Diabetische somatische Polyneuropathie

Zusammenfassung:

Die diabetische Polyneuropathie ist die häufigste Neuropathie in westlichen Ländern. In Deutschland sind 3,5 bis 4 Mio. Patienten an Diabetes mellitus erkrankt. Bei der Diagnosestellung sollten andere Polyneuropathie-Ursachen ausgeschlossen werden und wenigstens zwei der fünf Diagnosekriterien neuropathische Symptome, neuropathische Defizite, pathologische Nervenleitgeschwindigkeiten, pathologische quantitativ sensible Testung, pathologische quantitativ autonome Untersuchung nachweisbar sein. Bislang ist die Pathophysiologie der diabetischen Polyneuropathie noch nicht völlig geklärt. Zu den verschiedenen pathophysiologischen Konzepten zählen die Sorbitol-Myo-Inositol-Hypothese, nach der in Folge einer Anhäufung von Sorbitol und Fruktose eine Myo-Inositol-Verarmung eintritt, die Hypothese des Mangels an essenziellen Fettsäuren mit geminderter Verfügbarkeit von Gamma-Linolensäure und Prostanoiden, die Peudohypoxie- und Hypoxie-Hypothese, nach der endotheliale und axonale Störungen sowie strukturelle Schäden auf eine Vermehrung des oxidativen Stresses und der freien Radikalproduktion zurückzuführen sind. Wesentlich erscheint auch die Rolle der unter Hyperglykämie anfallenden advanced glycation end products (AGEs). AGEs tragen zu strukturellen Funktionsstörungen und Schäden bei. Erhöhte Spiegel zirkulierender Immunkomplexe und aktivierter T-Lymphozyten sowie der Nachweis von Antikörpern gegen Nervengewebe, z. B. den Vagusnerv oder sympathische Ganglienzellen, unterstützen die Hypothese einer immunvermittelten Neuropathie. Die Verminderung neurotropher Faktoren, wie etwa nerve growth factor, Neurotrophin-3 oder Insulin-like growth factor scheint auch zur Entstehung der diabetischen Neuropathie beizutragen.

Die symmetrisch-distal betonte und vorwiegend sensible Neuropathie ist weitaus häufiger anzutreffen als die symmetrisch-paretische Form oder die asymmetrischen Neuropathien. Die schmerzlose Neuropathie ist gekennzeichnet durch Störungen der Berührungsempfindung, des Lagesinns und des Vibrationsempfindens. Muskeleigenreflexe, insbesondere die Achillessehnenreflexe, sind gemindert oder fehlen. Die schmerzhafte sensible diabetische Neuropathie betrifft vor allem die kleinen Nervenfasern und verursacht eine Störung des Temperaturempfindens sowie Parästhesien. Die proximale, diabetische Amyotrophie entsteht akut oder subakut und verursacht Paresen der Beckengürtelmuskulatur und der vom Nervus femoralis innervierten Oberschenkelmuskulatur. Diabetische Hirnnervenausfälle beginnen oft akut und schmerzhaft. Diabetische Radikulopathien halten sich an das Versorgungsgebiet eines Spinalnerven im Rumpfbereich und verursachen gürtelförmige Schmerzen sowie gegebenenfalls Bauchwandparesen. Die autonome diabetische Polyneuropathie kann gleichzeitig mit oder ohne somatische Neuropathie auftreten.

Wichtigstes Therapieziel ist eine weitgehende Normalisierung der Blutglukosespiegel, die Reduktion von Übergewicht und erhöhten Blutfettwerten. Zur symptomatischen Therapie steht Alpha-Liponsäure zur Verfügung. Das Antioxidanz scheint neuropathische Symptome zu verbessern.

Aldosereduktasehemmer könnten die Sorbitol- und Fruktose-Produktion mindern und Myo-Inositolspiegel wieder erhöhen. Derzeit stehen jedoch keine Aldosereduktasehemmer in Europa zur Verfügung. Nachtkerzenöl, das einen hohen Gehalt an Gammalinolensäure hat, könnte nach Studienergebnissen Nervenleitgeschwindigkeiten, Temperaturempfinden, Muskelkraft, Muskeleigenreflexe und sensible Funktionen wieder bessern. Die Substitution von nerve growth factor schien in Pilotstudien vielversprechend zu sein, ergab jedoch in einer großen Multizenterstudie keinen Wirksamkeitsnachweis.

Zur symptomatischen Schmerzbehandlung können trizyklische Antidepressiva, selektive Serotonin-Wiederaufnahmehemmer, Antikonvulsiva wie Carbamazepin, Gabapentin, oder Lamotrigin sowie Antiarrhythmika wie z. B. Mexiletin eingesetzt werden. Topisches Capsaicin kann neuropathische Schmerzen lindern, verursacht zunächst aber lokale Reizerscheinungen und Hyperalgesie. Vasoaktive Substanzen konnten bislang keinen sicheren Nutzen für die Behandlung der schmerzhaften diabetischen Neuropathie aufzeigen. Krankengymnastik und sorgfältige Fußpflege sind von größter Bedeutung und helfen, Sekundärkomplikationen wie Fußulzerationen oder schließlich Amputationen zu vermeiden.

Diabetic Somatic Neuropathy - Pathogenesis, Clinical Manifestations and Therapeutical Concepts:

Diabetic polyneuropathy is the most frequent neuropathy in western countries. In Germany, there are 3.5 to 4 million diabetic patients. Diagnosis should rule out other polyneuropathies and assess two out of the five diagnostic criteria: neuropathic symptoms, neuropathic deficits, pathological nerve conduction studies, pathological quantitative sensory testing and pathological quantitative autonomic testing. So far, the pathophysiology of diabetic neuropathy remains to be fully understood. Among the various pathophysiological concepts are the Sorbitol-Myo-Inositol hypothesis attributing Myo-Inositol depletion to the accumulation of Sorbitol and Fructose, the concept of deficiency of essential fatty acids with reduced availability of gamma-linolenic-acid and prostanoids, the pseudohypoxia- and hypoxia-hypothesis attributing endothelial and axonal dysfunction and structural lesions to increased oxidative stress and free radical production. Obviously, the hyperglycemia induced generation of advanced glycation end products (AGEs) also contributes to structural dysfunctions and lesions. Elevated levels of circulating immune complexes and activated T-lymphocytes as well the identification of autoantibodies against vagus nerve or sympathetic ganglia support the concept of an immune mediated neuropathy. The reduction of neurotrophic factors such as nerve growth factor, neurotrophin-3 or insulin-like growth factors also seems to further diabetic neuropathy.

The symmetrical, distally pronounced and predominantly sensory neuropathy is far more frequent than the symmetrical neuropathy with predominant motor weakness or the asymmetrical neuropathy. The painless neuropathy manifests with impaired light touch sensation, position sense, vibratory perception and diminished or absent ankle deep tendon reflexes. The painful sensory diabetic neuropathy primarily affects small nerve fibers and accounts for decreased temperature perception and paresthesias. The proximal, diabetic amyotrophy evolves subacutely or acutely, induces motor weakness of the proximal thigh and buttock muscles and is painful. Cranial nerve III-neuropathy is also painful and has an acute onset. Truncal radiculopathy follows the distribution of truncal roots and frequently causes intense pain. Autonomic neuropathy occurs with and without somatic neuropathy. The most important therapy is to attempt optimal blood glucose control, to reduce body weight and hyperlipidemia. Symptomatic therapy includes alpha-lipoic acid treatment, as the antioxidant seems to improve neuropathic symptoms. Aldose reductase inhibitors might reduce sorbitol and fructose production and normalize myo-inositol levels. However, there are no aldose reductase inhibitors available in Europe as yet. Evening primrose oil, containing gamma-linolenic acid, might improve nerve conduction velocities, temperature perception, muscle strength, tendon reflexes and sensory function. Substitution of nerve growth factor showed promising results in pilot studies but failed in a large-scale multicenter study. Symptomatic pain treatment can be achieved with tricyclic antidepressants, selective serotonin reuptake inhibitors, anticonvulsants such as carbamazepine, gabapentin or lamotrigine, or antiarrhythmic drugs such as mexiletine. Topical capsaicin application should reduce neuropathic pain but also induces local discomfort in the beginning of therapy. Vasoactive substances, so far have not proven to be of major benefit in diabetic neuropathy.

Physical therapy and thorough footcare are of primary importance and allow prevention of secondary complications such as foot amputations.

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