Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Metabolic Neuropathy

  • Author: Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
 
Updated: Oct 27, 2014
 

Background

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.

Next

Pathophysiology

Little is known about the mechanisms underlying metabolic peripheral neuropathy. As stated above, metabolic impairment causes demyelination or axonal degeneration.

Diabetic polyneuropathy

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.[5] 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.[6]

A role for hypoglycemia has also been demonstrated; peripheral nerve damage has been demonstrated in insulinoma and in animal models of insulin-induced hypoglycemia.

Uremic polyneuropathy

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.

Thyroid neuropathy

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.

Previous
Next

Epidemiology

Frequency

United States

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%.[7] In a large prospective study done by Pirart, the prevalence rose from 7.5% at the time of diagnosis to 50% after 25 years.[8] Many patients with diabetes may have asymptomatic peripheral neuropathy; thus, the early use of neurophysiologic tests may help in clarifying the true incidence.[9]

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]

Mortality/Morbidity

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.[12]

Race

No significant differences in the incidence of metabolic neuropathy have been attributed to race.

Sex

Uremic neuropathy is more frequent in males than in females.

Age

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).
Previous
 
 
Contributor Information and Disclosures
Author

Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS Professor Emeritus of Neurology and Psychiatry, Clinical Professor of Medicine, Clinical Professor of Family Medicine, Clinical Professor of Neurosurgery, State University of New York Upstate Medical University; Neuroscience Director, Department of Neurology, Crouse Irving Memorial Hospital

Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS is a member of the following medical societies: American College of International Physicians, American Heart Association, American Stroke Association, American Academy of Neurology, American Academy of Pain Medicine, American College of Forensic Examiners Institute, National Association of Managed Care Physicians, American College of Physicians, Royal College of Physicians, Royal College of Physicians and Surgeons of Canada, Royal College of Surgeons of England, Royal Society of Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Glenn Lopate, MD Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Consulting Staff, Department of Neurology, Barnes-Jewish Hospital

Glenn Lopate, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, Phi Beta Kappa

Disclosure: Nothing to disclose.

Chief Editor

Nicholas Lorenzo, MD, MHA, CPE Founding Editor-in-Chief, eMedicine Neurology; Founder and CEO/CMO, PHLT Consultants; Chief Medical Officer, MeMD Inc

Nicholas Lorenzo, MD, MHA, CPE is a member of the following medical societies: Alpha Omega Alpha, American Association for Physician Leadership, American Academy of Neurology

Disclosure: Nothing to disclose.

Additional Contributors

Milind J Kothari, DO Professor, Department of Neurology, Pennsylvania State University College of Medicine; Consulting Staff, Department of Neurology, Penn State Milton S Hershey Medical Center

Milind J Kothari, DO is a member of the following medical societies: American Academy of Neurology, American Neurological Association, American Association of Neuromuscular and Electrodiagnostic Medicine

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors, Fernando Dangond, MD, and Luis Carlos Sanin, MD, to the development and writing of this article.

References
  1. Tamborlane WV, Ahern J. Implications and results of the Diabetes Control and Complications Trial. Pediatr Clin North Am. 1997 Apr. 44(2):285-300. [Medline].

  2. Pop-Busui R, Herman WH, Feldman EL, Low PA, Martin CL, Cleary PA, et al. DCCT and EDIC studies in type 1 diabetes: lessons for diabetic neuropathy regarding metabolic memory and natural history. Curr Diab Rep. 2010 Aug. 10(4):276-82. [Medline].

  3. Greene DA, Stevens MJ, Feldman EL. Diabetic neuropathy: scope of the syndrome. Am J Med. 1999 Aug 30. 107(2B):2S-8S. [Medline].

  4. Voulgari C, Psallas M, Kokkinos A, Argiana V, Katsilambros N, Tentolouris N. The association between cardiac autonomic neuropathy with metabolic and other factors in subjects with type 1 and type 2 diabetes. J Diabetes Complications. 2011 May-Jun. 25(3):159-67. [Medline].

  5. Stirban A. Microvascular dysfunction in the context of diabetic neuropathy. Curr Diab Rep. 2014 Nov. 14(11):541. [Medline].

  6. Dyck PJ, Norell JE, Dyck PJ. Microvasculitis and ischemia in diabetic lumbosacral radiculoplexus neuropathy. Neurology. 1999 Dec 10. 53(9):2113-21. [Medline].

  7. Harati Y. Frequently asked questions about diabetic peripheral neuropathies. Neurol Clin. 1992 Aug. 10(3):783-807. [Medline].

  8. Pirart J. [Diabetes mellitus and its degenerative complications: a prospective study of 4,400 patients observed between 1947 and 1973 (3rd and last part) (author's transl)]. Diabete Metab. 1977 Dec. 3(4):245-56. [Medline].

  9. Arezzo JC. New developments in the diagnosis of diabetic neuropathy. Am J Med. 1999 Aug 30. 107(2B):9S-16S. [Medline].

  10. Chalk CH. Acquired peripheral neuropathy. Neurol Clin. 1997 Aug. 15(3):501-28. [Medline].

  11. Dick PJ, Thomas PK, eds. Peripheral Neuropathy. 3rd ed. Philadelphia: WB Saunders Co; 1993.

  12. Comi G, Corbo M. Metabolic neuropathies. Curr Opin Neurol. 1998 Oct. 11(5):523-9. [Medline].

  13. Thomas PK, Tomlinson DR. Diabetic and hypoglycemic neuropathy. Dick PJ, Thomas PK, eds. Peripheral Neuropathy. Philadelphia: WB Saunders Co; 1993. 1221.

  14. Apfel SC. Neurotrophic factors in the therapy of diabetic neuropathy. Am J Med. 1999 Aug 30. 107(2B):34S-42S. [Medline].

  15. Misiunas A, Niepomniszcze H, Ravera B, et al. Peripheral neuropathy in subclinical hypothyroidism. Thyroid. 1995 Aug. 5(4):283-6. [Medline].

  16. Kyle RA. Monoclonal proteins in neuropathy. Neurol Clin. 1992 Aug. 10(3):713-34. [Medline].

  17. Barlogie B, Tricot G, Anaissie E, Shaughnessy J, Rasmussen E, van Rhee F, et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med. 2006 Mar 9. 354(10):1021-30. [Medline].

  18. Simmons DN, Lisle DA, Linklater JM. Imaging of Peripheral Nerve Lesions in the Lower Limb. Techniques in Foot & Ankle Surgery. 2008/12. 7(4):224-237.

  19. Lisle DA, Johnstone SA. Usefulness of muscle denervation as an MRI sign of peripheral nerve pathology. Australas Radiol. 2007 Dec. 51(6):516-26. [Medline].

  20. Burn DJ, Bates D. Neurology and the kidney. J Neurol Neurosurg Psychiatry. 1998 Dec. 65(6):810-21. [Medline].

  21. Krishnan AV, Lin CS, Park SB, Kiernan MC. Assessment of nerve excitability in toxic and metabolic neuropathies. J Peripher Nerv Syst. 2008 Mar. 13(1):7-26. [Medline].

  22. Callaghan B, Feldman E. The metabolic syndrome and neuropathy: therapeutic challenges and opportunities. Ann Neurol. 2013 Sep. 74(3):397-403. [Medline]. [Full Text].

  23. Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain. 1999 Dec. 83(3):389-400. [Medline].

  24. Lagueny A. [Metabolic and nutritional neuropathies]. Rev Prat. 2000 Apr 1. 50(7):731-5. [Medline].

  25. Freeman R, Durso-Decruz E, Emir B. Efficacy, safety, and tolerability of pregabalin treatment for painful diabetic peripheral neuropathy: findings from seven randomized, controlled trials across a range of doses. Diabetes Care. 2008 Jul. 31(7):1448-54. [Medline]. [Full Text].

  26. Azoulay D, Samuel D, Castaing D, et al. Domino liver transplants for metabolic disorders: experience with familial amyloidotic polyneuropathy. J Am Coll Surg. 1999 Dec. 189(6):584-93. [Medline].

  27. Kaminski HJ, Ruff RL. Neurologic complications of endocrine diseases. Neurol Clin. 1989 Aug. 7(3):489-508. [Medline].

  28. Kluding PM, Pasnoor M, Singh R, D'Silva LJ, Yoo M, Billinger SA, et al. Safety of Aerobic Exercise in People With Diabetic Peripheral Neuropathy. Phys Ther. 2014 Oct 2. [Medline].

  29. Parry GJ. Management of diabetic neuropathy. Am J Med. 1999 Aug 30. 107(2B):27S-33S. [Medline].

 
Previous
Next
 
Table 1. Symptoms and Signs of Peripheral Neuropathy*
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.[14]
Previous
Next
 
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.