Diabetic somatic neuropathy - Pathogenesis, clinical manifestations and therapeutical concepts

Diabetic polyneuropathy is the most frequent neuropathy in western countrie s. In Germany, there are 3.5 to 4 million diabetic patients. Diagnosis shou ld rule out other polyneuropathies and assess two out of the five diagnosti c criteria: neuropathic symptoms, neuropathic deficits, pathological nerve conduction studies, pathological quantitative sensory testing and pathologi cal quantitative autonomic testing. So far, the pathophysiology of diabetic neuropathy remains to be fully understood. Among the various pathophysiolo gical concepts are the Sorbitol-Myo-Inositol hypothesis attributing Myo-Ino sitol depletion to the accumulation of Sorbitol and Fructose, the concept o f deficiency of essential fatty acids with reduced availability of gamma-li nolenic-acid and prostanoids, the pseudohypoxia- and hypoxia-hypothesis att ributing endothelial and axonal dysfunction and structural lesions to incre ased oxidative stress and free radical production. Obviously, the hyperglyc emia induced generation of advanced glycation end products (AGEs) also cont ributes to structural dysfunctions and lesions. Elevated levels of circulat ing immune complexes and activated T-lymphocytes as well the identification of autoantibodies against vagus nerve or sympathetic ganglia support the c oncept of an immune mediated neuropathy. The reduction of neurotrophic fact ors such as nerve growth factor, neurotrophin-3 or insulin-like growth fact ors also seems to further diabetic neuropathy. The symmetrical, distally pr onounced 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 se nsation, position sense, vibratory perception and diminished or absent ankl e deep tendon reflexes. The painful sensory diabetic neuropathy primarily a ffects 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 a nd is painful. Cranial nerve III-neuropathy is also painful and has an acut e onset. Truncal radiculopathy follows the distribution of truncal roots an d frequently causes intense pain. Autonomic neuropathy occurs with and with out somatic neuropathy. The most important therapy is to attempt optimal bl ood glucose control, to reduce body weight and hyperlipidemia. Symptomatic therapy includes alpha-lipoic acid treatment, as the antioxidant seems to i mprove neuropathic symptoms. Aldose reductase inhibitors might reduce sorbi tol and fructose production and normalize myo-inositol levels. However, the re are no aldose reductase inhibitors available in Europe as yet. Evening p rimrose oil, containing gamma-linolenic acid, might improve nerve conductio n velocities, temperature perception, muscle strength, tendon reflexes and sensory function. Substitution of nerve growth factor showed promising resu lts in pilot studies but failed in a large-scale multicenter study. Symptom atic pain treatment can be achieved with tricyclic antidepressants, selecti ve serotonin reuptake inhibitors, anticonvulsants such as carbamazepine, ga bapentin or lamotrigine, or antiarrhythmic drugs such as mexiletine. Topica l capsaicin application should reduce neuropathic pain but also induces loc al discomfort in the beginning of therapy. Vasoactive substances, so far ha ve not proven to be of major benefit in diabetic neuropathy. Physical thera py and thorough footcare are of primary importance and allow prevention of secondary complications such as foot amputations.