- Author: Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE more...
The term metabolic neuropathy includes a wide spectrum of peripheral nerve disorders associated with systemic diseases of metabolic origin. These diseases include diabetes mellitus, hypoglycemia, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, disorders of lipid/glycolipid metabolism, nutritional/vitamin deficiencies, and mitochondrial disorders, among others. The common hallmark of these diseases is involvement of peripheral nerves by alteration of the structure or function of myelin and axons due to metabolic pathway dysregulation.
Diabetic mellitus is the most common cause of metabolic neuropathy, followed by uremia. Recognizing that some disorders involving peripheral nerves also affect muscles is important. This article reviews the general aspects of metabolic neuropathy; the reader is referred to other Medscape Reference articles on nutritional and diabetic neuropathy for more detailed information (see Differentials). This article mentions some aspects of diabetic neuropathy but does not discuss nutritional neuropathy.
Little is known about the mechanisms underlying metabolic peripheral neuropathy. As stated above, metabolic impairment causes demyelination or axonal degeneration.
Although controversial, most studies suggest that diabetic polyneuropathy has a multifactorial etiology. Results from the Diabetes Control and Complications Trial (DCCT) demonstrated that hyperglycemia and insulin deficiency contribute to the development of diabetic neuropathy and that glycemia reduction lowers the risk of developing diabetic neuropathy by 60% over 5 years.[1, 2] Decreased bioavailability of systemic insulin in diabetes may contribute to more severe axonal atrophy or loss. Different levels of involvement of peripheral nerve are found in type 1 and type 2 diabetes, with milder compromise in type 2.[3, 4]
Studies in rats have demonstrated involvement of the polyol pathway. Myoinositol and taurine depletion have been associated with reduced Na+/K+ -ATPase activity and decreased nerve conduction velocities (NCVs), all of which are corrected by aldose reductase inhibitors in rat studies. Recent studies have suggested that aldose reductase inhibitors may also improve NCVs and protect small sensory fibers from degeneration. Unfortunately, treatment with these agents so far has failed to show any significant benefits in humans.
Sural nerve biopsies from patients with diabetes have demonstrated changes suggestive of microvascular insufficiency, including membrane basement thickening, endothelial cell proliferation, and vessel occlusions. Rats with diabetes have been shown to have reduced blood flow to the nerves. Ischemia from vascular disease induces oxidative stress and injury to nerves via an increase in the production of reactive oxygen species. Some studies have suggested that antioxidant therapy may improve NCVs in diabetic neuropathy. These findings suggest that the metabolic and vascular hypotheses may be linked mechanistically.
Another mechanism in diabetic neuropathy is impaired neurotrophic support. Nerve growth factor (NGF) and other grow factors, such as NT3, IGF-I, and IGF-II, may be decreased in tissues affected by diabetic neuropathy. Other factors such as abnormalities in vasoactive substances and nonenzymatic glycation have demonstrated possible involvement in diabetic neuropathy development.
A glycoprotein called laminin promotes neurite extension in cultured neurons. Lack of expression of the laminin beta2 gene may contribute to the pathogenesis of diabetic neuropathy.
Recent studies suggest that microvasculitis and ischemia may play significant roles in development of diabetic lumbosacral radiculoplexoneuropathy.
A role for hypoglycemia has also been demonstrated; peripheral nerve damage has been demonstrated in insulinoma and in animal models of insulin-induced hypoglycemia.
In uremic polyneuropathy, conduction velocity slowing is believed to result from inhibition of axolemma-bound Na+/K+ -ATPase by uremic toxins, leading to intracellular sodium accumulation and altered resting membrane potentials. Eventually, this results in axonal degeneration with secondary segmental demyelination.
Little is known about thyroid neuropathy, but studies have shown microvascular and endoneurial ischemic involvement like that in diabetes. In rats with hypothyroidism, no significant changes of NCVs occurred 5 months after onset, but alterations in latencies in brainstem evoked potentials have been demonstrated. The earliest observation was the deposit of mucopolysaccharide-protein complexes within the endoneurium and perineurium, but these studies await confirmation. Reductions in myelinated fibers, mostly of large diameter, and Renaut bodies have been noted; other studies have shown axonal degeneration.
Rarely, hyperthyroidism may be associated with polyneuropathy.
Diabetic neuropathy is the most common metabolic peripheral neuropathy. Because of differences in definition of diabetic peripheral neuropathy, epidemiologic studies reviewing an absence of symptoms have shown different results, varying from 5% to as high as 60-100%. In a large prospective study done by Pirart, the prevalence rose from 7.5% at the time of diagnosis to 50% after 25 years. Many patients with diabetes may have asymptomatic peripheral neuropathy; thus, the early use of neurophysiologic tests may help in clarifying the true incidence.
The second most common metabolic neuropathy is that associated with uremia, with studies showing ranges of peripheral neuropathy prevalence of 10-80%. However, because uremia often presents in the setting of other systemic diseases associated with peripheral neuropathy, such as diabetes, prevalence studies are difficult to perform and interpret.
Most peripheral neuropathies have in common greater severity with poorer control of the underlying disease. When the underlying disease is controlled properly, other causes of peripheral neuropathy, unrelated to the metabolic condition, must be considered.[10, 11]
Metabolic neuropathies cause autonomic involvement, which can be so severe as to lead to sudden death. In patients with diabetes, it has been called the "death in bed syndrome," but its real prevalence is not known. Another complication in diabetic neuropathy is the development of foot ulcers, and some reports have estimated that this occurs in approximately 2.5% of patients with diabetes.
No significant differences in the incidence of metabolic neuropathy have been attributed to race.
Uremic neuropathy is more frequent in males than in females.
See the list below:
Diabetic neuropathy may be more common in elderly patients. Milder diabetic neuropathy has been reported in type 2 diabetes, which most commonly affects the elderly population.
Rarely, metabolic neuropathies are associated with congenital and hereditary causes and are more common in childhood (ie, inherited metabolic disorders, mitochondrial diseases).
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|Small-Fiber Sensory||Large-Fiber Sensory||Autonomic|
|Burning pain||Loss of vibration||Heart rate changes|
|Cutaneous allodynia||Proprioception loss||Postural blood pressure change|
|Paresthesias||Loss of reflexes||Abnormal sweating|
|Lancinating pain||Slowed NCVs||Gastroparesis|
|Loss pain/temperature||Sensory ataxia||Impotence|
|Foot ulcers||Weakness||Abnormal ejaculation|
|Visceral pain loss|
|* Modified from Apfel, 1999.|