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Abstract
Hereditary transthyretin (TTR) amyloidosis, traditionally referred to as familial amyloid polyneuropathy, is an autosomal dominant multisystemic disease caused by the extracellular accumulation of abnormally misfolded TTR developing multiorgan failure. Autonomic manifestations are frequently reported in these patients. Among these, orthostatic symptoms resulting from cardiovascular autonomic dysfunctions significantly disturb daily life. Usual manifestations include symptoms of peripheral neuropathy, which may evolve into severe manifestations of generalized autonomic dysfunction, in addition to cardiological, neurological (peripheral sensory-motor polyneuropathy), visual, genitourinary, renal, and gastrointestinal symptoms. Early detection is extremely important, aiming for treatment and preventing progression.
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The autonomic nervous system (ANS) regulates important functions in various organic systems such as cardiovascular, digestive, genital-urinary and sudomotor systems. Its dysfunctions can determine several clinical manifestations, some of which are debilitating and serious. Various pathologies can compromise the ANS and determine symptoms, increasing the risk of syncope, falls and higher cardiovascular mortality. Due to the different clinical manifestations and the poor familiarity of professionals, Dysautonomia is often underdiagnosed, being recognized at more advanced stages, with debilitating and incapacitating symptoms and worse prognosis.
The prevalence and significance of cardiac amyloidosis have been considerably underestimated in the past; however, the number of patients diagnosed with cardiac amyloidosis has increased significantly recently due to growing awareness of the disease, improved diagnostic capabilities and demographic trends. Specific therapies that improve patient prognosis have become available for certain types of cardiac amyloidosis. Thus, the earliest possible referral of patients with suspicion of cardiac amyloidosis to an experienced center is crucial to ensure rapid diagnosis, early initiation of treatment, and structured patient care. This requires intensive collaboration across several disciplines, and between resident physicians and specialized centers. The aim of this consensus statement is to provide guidance for the rapid and efficient diagnosis and treatment of light-chain amyloidosis and transthyretin amyloidosis, which are the most common forms of cardiac amyloidosis.
The cardiovascular branch of autonomic nervous system (ANS) is responsible for the regulation of heart rate, blood pressure, and maintaining homeostasis during physiological stress such as exercise and standing upright. ANS constantly controls the rate and force of heart contractions and the vascular tone with the aim to maintain the sufficient tissue perfusion with oxygenated blood and secure venous return to the heart. Dysautonomias, a result of ANS malfunction, are often found in patients with cardiovascular symptoms. Apart from the most prevalent one, arterial hypertension, the cardiovascular dysautonomic continuum encompasses other important although less known conditions: postural orthostatic tachycardia syndrome, inappropriate sinus tachycardia, orthostatic hypotension and reflex syncope. Moreover, heart diseases may evoke autonomic imbalance by themselves; cardiac pump failure is usually associated with sympathetic hyperactivity, neuroendocrine vasopressor activation, higher heart rate, reduced heart rate variability and baroreflex hyposensitivity, all of which are predictors of adverse outcomes.
Cardiologists and electrophysiologist frequently see patients for the evaluation and management of unexplained syncope, orthostatic intolerance, heart rhythm abnormalities and symptoms of palpitations. Recognizing the presence of cardiac dysautonomia is an important skill which is necessary for the appropriate evaluation and treatment of these patients. Clinical presentations may overlap, and the importance of a thorough history cannot be over-emphasized. In this review we will present a cases of a patients with cardiac dysautonomia which is illustrative of a typical patient experience, followed by a review of the autonomic nervous system and discussion of prevalence, clinical presentation, and pathophysiology of common cardiac dysautonomias.
Background
Autonomic dysfunction is a hallmark feature of hereditary ATTR amyloidosis. The aim of this study was to summarize the characteristics and natural history of autonomic dysfunction in patients with hereditary ATTR amyloidosis.
Methods
A systematic review of the natural history and clinical trials of patients with ATTR amyloidosis was performed. Alternative surrogate markers of autonomic function were analyzed to understand the prevalence and outcome of autonomic dysfunction.
Results
Patients with early-onset disease displayed autonomic dysfunction more distinctively than those with late-onset disease. The nutritional status and some autonomic items in the quality-of-life questionnaires were used to assess the indirect progression of autonomic dysfunction in most studies. Gastrointestinal symptoms and orthostatic hypotension were resent earlier than urogenital complications. Once symptoms were present, their evolution was equivalent to the progression of the motor and sensory neuropathy impairment.
Conclusion
The development of autonomic dysfunction impacts morbidity, disease progression, and mortality in patients with hereditary ATTR amyloidosis.
Purpose:
Hereditary transthyretin amyloidosis (hATTR amyloidosis) is a progressive disease primarily characterized by adult-onset sensory, motor, and autonomic neuropathy. In this article, we discuss the pathophysiology and principal findings of autonomic neuropathy in hATTR amyloidosis, the most common methods of assessment and progression, and its relation as a predictive risk factor or a measure of progression in the natural history of the disease.
Methods:
A literature search was performed using the terms "autonomic neuropathy," "dysautonomia," and "autonomic symptoms" in patients with hereditary transthyretin amyloidosis and familial amyloid polyneuropathy.
Results:
Various scales to measure autonomic function have been employed, particularly within the major clinical trials, to assess novel therapies for the disease. Most of the evaluations were taken from diabetic clinical trials. Questionnaires include the COMPASS-31 and Norfolk QOL autonomic nerve function domain, whereas clinical evaluations comprise HRDB and the orthostatic tolerance test. Several treatment options are being employed although only diflunisal and tafamidis have reported improvement in the autonomic abnormalities.
Conclusions:
Autonomic nerves are often affected before motor nerve impairment, and dysautonomia may support the diagnosis of hATTR amyloidosis when differentiating from other adult-onset progressive neuropathies and from other types of amyloidosis. Most of the progression of autonomic dysfunction is seen in early stages of the disease, commonly before motor impairment or affection of the overall quality of life. Unfortunately, there is no current single standardized approach to evaluate dysautonomia in hATTR amyloidosis.
Objective:
To develop a concise and statistically robust instrument to assess autonomic symptoms that provides clinically relevant scores of autonomic symptom severity based on the well-established 169-item Autonomic Symptom Profile (ASP) and its validated 84-question scoring instrument, the Composite Autonomic Symptom Score (COMPASS).
Patients and methods:
We assessed the internal consistency of COMPASS using Cronbach α coefficients based on the ASP of 405 healthy control subjects recruited and seen in the Mayo Clinic Autonomic Disorders Center between March 1, 1995, and March 31, 2010. Applying a simplified scoring algorithm, we then used exploratory factor analysis with orthogonal rotation and eigenvalue calculations to extract internally consistent domains and to reduce dimensionality. This analysis was followed by expert revisions to eliminate redundant content and to retain clinically important questions and final assessment of the new instrument.
Results:
The new simplified scoring algorithm alone resulted in higher Cronbach α values in all domains. Factor analysis revealed 7 domains with a total of 54 questions retained. Expert revisions resulted in further reduction of questions and domains with a remaining total of 31 questions in 6 domains (COMPASS 31). Measures of internal consistency were much improved compared to those for COMPASS. Following appropriate weighting, this instrument provides an autonomic symptom score from 0 to 100.
Conclusion:
COMPASS 31 is a refined, internally consistent, and markedly abbreviated quantitative measure of autonomic symptoms. It is based on the original ASP and COMPASS, applies a much simplified scoring algorithm, and is suitable for widespread use in autonomic research and practice.
Signs or symptoms of impaired autonomic regulation of circulation often attend Parkinson disease (PD). This review covers biomarkers and mechanisms of autonomic cardiovascular abnormalities in PD and related alpha-synucleinopathies. The clearest clinical laboratory correlate of dysautonomia in PD is loss of myocardial noradrenergic innervation, detected by cardiac sympathetic neuroimaging. About 30-40% of PD patients have orthostatic hypotension (OH), defined as a persistent, consistent fall in systolic blood pressure of at least 20 mmHg or diastolic blood pressure of at least 10 mmHg within 3 min of change in position from supine to standing. Neuroimaging evidence of cardiac sympathetic denervation is universal in PD with OH (PD+OH). In PD without OH about half the patients have diffuse left ventricular myocardial sympathetic denervation, a substantial minority have partial denervation confined to the inferolateral or apical walls, and a small number have normal innervation. Among patients with partial denervation the neuronal loss invariably progresses over time, and in those with normal innervation at least some loss eventually becomes evident. Thus, cardiac sympathetic denervation in PD occurs independently of the movement disorder. PD+OH also entails extra-cardiac noradrenergic denervation, but this is not as severe as in pure autonomic failure. PD+OH patients have failure of both the parasympathetic and sympathetic components of the arterial baroreflex. OH in PD therefore seems to reflect a "triple whammy" of cardiac and extra-cardiac noradrenergic denervation and baroreflex failure. In contrast, most patients with multiple system atrophy, which can resemble PD+OH clinically, do not have evidence for cardiac or extra-cardiac noradrenergic denervation. Catecholamines in the neuronal cytoplasm are potentially toxic, via spontaneous and enzyme-catalyzed oxidation. Normally cytoplasmic catecholamines are efficiently taken up into vesicles via the vesicular monoamine transporter. The recent finding of decreased vesicular uptake in Lewy body diseases therefore suggests a pathogenetic mechanism for loss of catecholaminergic neurons in the periphery and brain. Parkinson disease (PD) is one of the most common chronic neurodegenerative diseases of the elderly, and it is likely that as populations age PD will become even more prevalent and more of a public health burden. Severe depletion of dopaminergic neurons of the nigrostriatal system characterizes and likely produces the movement disorder (rest tremor, slowness of movement, rigid muscle tone, and postural instability) in PD. Over the past two decades, compelling evidence has accrued that PD also involves loss of noradrenergic neurons in the heart. This finding supports the view that loss of catecholaminergic neurons, both in the nigrostriatal system and the heart, is fundamental in PD. By the time PD manifests clinically, most of the nigrostriatal dopaminergic neurons are already lost. Identifying laboratory measures-biomarkers-of the disease process is therefore crucial for advances in treatment and prevention. Deposition of the protein, alpha-synuclein, in the form of Lewy bodies in catecholaminergic neurons is a pathologic hallmark of PD. Alpha-synucleinopathy in autonomic neurons may occur early in the pathogenetic process. The timing of cardiac noradrenergic denervation in PD is therefore a key issue. This review updates the field of autonomic cardiovascular abnormalities in PD and related disorders, with emphasis on relationships among striatal dopamine depletion, sympathetic noradrenergic denervation, and alpha-synucleinopathy.
Autonomic symptoms may occur frequently in diabetic and other neuropathies. There is a need to develop a simple instrument to measure autonomic symptoms in subjects with neuropathy and to test the validity of the instrument.
The Survey of Autonomic Symptoms (SAS) consists of 11 items in women and 12 in men. Each item is rated by an impact score ranging from 1 (least severe) to 5 (most severe). The SAS was tested in observational studies and compared to a previously validated autonomic scale, the Autonomic Symptom Profile (ASP), and to a series of autonomic tests.
The SAS was tested in 30 healthy controls and 62 subjects with neuropathy and impaired glucose tolerance or newly diagnosed diabetes. An increased SAS score was associated with the previously validated ASP (rank order correlation=0.68; p<0.0001) and with quantitative measures of autonomic function: a reduced quantitative sudomotor axon reflex test sweat volume (0.31; p<0.05) and an abnormal 30:15 ratio (0.53; p<0.01). The SAS shows a high sensitivity and specificity (area under the receiver operating characteristic curve 0.828) that compares favorably with the ASP. The SAS scale domains had a good internal consistency and reliability (Cronbach α=0.76). The SAS symptom score was increased in neuropathy (95% confidence interval [CI] 2.99-4.14) compared to control (95% CI 0.58-1.69; p<0.0001) subjects.
The SAS is a new, valid, easily administered instrument to measure autonomic symptoms in early diabetic neuropathy and would be of value in assessing neuropathic autonomic symptoms in clinical trials and epidemiologic studies.
This study assesses the value of standard quantitative autonomic (QAT) and sensation (QST) tests in detecting, characterizing, and quantitating the severity of transthyretin amyloid polyneuropathy (TTR-A-PN). This information is needed for prospective therapeutic trials, epidemiologic surveys, and medical practice. We reviewed 36 patients with TTR-A-PN who were evaluated between 1997 and 2007. They had neurologic, genetic, electrodiagnostic, and autonomic reflex screen evaluations and allowed their medical records and test results to be evaluated for research purposes. Of these, 22 patients had also been tested by quantitative sensation tests (QSTs). The median symptom duration was 4 years (range 1-30 years). Among quantitative nerve tests evaluated, composite scores of nerve conduction (Sigma5 NC nds), a composite score of QSTs (Sigma3 QST nds), and quantitative autonomic tests (QSART, HR(db), and CASS) gave high frequencies of abnormality. The results show that peripheral autonomic and small-fiber sensory dysfunction was prominent and characteristic of most of the patients we studied. However, this involvement was not selective for small-diameter sensory and autonomic nerve fibers; large motor and sensory fibers were also shown to be dysfunctional. Dysfunction of large fibers was approximately as frequent as that of small fibers. This study provides a rationale for the use of QAT, QST, and Sigma5 NC nds as standard, objective, and quantitative measures for assessing the severity of TTR-A-PN in epidemiologic surveys, therapeutic trials, and medical practice.
To develop a new specific instrument called the Autonomic Symptom Profile to measure autonomic symptoms and test its validity.
Measuring symptoms is important in the evaluation of quality of life outcomes. There is no validated, self-completed questionnaire on the symptoms of patients with autonomic disorders.
The questionnaire is 169 items concerning different aspects of autonomic symptoms. The Composite Autonomic Symptom Scale (COMPASS) with item-weighting was established; higher scores indicate more or worse symptoms. Autonomic function tests were performed to generate the Composite Autonomic Scoring Scale (CASS) and to quantify autonomic deficits. We compared the results of the COMPASS with the CASS derived from the Autonomic Reflex Screen to evaluate validity.
The instrument was tested in 41 healthy controls (mean age 46.6 years), 33 patients with nonautonomic peripheral neuropathies (mean age 59.5 years), and 39 patients with autonomic failure (mean age 61.1 years). COMPASS scores correlated well with the CASS, demonstrating an acceptable level of content and criterion validity. The mean (+/-SD) overall COMPASS score was 9.8 (+/-9) in controls, 25.9 (+/-17.9) in the patients with nonautonomic peripheral neuropathies, and 52.3 (+/-24.2) in the autonomic failure group. Scores of symptoms of orthostatic intolerance and secretomotor dysfunction best predicted the CASS on multiple stepwise regression analysis.
We describe a questionnaire that measures autonomic symptoms and present evidence for its validity. The instrument shows promise in assessing autonomic symptoms in clinical trials and epidemiologic studies.
A textbook of clinical disorders of the autonomic nervous system
- C J Mathias
- R Bannister
- Autonomic Failure
Autonomic failure A textbook of clinical disorders of the autonomic nervous system Fifth edition Oxford
- A Bronchtein
- O F Souza
- Revintervolume
- C J Mathias
- R Bannister