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Original Research Article
Department of Chronic Complications, Vuk Vrhovac University
Clinic, Merkur University Hospital, Zagreb, Croatia
DIABETIC AUTONOMIC NEUROPATHY
S. Vučković-Rebrina, A. Barada, L. Smirčić-Duvnjak
IntroductIon
Key words: diabetic autonomic neuropathy,
diagnosis,
treatment
SUMMARY
Diabetic autonomic neuropathy is a common and
serious complication of diabetes. In its course, it can
affect any organ in the body and result in a variety of
symptoms and signs. Unfortunately, it is often
recognized too late and then it can have serious
consequences for patient health and even life. With the
help of simple cardiovascular autonomic tests,
autonomic neuropathy can be diagnosed already in the
asymptomatic phase. Strict blood glucose control is
still the only causal therapy aimed at preventing,
halting or slowing the progression of diabetic
autonomic
neuropathy.
Symptomatic
treatment
consists of simple measures and lifestyle changes and,
in severe cases, medication therapy may be needed.
Corresponding author: Sandra Vučković-Rebrina MD, PhD, Vuk Vrhovac
University Clinic, Dugi dol 4a, HR-10000 Zagreb, Croatia
E-mail: [email protected]
Diabetologia Croatica 42-3, 2013
Diabetic autonomic neuropathy (DAN) is the most
neglected, yet one of the most serious complications of
diabetes. It is a form of peripheral neuropathy, i.e.
damage to parasympathetic and/or sympathetic nerves
in people with diabetes, and excluding other causes of
neuropathy.
The prevalence of DAN varies from 1% to 90% in
patients with type 1 diabetes and from 20% to 73% in
patients with type 2 diabetes. The great diversity of
data is a result of inconsistencies in the criteria used
for the diagnosis of DAN, as well as major differences
in the groups of patients included in the research,
particularly in relation to risk factors (e.g., patient age,
sex, duration of diabetes) (1). After extensive analysis
of published papers, the Consensus Panel on Diabetic
Neuropathy has concluded that the prevalence of
confirmed cardiovascular autonomic neuropathy
(CAN) in an unselected group of patients with type 1
and type 2 diabetes is about 20%, but can be up to 65%
with increasing age and diabetes duration (2).
The importance of this diabetic complication is best
illustrated by the fact that the mortality rate in patients
with CAN is 5-6 times higher in the period of 5-6
years than the mortality in patients with diabetes but
without CAN in the same period (3). DAN results in
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S. Vučković-Rebrina, A. Barada, L. Smirčić-Duvnjak / DIABETIC AUTONOMIC NEUROPATHY
significant morbidity and may lead to mortality in
some patients with diabetes. Longitudinal studies have
shown that the 5-year mortality rates of people with
CAN are 16%-50% in patients with type 1 and type 2
diabetes, most often due to sudden cardiac death. A
meta-analysis of 15 studies reports a relative risk of
mortality of 3.45 in patients with CAN. It is known
that CAN significantly increases the risk of lifethreatening arrhythmias and sudden death with the
contribution from other risk factors such as
hypoglycemia, drug side effects, hypokalemia,
hypotension, ischemia, etc. (4,5).
Risk factors for autonomic neuropathy are age,
duration of diabetes, glycemic control, microvascular
complications (polyneuropathy, retinopathy, nephropathy) and other factors such as hypertension,
dyslipidemia, smoking, obesity and alcohol consumption. The main factor among the listed is
glycemic control. The results of the Diabetes Control
and Complication Trial (DCCT) showed that tight
glycemic control resulted in 50% reduction of the
incidence of CAN during 6.5-year follow up. This
protective effect persisted for 14 years after the end of
the study despite the disappearance of HbA1c
differences that were reached between the groups
during the randomized phase (6). Steno-2 study in
patients with type 2 diabetes and microalbuminuria
has shown that intensive pharmacological treatment of
hypertension, hyperlipidemia and microalbuminuria
together with lifestyle changes significantly
diminishes not only the risk of DAN, but the risk of
cardiovascular disease as well, and reduces overall
diabetic patient mortality (7). Investigation results also
indicate a significant correlation between DAN and
microvascular disease. Diabetic nephropathy,
retinopathy and polyneuropathy are considered
clinical predictors for DAN, which is understandable
because all diabetic microvascular complications
share a common pathogenic mechanism and the same
risk factors (8,9).
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PathogeneSIS
The etiology of diabetic neuropathy is complex and
still completely unclear. Hyperglycemia leads to a
number of metabolic, neurotrophic, vascular and
immune changes that result in progressive damage and
nerve fiber loss.
A simplified pathogenesis of diabetic neuropathy
includes the following:
- increased activity of aldose reductase, resulting
in the accumulation of sorbitol and fructose, and
imbalance in the ratio of nicotinamide adenine
dinucleotide phosphate and nicotinamide
adenine dinucleotide
- increase in vascular oxidative stress with the
formation of reactive oxygen species (ROS)
- creating products of glycoxygenation through
hexosamine pathway, glycation of intracellular
and extracellular proteins with the formation of
advanced glycation end (AGE) products
- inadequate activation of protein kinase C
pathway
- increased cytokine release; and
- deficit of neurotrophic factors (10,11).
Results of recent studies indicate a possible
protective role of residual b-cell function in the
development and incidence of microvascular
complications in patients with type 1 diabetes. It is
assumed that C-peptide activates Na/K channels,
reduces inflammation and improves endothelial
function (12). The latest researches seek to identify
genes associated with a higher prevalence of DAN, but
unfortunately, the results are still contradictory
(13,14).
All these pathogenic mechanisms may act
independently or interdependently and thus lead to the
development of diabetic neuropathy by direct damage
to nerve cells or indirectly through damage to vasa
nervorum.
The pathophysiological changes result in
degeneration of neurons, axonal degeneration with the
loss of nerve fibers, demyelination and impairment of
the nerve fiber regenerability. This creates an
imbalance between degeneration and regeneration of
nerve fibers at the expense of the degenerate ones.
S. Vučković-Rebrina, A. Barada, L. Smirčić-Duvnjak / DIABETIC AUTONOMIC NEUROPATHY
Most sensitive are neurons with the longest axons.
This may explain earlier affection of parasympathetic
than sympathetic nerves in the course of DAN.
courSe oF the dISeaSe
Diabetic neuropathy is a ‘length dependence’ disease
resulting in affection of the neurons with the longest
axons at the beginning. Vagus, the tenth cerebral nerve
that is responsible for 75% of the parasympathetic
activity of the body, is the longest nerve of the
autonomic nervous system and because of that it is
damaged early in the course of the disease. Therefore,
in an early phase of DAN, we can find decreased
parasympathetic activity resulting in sympathetic
predominance. The sympathetic dominance lasts until
the late stages of the disease when sympathetic
denervation takes place. During DAN, asymptomatic
(subclinical) and symptomatic phases can be
recognized. Using simple cardiovascular tests, DAN
can be detected already during the asymptomatic
phase of the disease.
Symptomatic autonomic neuropathy can affect any
organ in the body and therefore varies considerably in
symptoms and signs. The famous phrase “who knows
DAN knows the whole medicine” best illustrates the
diversity of clinical presentations. It should be kept in
mind that the symptoms of DAN occur late in the
course of the disease, i.e. when significant impairment
of the autonomic nervous system has already occurred.
clInIcal PreSentatIon (SYMPtoMS
and SIgnS)
The symptoms and signs of DAN vary widely and
depend on the affected organ (1,2,15,16).
Cardiovascular system (CAN)
1. loss of circadian rhythm of blood pressure
(‘nondipping’)
2. resting tachycardia
3. exercise intolerance
4. intraoperative cardiovascular lability
5. ‘silent ischemia’ and ‘painless’ myocardial
infarction
Diabetologia Croatica 42-3, 2013
6. diabetic cardiomyopathy
7. arrhythmias, cardiac arrest
8. orthostatic hypotension
Gastrointestinal system
1.
2.
3.
4.
dysfunction of the esophagus
gastroparesis
change in gut motility (constipation, diarrhea)
anorectal dysfunction (fecal incontinence)
Genitourinary system
1. bladder dysfunction
2. sexual dysfunction in both sexes
Respiratory system
1. central dysregulation of breathing
2. reduced bronchial reactivity
Neurovascular system
1. sweating abnormalities (anhidrosis,
hyperhidrosis, gustatory sweating)
2. changes in skin blood flow (warm skin, varicose
veins, peripheral edema)
Neuroendocrine system
1. decrease or loss of signs of hypoglycemia
2. impaired counter-regulation mechanism in
hypoglycemia
3. change in the formation of renin
Pupillomotor
1. pupil dysfunction
autonoMIc nerVouS SYSteM
teStIng
To confirm the diagnosis of DAN, a series of tests
(depending on the organic system to be tested) can be
used. Because of noninvasiveness, sensitivity,
specificity and standardization, a standard ‘battery’ of
cardiovascular tests is used as a gold standard.
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Testing is conducted using a computerized system
based on heart rate variation (RR interval)
measurements, during resting, deep breathing,
Valsalva maneuvering and active orthostatic test.
Blood pressure is measured three times in supine
position and in the same way after standing up. Testing
should be conducted in a quiet room, without
interruption, the patient being informed about the tests
that are to be performed. Test conditions should be
standardized, i.e. testing should be done in the
morning, fasting or at least 2 hours after a light
breakfast, and the patient is specifically asked to avoid
smoking, coffee and black tea consumption for at least
3 h prior to testing. Three disposable, self-adhesive
ECG electrodes are applied to the chest and a
breathing sensor is placed using adhesive tape. Testing
begins after checking the signal on the screen of the
device. Statistical data are processed by standard,
vector and spectral analysis and the following
parameters are obtained: coefficient of variation of RR
intervals at rest; spectrum of very low frequency, low
frequency and high frequency in spectral analysis;
coefficient of variation of RR intervals during deep
breathing; E/I ratio; 30:15 ratio; and Valsalva ratio.
The results obtained are then compared with normal
values adjusted for age.
The data obtained indicate mainly the function of the
parasympathetic nerves, while a drop in the systolic
blood pressure in orthostasis by more than 30 mm Hg
provides indications of sympathetic dysfunction
(17,18).
CAN could be graded regarding the results of the
testing as follows:
-
the presence of one abnormal finding indicates
a possible CAN
- at least two abnormal findings are required to
confirm the diagnosis of CAN
- the presence of orthostatic hypotension in
addition to other abnormal findings indicates
advanced CAN (3).
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Other methods
Among other methods used to confirm the diagnosis
of DAN are baroreflex sensitivity measures,
quantitative sudomotor axon reflex test (known as
QSART), muscle sympathetic nerve activity, dynamic
pupillometry and, more rarely, direct scintigraphic
analysis of cardiac sympathetic fibers using SPECT or
PET scans (2,15,19,20). As the mentioned tests are
often very demanding, a standard battery of
cardiovascular autonomic tests is considered a
surrogate for confirmation of DAN in general.
Recommendations
All patients with the symptoms and/or signs of DAN
should be evaluated. As the symptoms of DAN occur
in the late stages of the disease, it is even more
important to make the diagnosis in asymptomatic
patients. According to the American Neurological
Society guidelines, screening for autonomic
dysfunction should be carried out immediately after
the diagnosis of type 2 diabetes and 5 years after the
diagnosis of type 1 diabetes. Patients at a greater risk
because of poor glycemic control, cardiovascular risk
factors and with the presence of other micro- and
macrovascular complications of diabetes should be
tested in particular. Each patient that is about to begin
any kind of intense physical activity except for
vigorous walk and any patient that is going to have a
surgery in general anesthesia should be tested as well
(3,19,21-23).
If the patient has symptomatic DAN, after
confirming the diagnosis by autonomic testing, it is
necessary to do further examinations to rule out other
causes of the patient’s symptoms, since DAN
symptoms are not specific. It should also be borne in
mind that about 10% of the patients with diabetic
neuropathy in general have another cause of
neuropathy other than diabetes.
dIFFerentIal dIagnoSIS oF dan
* hereditary neuropathies (with affection of the
autonomic nervous system)
* metabolic diseases (amyloidosis, chronic liver
S. Vučković-Rebrina, A. Barada, L. Smirčić-Duvnjak / DIABETIC AUTONOMIC NEUROPATHY
*
*
*
*
*
*
and kidney disease)
endocrine diseases (panhypopituitarism,
pheochromocytoma)
inflammatory diseases (Chagas’ disease, HIV,
botulism, leprosy, Guillain-Barré syndrome)
cardiovascular disease (syncope, idiopathic
orthostatic hypotension, POTS)
chronic dysautonomies (PAF, Shy-Dräger
syndrome, autonomic dysfunction in
Parkinson’s disease)
toxic neuropathy (heavy metals, chemotherapeutic drugs – vincristine, cisplatin, paclitaxel,
alcohol)
paraneoplastic neuropathy (24).
treatMent
Basic measures
A long-term strict glycemic control has the most
important role in preventing the appearance and
progression of DAN. Intensive pharmacological
treatment of other risk factors (hypertension,
dyslipidemia), as well as lifestyle modifications
(healthy diet, physical activity, smoking cessation)
also have a favorable effect.
If the symptoms of DAN are already present, patients
need to be advised about simple behavioral measures
and lifestyle changes that can alleviate the symptoms
(18,25):
* Orthostatic hypotension
- getting up in gradual stages; perform physical
counter-maneuvers (leg crossing, stooping,
squatting); wearing elastic stockings reaching to
the waist; increasing fluid and salt intake;
reducing the dosage or excluding medications
that may precipitate orthostatic hypotension;
raising the head of the bed by 10-20°
(stimulation of renin-angiotensin-aldosterone
system)
* Gastroparesis
- multiple, small meals; staying upright for half
an hour after each meal; if necessary semi-liquid
or liquid food; low fat/fiber diet; omission of
Diabetologia Croatica 42-3, 2013
*
*
*
-
drugs that slow gastric emptying (e.g., calcium
channel blockers, GLP-1 analogs, tricyclic
antidepressants)
Constipation
increasing fluid intake; regular exercise;
increasing intake of foods rich in fiber
Diarrhea
restriction of gluten and lactose in the diet
Loss of hypoglycemic signs
often self-control; recognition of some unusual
symptoms (e.g., tingling in the hands or feet).
Symptomatic treatment
In cases of advanced, symptomatic DAN, it is
sometimes necessary to use drugs. Medicines are
prescribed by specialists depending on the affected
organ. Unfortunately, there are currently no generally
accepted guidelines for the treatment of DAN (18,25).
* Orthostatic hypotension
- a-receptor agonist – midodrine;
mineralocorticoid – 9-a-fluorohydrocortizone;
somatostatin and its analogs; erythropoietin;
sympathomimetic – ephedrine
* Gastroparesis
- antiemetics – metoclopramide, domperidone;
antibiotics – erythromycin; gastric electrical
stimulation
* Constipation
- osmotic laxatives – lactulose; motility or
secretion stimulating laxatives – magnesium
sulfate, sodium sulfate; prokinetics (dopamine
antagonists) – metoclopramide
* Diarrhea
- broad-spectrum antibiotics – erythromycin,
tetracycline, ampicillin; synthetic opioids –
loperamide; agonists of a-2 receptors –
clonidine; somatostatin analog – octreotide
* Bladder dysfunction
- mechanical methods (suprapubic pressure,
intermittent self-catheterization); anticholinergics (detrusor hyperreflexia); parasympathomimetics (reduced contractility of the
detrusor)
* Sexual dysfunction
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S. Vučković-Rebrina, A. Barada, L. Smirčić-Duvnjak / DIABETIC AUTONOMIC NEUROPATHY
-
5-phosphodiesterase inhibitors; intracavernous
injection;
transurethral
application
of
prostaglandins; penile implants; vaginal
lubricants
* Hyperhidrosis and gustatory sweating
- anticholinergics; agonist of α-2 receptors –
clonidine.
concluSIon
Diabetic autonomic neuropathy is a common and
serious complication of diabetes. It is present in a
quarter of patients with type 1 and one-third of patients
with type 2 diabetes. In its course, it can affect any
organ in the body and therefore result in a variety of
symptoms and signs. The most common symptoms
and signs are exercise intolerance, silent myocardial
ischemia, orthostatic hypotension, impaired intestinal
motility, bladder and erectile dysfunction, sweating
disturbances and hypoglycemia unawareness. The
consequences of DAN significantly affect the survival
of diabetic patients and are associated with increased
mortality from malignant arrhythmias and sudden
cardiac death. DAN is unfortunately often recognized
too late. Thanks to a standard battery of cardiovascular
autonomic tests, which is the gold standard for
confirming the diagnosis of CAN today, damage can
be diagnosed in the asymptomatic phase. Screening
testing is necessary in patients with type 1 and type 2
diabetes, especially those who have additional risk
factors such as poorly controlled glycemia, other
vascular disease factors, as well as other micro- and
macrovascular diabetic complications.
Strict blood glucose control is still the only causal
therapy that allows delaying, halting or slowing the
progression of DAN. Symptomatic treatment consists
of simple measures and lifestyle modifications and, in
severe cases, pharmacological treatment.
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