Neuropathy, diabetic E14.40+G63.2*

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).

Diabetic neuropathy is understood to be all diabetes-relateddisorders of the peripheral sensorimotor and autonomic nervous systems (Siegenthaler 2006) with damage to the cholinergic, noradrenergic and peptidergic systems (Kasper 2015). This is a diagnosis of exclusion (Häring 2011).

Classification of diabetic neuropathies according to Thomas and Tomlinsen:

• Symmetric neuropathies:
  • sensory or sensorimotor polyneuropathy
  • autonomic neuropathy
  • symmetrical proximal neuropathy of the lower extremity
• Focal and multifocal neuropathies:
  • cranial neuropathy
  • mononeuropathy of the trunk (diabetic radiculopathy) and extremities
  • asymmetric proximal neuropathy of the lower extremity (diabetic amyotrophy)
• Mixed forms (German Medical Association 2016).

Diabetic neuropathy includes:

• 1. peripheral sensorimotor polyneuropathy: This refers to a distal symmetric sensorimotor polyneuropathy (Ziegler 2020), which according to Neundörfer (2007) always occurs together with other secondary diseases such as diabetic nephropathy or diabetic retinopathy. For more details see d.
• 2. autonomic diabetic neuropathy (ADN). ADN affects the autonomic nervous system, both sympathetic and parasympathetic. (Herold 2020) ADN includes:
  • 2.1. cardiovascular ADN
  • 2.2. ADN of the gastrointestinal tract
  • 2.3. ADN of the genitourinary system
  • 2.4. ADN of the neuroendocrine system
  • 2.5. ADN of the thermoregulation system
  • 2.6. ADN of the pupils
  • 2. 7. ADN of the respiratory tract
• 3. rare manifestations:
  • 3.1. diabetic focal polyneuropathy
  • 3.2. peripheral facial nerve paresis
  • 3.3. paresis of the eye muscles
  • 3.4. diabetic radiculopathy (Herold 2020)
  • 3.5. diabetic amyotrophy (Claus 1996)

According to the 1988 Consensus Statement, one differentiates between subclinical ADN, which is detectable only by testing, and clinical ADN, which manifests itself in symptoms (Häring 2011).

Diabetic neuropathy occurs in both type 1 and type 2 diabetes and correlates with diabetes duration and glycemic control (Kasper 2015). The prevalence in type 1 ranges from 8 - 54 % and in type 2 from 13 - 46 % (Bundesärztekammer 2016).

- Peripheral sensorimotor polyneuropathy: dPNP occurs in one in three diabetics (Ziegler 2020) and represents the most common form of diabetic neuropathy at 80 % (Herold 2020). Up to 25 % (Gerber [2019] speaks of 20 %) of affected patients experience pain, while up to 50 % remain asymptomatic (Ziegler 2020). The dPNP is found more frequently in men than in women. The longer diabetes is clinically manifest, the more likely it is that dPNP will occur (Neundörfer 2007).

- Autonomic diabetic neuropathy: Autonomic diabetic neuropathy is the second most common, occurring in approximately 30% of cases (Berlit 2012).

-Cardiovascular ADN is detectable in 15% of diabetics at diagnosis and in >50% after 20 years of disease.

-Erectile impotence affects up to 50% of 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 the development of diabetic neuropathy, a role is played by:

• Hyperglycemia (diabetes control)
• Duration of diabetes
• Obesity (especially visceral obesity [German Medical Association 2016]).
• Dyslipidemia

Dyslipidemia plays a major role in type 2 diabetes in particular (Baum 2019).

Diabetes mellitus does not increase low-density lipoprotein (LDL) itself, but the small LDL particles that are present, especially in type 2, are more readily glycated and thus more atherogenic and susceptible to oxidation (Kasper 2015).

• Smoking
• arterial hypertension
• cardiovascular diseases (Kasper 2015)
• Alcohol
• peripheral AVK
• diabetic retinopathy
• diabetic nephropathy
• mediasclerosis of the Mönckeberg type
• demographic factors such as age, body weight, height) (Info from the German Medical Association 2016).

However, if the HbA1c value is lowered too quickly, there is a risk of iatrogenically induced small fiber neuropathy. Animal experiments found evidence of intraneural cell-mediated inflammatory processes leading to terminal nerve fiber degeneration. This was exacerbated by iron deficiency in animal experiments (Baum 2019).

So far, the pathophysiology of diabetic neuropathy is not clearly understood. Various factors certainly play a role. The degeneration of terminal nerve cells is primarily triggered by hyperglycemia (Baum 2019). Both myelinated and unmyelinated nerve fibres are lost in the disease (Kasper 2015).

Diabetic neuropathy depends on the metabolic control and the duration of diabetes. After 10 years, 50 % of diabetics already suffer from neuropathy (Herold 2020).

The sensorimotor diabetic neuropathy occurs symmetrically in the area of the lower extremities and is manifested by paresthesia, pain, numbness. Sensory disturbances are common, but motor disturbances are less frequent.

Autonomic diabetic neuropathy leads to disturbances in the autonomic innervation of various organs and systems (Siegenthaler 2006).

1. peripheral sensorimotor polyneuropathy: up to 50% of patients are asymptomatic, from therefore dPNP is still underdiagnosed nowadays (Ziegler 2020).

Typical neuropathic symptoms are:

• Paresthesias (tingling, stinging, burning in the area of the sole of the foot, the forefoot or the entire foot, so-called "burning feet" [Grifka 2007]).
• Pain
• Numbness, especially in the area of the feet and lower legs [Ziegler 2020].

2. autonomic diabetic neuropathy (ADN): the symptoms of ADN depend on the localization.

2.1. Cardiovascular ADN: The typical complaints of patients with cardiovascular ADN are:

• resting tachycardia due to vagus damage
• asympathicotonic orthostatic hypotension due to sympathetic nervous system damage with absence of reflex tachycardia on standing exercise and drop in both systolic and diastolic blood pressure (Herold 2020)
• exercise intolerance (Häring 2011)
• painless myocardial infarction
• painless myocardial ischemia
• Heart rate variability decreased up to frequency rigidity during
  • resting ECG
  • 24 h ECG
  • maximal inspiration and expiration (normally the difference in 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)

2.2. ADN of the gastrointestinal tract (parasympathetic damage rarely occurs in this case):

• Gastroparesis with pressure in the upper abdomen and a feeling of fullness, as well as postprandial hypoglycemia.
• Esophageal motility disorder
• Gallbladder contractility disorder 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)

Type 1 diabetic patients should also always be screened for celiac disease if they have typical symptoms, as this is more common than average in them (Kasper 2015).

2.3. ADN of the urogenital system (in this case, parasympathetic damage often occurs):

• erectile dysfunction with absence of nocturnal or morning spontaneous erection.
• 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)

2.4 ADN of the neuroendocrine system:

• Reduced perception of hypoglycemia due to reduction or absence of a hormonal counter-response to existing hypoglycemia.
• Release of catecholamines reduced under physical and orthostatic stress (Herold 2020).

2.5 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 the decreased sweat secretion and vasodilation. Due to the disturbance of the sympathetic nervous system, there may additionally be hyperhidrosis of the upper extremities (Kasper 2015).

2.6 ADN of the pupils: In this case, there are disturbed pupillary reflexes and a 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).

2. 7. ADN of the respiratory tract: The respiratory drive is reduced in hypoxemia and hypercapnia. Apnea may also occur and respiratory arrest (Häring 2011).

3.1. diabetic focal polyneuropathy: In diabetic focal polyneuropathy, there may be:

• asymmetric proximal pain in the hip region and in the area of the anterior thigh with a focus on the iliopsoas and quadriceps muscles supplied by the femoral nerve
• Attenuation of the ipsilateral PSR
• Paresis of the quadriceps muscle is possible (Herold 2020)
• Absence of sensory disturbances in the area of the femoralis muscle (Berlit 2012)

3.2. Peripheral facial nerve paresis: In thisparesis, the following are present:

• Forehead smooth to wrinkleless
• Eyebrow hangs slightly
• Eyelid closure is deficient
• Wrinkling of the nose is disturbed
• Corner of the mouth and tips of the mouth can only be raised to a limited extent
• Loss of whistling
• Cheeks can only be puffed out to a reduced extent
• Problems with the pronunciation "P
• Tension of the platysma not possible (Hopf 2006)

3.3. paresis of the eye muscles: double vision occurs (Herold 2020).

3.4. Diabetic radiculopathy: In diabetic radiculopathy, there is girdling pain and sensory disturbances in the area of the trunk (Herold 2020).

3.5. Diabetic amyotrophy (Claus 1996): In this case, due to the predominantly unilateral lumbosacral plexopathy, there are:

• severe pain radiating from the lumbosacral region to the hip and to the front and inner side of the thigh.
• Patellar tendon reflex not triggerable
• only slight sensory disturbances (Claus 1996)
• rapid weight loss
• poor general condition
• after pain relief, rapidly developing progressive weakness and atrophy of the quadriceps muscle (Patten 2013)

Clinical symptoms, clinical findings and neurophysiological tests play a major role in the diagnosis of diabetic neuropathy (Siegenthaler 2006).

• 1. peripheral sensorimotor polyneuropathy: for detailed information see d.
• 2. autonomic diabetic neuropathy (ADN)

During the anamnesis, the typical symptoms of an ADN should be asked for in particular (Bundesärztekammer 2016).

• 2.1. cardiovascular ADN (CADN)
  • Resting ECG
  • Long-term ECG
  • Checking the HRV by means of appropriate tests (records the parasympathetic function [Bundesärztekammer 2016]).
  • Orthostasis test to record the sympathetic component (German Medical Association 2016).
  • MIBG scintigraphy = Metajodobenzylguanidine scintigraphy (Claus 1996)
• 2.2. 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)
• 2.3. ADN of the urogenital system
  • cystometry
  • urodynamic examinations (Kasper 2015)
  • Uroflowmetry
  • Residual urine determination
  • Determination of total testorone concentration (Bundesärztekammer 2016)
• 2.4. ADN of the neuroendocrine system
  • Determination of catecholamines
  • Close-meshed blood glucose monitoring (especially at night [Bundesärztekammer 2016])
• 2.5. ADN of thermoregulation
  • Sweat test
  • Determination of the sympathetic skin response
  • Ninhydrin test (German Medical Association 2016)
• 2.6. ADN of the pupils: The diagnosis is made by pupillometry (a reduced mydriatic velocity is found [Herold 2020]).
• 2.7. ADN of the respiratory tract
  • Sleep lab
  • Pulmonary function (Ziegler 2020)
• 3.1. diabetic focal polyneuropathy
  • motor femoral neurography (Vogel 2006)
• 3.2. peripheral facial nerve paresis
  • the frontal musculature is affected - in contrast to central facial paresis
  • MRT (Bähr 2003)
• 3.3. paresis of the eye muscles
  • clinical examination with bulbar position and ocular sequential movements
  • double-image test with red-green glasses
  • MRI (Bähr 2014)
• 3.4. diabetic radiculopathy
  • CT / MRT for differential diagnostic clarification (Henke 2020)
• 3.5. diabetic amyotrophy
  • Clarification by a neurologist (Lehnert 2014)

Lumbar puncture: CSF examination is appropriate in case of differential diagnostic difficulties. One typically finds a slight increase in total protein in diabetic neuropathy (indicating co-involvement of the nerve roots) and a normal cell count (Claus 1996).

Electromyography (EMG) : With the help of EMG, the involvement of the motor fibres can be detected at an early stage - without clinical evidence of paresis (Claus 1996).

Electroneurography (ENG): The motor and sensory nerve conduction velocity (NLG) is often normal to slightly slowed. Sensory NLG is pathologically altered earlier than motor NLG (Siegenthaler 2006).

• Neuropathy of other genesis such as ethyl toxic, autoimmune etc. (Häring 2011)
• Celiac disease (Kasper 2015)
• Root irritation L 4
• Guillain-Barré syndrome

(Claus 1996)

• Non-diabetic polyneuropathy such as:(Summer 2019).
  • myxedema- PNP
  • nephrogenic PNP
• peripheral arterial occlusive disease (pAVK)
• muscular imbalances in afferent disorders (Geber 2019)
• paraneoplastic sensory PNP (so-called Denny-Brown syndrome)
• amyloid neuropathy
• other causes of polyneuropathy such as alcohol, anorexia, medication etc. (Neundörfer 2007)

• diabetic foot syndrome (Api 2020)

Therapeutic measures to date have all been unsatisfactory.

Improved glycemic control should be aimed at, risk factors such as arterial hypertension, hypertriglyceridemia should be treated accordingly. Nutritional counseling for obesity, cessation of smoking and avoidance of neurotoxins such as alcohol are urgently required. Possible sublimation of B 12, folic acid and iron (Baum 2019) is recommended (Kasper 2015).

The patient should be urged to check the feet daily, calluses and ulcers should be avoided by appropriate footwear (Kasper 2015).

• 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 urogenital system:
  • Self-catheterization
  • Phosphodiesterase type 5 (although efficacy is reduced in diabetics).
  • Vaginal lubricants in affected women (Kasper 2015).
• Diabetic focal polyneuropathy: analgesics should be used in the acute phase as well as physiotherapy for rehabilitation (Berlit 2012).

For detailed information on diabetic polyneuropathy , see d.

In case of pain, appropriate adjustment with medication is required such as:

• NSMRI such as amitriptyline: dosage recommendation: initial 10 mg / d, every 4 days increase the dose by 10 - 25 mg until the effective dose, which is between 25 - 75 mg / d (Bundesärztekammer 2016).
• SNRI such as duloxetine: dosage recommendation: starting dose at 30 mg / d, subsequent increase after 7 - 14 days to the target dose of 60 mg / d (Bundesärztekammer 2016).
• Gabapentin: The starting dose should be 30 mg, increasing after 7 - 14 days to the target dose of 60 mg / d. It should be taken as a single dose in the morning (Bundesärztekammer 2016).
• Calcium channel alpha2-delta modulators such as pregabalin: the starting dose is between 75 - 150 mg / d, the target dose is 300 - 600 mg / d. The up-dosing can usually be done quickly in younger patients, in the elderly, a gradual increase should be carried out every 3 days(Bundesärztekammer 2016).
• Opioids such as tramadol: dosage recommendation: 2 - 3 x / d 100 - 200 mg (Kasper 2015 / Häring 2011).
• Valproate: Valproate should not be used due to insufficient evidence of an analgesic effect in diabetic neuropathy and taking into account serious side effects (Bundesärztekammer 2016).
• NSAIDs: NSAIDs should also not be used in diabetic neuropathy due to the lack of safe studies on efficacy (Bundesärztekammer 2016).
• Tilidine / naloxone: There are also no controlled studies for tilidine or in diabetic neuropathy. However, it is still recommended in the guidelines. Dosage recommendation: 2 - 3 x / d 50 - 200 mg (German Medical Association 2016).

Not only the pain reduction is in the foreground of the treatment, but also

• an improvement of sleep
• Improvement of the quality of life
• Preservation of the ability to work
• Preservation of social activities

If there is no satisfactory improvement after 12 weeks of pain therapy, presentation to an outpatient pain clinic is recommended (Bundesärztekammer 2016).

Hyperlipidemia: The target values for lipids in diabetics are:

• > 40 years and male:
  • LDL < 2.6 mmol / l (100 mg / dl).
  • HDL > 1 mmol / l (40 mg / dl)
  • Triglycerides < 1.7 mmol / l (150 mg / dl)
• > 40 years and female:
  • LDL < 2.6 mmol / l (100 mg / dl)
  • HDL > 13 mmol / l (50 mg / dl)
  • Triglycerides < 1.7 mmol / l (150 mg / dl)

Drug treatment is based on the pattern of lipoprotein abnormalities. HMG- CoA reductase inhibitors are the drug of choice for lowering LDL levels. In addition, fibrates or another lipid-lowering agent such as ezetimibe, niacin, etc. can be used.

Regardless of the LDL level, the American Diabetes Association ADA recommends the administration of a statin in patients with CHD or with CHD risk factors (Kasper 2015).

Arterial hypertension: The target value should be < 140 / 80 mmHg in diabetics and < 130 / 80 mmHg in younger patients. Medications recommended are ACE inhibitors (angiotensin converting enzymes) or ARBs (angiotensin II receptor blockers) (Kasper 2015).

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

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

Drugs that favorably affect sinus tachycardia include:

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

• Orthostatic hypotension:

Treatment of orthostatic hypotension is difficult. In this case, the following can be administered:

• Clonidine
• Fludrocortisone
• Midodrine (1st choice [Häring 2011])
• Octreotide
• Yohimbine

However, some of the drugs have significant side effects and have limited success. General measures such as adequate salt intake, avoidance of dehydration, crossing the legs while standing, preference for a squatting position, etc. (German Medical Association 2016) should be recommended to the patient (Kasper 2015).

• ADN of the gastrointestinal tract:

Medication used was metoclopramide. However, long-term treatment is not recommended (Kasper 2015).

Symptomatic autonomic diabetic neuropathy is not only associated with a reduced quality of life, it is also associated with an unfavorable prognosis (Häring 2011). Mortality after myocardial infarction is increased, and autonomic dysfunction is also a risk factor for apoplexy (Bundesärztekammer 2016).

In the DCCT- study (Diabetes Control and Complications Trial), improved glycemic control has been shown to reduce neuropathy by up to 60% (Kasper 2015).

The prognosis of diabetic focal polyneuropathy is good (Berlit 2012).

In cardiovascular ADN, mortality from ventricular extrasystoles to ventricular fibrillation is increased fourfold (Herold 2020).

Peripheral facial nerve palsy caused by diabetes has a good prognosis (Hopf 2006).

Diabetic amyotrophy usually regresses after about 6 months of disease, although complete regression can take up to 24 months (Patten 2013).

Screening for diabetic neuropathy should be performed at the time of initial diagnosis in type 2 diabetics and no later than 5 years after diagnosis in type 1 diabetics.

Subsequent screenings are recommended 1 x per year.

These should include:

• anamnesis with recording of diabetes-specific data
• Recording of risk factors
• Inspection (skin colour, trophic disorders, skin temperature, foot deformities, injuries, foot ulcer)
• screening for complications, e.g. peripheral AVK, foot ulcer
• Simple neurological examination, e.g. reflex status, vibration sensation, pressure and touch sensation
• Assessment of neuropathic plus and minus symptoms such as pain, pain intensity, pain localization and pain-inducing situation, numbness, cramps, sensory irritations with the aid of a validated questionnaire.
• Resting tachycardia
• disturbed hypoglycemia perception
• Sweating disorders
• bladder dysfunction
• sexual disorders
• gastrointestinal disorders
• Blood glucose fluctuations that cannot be explained in any other way

(German Medical Association 2016)

In the case of diabetic neuropathy or evidence of diabetic neuropathy, at least six-monthly check-ups are required; in the case of additional pAVK or foot deformities, an examination interval of three months is recommended (Bundesärztekammer 2016).

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