**2. A bit of history and a bit of anatomy**

In 1973, the British Medical Journal and the Lancet published three articles on diabetic auto‐ nomic neuropathy [13-15], which would then be followed over the years by an unbroken series of studies and publications. Wheeler and Watkins identified vagal denervation of the heart as a feature of diabetic autonomic neuropathy that could be evaluated by monitoring beat-to-beat variation in heart rate [14]. Ewing et al. found the vascular responses to the Val‐ salva manoeuvre and sustained handgrip useful in providing an objective assessment of the integrity of the autonomic nervous system in diabetes [15]. Ewing himself later developed

© 2013 Matteucci and Giampietro; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

the cardiovascular autonomic function test battery still in use to provide an objective diag‐ nosis of autonomic nervous system involvement [16]. The battery included: Valsalva ma‐ noeuvre, heart rate response to standing up, heart rate response to deep breathing, blood pressure response to standing up, and blood pressure response to sustained handgrip (Ap‐ pendix 1).

sels, adrenal glands, and kidneys [17]. The arterial baroreflex modulates beat-to-beat blood pressure oscillations: afferent baroreceptor discharge from the carotid sinus and aortic arch is relayed to the nucleus tractus solitarius in the dorsomedial region of the medulla. As a result, changes in the efferent sympathetic and parasympathetic outflow to the heart and blood vessels adjust cardiac output and vascular resistance to return blood pressure to base‐ line. Similarly, the cardiopulmonary baroreceptors minimise changes in arterial blood pres‐

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sure in response to changes in blood volume.

Spectral analysis of heart rate variation (high frequency

component)

**Cardiovascular tests in diagnosing diabetic autonomic neuropathy Parasympathetic Sympathetic** Resting heart rate Resting heart rate

Heart rate response to deep breathing Blood pressure response to standing up

Valsalva manoeuvre Blood pressure response to cold

**Table 1.** Classification of cardiovascular tests for the diagnosis of diabetic neuropathy.

are independently related to respiration via nonbaroreflex mechanisms?

dia and increased feed forward gain from heart rate to arterial pressure [19].

Heart rate response to standing up Blood pressure response to sustained handgrip

component)

The complexity of the autonomic pathways is exemplified by the following quotations. The act of breathing modulates autonomic neural outflow from the brainstem, but the mecha‐ nisms underlying the respiratory sinus arrhythmia are still unclear [18]: only fluctuations in efferent cardiac vagal activity or combined vagal/sympathetic heart rate modulation? More‐ over, is respiratory sinus arrhythmia driven by respiratory synchronous oscillations in blood pressure via the arterial baroreflex or both respiratory sinus arrhythmia and blood pressure

Small negative changes of central volume reduce cardiac output without significant altera‐ tions of arterial blood pressure: 1) short-term cardiovascular control through respiratory si‐ nus arrhythmia and baroreflex feedback are optimised at mild hypervolemia; 2) both the time and frequency domain data support the presence of a Bainbridge reflex (i.e. hypervole‐ mia-induced tachycardia) at moderately elevated levels of central volume, to reduce cardiac preload under volume loading conditions. Finally, mild to moderate levels of hypovolemia do not cause significant reductions in arterial pressure, explained in part by a mild tachycar‐

Physical activity produces intensity-dependent increases in arterial blood pressure that are mediated by central signals arising from higher brain centres and by peripheral feedback from skeletal muscle (exercise pressor reflex) with further modulation provided by the arte‐ rial baroreflex. The sensory component of the exercise pressor reflex is comprised of myeli‐ nated group III and unmyelinated group IV skeletal muscle afferents that respond to both

Spectral analysis of heart rate variation (very low frequency

Brief description of the five non invasive cardiovascular reflex tests used by Ewing et al. [15] to assess autonomic func‐ tion in diabetic subjects.

Valsalva manoeuvre: the subject sits quietly and then blows in a mouthpiece at a pressure of 40 mmHg for 15 s. The heart rate normally increases during the manoeuvre and decreases after release. The ratio of the longest R-R interval shortly after the manoeuvre to the shortest R-R interval during the manoeuvre is measured.

Heart rate response to standing up: the subject lies quietly and then stands up unaided. The heart rate normally in‐ creases with a maximum at about the 15th beat after starting to stand and thereafter decreases with a minimum around the 30th beat. Electrocardiogram tracings are used to determine the 30:15 ratio, calculated as the ratio of the longest R-R interval around the 30th beat to the shortest R-R interval around the 15th beat.

Heart rate response to deep breathing: the subject sits quietly and then breathes deeply at a rate of six breaths per mi‐ nute. The maximum and the minimum heart rate during each breathing cycle are measured, and the mean of the dif‐ ferences during successive breathing cycles is measured.

Blood pressure response to standing up: the blood pressure is measured using a sphygmomanometer while the subject is lying down and after standing. The difference in systolic blood pressure is a measure of postural blood pressure change.

Blood pressure response to sustained handgrip: handgrip is maintained at 30% of the maximum voluntary contraction up to a maximum of five minutes and the blood pressure is measured each minute. The difference between the diastol‐ ic blood pressure just before release of handgrip, and before starting, is measured.

Based on his 10-yr experience, Ewing et al. 1) stressed the fallacy of relying on a single test, particularly heart rate variation during deep breathing, to make diagnosis of autonomic neuropathy, and 2) stated that the previous classification of tests into parasympathetic and sympathetic (Table 1), although clinically useful, should not be considered physiologically precise because of the complexity of the autonomic pathways [16].

Blood flow adjustments are achieved by local vascular control mechanisms (mechanical forces and chemical stimuli) but require to be coordinated by a remote central neural control [17]. Autonomic motor control is effected by long parasympathetic preganglionic fibres and short sympathetic preganglionic fibres that originate within the central nervous system. The former synapse on short postganglionic fibres arising from ganglia located close to the effec‐ tor targets, the latter synapse on long postganglionic fibres arising from the paravertebral chain ganglia or collateral ganglia. Parasympathetic neurons limit their influence mainly to the control of cardiac function, whereas sympathetic neurons innervate the heart, blood ves‐ sels, adrenal glands, and kidneys [17]. The arterial baroreflex modulates beat-to-beat blood pressure oscillations: afferent baroreceptor discharge from the carotid sinus and aortic arch is relayed to the nucleus tractus solitarius in the dorsomedial region of the medulla. As a result, changes in the efferent sympathetic and parasympathetic outflow to the heart and blood vessels adjust cardiac output and vascular resistance to return blood pressure to base‐ line. Similarly, the cardiopulmonary baroreceptors minimise changes in arterial blood pres‐ sure in response to changes in blood volume.


**Table 1.** Classification of cardiovascular tests for the diagnosis of diabetic neuropathy.

the cardiovascular autonomic function test battery still in use to provide an objective diag‐ nosis of autonomic nervous system involvement [16]. The battery included: Valsalva ma‐ noeuvre, heart rate response to standing up, heart rate response to deep breathing, blood pressure response to standing up, and blood pressure response to sustained handgrip (Ap‐

Brief description of the five non invasive cardiovascular reflex tests used by Ewing et al. [15] to assess autonomic func‐

Valsalva manoeuvre: the subject sits quietly and then blows in a mouthpiece at a pressure of 40 mmHg for 15 s. The heart rate normally increases during the manoeuvre and decreases after release. The ratio of the longest R-R interval

Heart rate response to standing up: the subject lies quietly and then stands up unaided. The heart rate normally in‐ creases with a maximum at about the 15th beat after starting to stand and thereafter decreases with a minimum around the 30th beat. Electrocardiogram tracings are used to determine the 30:15 ratio, calculated as the ratio of the

Heart rate response to deep breathing: the subject sits quietly and then breathes deeply at a rate of six breaths per mi‐ nute. The maximum and the minimum heart rate during each breathing cycle are measured, and the mean of the dif‐

Blood pressure response to standing up: the blood pressure is measured using a sphygmomanometer while the subject is lying down and after standing. The difference in systolic blood pressure is a measure of postural blood pressure

Blood pressure response to sustained handgrip: handgrip is maintained at 30% of the maximum voluntary contraction up to a maximum of five minutes and the blood pressure is measured each minute. The difference between the diastol‐

Based on his 10-yr experience, Ewing et al. 1) stressed the fallacy of relying on a single test, particularly heart rate variation during deep breathing, to make diagnosis of autonomic neuropathy, and 2) stated that the previous classification of tests into parasympathetic and sympathetic (Table 1), although clinically useful, should not be considered physiologically

Blood flow adjustments are achieved by local vascular control mechanisms (mechanical forces and chemical stimuli) but require to be coordinated by a remote central neural control [17]. Autonomic motor control is effected by long parasympathetic preganglionic fibres and short sympathetic preganglionic fibres that originate within the central nervous system. The former synapse on short postganglionic fibres arising from ganglia located close to the effec‐ tor targets, the latter synapse on long postganglionic fibres arising from the paravertebral chain ganglia or collateral ganglia. Parasympathetic neurons limit their influence mainly to the control of cardiac function, whereas sympathetic neurons innervate the heart, blood ves‐

shortly after the manoeuvre to the shortest R-R interval during the manoeuvre is measured.

longest R-R interval around the 30th beat to the shortest R-R interval around the 15th beat.

ic blood pressure just before release of handgrip, and before starting, is measured.

precise because of the complexity of the autonomic pathways [16].

ferences during successive breathing cycles is measured.

pendix 1).

360 Type 1 Diabetes

change.

tion in diabetic subjects.

The complexity of the autonomic pathways is exemplified by the following quotations. The act of breathing modulates autonomic neural outflow from the brainstem, but the mecha‐ nisms underlying the respiratory sinus arrhythmia are still unclear [18]: only fluctuations in efferent cardiac vagal activity or combined vagal/sympathetic heart rate modulation? More‐ over, is respiratory sinus arrhythmia driven by respiratory synchronous oscillations in blood pressure via the arterial baroreflex or both respiratory sinus arrhythmia and blood pressure are independently related to respiration via nonbaroreflex mechanisms?

Small negative changes of central volume reduce cardiac output without significant altera‐ tions of arterial blood pressure: 1) short-term cardiovascular control through respiratory si‐ nus arrhythmia and baroreflex feedback are optimised at mild hypervolemia; 2) both the time and frequency domain data support the presence of a Bainbridge reflex (i.e. hypervole‐ mia-induced tachycardia) at moderately elevated levels of central volume, to reduce cardiac preload under volume loading conditions. Finally, mild to moderate levels of hypovolemia do not cause significant reductions in arterial pressure, explained in part by a mild tachycar‐ dia and increased feed forward gain from heart rate to arterial pressure [19].

Physical activity produces intensity-dependent increases in arterial blood pressure that are mediated by central signals arising from higher brain centres and by peripheral feedback from skeletal muscle (exercise pressor reflex) with further modulation provided by the arte‐ rial baroreflex. The sensory component of the exercise pressor reflex is comprised of myeli‐ nated group III and unmyelinated group IV skeletal muscle afferents that respond to both mechanical (mechanoreflex) and metabolic (metaboreflex) stimuli. However, the receptors activating muscle afferent fibres as well as the factors contributing to a decrease in reflex ac‐ tivity in oxidative muscle are still not precisely characterised [20].

[21-22, 24]. Cardiac autonomic neuropathy can manifest as tachycardia (heart rate > 100 bpm), decreased exercise tolerance, orthostatic hypotension (a fall in systolic blood pressure > 20 mmHg upon standing without appropriate heart rate response), cardiac denervation syndrome with silent myocardial infarction, paradoxical supine or nocturnal hypertension, intra- and peri-operative cardiovascular instability, left ventricular diastolic dysfunction.

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Peripheral diabetic autonomic neuropathy can manifest as decreased thermoregulation, de‐ creased sweating, altered blood flow, impaired vasomotion, and oedema. From the metabol‐ ic point of view, there may be hypoglycaemia unawareness with decreased counterregulatory catecholamine responses as well as hypoglycaemia unresponsiveness with reduction in glucagon and epinephrine secretion in response to hypoglycaemia. Gastrointes‐ tinal diabetic autonomic neuropathy can manifest as oesophageal dysmotility, gastro-paresis diabeticorum, diarrhoea or constipation, faecal incontinence. Genitourinary symptoms in‐ clude erectile dysfunction, retrograde ejaculation, neurogenic bladder and cystopathy, fe‐ male sexual dysfunction. Sudomotor diabetic autonomic neuropathy may manifest as anhidrosis, hyperhidrosis, heat intolerance, gustatory sweating, and dry skin. Pupillomotor

function impairment and pseudo-Argyll-Robertson pupil have also been described.

**1.** a comprehensive diabetes evaluation should include a history of diabetes related micro‐ vascular complications: retinopathy, nephropathy, and neuropathy (sensory, including history of foot lesions; autonomic, including sexual dysfunction and gastro-paresis);

**2.** a comprehensive diabetes evaluation should include presence/absence of patellar and Achilles reflexes as well as determination of proprioception, vibration, and monofila‐

**3.** all patients should be screened for distal symmetric polyneuropathy at diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes and at least annually thereafter, using simple clinical tests. Electrophysiological testing is rarely needed, ex‐

**4.** screening for signs or symptoms of cardiac autonomic neuropathy should be instituted at diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes. Special

**5.** medications for relief of specific symptoms related to distal symmetric polyneuropathy or diabetic autonomic neuropathy are recommended as they improve the quality of life

**6.** foot examination should include testing for loss of protective sensation, i.e. 10-g mono‐ filament plus testing for any one of the following: vibration using 128-Hz tuning fork,

The American Diabetes Association [11] recommends that:

cept in situations where clinical features are atypical;

pinprick sensation, ankle reflex, vibration sensation threshold.

ment sensation;

testing is rarely needed;

of the patient;
