of a direct viral infection of the inflamed cardiac nerves was detectable by immunohistochemistry (HSV, CMV, influenza virus) nor by electron microscopy. The neuritis cordis was classified as an inflammatory cardioneuropathy secondary to a patchy acute polyneuritis of the Guillain-Barré syndrome, involving the autonomic nervous system. Myocarditis could be discounted, and the neuritis cordis was thought to be responsible for the sudden cardiac death.Dedicated to Professor Dr.med. Otto StochdorphPresented in part at 71. Jahrestagung der Deutschen Gesellschaft für Pathologie, Salzburg, Juni 1987     

Autonomic function in patients with hereditary motor and sensory neuropathy type I and Lambert-Eaton myasthenic syndrome.

Noninvasive tests of four autonomic organ systems (vasomotor control, baroreceptor reflexes, sudomotor function and pupillary reflexes) were performed on nine patients with hereditary motor and sensory neuropathy (HMSN) type I and three patients with Lambert-Eaton myasthenic syndrome (LEMS). The results were compared with those of 33 control subjects. Autonomic dysfunction was considered present when at least two of the four organ system tests were abnormal. The three patients with LEMS had abnormal results in two or more different systems, whereas only one of the nine patients with HMSN type I had two abnormal test results. This study demonstrates that autonomic dysfunction is not a common finding in patients with HMSN type I and its presence should alert us to find the cause of this autonomic disorder.     

Autonomic innervation of the developing heart: origins and function

Maintenance of homeostatic circulation in mammals and birds is reliant upon autonomic innervation of the heart. Neural branches of mixed cellular origin and function innervate the heart at the arterial and venous poles as it matures, eventually coupling autonomic output to the cardiac components, including the conduction system. The development of neural identity is controlled by specific networks of genes and growth factors, whereas functional properties are governed by the use of different neurotransmitters. In this review, we summarize briefly the anatomic arrangement of the vertebrate autonomic nervous system and describe, in detail, the innervation of the heart. We discuss the timing of cardiac innervation in the chick and mouse, emphasizing the relationship of the cardiac neural networks to the anatomical structures within the heart. We also discuss the variable contribution of the neural crest to vagal cardiac nerves, and summarize the main neurotransmitters secreted by the developing sympathetic and parasympathetic autonomic divisions. We provide an overview of the main growth factor and gene families involved in neural development, discussing how these factors may impact upon the development of cardiac abnormalities in congenital syndromes associated with autonomic dysfunction.     

Methods of evaluation of autonomic nervous system function

Disturbances of the autonomic nervous system play a crucial role in the pathogenesis and clinical course of many diseases. Recently, rapid development has occurred in the clinical assessment of autonomic function. Various procedures have been described as diagnostic tools to monitor autonomic dysfunction. Some of them are mostly used for research purposes. Many, however, have found their place in routine clinical evaluation. Our paper presents selected methods of assessment of the autonomic nervous system with particular emphasis on those that are useful in diagnosis and treatment of diseases of the cardiovascular system. We discuss multiple tests based on cardiovascular reflexes, methods of studying heart rate variability as well as direct catecholamine measurements. Moreover, we outline tests of sudomotor function and microneurography.     

Diabetic gastroparesis in association with autonomic neuropathy and microvasculopathy

Gastroparesis is a frequent and sometimes life-threatening complication of diabetes mellitus. Autonomic neuropathy seems to be one of the most important mechanisms underlying this entity, together with the other probable pathologies. The present study was performed in order to identify an alternative to gastric scintigraphy as a screening test. The gastric emptying times of 60 subjects (Group 1: 20 insulin-dependent patients, Group 2: 20 non-insulin-dependent diabetes mellitus patients, and Group 3: 20 healthy volunteers) were monitored by gastric scintigraphy. Perception thresholds for cold, heat, and vibration were tested by a quantitative sensory test, and QTc dispersions were calculated from standard electrocardiography recordings. In addition, fasting blood glucose, hemoglobin A1c and urine beta2-microglobulin and microalbumin concentrations were determined for the patient groups. Funduscopic examination was performed by an independent ophthalmologist. Gastroparesis was determined in both patient groups, regardless of fasting blood glucose and hemoglobin A1c concentrations. A strong correlation was observed between nephropathy, retinopathy, and cardiac autonomic denervation (QTc) and gastroparesis. In conclusion, retinal and renal microvasculopathy parameters and cardiac autonomic function tests may be useful for screening diabetic patients for gastroparesis.     

Left ventricular dysfunction and altered autonomic activity: a possible link to sudden cardiac death

There is now a growing body of clinical evidence that suggests a strong association between left ventricular dysfunction and sudden cardiac death in patients recovering from myocardial infarction. The mechanisms underlying this association remain to be determined. Alterations within the autonomic nervous system may represent one factor that links an impairment in cardiac function to an increased mortality. Since ventricular dysfunction would tend to reduce stroke volume, an increased sympathetic and/or decreased parasympathetic efferent activity may compensate for this fall in stroke volume by increasing heart rate and/or the force of contraction (inotropic state) in an attempt to maintain a more normal cardiac output. Similar changes in autonomic activity are, in fact, known to increase the vulnerability to ventricular fibrillation. Therefore, I propose that myocardial infarction induces changes in cardiac function which in turn elicits autonomic efferent changes. As a consequence of these compensatory reflex changes the heart becomes less electrically stable and thereby more prone to lethal arrhythmias.     

Depression, the autonomic nervous system, and coronary heart disease

Depression is a risk factor for medical morbidity and mortality in patients with coronary heart disease (CHD). Dysregulation of the autonomic nervous system (ANS) may explain why depressed patients are at increased risk. Studies of medically well, depressed psychiatric patients have found elevated levels of plasma catecholamines and other markers of altered ANS function compared with controls. Studies of depressed patients with CHD have also uncovered evidence of ANS dysfunction, including elevated heart rate, low heart rate variability, exaggerated heart rate responses to physical stressors, high variability in ventricular repolarization, and low baroreceptor sensitivity. All of these indicators of ANS dysfunction have been associated with increased risks of mortality and cardiac morbidity in patients with CHD. Further research is needed to determine whether ANS dysfunction mediates the effects of depression on the course and outcome of CHD, and to develop clinical interventions that improve cardiovascular autonomic regulation while relieving depression in patients with CHD.     

Massive myocardial necrosis in thrombotic thrombocytopenic purpura: a case report and review of the literature.

Thrombotic thrombocytopenic purpura (TTP) is an uncommon syndrome resulting from diffuse occlusion of small arterioles and capillaries by hyaline microthrombi. It is characterized by fever, thrombocytopenic purpura, microangiopathic hemolytic anemia, and neurologic and renal dysfunction. While cardiac pathology in TTP is commonly seen at autopsy, clinical cardiac dysfunction is rare and typically results from conduction system involvement. While 3% to 8% of patients with TTP report chest pain on admission, reports of fatal ventricular pump failure are extremely rare. We now report a case of TTP resulting in death from widespread myocardial necrosis. This patient presented with elevated cardiac enzymes and electrocardiographic disturbances that mimicked viral myocarditis, as well as a profound thrombocytopenia. Such a case may represent the extreme of a distribution of cardiac involvement in TTP or the consequence of an unidentified autoimmune process capable of precipitating severe myocardial TTP.     

Phenylephrine and pilocarpine eye drop test for dementia with Lewy bodies and Alzheimer's disease

Pupillary response test using dilute phenylephrine, a sympathetic agonist, and dilute pilocarpine, a cholinergic agonist, were performed in 24 patients with dementia with Lewy bodies (DLB), 40 patients with Alzheimer's disease (AD), and 23 normal elderly subjects. The mydriatic response to 0.5% phenylephrine was significantly greater in the DLB group than in the AD and control groups. The mydriatic change correlated inversely with the reduction in cardiac 123I-metaiodobenzylguanidine uptake. In contrast, miotic response to 0.0625% pilocarpine was significantly greater in the DLB and AD groups than in the control group. The pupil assay using combined phenylephrine and pilocarpine eye drop test may be useful in the detection of patients with DLB and AD and in distinguishing between them.     

123I-Methyljodbenzylguanidin- (MIBG-) Szintigraphie

(123)I-metaiodobenzylguanidine (MIBG), a radio-labeled catecholamine analogue, is used for the imaging of pheochromocytoma based on the selective uptake of MIBG by chromaffin tissues. MIBG scintigraphy displays high sensitivity (90%) and specificity (close to 100%). In contrast, the false-positive uptake of MIBG by adrenal cortical carcinoma is rare. Here, we report a metastatic oncocytic adrenal cortical carcinoma with MIBG uptake used for therapeutic purposes.     

Sympathetic skin response in diabetic neuropathy

Autonomic neuropathy is a complication of diabetes mellitus (DM) in substantial proportion of cases and may cause definite autonomic symptoms. Because conventional electrophysiological methods do not assess the autonomic nervous system, simple reproducible tests were developed. One of them is sympathetic skin response (SSR) which provides useful information about the status of sympathetic postganglionic function. The aim of this study is to perform SSR in diabetic patients to see whether this test can be used as an electrophysiological method for the diagnosis and confirmation of diabetic autonomic neuropathy. 20 diabetic patients who had electrophysiologically confirmed polyneuropathy but showed no symptoms or signs referable to autonomic system dysfunction were included. 14 (70%) patients demonstrated abnormal SSR. 2 abnormal patterns were observed. An absent response in at least one tested lower extremity (50%) and prolonged foot with normal hand latency (20%). 6 patients (30%) demonstrated no abnormalities. Foot and hand latencies in diabetics did not differ significantly from those of normal controls (p: 0.4, p: 0.1) and no correlation could be found with latencies and duration of sickness, patient's age and HbA1c values. We believe latency measurement is an objective measure of conduction in multineural pathways and can detect subclinical involvement of sympathetic nervous system in diabetics who do not manifest symptoms or signs referable to autonomic system dysfunction.     

Anthracycline-induced cardiomyopathy: long-term effects on myocardial cell integrity, cardiac adrenergic innervation and fatty acid uptake.

Cardiotoxicity of anthracyclines is a clinical challenge in cancer chemotherapy. Limited data is available on the physiological mechanisms responsible for anthracycline-induced heart failure or its recovery. We studied four patients with a history of severe anthracycline-induced heart failure manifested 2-116 months earlier by using radionuclide ventriculography for the measurement of left ventricular function, indium-111-antimyosin scintigraphy for the detection of myocardial cell injury and iodine-123-metaiodobenzylguanidine (MIBG) scintigraphy for the assessment of cardiac adrenergic innervation. Myocardial perfusion and fatty acid utilization were assessed with iodine-123-paraphenyl pentadecanoid acid (pPPA) and single photon emission computed tomography (SPECT). Symptoms of congestive heart failure (CHF) were still present in two patients whereas the others were asymptomatic at the time of the study. The patients who showed complete clinical recovery had normal or near normal left ventricular ejection fraction (LVEF) (47 and 52%), whereas the patients with symptoms of heart failure had low ejection fractions (21 and 31%). All patients presented with abnormal antimyosin uptake and decreased myocardial MIBG uptake. Patients with low ejection fraction tended to have higher antimyosin uptake suggesting more severe, persistent myocyte injury. All but one patient showed normal fatty acid utilization. These data suggest that patients with a history of severe anthracycline-induced cardiomyopathy have persistent myocardial cell injury and adrenergic dysfunction up to 10 years after the development of heart failure. These findings seem to be present regardless of recovery of left ventricular function.     

Neurophysiological assessment of peripheral neuropathy in primary Sjögren's syndrome

Peripheral nervous system complications are rare in patients with primary Sjögren's syndrome. We investigated a group of six women aged 43–64 years who complained of pain and sensory symptoms. Conventional neurophysiological tests reflecting large nerve fiber function revealed normal motor conduction in all patients, whereas sensory nerve action potentials were absent in two. On the other hand, quantitative thermometry and autonomic nerve function tests indicating small nerve fiber function were more sensitive in the assessment of nerve dysfunction; these showed abnormalities in all cases. Vibrametry showed dysfunctions in four patients. The latter methods possess great sensitivity in discovering sensory disturbances. Neurophysiological assessment of the sensory and autonomic nervous system demonstrating sensory neuropathy contributes to early diagnosis of primary Sjögren's syndrome.Abbreviations HRV heart rate variation - PNS peripheral nervous system - pSS primary Sjögren's syndrome - SSEP short-latency somatosensory evoked potentials - SSR sympathetic skin response - SuCV sudomotor nerve conduction velocity     

Clearance kinetics and fate of macromolecular IgA in patients with IgA nephropathy

IgA glomerulonephritis is associated with macromolecules of polymeric IgA in the circulation and mesangial deposits. An impairment in the reticulophagocytic function of patients with IgA nephropathy has been postulated as the potential cause for persistence of IgA immune complexes in the circulation and their eventual glomerular deposition. Since the fate and removal mechanisms of circulating macromolecular IgA are unknown in humans, we examined the blood clearance and organ uptake of purified IgA polymers and macromolecules in patients with IgA nephropathy and normal controls. The IgA macromolecules were prepared by covalent cross-linking of purified human polymeric IgA with a heterobifunctional reagent, N-succinimidyl 3-(2-pyridyldithio) propionate. After intravenous injection, large IgA molecules were removed rapidly from the circulation of patients (t1/2 = 3.8 +/- 1.0 minutes) and controls (t1/2 = 4.9 +/- 1.5 minutes). Dynamic gamma camera scintigraphy revealed the liver as the major organ that mediated the removal of the macromolecular IgA with no significant difference in the rate of hepatic uptake for patients (t1/2 = 3.4 +/- 0.6 minutes) and controls (t1/2 = 3.3 +/- 0.9 minutes). No significant amount of radioactivity could be detected in the lungs, kidneys, and spleen. The small polymers had a slower and similar clearance rates for patients (t1/2 = 29.3 +/- 7.9 h) and controls (t1/2 = 29.0 +/- 8.6 h). These findings have general significance in showing the liver as a major organ for removal of macromolecular IgA. In addition, the results have specific importance in showing that patients with IgA nephropathy do not suffer from an IgA removal dysfunction.     

Cardiac repolarization abnormalities and increased sympathetic activity in scleroderma

BACKGROUND: Cardiac involvement in scleroderma is a poor prognostic sign and is usually underdiagnosed, particularly in asymptomatic patient. This paper focuses on QT dynamicity and heart rate variability (HRV) in patients with scleroderma and controls in an attempt to investigate the cardiac autonomic system and ventricular repolarization. METHODS: Sixty patients with scleroderma and 30 age- and sex-matched healthy controls who had no cardiovascular risk factors were included in this study. All patients and the controls underwent a 24-hour holter recording as well as a transthoracic echocardiography. HRV and QT dynamicity parameters were calculated. RESULTS: In HRV analysis, autonomic balance was changed in favor of the sympathetic system in patients with diffuse scleroderma. In QT dynamicity analysis, QT/RR slopes were significantly steeper in patients with diffuse scleroderma compared to patients with limited scleroderma and controls (QTapex/RR: 0.24 +/- 0.16, 0.15 +/- 0.03, 0.14 +/- 0.03 respectively p < 0.001; QTend/RR: 0.26 +/- 0.17, 0.14 +/- 0.04, 0.13 +/- 0.05, respectively p < 0.001). CONCLUSIONS: Patients with diffuse scleroderma may have asymptomatic cardiac repolarization abnormalities and autonomic dysfunction. Our results may indicate that QT dynamicity and HRV can be useful noninvasive methods that may detect impaired state of autonomic balance and cardiac repolarization in patients with diffuse scleroderma.     

The influence of major depression and its treatment on heart rate variability and pupillary light reflex parameters

BACKGROUND: The link between depression and autonomic dysfunction has attracted more attention since epidemiological studies have revealed that depressed patients have an augmented risk of cardiovascular morbidity and mortality. Former studies of autonomic dysfunction in major depression have shown inconclusive results. AIMS: To further elucidate the effect of depression and medication on autonomic function, 18 patients and 18 matched control subjects were comprehensively assessed once medicated and once non-medicated as well as after full clinical recovery. METHODS: Cardiac autonomic function was evaluated by measuring heart rate variability (HRV) parameters, and central autonomic tone was investigated by obtaining parameters of the pupillary light reflex (PLR). RESULTS: Acutely depressed patients who had not taken antidepressant medication for 8 weeks prior to the investigation differed significantly neither in heart rate parameters nor in parameters of the PLR from their controls. However, after 2 days of antidepressant treatment (SSRI and NaSSRI), parameters of heart rate analysis and PLR (except relative amplitude) changed significantly and remained significantly different after clinical recovery. LIMITATIONS: The study needs to be repeated using larger patient groups. Long-term studies are absolutely essential. CONCLUSION: The state of depression did not influence autonomic parameters significantly. In fact, treatment influenced autonomic function far more than the disease itself. Other branches of the autonomic nervous system (ANS), as well as new techniques should be applied to elucidate whether small changes in autonomic function exist. This might clarify whether disease or treatment might influence cardiac mortality in depression.     

Neuraxial modulation for treatment of VT storm

In the hyperadrenergic state of VT storm where shocks are psychologically and physiologically traumatizing, suppression of sympathetic outflow from the organ level of the heart up to higher braincenters plays a significant role in reducing the propensity for VT recurrence. The autonomic nervous system continuously receives input from the heart (afferent signaling), integrates them, and sends efferent signals to modify or maintain cardiac function and arrhythmogenesis. Spinal anesthesia with thoracic epidural infusion of bupivicaine and surgical removal of the sympathetic chain including the stellate ganglion has been shown to decrease recurrences of VT. Excess sympathetic outflow with catecholamine release can be modified with catheter-based renal denervation. The insights provided from animal experiments and in patients that are refractory to conventional therapy have significantly improved our working understanding of the heart as an end organ in the autonomic nervous system.     

Present and future of cardiac function tests: electrophysiologic tests]

Various electrocardiographic and physiologic tests have been developing for almost 100 years since Einthoven established the standard 12 lead electrocardiogram(ECG) system. Recently, interest has focused on the new developing parameters associated with cardiac ventricular repolarization, such as transmural dispersion of repolarization, T wave alternans and QT dispersion. QT dispersion, measured as interlead difference of QT interval, has been suggested to reflect regional variation of ventricular repolarization. However, still unsolved basic problems give difficulties for clinical acceptance of this parameter. On the other hand, it is generally accepted that heart rate variability obtained from Holter ECG is useful tool to assess the autonomic tone. Head-up tilt test is a valuable diagnostic tool to identify patients with neurally mediated syncope and also useful for assessment of reflex cardiac autonomic function, such as baroreflex sensitivity. The number of electrophysiologic study(EPS) dramatically increased together with increase of radiofrequency catheter ablation. A new three-dimensional nonfluoroscopic electroanatomical mapping system(CARTO) is an exciting development in catheter ablation treatment. Transtelephonic ECG and its computer-assisted answering system are also useful for diagnose and treatment in the patients of paroxysmal cardiac symptoms.