Autonomic Dysfunction Versus Neuropathy

, Rohit Arora3, 4, Nicholas L. DePace5 and Aaron I. Vinik6



(1)
Autonomic Laboratory Department of Cardiology, Drexel University College of Medicine, Philadelphia, PA, USA

(2)
ANSAR Medical Technologies, Inc., Philadelphia, PA, USA

(3)
Department of Medicine, Captain James A. Lovell Federal Health Care Center, North Chicago, IL, USA

(4)
Department of Cardiology, The Chicago Medical School, North Chicago, IL, USA

(5)
Department of Cardiology, Hahnemann Hospital Drexel University College of Medicine, Philadelphia, PA, USA

(6)
Department of Medicine, Eastern Virginia Medical School Strelitz Diabetes Research Center, Norfolk, VA, USA

 





Autonomic neuropathy affects every system in the body including the eyes and the cardiovascular, respiratory, gastrointestinal, and neurovascular systems. The diagnosis confers an attenuated life expectancy, but much can be done to alleviate symptoms and to address the underlying disorder [1].

The title “autonomic neuropathy” is often misunderstood. The perception is “dead nerves.” “Dead nerves” is of course an end-stage phenomenon and perceived of as untreatable. With more information, this is often not the case. Autonomic dysfunction (AD) precedes autonomic neuropathy (AN) and is typically asymptomatic. Chronic diseases known to lead to AN are sufficient reasons for P&S assessment (see Chap. 11). AD is characterized by autonomic imbalance or abnormal sympathovagal balance (SB). For example, heightened activity of the SNS and suppressed activity of the PSNS impair the ability of the ANS to regulate the cardiovascular system [2]. Autonomic imbalance may be a key component involved in both the etiology and the clinical course of CVD, regardless of the primary disease or causal factor. Heightened parasympathetic activity is associated with depression and depression is also known to elevate mortality risk in CVD [3]. AN may be symptomatic; however, symptoms are often subtle and many are not aware of them as related to AN.

What is emerging is the need to distinguish the difference between autonomic imbalance (dysfunction) and clear evidence of AN. Autonomic imbalance produces a number of trying clinical situations such as orthostatic tachycardia, orthostatic bradycardia, and hypotension and may be responsible for predisposition to arrhythmias and sudden death [4], as well as difficult to manage patients (e.g., BP, blood glucose, or hormone level). For example, loss of SB is associated with the catastrophic increase of sudden death after intensive lowering of blood glucose in the ACCORD study. The combination of numbness of the feet and loss of HRV increased the susceptibility to an event with a risk ratio (RR) of 4.43 [5, 6].

The Toronto Diabetic Neuropathy Expert Group [7] updated the definition of AN. In addition to the effects of AN on the cardiovascular system (resulting in CAN), AN may affect the GI and urogenital systems and sudomotor function. It may result in signs and symptoms or may only be subclinically detectable. Clinical correlates and predictors of CAN include abnormal glycemic control; presence of peripheral neuropathy, nephropathy, and retinopathy; abnormal BP, cholesterol, and triglyceride levels; obesity; smoking; and other traditional and nontraditional risk factors [8–11]. CAN is significantly associated with overall mortality and morbidity such as silent MI, CAD, stroke, diabetic nephropathy progression, and perioperative morbidity [8, 9, 12]. Thus, CAN assessment may be used for cardiovascular risk stratification in patients with and without established CVD, as a marker for patients requiring more intensive monitoring during the perioperative period and other physiologic stresses, and as an indicator for more intensive pharmacotherapeutic and lifestyle management of comorbid conditions. Features of cardiac AD, such as unexplained or resting tachycardia, orthostatic hypotension, poor exercise tolerance, and difficult to manage BP, with or with other symptoms of AD, should be evaluated for the presence of CAN [13]. Progressive stages of AN (as defined elsewhere in this book) are associated with an increasingly worse prognosis [8, 9, 12].

In addition to P&S testing, attenuation (non-dipping) and loss of fall in nocturnal BP (reverse dipping) as measured by ambulatory BP monitoring have been associated with CAN and attributed to the disruption of the circadian variation in sympathovagal activity and are independent predictors of cardiovascular events and the progression of diabetic nephropathy [14]. QT prolongation is an independent predictor of mortality and is weakly associated with CAN [15]. Cardiac vagal BRS is a well-established prognostic index [16]. BRS testing may be indicated if NIBP response to Valsalva (as compared to resting baseline is abnormal (<10 % increase). Abnormal BRS is associated with abnormally low sympathetic activity.

Scintigraphic studies with radio-labeled noradrenaline analogues allow a direct semiquantitative ([123I]-metaiodobenzylguanidine (MIBG) and single-photon emission computed tomography) and quantitative assessment ([11C]-hydroxyephedrine (HED) and positron emission tomography) of cardiac sympathetic integrity. Scintigraphic abnormalities are associated with CAN but may also be present in patients with normal cardiovascular autonomic tests [17]. No standardized methodology or normative values exist, and available data on reproducibility are limited. Scintigraphic studies are appropriate to explore the effects of sympathetic dysfunction on cardiac metabolism and function and are useful in assessing cardiac sympathetic function in research studies.

AN underlies GI and urogenital dysfunction. GI motor, sensory, and secretory functions are modulated by the interaction of the autonomic and enteric nervous systems. AN has been regarded as the cause of disordered gut motility; recent evidence indicates a heterogeneous picture with a range of fixed pathology and reversible functional abnormalities [18–20]. AN is one of the leading causes of erectile dysfunction (ED), along with glycation of elastic fibers, peripheral vasculopathy, endothelial dysfunction, psychological factors, drugs, and hormonal changes [21]. AN affects women as well, the correlate of ED in females is poor vaginal lubrication. ED seems to be associated with a higher rate of abnormal sensory and autonomic tests. ED is a predictor of cardiovascular events and is associated with silent MI [22]. Alteration of quality of life and depressive symptoms seem to precede ED. Bladder complications may be due to an alteration of the detrusor smooth muscle, autonomic neuronal dysfunction, and urothelial dysfunction [23, 24].

Sweat glands are innervated by the sudomotor, postganglionic, unmyelinated cholinergic sympathetic C-fibers. Sudomotor dysfunction may result in dryness of foot skin and has been associated with foot ulceration [25]. Assessment of sudomotor dysfunction contributes to the detection of AD. The quantitative sudomotor axon reflex test (Q-SART) may be considered the reference method for the detection of sudomotor dysfunction.

Our lab has discovered two forms of CAN: functional and structural (see Fig. 13.1). Structural CAN is irreversible and, while important in reducing morbidity and mortality risk, responses to therapy only effect resting sympathetic activity, helping to establish or maintain proper SB. Functional CAN is reversible. In addition to establishing or maintaining proper SB through effecting sympathetic activity, responses to therapy also improve parasympathetic activity. Therapy may, in fact, seem to “cure” CAN by resulting in a resting parasympathetic state (initial baseline RFA) >0.1 bpm2. A possible explanation for this response comes from engineering. It is well known in closed-loop feedback systems (which describes P&S interactions) that these systems may “get stuck” in abnormal operational states. It is also well known that a perturbation of the system, while in this abnormal state, may return it to a normal operational state. Therapy is such a perturbation and has been observed to return the ANS to a more normal operational state.

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Fig. 13.1
If CAN is structural, then only responses around the point A1 are possible and CAN is irreversible. If CAN is functional, then both the responses around the point A1 and the responses around the point A2 are possible. AAD advanced autonomic dysfunction, CAN cardiovascular autonomic neuropathy, DAN diabetic autonomic neuropathy


Epidemiology of CAN


Establishing the prevalence of CAN has been hampered by heterogeneous and inadequate diagnostic criteria and population selection [13]. The Toronto Panel, after extensive review of the literature, concluded that the prevalence of confirmed CAN in unselected people with type 1 and type 2 DM is approximately 20 % but may be as high as 65 % with increasing age and diabetes duration [7]. Underlying this underestimation is the lack of recognition and treatment of the early constellation of symptoms as from a single source (e.g., AN) rather than isolated symptoms. Clinical correlates or risk markers for CAN in diabetics are age, diabetes duration, glycemic control, microvascular complications (peripheral polyneuropathy, retinopathy, and nephropathy), hypertension, and dyslipidemia. Similarly, in other diseases, the duration of symptoms and cardiovascular dysfunction, including hypertension, are risk markers. Established risk factors for CAN in diabetes are glycemic control in type 1 diabetes and a combination of hypertension, dyslipidemia, obesity, and glycemic control in type 2 diabetes [26]. In general, traditional and nontraditional risk factors for cardiovascular diseases (for which diabetes is a significant risk factor) are risk factors for CAN in the general population [8, 9].

Results from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial confirmed that individuals with baseline CAN were 1.55–2.14 times as likely to die as individuals without CAN [27]. Furthermore, CAN in the presence of peripheral neuropathy was the highest predictor of mortality from cardiovascular disease (i.e., hazard ratio 2.95, p < 0.008). Indeed, combining indices of autonomic dysfunction have been shown to be associated with the risk of mortality [28–30].

Resting tachycardia, exercise intolerance, and orthostatic hypotension are characteristic late findings in patients with autonomic impairment. A blunted HR response to adenosine receptor agonists is attributed to earlier stages of CAN [31]. The prognostic value of resting HR is a useful tool for cardiovascular risk stratification and as a therapeutic target in high-risk patients [4, 26, 32]. Patients who are likely to have CAN should be tested for cardiac stress before undertaking an exercise program. Patients with CAN need to rely on their perceived exertion, not HR, to avoid hazardous levels of intensity of exercise. Intraoperative cardiovascular lability and perioperative cardiovascular morbidity and mortality are increased two- to threefold in patients with diabetes, manifested as greater declines in HR and BP during induction of anesthesia, a greater need for vasopressor support [33], and more severe intraoperative hypothermia with consequent impaired wound healing [34]. Preoperative cardiovascular autonomic screening of diabetic patient may help anesthesiologists identify those at greater risk of intraoperative complications [12]. Evidence extends these observations to nondiabetic patients [35]. Patients with (preclinical) orthostatic hypotension may present with lightheadedness and pre-syncopal symptoms or may remain asymptomatic despite significant drops in BP. Orthostatic symptoms may also be misjudged as hypoglycemia and may be aggravated by several drugs, including vasodilators, diuretics, phenothiazines, and particularly TCAs and insulin [12].

The Toronto Consensus Panel on Diabetic Neuropathy concluded the following in relation to treating CAN in patients with diabetes [7]:

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May 23, 2017 | Posted by in CARDIOLOGY | Comments Off on Autonomic Dysfunction Versus Neuropathy

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