Diabetic polyneuropathy E14.40+G63.2*

Diabetic polyneuropathy (dPNP) is a distal symmetric sensorimotor polyneuropathy occurring in diabetics (Ziegler 2020), which according to Neundörfer (2007) always occurs with other secondary diseases such as diabetic nephropathy or diabetic retinopathy.

The dPNP belongs to the diabetic neuropathies. According to Thomas and Tomlinson, these are subdivided on the basis of clinical criteria into:

• symmetrical neuropathies:
  • sensory or sensorimotor polyneuropathy (most common at about 80% [Herold 2020]))
  • autonomic neuropathy (second most common [Herold 2020])
  • symmetrical proximal neuropathy of the lower extremity
• focal and multifocal neuropathies:
  • cranial neuropathy
  • mononeuropathy of the trunk (so-called diabetic radiculopathy) and extremities
  • asymmetric proximal neuropathy of the lower extremity (so-called diabetic amyotrophy)
• Mixed forms (BÄK 2015)

A distinction is made between acute polyneuropathy, i.e. existing for < 12 months, and chronic polyneuropathy, existing for > 12 months (Kasper 2015).

Clinical manifestations

• subclinical neuropathy:
  • Asymptomatic
  • no clinical findings
  • quantitative neurological tests, however, pathological
• chronic painful neuropathy:
  • frequently occurring
  • painful symptoms at rest
  • symmetrical affection
  • loss of sensibility of different quality
  • muscle reflexes reduced on both sides
• acute painful neuropathy:
  • rarely occurring
  • symmetrical pain of the lower extremities
  • possibly pain in the trunk area
  • Hyperaesthesia possible
  • Sensory disturbances in the lower extremities
  • Neurological findings normal
  • not infrequently associated with the start of intensification of insulin therapy (so-called "insulin neuritis")
• painless neuropathy:
  • frequently occurring
  • absent symptoms or also paresthesia possible
  • Sensitivity reduced or absent
  • Muscle reflexes absent
  • gait insecurity
  • injuries not noticed by the patient
• Long-term complications of distal symmetric polyneuropathy with varying degrees of penetration:
  • neuropathic foot lesions in the form of e.g. a foot ulcer
  • non-traumatic amputation
  • diabetic neuropathic osteoarthropathy (DNOAP) or Charcot arthropathy (BÄK 2015)

The dPNP is the most common cause of polyneuropathies (Geber 2019). It is also the most common form of diabetic neuropathies, accounting for >90% (Neundörfer 1996).

The dPNP occurs in every third diabetic. Up to 25 % (Gerber [2019] speaks of 20 %) of affected patients experience pain, while up to 50 % are asymptomatic (Ziegler 2020).

The dPNP is found more frequently in men than in women. The longer the diabetes is clinically manifest, the more likely it is that dPNP will occur (Neundörfer 2007).

dPNP can be caused by both type 1 and type 2 diabetes (Neundörfer 1996). Both myelinated and nonmyelinated nerve fibers are lost (Kasper 2015).

The pain triggered by a dPNP can be caused, among other things, by a too rapid lowering of the blood glucose level during a prolonged diabetic metabolic state. It is then referred to as "treatment-induced neuropathy of diabetes (TIND)" (Geber 2019).

Risk factors for dPNP are:

• Duration of diabetes
• adjustment of diabetes
• Presence of
  • arterial hypertension
  • Hyperlipidemia
  • diabetic retinopathy
  • diabetic nephropathy

  • diabetic dermopathy

  • malum perforans

  • peripheral arterial occlusive disease (pAVK)

  • alcohol and/or nicotine abuse
  • visceral obesity
  • mediasclerosis of the Mönckeberg type
  • demographic factors such as age, height, body weight (BÄK 2015)

So far, no unified hypothesis on the pathogenesis of a dPNP could be established. Presumably, the following factors play a role:

• vascular
• autoimmune
• hyperglycemia
• hyperinsulinemia
• hypoinsulinemia
• oxidative stress
• C- peptidemia
• deficiency of neutrophic factors

There is evidence of an association between impaired glucose processing and polyneuropathy (Neundörfer 2007).

The pathophysiology of neuropathic pain triggered by dPNP is complex. In addition to general pathomechanisms of neuropathic pain, factors specific to diabetes certainly play a role, such as the metabolite methylglyoxal and the voltage-dependent sodium ion channel at NaV1.7, also referred to as "gain of function mutations" (Geber 2019).

The dPNP can occur at an early stage of diabetes mellitus (Stiefelhagen 2018).

Since up to 50% of patients are asymptomatic, dPNP is still underdiagnosed today (Ziegler 2020).

Typical neuropathic symptoms are (Ziegler 2020):

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

In the guidelines, the following screening tests are recommended in cases of suspected dPNP:

• Tuning fork test
• Achilles tendon reflex
• Monofilament

If one of these is positive, the diagnosis of a dPNP is obvious and further examinations are recommended (see below) (BÄK 2015).

In the diagnosis of a dPNP, the medical history, including family history, plays a major role (Heuß 2019), since the diagnosis can usually already be made through this and the described complaints and the clinical neurological findings (Haag 2012).

Physical examination: The clinical examination reveals a distally accentuated symmetrical sensory-motor sensitivity disorder with weakening of the reflexes (usually the Achilles tendon reflex disappears first). The sensory disturbances particularly affect temperature sensation and pain sensation (Heuß 2019). Characteristically, the insensations or pain increase when lying down and at night.

There is often a sometimes pronounced atrophy of the small foot muscles with resulting claw toe formation (Grifka 2007).

In late stages, motor disturbances may be present (Herold 2020).

Vibration sensation: The examination of the vibration sensation with the 128 Hz tuning fork according to Rydel-Seiffer is carried out on the metatarsophalangeal joint of the big toe, the inner and outer ankles (Grifka 2007). The reduced vibration sensation represents an early symptom (Herold 2020).

In patients < 30 years of age, the vibration sensation at the metatarsophalangeal joint should be at least 6/8, in > 30 years of age at least 5/8, and in the region of the medial malleolus in < 40 years of age at least 6/9 and in > 40 years of age at least 5/8. In all other cases, one speaks of pallhypaethesia (Haak 2012).

Monofilament according to Semmes- Weinstein: This examination is used to determine surface sensitivity. Here, a 10 g pressure is applied to defined points on the sole of the foot (Herold 2020).

Tip Therm: Temperature sensation can be determined with the Tip Therm (Herold 2020).

Neurotip: In order to better record the dysfunctional pain fibers, a pain stimulus is applied with a sterile disposable needle in the Neurotip. (Herold 2020).

Pedography: This is used to check the dynamic pressure distribution pattern of the sole of the foot during walking (Herold 2020).

Neuropathy symptom score (NSS) and neuropathy deficit score (NDS): Using these two scores, the deficits or symptoms such as burning sensation, numbness, paresthesias, feeling of weakness, cramps, pain can be presented.

Minimum criteria for the diagnosis of a dPNP are (BÄK 2015):

• Neurological deficits moderately pronounced (NDS 6 - 8 points) with or without complaints.
• or
• neurological deficits only slightly present (NDS 3 - 5 points) with pronounced complaints (NSS 4 - 6 points).

Electrophysiological examinations: These can be used to determine

• determine the type of damage (axonal vs. demyelinating)
• determine the type of distribution (symmetrical vs. asymmetrical, distal vs. proximal)
• identify specific patterns of damage (e.g. conduction blocks)
• Demonstrate extent of muscle damage (denervation or neurogenic remodeling) (Heuß 2019).

Nerve conduction velocities: Measuring nerve conduction velocity (NLG) is another diagnostic measure in polyneuropathy. However,it should be taken into account that the current blood glucose level influences the NLG. The sensible NLG is determined by the sural and ulnar nerve, the motor NLG by the tibial and ulnar nerve (Neundörfer 2007).

Temperature and temperature pain thresholds: This is used to detect damage to the small, little-marked A- delta or the unmarked C- nerve fibers (Haag 2012). The examination can be done, for example, with a Thermotest device (Khani 2009).

CSF examination: Due to the slight to moderate barrier disturbance, there is often an increase in CSF protein in dPNP (Neundörfer 2007).

• Fasting blood glucose (may be normal [Neundörfer 2007])
• Glucose tolerance test (this is often pathological, even with normal fasting blood glucose and HbA1c [Neundörfer 2007])
• Daily blood glucose profile
• HbA1c (may be normal [Neundörfer 2007]) (Heuß 2019).

For differential diagnostic workup:

• Blood count
• ESR
• Creatinine
• Uric acid
• Transaminases
• Electrolytes
• Immunoelectrophoresis due to paraproteinemia (BÄK 2015)
• vitamin B12
• Folic acid
• Thyroid parameters
• Alanine aminotransferase (ALAT [BÄK 2015])
• ANA, ENA, rheumatoid factors

If the differential diagnostic values are normal, diabetes mellitus can be assumed as the cause of the polyneuropathy (Neundörfer 2007).

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

Patients with dPNP experience pain in up to 20% (Ziegler [2020] speaks of 25%) of cases (Geber 2019).

• Diabetic foot syndrome, also known as Charcot arthropathy (Stiefelhagen 2018) with indolent foot ulcers (Ziegler 2020)

Therapeutically of greatest importance is:

• the change of lifestyle

in addition there is:

• causal therapy of diabetes mellitus with the aim of achieving normoglycaemia
• intervention of the cardiovascular risk
• symptomatic, multimodal treatment of neuropathic pain (Ziegler 2020).

Patients should be presented to a neurologist in cases of rapid progression, familial clustering of neuropathic disease, or marked asymmetry of findings (Haak 2012).

In addition, the involvement of a physiotherapist, diabetes training, nutritional counseling, psychological interventions, social and vocational counseling are recommended (BÄK 2015).

Patients with proven dPNP and a loss of sensation should receive a guideline-based shoe fitting (BÄK 2015).

An HbA1c value < 6.5 - 7 % should be aimed for, although no reduction should be too rapid as this may trigger dPNP (Herold 2020).

It is recommended to start pain treatment as early as possible and, in addition to pain relief, to enable an improvement in sleep quality, quality of life, maintenance of social activities and ability to work (BÄK 2015).

For pain treatment, the following are considered for dPNP (Haak 2012):

• Serotonin-norepinephrine reuptake blockers (SSNRIs) such as:
  • Duloxetine up to 60 mg / d 1 - 0 - 0
• tricyclic antidepressants such as:
  • Amitriptyline (10-) 25 - 75 mg 0 - 0 - 1
• Anticonvulsants such as:
  • Gabapentin 1,500 - 3,400 mg
• Non-opioids such as:
  • Paracetamol 500 - 1,000 mg, max. 3,00 mg 2 - 3 x / d
  • Metamizole 500 - 1,000 mg 2 - 4 x / d, max. 4,000 mg / d
• moderate opiates such as:
  • Tramadol 2 -3 x 100 - 200 mg / d
• strong opiates such as:
  • Oxycodone 2 x 10 mg / d
  • Morphine 2 (-3) x 10 - 30 mg / d

Shouldnotbe used:

• Selective serotonin reuptake inhibitors (SSRI)
• Venlafaxine (because of the risk of cardiac side effects and insufficient evidence of analgesic efficacy)
• Lacosamide
• Lamotrigine
• Oxcarbazepine (risk of hyponatremia)
• Topiramate
• Valproate (liver toxic)
• Zonisamide
• Cannabinoids
• Vit. B 1
• Lidocaine plaster
• Capsaicin ointment

If sufficient pain treatment is not possible after 12 weeks, the patient should be referred to a pain therapist (BÄK 2015).

In patients with dPNP, the need for rehabilitation should be assessed and initiated if necessary (Sommer 2019).

Optimizing the metabolic state has only a minor effect in dPNP (Heuß 2019).

In diabetes patients with previously unremarkable examination results, neuropathy screening should be performed once a year (BÄK 2015).

1. Bundesärztekammer (BÄK), Kassenärztliche Bundesvereinigung (KBV), Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF). National health care guideline on neuropathy in adult diabetes - abridged version, 1st edition. Version 2. 2012, last modified: January 2015. Available from: http://www.dm-neuropathie.versorgungsleitlinien.de; [cited: dd.mm.yyyy]; DOI: 10.6101/AZQ/000224. Internet: http://www.versorgungsleitlinien.de, http://www.awmf-leitlinien.de
2. Geber C et al (2019) Pathophysiology of pain in diabetic polyneuropathy. The Diabetologist (15) 641 - 646
3. Grifka J, Köck F X et al (2007) Praxiswissen Halte- und Bewegungsorgane: diabetic foot syndrome. Thieme Verlag 54 - 58
4. Haag T et al. (2012) Diabetology for practice: case-oriented presentation - diagnostics and therapy. Thieme Verlag 201 - 202, 443 - 447
5. Herold G et al (2020) Internal medicine. Herold Publishers 726 - 727, 741
6. Heuß D et al. (2019) Polyneuropathies, S1 guideline, 2019, in: German Society of Neurology (ed.), Guidelines for diagnosis and therapy in neurology. Online: www.dgn.org/leitlinien
7. Khani A (2009) Studies on the influence of stimulus interval on the habituation of pain threshold elevation. Dissertation for the degree of doctor of medicine in Hannover Medical School.
8. Kasper D L et al (2015) Harrison's Principles of Internal Medicine. Mc Graw Hill Education 2426 - 2427
9. Neundörfer B et al (1996) Series: Diabetic neuropathy - pathogenense and therapy of peripheral diabetic polyneuropathies. Dtsch Arztebl 93 (15) A: 963 / B: 821 / C:745
10. Neundörfer B et al. (2007) Reference series Neurology- Clinical neurology: Polyneuropathies. Thieme Verlag 77 - 78
11. Sommer C (2019) Neuropathy in diabetes: always diabetic polyneuropathy? The Diabetologist (15) 622 - 627
12. Stiefelhagen P (2018) Poor prognosis in diabetic polyneuropathy. MMW- Advances in Medicine (160) 10 - 11
13. Ziegler D (2020) Diabetic polyneuropathy. The Diabetologist (16) 195 - 206