Adn E14.40+G99.0*

As early as the 17th century, the surgeon Thomas Willis (1621 - 1675) described the symptoms of diabetic neuropathy (Gerabek 2011).

But only Rundles perceived the clinical entity of the disease and published a description of the clinical picture in 1945 (Mogensen 1989).

ADN (autonomic diabetic neuropathy or DAN = diabetic autonomic neuropathy [Peter 2007]) is a frequent and serious complication of diabetes mellitus (Schönauer 2007), which is sometimes diagnosed far too rarely (Sharma 2020).

It is understood to be a neuropathy of the entire autonomic nervous system - both sympathetic and parasympathetic (Herold 2021).

ADN occurs together with sensorimotor diabetic neuropathy in 50% of cases. Long-term complications of diabetes mellitus such as diabetic nephropathy and diabetic retinopathy are also often associated with it (Schönauer 2007).

ADN belongs to the group of forms of diabetic neuropathies and is divided into:

• 1. cardiovascular ADN (CADN or CAN [Agashe 2018]).
• 2. ADN of the gastrointestinal tract
• 3. ADN of the genitourinary system
• 4. ADN of the neuroendocrine system
• 5. ADN of thermoregulation
• 6. ADN of the pupils
• 7. ADN of the respiratory tract (Herold 2021)
• 8. ADN of the skin and connective tissue (Hien 2010)

Another classification concerns subclinical and clinical form, defined by the 1988 Consensus Statement as:

• subclinical ADN, which can only be detected by testing.
• clinical ADN, which manifests itself in symptoms (Häring 2011).

In clinical ADN, sympathetic activity predominates (Agashe 2018).

Autonomic diabetic neuropathy is the second most common of all diabetic neuropathies, occurring in about 30 % of cases (Berlit 2012).

Cardiovascular ADN is detectable in 15 % of diabetics at diagnosis and in > 50 % after 20 years of disease (Bundesärztekammer 2016). CADN occurs in type 1 DM in up to 91 % of diabetics and in type 2 in up to 75 % (Agashe 2018).

Erectile impotence affects up to 50% of all diabetics, depending on the duration of the disease and the age of the patient (Herold 2020). The incidence is twice as high as in non-diabetics (Bundesärztekammer 2016).

Diabetic amyotrophy occurs in 5 % of diabetics (Berlit 2012) and more frequently affects the male sex and non-insulin-dependent diabetics (Patten 2013).

In type 1 DM, two major studies (Pittsburgh Epidemiology of Diabetes Complications Study and the EURODIAB IDDM Complications Study) have shown correlations between ADN and cardiovascular risk factors such as increased triglycerides, decreased HDL cholesterol, arterial hypertension, smoking, etc. In type 2 DM, hyperinsulinemia is another predictor.

In type 2 DM, another predictor is hyperinsulinemia.

In both type 1 DM and type 2, inadequate diabetes control is a strong predictor (Ziegler 2005).

Risk factors for the development of cardiac ADN are:

• poor glycemic control
• arterial hypertension
• smoking
• dyslipidemia (Agashe 2018).

- Cardiac ADN:

The pathophysiology of CADN is the best studied.

The pathophysiological mechanisms represent the result of complex interactions between glycemic control, disease duration, systolic and diastolic blood pressure, and age-related neuronal death (Agashe 2018).

In this context, hyperglycemia appears to be the main culprit in a complex cascade that initiates multiple mechanisms, induces oxidative stress and toxic glycosylation products, and ultimately leads to neuronal dysfunction and death.

Associated with CAN are genetic susceptibility, low C- peptide levels, obstructive sleep apnea, and autoimmune antibodies (Agashe 2018).

Since the pathogenesis of CAN is multifactorial, it requires further investigation (Agashe 2018).

In principle, ADN can lead to clinical symptoms in all autonomously innervated organs (Strian 2013).

• 1. cardiovascular ADN:

The typical complaints of patients with cardiovascular ADN are:

• Resting tachycardia:

This results from vagus damage and the resulting sympathicotonic overload. After an average 5-year latency period, damage to sympathetic nerve fibers occurs, resulting in (partial) regression of tachycardia. Overall, however, the heart rate remains higher than in healthy individuals (Schönauer 2007).

• asympathicotonic orthostatic hypotension due to damage to the sympathetic nervous system with a lack of reflex tachycardia during standing exercise and a drop in both systolic and diastolic blood pressure (Herold 2020)
• exercise intolerance (Häring 2011)
• Painless myocardial infarction (lack of pain perception due to damage to sensory nerve fibers [Schönauer 2007])
• painless myocardial ischemia
• Heart rate variability decreased up to frequency rigidity during
  • resting ECG
  • 24 h ECG
  • maximal inspiration and expiration (normally the difference of the heart rate is < 9 / min)
  • Orthostasis test
  • Valsalva compression test (Herold 2020)
• QTc prolongation (German Medical Association 2016)
• abolished or reversed circadian blood pressure curve with increased blood pressure values at night (so-called non- dipper)
• perioperative instability (Häring 2011)

• 2. ADN of the gastrointestinal tract (parasympathetic damage rarely occurs in this area):
  • gastroparesis with pressure in the upper abdomen and feeling of fullness
  • postprandial hypoglycemia (occurs about 30 min p.p. [Hien 2010])
  • Esophageal motility disorder
  • Disturbance of gallbladder contractility with increased formation of gallstones (German Medical Association 2016)
  • anorectal dysfunction with incontinence
  • postprandial diarrhea with alternating phases of constipation due to motility disorders in the lower intestinal segments (Siegenthaler 2006; Herold 2020)

Diabetes type 1 patients should also always be examined for celiac disease if they have typical symptoms, as this occurs more frequently than average in them (Kasper 2015).

• 3. ADN of the urogenital system (parasympathetic damage often occurs in the urogenital system):
  • Early symptoms are:
    • the bladder can no longer be emptied completely
    • a full bladder can no longer be perceived (Kasper 2015)
  • erectile dysfunction with failure to achieve a spontaneous erection at night or in the morning
  • Bladder emptying disorders in bladder atony with residual urine formation and resulting predisposition to recurrent urinary tract infections (Herold 2020)
  • Incontinence and decrease in bladder capacity due to delayed bladder contractility (Kasper 2015)

• 4. ADN of the neuroendocrine system:
  • Decreased perception of hypoglycemia due to reduction or absence of hormonal counter-response in the presence of hypoglycemia (Kasper 2015)
  • Reduced release of catecholamines under physical and orthostatic stress (Herold 2020)

• 5. ADN of thermoregulation: ADN of thermoregulation leads to:
  • Vasodilation
  • Decreased sweat secretion

The dry and warm diabetic foot typical of diabetics [Herold 2020]) exist due to decreased sweat secretion and vasodilation.

Due to the disturbance of the sympathetic nervous system, there may also be hyperhidrosis of the upper extremities (Kasper 2015).

• 6. ADN of the pupils:

In this case, there are disturbed pupillary reflexes and reduced brightness adaptation (Häring 2011). Spontaneous fluctuations of the pupil diameter are - compared to healthy people - only diminished.

If sympathetic damage is in the foreground, there is miosis (Bundesärztekammer 2016).

• 7. ADN of the respiratory tract:

Respiratory drive is decreased in hypoxemia and hypercapnia. Apnea and respiratory arrest may also occur (Häring 2011).

• 8. ADN of the skin:

The skin is - due to lack of impulses to connective tissue and skin - doughy and atrophic. This is particularly observable in the "diabetic foot" (Hien 2010).

During the anamnesis, the typical symptoms (see below "Clinical picture") of an ADN should be asked for (Bundesärztekammer 2016).

• 1. cardiovascular ADN (KADN)
  • Resting ECG
  • Long-term ECG
  • Testing of HRV by appropriate tests (records parasympathetic function [Bundesärztekammer 2016]); reduction in HRV is the earliest symptom of CAN and is best visualized in deep inspiration (Schönauer 2007). The gold standard of testing is the "cardiac autonomic reflex tests (CARTs)" discovered by Ewing in the 1970s, which include the following measurements:
    • Heart rate
    • Blood pressure
    • Sudomotor reactions (Agashe 2018)
  • Orthostasis test to detect the sympathetic component (Bundesärztekammer 2016)
  • MIBG scintigraphy = metaiodobenzylguanidine scintigraphy (Claus 1996)

CAN is subdivided into 3 categories based on diagnostic tests:

• 1. early involvement

In this case there is an abnormal HR test or 2 borderline events.

• 2. definite involvement

There are 2 or more abnormal events.

• 3. severe involvement

Orthostatic hypotension is present (Agashe 2018).

• 2. ADN of the gastrointestinal tract
  • Sonography
  • Gastric emptying scintigraphy
  • 13 C- octanoic acid breath test (Herold 2020).
  • Esophagogastroduodenoscopy
  • 24- hour esophageal impedance measurement
  • Hinton test to determine the colon transit time
  • (MRT-) defecography
  • anorectal manometry (German Medical Association 2016)

• 3. ADN of the genitourinary system
  • cystometry
  • urodynamic examinations (Kasper 2015)
  • Uroflowmetry
  • Residual urine determination
  • Determination of total testorone concentration (Bundesärztekammer 2016)

• 4. ADN of the neuroendocrine system
  • Determination of catecholamines
  • Close-meshed blood glucose monitoring (especially at night [Bundesärztekammer 2016])

• 5. ADN of thermoregulation
  • Sweat test
  • Determination of the sympathetic skin response
  • Ninhydrin test (German Medical Association 2016)

• 6. ADN of the pupils:
  • Diagnosis by means of pupillometry (a reduced mydriatic velocity is found here [Herold 2020]).

• 7. ADN of the respiratory tract:
  • Sleep laboratory
  • Lung function (Ziegler 2020)

ADN is a risk factor for apoplexy (Ziegler 2005).

• ADN of the gastrointestinal tract:

Patients should eat frequent small meals that are easily digestible and low in fat or fiber (Kasper 2015).

• ADN of the genitourinary system:
  • Self-catheterization
  • Phosphodiesterase type 5 (although efficacy is reduced in diabetics).
  • vaginal lubricants in affected women (Kasper 2015).

• Cardiovascular ADN:

Two different therapeutic approaches are found here:

1. prevention of the development or progression of CADN.

2. symptomatic control of CADN (Agashe 2018).

Intensive glycemic control can initially reduce the incidence of CAN by more than 50 in type 1 DM according to the DCCT / EDIC- study. This benefit is maintained 13 - 14 years later. In type 2 DM , weight loss and exercise in particular show a beneficial effect (Agashe 2018).

Drugs that can favorably affect autonomic tone by increasing heart rate variability (HRV) are:

• ACE inhibitors
• Angiotensin II receptor blockers (type 1).
• beta-blockers without intrinsic sympathomimetic activity such as metoprolol
• Digoxin
• Verapamil

Drugs that favorably affect sinus tachycardia include:

• Beta- 1- selective beta blockers such as bisoprolol, metoprolol, nebivolol (German Medical Association 2016).

Orthostatic hypotension can be treated symptomatically:

• non-medicinal with:
  • Squatting
  • slow change of posture
  • Change of lifestyle with e.g.:
    • avoidance of meals rich in carbohydrates
    • Increase of fluid intake
• medicinal with:
  • Alpha-1 adrenergic agonist such as midodrine
  • Fludrocortisone
  • Desmopressin
  • Somatostatin analogues
  • Non-selective beta blockers (Agashe 2018).

• ADN of the gastrointestinal tract:

Medication metoclopramide can be used. However, long-term treatment is not advised (Kasper 2015).

The macrolide antibiotic erythromycin (a motilin agonist) is used for severe forms of gastroparesis (Hien 2010).

In cases of bacterial colonization of the intestine with disturbances of motility, the administration of metronidazole or vibramycin / doxycycline for 7 d is recommended (Hien 2010).

• CADN:

In cardiovascular ADN, orthostatic hypotension indicates a severe course and poor prognosis (Agashe 2018). Perioperative complications are significantly increased in these patients (Bundesärztekammer 2016).

Mortality in CADN is increased fourfold by ventricular extrasystoles to ventricular fibrillation (Herold 2020).

According to the 2003 Steno- 2 study, strict BG settings and lifestyle modification in type 2 DM reduce the development of autonomic neuropathy but have no significant effect on further progression of diabetic (poly-) neuropathy ( Agashe 2018).

1. Agashe S et al (2018) Cardiac autonomic neuropathy in diabetes mellitus. Methodist Debakey Cardiovasc J. 14: 251 - 256.
2. Berlit P et al. (2012) Neurology questions and answers: over 1000 facts for the residency exam. Springer Verlag 18
3. German Medical Association (2016) National health care guideline: neuropathy in diabetes in adults. Version 5 Guideline currently under review. AWMF Register No: nvl-001e.
4. Claus D et al (1996) Series: Diabetic neuropathy - clinic and therapy of sensorimotor diabetic polyneuropathy. Dtsch Arztebl 93 (23) A- 1529 / B- 1301 / C- 1217
5. Gerabek E et al. (2011) Encyclopedia of medical history. de Gruyter Verlag p 1499.
6. Häring H U et al (2011) Diabetology in clinic and practice. Thieme Verlag p 473 - 475
7. Herold G et al (2021) Internal medicine. Herold Verlag p 727 - 732
8. Hien B et al. (2010) Diabetes handbook: a guide for practice and clinic. Springer Verlag Heidelberg p 207 - 209
9. Kasper D L et al (2015) Harrison's Principles of Internal Medicine. Mc Graw Hill Education p 2426
10. Mogensen C E et al (1989) Prevention and Treatment of Diabetic Late Complications. Walter de Gruyter Publishers 5
11. Patten J P (2013) Neurological differential diagnosis. Springer Verlg p 332
12. Peter H et al (2007) Encyclopedia of sleep medicine. Springer Verlag Heidelberg 252
13. Schoenauer M (2007) Cardiac autonomic diabetic neuropathy. Diabetology (2) 175 - 182
14. Shamar J K et al (2020) Diabetic autonomic neuropathy: a clinical update. J R Coll Physicians Edinb. 50: 269 - 273
15. Siegenthaler W et al (2006) Clinical pathophysiology. Thieme Verlag 98
16. Strian F et al (2013) Autonomic neuropathy. Springer Verlag Berlin / Heidelberg / New York / Tokyo 55 - 64.
17. Ziegler D. (2005) Cardiovascular autonomic diabetic neuropathy. In: Meinertz T., Rösen P., Ziegler D., Schömig A., Tschöpe D. (eds) Diabetes and heart. Steinkopff Publishers 174 - 175
18. Ziegler D (2020) Diabetic polyneuropathy. The Diabetologist (16) 195 - 206