TY - JOUR
AU1 - Zalewski,, Pawel
AU2 - Słomko,, Joanna
AU3 - Zawadka-Kunikowska,, Monika
AB - Abstract Introduction The majority of chronic diseases are accompanied by symptoms of more or less pronounced dysautonomia, which frequently and noticeably deteriorate the quality of patients’ life. Sources of data Pubmed. Areas of agreement Functional disorders in the autonomic nervous system (ANS) require very precise diagnostics; frequently involving several specialists and a number of diagnostic tests. Areas of controversy Dysautonomia symptoms are of a very discrete nature and may develop much earlier than symptoms specific for a given chronic disease, significantly influencing the treatment process itself. Growing points ANS dysfunctions should be considered at each stage of the diagnostic and treatment processes, as a predictor for the patient’s clinical condition. Areas timely for developing research Many researchers indicate that a decrease in dysautonomia intensity has a direct effect on the progress of the underlying disease and undoubtedly contributes to the improvement of the general health condition or to symptoms remission. autonomic dysfunction, dysautonomia, chronic disease Introduction The autonomic nervous system (ANS) forms a part of the nervous system functionally closely associated with the hormonal and the immunological systems. All these three systems are responsible for maintaining homoeostasis by dynamic integration of internal and external stimuli. Therefore, the basic function of the autonomic system ensuring maintenance of homoeostasis are reflex reactions controlled by many structures of the nervous system. A functional response of the ANS and organs innervated by it is a very sensitive indicator of adaptation to and compensation of factors disrupting homoeostasis, independent of the human will. The ANS has a double antagonistic innervation, thus, its regulatory possibilities are greater, and it is easier to reverse homoeostatic anomalies. A characteristic parameter of ANS efferent parts, i.e. sympathetic and parasympathetic parts of the ANS, is their continuous activity, even at rest.1–3 The ergotropic sympathetic system predominates in the daytime activity, while the activity of the trophotropic parasympathetic system dominates during sleep. Particular attention should be paid to the trophic effect of ANS on the body through a series of transmitters and neuromodulators, which induce a series of secondary reactions, the so-called secondary information transmitters, which activate, both directly and indirectly, regulatory genes, transcription and post-transcription expression factors of enzymes participating in the biosynthesis of structural, receptor and membrane ion channel proteins, and a number of other factors being a part of elementary catabolic and anabolic processes in the body. A number of transmitters and neurotransmitters function within the ANSs, and they are connected by many complex functional relations. The main neurotransmitters released from synaptic terminals of ANS neurons include acetylcholine and noradrenaline. Nerve fibres releasing acetylcholine are called cholinergic fibres, while those releasing noradrenaline are called noradrenergic fibres. Preganglionic neurons, both sympathetic and parasympathetic, are cholinergic fibres, while majority of postganglionic neurons of the sympathetic system are noradrenergic fibres, contrary to parasympathetic postganglionic neurons, which are cholinergic fibres. Postganglionic neurons innervating sweat glands are an exception amongst sympathetic fibres. A very characteristic feature of sympathetic and parasympathetic neurons and pre and postganglionic fibres is their rhythmical activity controlled by the neuronal network with mutual feedbacks and including inhibitory interneurons.1,2 Maintaining an undisturbed sympathetic and parasympathetic balance is a fundamental prerequisite for maintaining a relatively stable internal environment. Functional changes within the ANS may be of a transient nature in relatively healthy people, but they also may represent an important disorder directly or indirectly influencing the underlying disease, and frequently exacerbate its course. The majority of chronic diseases are accompanied by symptoms of more or less pronounced dysautonomia, which frequently and noticeably deteriorate the quality of patients’ life. Symptoms of functional disorders in the ANS are usually a consequence of neurodegenerative influence on ANS neurons of the underlying disease (Table 1, Fig. 1). In other cases, symptoms associated with the ANS predominate over other, less noticeable symptoms of the chronic disease, and such a condition is defined as pure autonomic failure (PAF). Taking into account the clinical characteristics of this disease, a classification into separate subtypes, i.e. PAF with manifested symptoms of orthostatic hypotension (OH) without signs of neurodegeneration of central neurons, multiple system atrophy (MSA) characterized by symptoms characteristic for PAF with pronounced neurodegenerative changes visible in neuroimaging and typical dysautonomia disorders accompanying Parkinson’s disease (PD) or multiple sclerosis (MS). Frequently, symptoms of dysautonomia hinder diagnostic and differentiation processes for the chronic disease, due to the unspecific nature of its symptoms. In many cases, dysautonomia symptoms are of a very discrete nature and may develop much earlier than symptoms specific for a given chronic disease, significantly influencing the treatment process itself (Fig. 2).2–4 Table 1 Classification and the most common symptoms of autonomic dysfunction Autonomic disorders Disease Symptoms of dysautonomia Structural central MSA OH, urinary bladder dysfunction, sexual dysfunctions, gastrointestinal disorders, dysphagia, constipations, abnormal sweating PD Peripheral Diabetes OH, dizziness, sinus tachycardia, abnormal blood pressure, gastrointestinal disorders, pupillary reflex disorders, thermoregulatory disorders, loss of reaction to hypoglycaemia, failure of a mechanism of renal sodium retention, exercise intolerance Familial dysautonomia Inability to produce tears, abnormal sweating, vomiting, tachycardia, high blood pressure Functional Chronic fatigue syndrome Postural tachycardia syndrome, sleep disorders, secretomotor issues, pupillary reflex disorders, thermoregulatory disorders, gastrointestinal disorders Fibromyalgia Orthostatic intolerance, fatigue, pain, sleep disorders, headache, nausea, anxiety, sicca syndrome, Reynaud’s phenomenon, irritable colon syndrome Migraine Nausea/vomiting, hyperhidrosis, flushing, pallor, palpitations, diaphoresis, lightheadedness, constipation, diarrhoea, polydipsia, polyuria, piloerection, pupillary dilation, chemosis, lacrimation, rhinorrhea, facial oedema, presyncope/syncope Irritable bowel syndrome Gastrointestinal disorders, diarrhoea, constipation, nausea/vomiting. Autonomic disorders Disease Symptoms of dysautonomia Structural central MSA OH, urinary bladder dysfunction, sexual dysfunctions, gastrointestinal disorders, dysphagia, constipations, abnormal sweating PD Peripheral Diabetes OH, dizziness, sinus tachycardia, abnormal blood pressure, gastrointestinal disorders, pupillary reflex disorders, thermoregulatory disorders, loss of reaction to hypoglycaemia, failure of a mechanism of renal sodium retention, exercise intolerance Familial dysautonomia Inability to produce tears, abnormal sweating, vomiting, tachycardia, high blood pressure Functional Chronic fatigue syndrome Postural tachycardia syndrome, sleep disorders, secretomotor issues, pupillary reflex disorders, thermoregulatory disorders, gastrointestinal disorders Fibromyalgia Orthostatic intolerance, fatigue, pain, sleep disorders, headache, nausea, anxiety, sicca syndrome, Reynaud’s phenomenon, irritable colon syndrome Migraine Nausea/vomiting, hyperhidrosis, flushing, pallor, palpitations, diaphoresis, lightheadedness, constipation, diarrhoea, polydipsia, polyuria, piloerection, pupillary dilation, chemosis, lacrimation, rhinorrhea, facial oedema, presyncope/syncope Irritable bowel syndrome Gastrointestinal disorders, diarrhoea, constipation, nausea/vomiting. Notes: Structural disorders are defined as having demonstrable pathological abnormalities that directly affect autonomic function. Functional disorders currently have no consistently demonstrable pathological basis, are primarily defined by symptomology. Table 1 Classification and the most common symptoms of autonomic dysfunction Autonomic disorders Disease Symptoms of dysautonomia Structural central MSA OH, urinary bladder dysfunction, sexual dysfunctions, gastrointestinal disorders, dysphagia, constipations, abnormal sweating PD Peripheral Diabetes OH, dizziness, sinus tachycardia, abnormal blood pressure, gastrointestinal disorders, pupillary reflex disorders, thermoregulatory disorders, loss of reaction to hypoglycaemia, failure of a mechanism of renal sodium retention, exercise intolerance Familial dysautonomia Inability to produce tears, abnormal sweating, vomiting, tachycardia, high blood pressure Functional Chronic fatigue syndrome Postural tachycardia syndrome, sleep disorders, secretomotor issues, pupillary reflex disorders, thermoregulatory disorders, gastrointestinal disorders Fibromyalgia Orthostatic intolerance, fatigue, pain, sleep disorders, headache, nausea, anxiety, sicca syndrome, Reynaud’s phenomenon, irritable colon syndrome Migraine Nausea/vomiting, hyperhidrosis, flushing, pallor, palpitations, diaphoresis, lightheadedness, constipation, diarrhoea, polydipsia, polyuria, piloerection, pupillary dilation, chemosis, lacrimation, rhinorrhea, facial oedema, presyncope/syncope Irritable bowel syndrome Gastrointestinal disorders, diarrhoea, constipation, nausea/vomiting. Autonomic disorders Disease Symptoms of dysautonomia Structural central MSA OH, urinary bladder dysfunction, sexual dysfunctions, gastrointestinal disorders, dysphagia, constipations, abnormal sweating PD Peripheral Diabetes OH, dizziness, sinus tachycardia, abnormal blood pressure, gastrointestinal disorders, pupillary reflex disorders, thermoregulatory disorders, loss of reaction to hypoglycaemia, failure of a mechanism of renal sodium retention, exercise intolerance Familial dysautonomia Inability to produce tears, abnormal sweating, vomiting, tachycardia, high blood pressure Functional Chronic fatigue syndrome Postural tachycardia syndrome, sleep disorders, secretomotor issues, pupillary reflex disorders, thermoregulatory disorders, gastrointestinal disorders Fibromyalgia Orthostatic intolerance, fatigue, pain, sleep disorders, headache, nausea, anxiety, sicca syndrome, Reynaud’s phenomenon, irritable colon syndrome Migraine Nausea/vomiting, hyperhidrosis, flushing, pallor, palpitations, diaphoresis, lightheadedness, constipation, diarrhoea, polydipsia, polyuria, piloerection, pupillary dilation, chemosis, lacrimation, rhinorrhea, facial oedema, presyncope/syncope Irritable bowel syndrome Gastrointestinal disorders, diarrhoea, constipation, nausea/vomiting. Notes: Structural disorders are defined as having demonstrable pathological abnormalities that directly affect autonomic function. Functional disorders currently have no consistently demonstrable pathological basis, are primarily defined by symptomology. Fig. 1 View largeDownload slide Clinical classification of autonomic disorders—organization level. Fig. 1 View largeDownload slide Clinical classification of autonomic disorders—organization level. Fig. 2 View largeDownload slide Symptoms of autonomic dysfunction. Fig. 2 View largeDownload slide Symptoms of autonomic dysfunction. Nature of dysautonomia symptoms Functional disorders in the ANS require very precise diagnostics; frequently involving several specialists and a number of diagnostic tests. In recent decades, the issue of a correct diagnosis of autonomic disorders accompanying many chronic diseases has noticeably gained in importance. Increasingly often, specialists are aware that correct diagnostics of autonomic disorders and paying more attention to them translate into measurable therapeutic effects and improved quality of patients’ life. In recent years, a very robust development of diagnostic techniques has resulted in better availability of the functional evaluation of the ANS, and the obtained diagnostic test results are valid, reliable and repeatable. In this respect, evaluation of main effectors of the autonomic nerves and the cardiovascular system offers extensive diagnostic possibilities, and the obtained results can frequently be successfully referred to the functional evaluation of the ANS as the whole. The rhythmic activity of the sympathetic and parasympathetic components mentioned above translates directly to heart rate variability (HRV) and blood pressure variability (BPV). With the available advanced and computerized diagnostic methods, it is possible to present the current tonic activity of the autonomic nerves in a reliable way, and at the same time, to analyse autonomic regulation more extensively, using provocation tests.3–5 Many studies concerning primary and secondary autonomic disorders refer to signs of orthostatic intolerance (Table 2). Very frequently, symptoms of orthostatic intolerance are the first signs of developing deregulation of neuronal mechanisms controlling the brain flow, strictly controlled by ANS. Table 2 OH in chronic autonomic failure OH Primary chronic autonomic failure Secondary chronic autonomic failure PD MSA PAF Familiar dysautonomia Autoimmune autonomic gangliopathy Idiopathic Diabetes mellitus Cardiovascular diseases MS Autoimmune diseases Endocrine disorders Renal failure Amyloidosis Spinal cord diseases OH Primary chronic autonomic failure Secondary chronic autonomic failure PD MSA PAF Familiar dysautonomia Autoimmune autonomic gangliopathy Idiopathic Diabetes mellitus Cardiovascular diseases MS Autoimmune diseases Endocrine disorders Renal failure Amyloidosis Spinal cord diseases Table 2 OH in chronic autonomic failure OH Primary chronic autonomic failure Secondary chronic autonomic failure PD MSA PAF Familiar dysautonomia Autoimmune autonomic gangliopathy Idiopathic Diabetes mellitus Cardiovascular diseases MS Autoimmune diseases Endocrine disorders Renal failure Amyloidosis Spinal cord diseases OH Primary chronic autonomic failure Secondary chronic autonomic failure PD MSA PAF Familiar dysautonomia Autoimmune autonomic gangliopathy Idiopathic Diabetes mellitus Cardiovascular diseases MS Autoimmune diseases Endocrine disorders Renal failure Amyloidosis Spinal cord diseases Thus, functional evaluation of the cardiovascular system in the beat-to-beat mode offers very extensive possibilities for interpretation of autonomic disorders. Numerous studies point to changes in time and spectral parameters in the heart rhythm and BPV when evaluated at rest and during orthostatic provocation. With an easier access to ambulatory functional evaluation of the ANS, specialists use this type of diagnostics increasingly often, and this supports both making better diagnoses, as well as evaluations of the therapeutic process.4,5 Apart from orthostatic intolerance, there are numerous other symptoms that should be taken into account in the diagnostic process. They include the previously mentioned symptoms from the cardiovascular system, symptoms of peripheral vascular hyperreactivity, including pallor or hyperperfusion of skin vessels, an inadequate reaction to cold stimuli and secretory disorders within sweat, salivary or lachrymal glands. Very frequently, functional disorders in the ANS include problems in the gastrointestinal tract and the urinary and reproductive systems. Therefore, the functional disorders in these systems should also be verified in the physical examination.4 The aim of this review was to show the extensiveness of the subject of disorders in the ANS in chronic diseases, as well as the importance of taking these disorders into account during diagnostic processes. A steadily growing number of studies in this field indicate that the clinical specialists’ demand for knowledge in this area is continuously increasing. Literature search We searched the PubMed database without language restrictions for full papers up to March 2018, using the following search terms: ‘dysautonomia’, ‘chronic disease’, ‘autonomic dysfunction’. References to original articles, reviews and meta-analyses were reviewed manually and cross-checked (Fig. 3). Fig. 3 View largeDownload slide Flowchart of studies. Fig. 3 View largeDownload slide Flowchart of studies. Autonomic dysfunction in cardiovascular conditions The ANS is the main regulator of the systemic homoeostasis, including the regulatory mechanisms in the cardiovascular system. This regulation adjusts the heart rate and the blood pressure to changing physiological conditions. Most commonly, this is a reflex reaction using negative feedbacks. Disorders in the autonomic reflex regulation may manifest as presyncope or syncope, that is, a temporary generalized reduction in brain perfusion characterized by a rapid onset, short duration and spontaneous complete reversal. Typical syncope, secondary to the autonomic dysfunction, is usually caused by central neuropathy or peripheral gangliopathy. A correct diagnosis of aetiology of orthostatic disorders requires detailed physical examination and an analysis of responses to provocation tests. The most commonly diagnosed conditions include neurally mediated syncope (vasovagal, situational, and carotid sinus syncope), OH and postural tachycardia syndrome (POTS).5–9 Neurally mediated syncope is usually classified on the basis of the predominating efferent pathway (sympathetic or parasympathetic), or on the basis of a stimulus causing its occurrence, i.e. the afferent pathway. Vasovagal syncope is the most common type of syncope of unknown aetiology. It is associated with orthostatic stress, but can also be provoked by emotions or pain. A high incidence of this condition is observed in women up to 35 years of age. Pathophysiology of syncope is very complex. It includes changes in the ANS tone and in vascular resistance, with reflex hypotension and bradycardia. Vasovagal syncope is not threatening to health or life, but may be a health problem negatively affecting the quality of life. Certain types of situational syncope (defecation and micturition syncope) are triggered by vagal reflexes from gastrointestinal and genitourinary mechanoreceptor stimulation rather than from cardiac mechanoreceptor stimulation. The pathophysiology of carotid sinus hypersensitivity is not well understood. It has been suggested that the neuromuscular structures surrounding the carotid mechanoreceptors are involved as well as autonomic dysregulation with increased resting sympathetic activity along with increased baroreflex sensitivity.6 Orthostatic hypotonia is defined as an abnormal drop in the blood systolic (sBP ≥ 20 mmHg) or diastolic (dBP ≥ 10 mmHg) pressure within 3 min of standing up. Contrary to reflex syncope, in this case a permanent damage of sympathetic efferent activity occurs, resulting in impaired vasoconstriction. OH incidence increases with age, it also may concur with hypertension, diabetes, cardiovascular diseases or neurodegenerative diseases. Furthermore, study results indicate that OH in adults of middle age predisposes to the development of left ventricular hypertrophy, regardless of whether hypertension is present or not. What is important, OH is a significant predictor of cardiovascular events and is associated with all-cause mortality. Postural tachycardia syndrome (POTS) is associated with severe orthostatic intolerance without accompanying syncope, but with a significant increase in heart rate, by over 30 beats per minute or up to over 120 beats per minute, and unstable blood pressure (Table 3). Most commonly, this disorder affects women (75%) of 13–50 years of age. Very frequently, POTS concurs with chronic fatigue syndrome (CFS). The pathophysiology of POTS is not well understood, it is not associated with significant mortality. Several mechanisms have been proposed: β-receptor hypersensitivity, peripheral denervation, hypovolaemia or impaired cerebral autoregulation.5,7 Table 3 The grading for POTS Postural tachycardia syndrome Grade 0 Normal orthostatic tolerance Grade I Symptoms infrequent/occur under increased orthostatic stress conditions Able to stand >15 min Grade II Symptoms frequent (at least once a week) commonly develop with orthostatic stress Able to stand >5 min Grade III Symptoms develop on most occasion, regularly unmasked by orthostatic stress Able to stand >1 min Syncope/presyncope common if patient attempts to stand Postural tachycardia syndrome Grade 0 Normal orthostatic tolerance Grade I Symptoms infrequent/occur under increased orthostatic stress conditions Able to stand >15 min Grade II Symptoms frequent (at least once a week) commonly develop with orthostatic stress Able to stand >5 min Grade III Symptoms develop on most occasion, regularly unmasked by orthostatic stress Able to stand >1 min Syncope/presyncope common if patient attempts to stand Table 3 The grading for POTS Postural tachycardia syndrome Grade 0 Normal orthostatic tolerance Grade I Symptoms infrequent/occur under increased orthostatic stress conditions Able to stand >15 min Grade II Symptoms frequent (at least once a week) commonly develop with orthostatic stress Able to stand >5 min Grade III Symptoms develop on most occasion, regularly unmasked by orthostatic stress Able to stand >1 min Syncope/presyncope common if patient attempts to stand Postural tachycardia syndrome Grade 0 Normal orthostatic tolerance Grade I Symptoms infrequent/occur under increased orthostatic stress conditions Able to stand >15 min Grade II Symptoms frequent (at least once a week) commonly develop with orthostatic stress Able to stand >5 min Grade III Symptoms develop on most occasion, regularly unmasked by orthostatic stress Able to stand >1 min Syncope/presyncope common if patient attempts to stand Clinical observations imply a relationship between the level of the ANS dysfunction and an increased risk of cardiovascular diseases. The increased activity of the sympathetic ANS is correlated with the progression of myocardial hypertrophy and with increased cardiovascular morbidity and mortality. Chronic hyperactivity of the parasympathetic ANS possibly results from multiple factors. A peripheral mechanism described in the reports, associated with the abnormal function of ANS receptors, involves a decrease in the sensitiveness of arterial baroreceptors, cardiopulmonary mechanoreceptors and an increase in activity of renal receptors. Another mechanism is associated with the abnormal function of the efferent part of the sympathetic system, in the form of increased release combined with reduced reuptake of mediators. The central mechanism involves cerebral excessive expression of angotensin II, leading to inactivation of cerebral nitrogen oxide (NO) and limited NO inhibition of the rostral ventrolateral medulla.8 A dysfunction within the ANS, with accompanying impaired reflex regulation in the cardiovascular system is a crucial component of pathophysiology of many diseases, including hypertension and heart failure. In patients with hypertension, hyperactivity of the sympathetic system at rest occurs already at an early stage of the disease and manifests as increased blood noradrenaline levels. The increase in noradrenaline levels noted in the studies concerns mainly the heart and kidneys and is possibly a product of increased noradrenaline release and its impaired reuptake. Furthermore, in patients with primary and with renovascular hypertension, an increase in the activity of sympathetic nerves of the skeletal muscles was observed.8,9 Stimulation of the sympathetic system is a crucial component of the disrupted sympathetic and parasympathetic balance in heart failure. The chronic adrenergic activation results in adverse effects in the cardiovascular system, contributing to disease progression and to poor prognosis for this syndrome. Prolonged sympathectomy supports the development of malignant ventricular arrhythmias, and together with a reduced threshold for ventricular fibrillation, resulting from an impaired function of the parasympathetic system, may result in a sudden cardiac death. Moreover OH is common co-morbidity in heart failure. The prevalence of OH in patients with HF remains uncertain. Reported data vary from 8% to as much as 83% among elderly patients hospitalized due to HF exacerbation.10,11 The ANS has a significant impact on cardiac electrophysiology and arrhythmogenesis. The pathophysiology mechanisms are different for specific arrhythmias. In atrial fibrillation, simultaneous sympathetic and parasympathetic activations are the most common trigger. In ventricular fibrillation in the setting of cardiac ischaemia, sympathetic activation is proarrhythmic, parasympathetic activation is antiarrhythmic. In inherited arrhythmia syndromes, sympathetic stimulation precipitates ventricular tachyarrhythmias and sudden cardiac death except in Brugada and J-wave syndromes where it can prevent them.12 Autonomic disorders in paediatrics ANS dysfunctions in children are still not fully known. Many autonomic disorders are visible immediately after birth or during the first years of life. They may be a result of premature birth, a generalized dysfunction of the nervous system or development disorders associated with gene mutations. However, structural disorders in the ANS are much less common than functional ones. Several disorders harbour both aberrant respiratory control and autonomic regulation including familial dysautonomia (FD), rapid onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome, congenital central hypoventilation syndrome (CCHS), Rett syndrome and Prader–Willi syndrome (PWS).13–18 FD belongs to rare developmental syndromes and is classified as a neuropathy with autonomic episodes. It is characterized by the inability to produce tears, increased sweating, disrupted regulatory mechanisms in the cardiovascular system and lack of fungiform papillae on the tongue. Autonomic episodes are provoked by physical exercise, pain or stress, and are manifested as vomiting, tachycardia and high blood pressure. Furthermore, ANS participates in many other seizures in children, and the maturing of central structures influences their clinical course.13 The most common seizures in children and youth include syncope resulting from excessive central sympathetic stimulation and insufficient peripheral stimulation. Furthermore, in young girls the postural tachycardia syndrome (POTS) is observed. The result confirming this diagnosis in children is an increase in the heart rate by 40 beats per minute during the first 10 min after assuming a vertical position, or chronic tachycardia with clinical symptoms including: dizziness, weakness, orthostatic syncope, palpitations, nausea, fatigue, exercise intolerance, headaches, poor sleep, abdominal pain or oedema. Mechanisms of POTS in children can be divided into five categories: neuropathy, hyperadrenergic state, abnormal vascular endothelial function, volume dyregulation and muscle pump defects.14,15 Panayiotopoulos syndrome is an epileptic syndrome frequently occurring in children, and its main symptoms include seizures associated with dysfunction of the ANS, such as vomiting, disrupted sweating, diarrhoea, fainting and tachycardia.13 Concluding, functional evaluation of the ANS in children and youth appears to be very important both during the interview and physical examination, due to the fact that symptoms of dysfunction may signal a possible threat to life. Autonomic dysfunctions in neurodegenerative disorders Neurodegenerative disorders, including PD, MSA and MS, are diseases of a chronic nature and complex multifactor aetiopathogenesis, in which environmental factors add to genetic predispositions. Although these diseases are characterized by a different clinical picture, an opinion prevails that their common features are neurodegnerative changes in the centres of central and peripheral autonomic regulation, manifested as signs of ANS injury.16–18 PD and MSA Primary autonomic disorders, including PD and MSA, are a group of diseases classified as α-synucleinopathies, characterized by the presence of a protein, α-synuclein in cytoplasm of neurones in the central nervous system, glial cells and peripheral autonomic nerves (pre and postganglionic).17 The results of neuroimaging and neuropathological tests indicate that the autonomic dysfunction mainly affects the central level in MSA, and not the peripheral ANS, as is typical for PD.16 Neuroimaging of the heart using 123I-meta- iodobenzylguanidine (123I-MIBG) and 6-[18 F]-fluorodopamine suggests a reduced marker uptake in postganglionic fibres, confirming the hypothesis of peripheral cardiac sympathetic denervation.19 Other studies in PD patients indicate α-synuclein accumulation also in nuclei within central noradrenergic (locus coeruleus) and dopaminergic (substantia nigra) neurons, and nuclei of the vagus nerve.20 In neuroimaging tests, MSA patients demonstrate injuries in the central autonomic centres and impairment in the baroreceptor reflex, without disorders affecting postganglionic sympathetic innervation of the heart.16,18,20 ANS disorders occurring at early MSA stages and mainly involving the cardiovascular system may be an additional component of differentiation diagnostics for these diseases.19,20 A dysfunction in the autonomic regulation of the cardiovascular system involves: OH, reversal of the daily blood pressure profile and reduced heart rhythm variability.18,19,21 In over 80% of patients, additional comorbidities include supine hypertension (SH) and postprandial hypotonia. Pathomechanism underlying the development of SH may be associated with baroreceptor dysfunction, fluid retention at night, adrenergic hypersensitivity and OH therapy. SH affects 47% MSA patients and 50% PD patients.16–19 The main symptom of cardiovascular ANS dysregulation in PD and MSA is orthostatic hypotonia, affecting 30–50% and 70–80% patients, respectively. OH may be asymptomatic.16 Due to the reduced perfusion of tissues and organs, patients may report numerous non-specific symptoms, i.e. dizziness, dyspnoea, generalized weakness, visual acuity dysfunction or chronic fatigue. Due to sympathetic innervation disorders, low serum NA levels were found in OH patients with synucleinopathy resting in a supine position.16 Disruptions in the autonomic cardiac regulation may be a cause of severe, life-threatening complications. In MSA and PD patients, an increased risk of cardiovascular diseases, ischaemic brain stroke and increased mortality rate were found vs the general population. In neuroimaging, an increased risk of injury in cerebral vessels was observed, including the presence of hyperintense foci in the white matter and lacunar strokes. It is suspected that the disrupted baroreceptor function, which includes SH, OH and blood pressure dropping at night, is more strongly associated with damage to brain vessels in PD.17 Another disorder in the ANS in patients with synucleinopathies is the urinary bladder dysfunction manifested as hypersensitivity of the detrusor muscle and lost coordination of the urinary sphincters and detrusor. Urination disorders are also described including problems with starting it, frequent urination and urination at night. In MSA, urinary incontinence (63%) develops early and is more pronounced.16,20,21 It is associated with damage to the Onuf nucleus where urination centres are located, and urine retention in the bladder (8%) with the bladder atony. At the later stages of MSA, atrophy of parasympathetic nerves of the bladder detrusor muscle is observed, together with a reduction in its contractile function or urine retention in the bladder, with urine outflow caused by its overfilling.20 Sexual dysfunctions accompanying synucleinopathy affect both sexes, and their intensity increases with the disease duration. Disruptions in the sexual drive and function may reflect dopamine deficiency, as well as disrupt autonomic pathways. Erectile dysfunctions develop at early stages of the disease in MSA and at later stages of PD. It is estimated that this problem affects 79% of men with PD and nearly all MSA patients.16 Gastrointestinal disorders in synucleinopathies mainly include problems with swallowing, drooling, constipations and delayed gastric emptying, which are controlled by central and peripheral autonomic centres and visceral innervation of the gastrointestinal tract. In PD, neuroimaging indicates the presence of α-synuclein in paravertebral and visceral ganglia, and in myenteric and submucosal plexi of the gastrointestinal tract. Studies in MSA patients, on the other hand, indicate neurodegeneration in nuclei of the brain stem (dorsal nucleus of the vagus nerve) and in the enteric nervous system (ENS).16 A pathomechanism underlying problems with swallowing in PD is associated with the loss of coordination in contraction of muscles in the mouth, throat and proximal oesophagus due to dysfunction of central centres of the autonomic regulation and increased inhibition of the brain cortex to the interpeduncular nucleus of the midbrain tegmentum. Dysphagia in MSA patients is more pronounced and characterized by an earlier onset than in PD patients. The most common symptom of disrupted colonic motor activity, developing before motor symptoms, is constipation, and it is assumed it increases the risk of PD by 2 to 4 times.16,20,21 Multiple sclerosis MS is a chronic, inflammatory and demyelinating disease of the central nervous system, during which both somatomotor and autonomic dysfunctions are observed. Among disorders in the ANS, dysfunctions of the urinary bladder (urinary incontinence, problems with urination, bladder dyssynergia; 10–97% of cases), constipations (36–54%) and sexual dysfunctions (60%) predominate.22,23 In MS, cardiovascular disorders are frequently omitted in medical examinations, due to their significant variability and intermingling of different clinical symptoms during the course of this disease.23,24 Standard tests evaluating cardiovascular reflexes indicate sympathetic and parasympathetic dysfunction in autonomic regulation of the cardiovascular system. Cardiovascular dysfunctions in MS include reduced heart rate and BPV and weakened arterial baroreceptor reflex. The impaired sympathetic mediated vasomotor control might be responsible for the orthostatic intolerance and lightheadedness reported in 25–50% of MS patients. Some studies indicate a significant relationship between signs of fatigue and sympathetic vasomotor dysfunction in MS.22–24 Autonomic dysfunction in ME/CFS and fibromyalgia Chronic fatigue syndrome (ME/CFS) is a complex disease of aetiology that still remains unknown. The axial symptom of this disease is the presence of unexplained mental and physical fatigue of the onset time defined relatively precisely in the past. The occurrence of the disease contributes significantly to a reduction in physical activity, and any, even limited physical exercise results in the visible exacerbation of the symptoms. In the adapted methodology, the clinical diagnosis of ME/CFS is based, in general, on meeting quality criteria for problems suffered. To this day, no clear biomarkers were found allowing unambiguous diagnosis. Nevertheless, functional dysfunctions in the ANS are extensively described by many authors. Symptoms of dysautonomia, particularly concerning orthostatic hypotonia, are very frequently found in ME/CFS patients and represent a very important element for diagnosis differentiation. Research conducted by many authors indicates differences in response to an orthostatic stimulus vs healthy people; a decreased cardiac adrenergic response and blood pressure parameters are observed. In ME/CFS patients, an increased tonic sympathetic activity is observed; however, the adrenergic response to the orthostatic stimulus is pathologically modified. The abnormal response to the orthostatic response was observed both for active standing and for head-up tilt testing.25–27 Another, relatively common disorder of a dysautonomic nature in the group of ME/CFS patients is the previously described postural orthostatic tachycardia syndrome (POTS). The studies indicate that this dysfunction is more frequent in this group of patients, and this also indicates neurogenic desynchronization of the response to the orthostatic stimulus.28 Fibromyalgia syndrome (FMS) is a clinical condition characterized by widespread pain and abnormal discomfort on palpation of specific tender point sites. Many patients with FM frequently report various symptoms which are quite specific for dysautonomia symptoms such as fatigue, sleep disorders, headache, anxiety, Sicca syndrome, Reynaud’s phenomenon and irritable colon syndrome.29,30 Researchers indicate that in FMS, the manifestations of dysautonomia symptoms are observed both for sympathetic and parasympathetic systems; however, sympathetic symptoms are definitely more frequent, and their exacerbation usually results in a deterioration of the patient’s general condition. However, the great variability of the symptoms and a degree of their intensity do not allow for an unambiguous determination of a dysautonomia model in FMS. Possible presence of local hypoxic areas due to increased sympathetic activity is implied, which in consequence, may result in pain characteristic for FMS; however, studies in this area do not give a clear answer, as disrupted cardiovascular regulation in response to stimulation or modified muscle sympathetic nerve activity (MSNA) is not observed frequently in this group of patients.31 Autonomic dysfunction in sleep disease The normal ANS function is crucial for maintaining the normal circadian rhythm (sleep/wake system). Primary disorders in the ANS very frequently contribute to sleep disorders. Recent studies indicate a very important role of ANS in the process for sleep onset and maintenance, as well as its influence on qualitative and quantitative parameters of sleep. There are several theories describing neuronal mechanisms underlying autonomic sleep control. The influence of the ANS on sleep is visible in several aspects, of which control of the respiratory rate, heart rhythm and blood pressure parameters appear to be of the greatest importance. Following studies in animal models and in humans, it is known that in the NREM phase, the heart rate slows due to the increased parasympathetic activity. In the REM phase, further reduction in the heart rate and in blood pressure is observed, following further increased parasympathetic activity and reduced sympathetic activity. During the REM phase, when quick movements appear, strong fluctuations in the heart rate and in blood pressure are observed, which result from a physiological variability in the activity of higher brain centres under the influence of cholinergic neuronal discharges in pedunculopontine and laterodorsal tegmental nuclei of the pons and thalamus.32–35 Primary ANS dysfunctions frequently result in the development of sleep disorders; also a chronic disease may lead to disruptions in autonomic control during sleep. One of the most common primary sleep disorders is obstructive sleep apnoea (OSA). Periods of shallow breath and apnoea occurring during disrupted sleep very strongly contribute to the development of ANS dysfunctions, which frequently lead to the exacerbation of the underlying disease and to the development of secondary diseases. OSA patients frequently develop a pathological ‘reverse-dipping’ mechanism, that is, an increase in blood pressure, instead of its physiological drop, being a consequence of sustained hyperactivity of the sympathetic system due to recurring hypoxia. Sustained excessive sympathetic activity in OSA patients contributes to the weakening in arterial baroreceptor reflex sensitivity and increased occurrence of hypertension, cardiovascular disease, ischaemia stroke, cardiac arrhythmias and sudden cardiac death.33,34 Recent studies indicate a very important role of OSA in a wide range of patients with cardiovascular diseases. The increasing number of guidelines recommend the exclusion of OSA in this group of patients, and when this diagnosis is confirmed, appropriate management of this condition must be initiated. An effective OSA therapy significantly contributes to a reduction of the cardiovascular risk and improves the patient’s prognosis, even in advanced cardiovascular conditions.35 Another very large group of patients, in which the concurrence of autonomic dysfunctions and sleep disorders are observed, is people with insomnia of varying severity. This group includes patients diagnosed with severe diseases such as fatal familial insomnia (FFI), as well as patients suffering from various problems with falling asleep and sustaining sleep in response to behavioural and environment stimuli. In FFI, in a short period from the development of the first symptoms of this disease, a number of sympathetic hyperreflexia symptoms develop, such as hypertension, tachycardia, tachypnea, hyperhidrosis, urinary dysfunction and impotence. At the same time, a circadian increase in catecholamine, cortisol and prolactin levels and reduced melatonin levels at night are observed. With the disease progression, dysautonomia increases up to the terminal phase.36 In milder forms of sleep disorders, similar symptoms are observed, but they are less intense. People suffering from sleep disorders are also characterized by increased sympathetic activity, which frequently becomes chronic, even after periods of improved sleep effectiveness. The research indicates that in people with insomnia or those subjected to chronic sleep deprivation, a heightened hypothalamic–pituitary–adrenal tone and increased catecholamine and cortical secretion develop, and this directly influences the development of a temporary or sustained increased sympathetic activity. Initiation of treatment focusing on the primary causes of sleep disorders also results in the reduction of dysautonomia symptoms, and thus, mainly in the reduction of the cardiovascular risk.36 Autonomic dysfunction in diabetes mellitus Diabetes is a widely spread metabolic disease, in which chronic complications lead to the development of autonomic dysfunction. It is estimated that it may affect about 1–90% of patients with type 1 diabetes and 1–70% of patients with type 2 diabetes. Diabetic autonomic neuropathy (DAN) may either be subclinical or with clinical symptoms resulting from damages to somatic and peripheral ANS. DAN develops due to atrophy of nerves in the ANS and of afferent sensory fibres accompanying autonomic fibres. It is assumed that sympathetic denervation affects the heart from the apex towards the base, gradually damaging ventricle function.37 The clinical picture of damages to the ANS fibres includes cardiovascular, gastrointestinal and urinary and reproductive symptoms, pupillary reflex disorders, thermoregulatory disorders, loss of reaction to hypoglycemia, failure of a mechanism of renal sodium retention and exercise intolerance. One of the most severe forms of autonomic dysfunction in diabetes is cardiac autonomic neuropathy, affecting 30–70% of patients. In diabetes patients, CAN increases the risk of death caused by cardiovascular factors fivefold.17,38 The increase in the QT interval (time between the start of the Q wave and the end of the T wave in the heart's electrical cycle) and heart rhythm anomalies, particularly with ventricular arrhythmias, may contribute to sudden cardiac deaths. Symptomatic manifestations of CAN in diabetes mellitus (DM) include dizziness, sinus tachycardia, decreased HRV and abnormal blood pressure. Resting HR could be a predictive value for CAN. Disrupted blood pressure control manifests as significant fluctuations in the blood pressure value during the day, and it does not decrease at night or decreases only slightly. A frequent symptom indicating sympathetic denervation of the heart is OH, accompanied by weakening of the arterial baroreceptor reflex.17,37,38 Autonomic dysfunction in irritable bowel syndrome Irritable bowel syndrome (IBS) is one of the most common functional disorders involving the gastrointestinal tract, affecting 10% of the general population. The range of clinical symptoms in IBS is wide and covers both symptoms associated with gastrointestinal motor function (diarrhoea, constipation) and extraintestinal symptoms, including ANS dysfunction.39 Pathogenesis of IBS remains unsolved, but it is increasingly accepted that the central–peripheral regulatory mechanism may be also involved. Dysregulation of the gut–brain axis (GBA), disruption in the autonomic balance and the immunological intestinal response are thought to be the main cause of these disorders. In IBS patients, a significant correlation between mental factors and pain and bowel irritability was noticed.40 Stress and anxiety disrupt the GBA function and communication between CNS and ENS. The problem of ANS dysregulation in gastrointestinal dysfunctions is not yet fully known. In IBS patients, an increased sympathetic activity was observed in functional ANS tests and in microcirculatory reactivity tests using the laser Doppler flowmetry technique.39,40 Other research observed a decreased parasympathetic activity in IBS subjects with diarrhoeal variant, whereas the constipation variant was associated with the opposite effect. Changes in the sympathetic modulation of GBA in IBS may contribute to the development of myoelectrical dysfunctions, resulting in delayed gastric emptying and dyspeptic problems.39 Summary and limitations This study does not exhaust the subject of the dysfunctions of the ANS in chronic diseases. This subject is so extensive that an independent review of literature could also be conducted for each of the described issues. Nevertheless, the review indicates the nature and the significance of dysautonomia in chronic diseases. 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TI - Autonomic dysfunction and chronic disease
JF - British Medical Bulletin
DO - 10.1093/bmb/ldy036
DA - 2018-12-01
UR - https://www.deepdyve.com/lp/oxford-university-press/autonomic-dysfunction-and-chronic-disease-oDp3T0mVop
SP - 61
VL - 128
IS - 1
DP - DeepDyve
ER -