Peripheral Neuropathies Associated with Diabetes Mellitus; A Review Article
Maruf Raza AKM1*
1. Assistant Professor of Pathology, Jahurul Islam Medical College, Bajitpur, Kishoregonj, Bangladesh.
Objective: To describe diabetes mellitus associated various peripheral neuropathies related various diseases and clinical features.
Methods: English-language literature search using a combination of words (diabetic neuropathy, diagnosis,) was used to identify original studies, consensus statements, and reviews published in the last few years.
Results: The diverse neuropathies of diabetes mellitus seen in various research article which is found in clinical practice.
Conclusion: Prompt diagnosis and recognition of these with the institution of appropriate treatment measures would go a long way towards reducing morbidity and mortality outcomes.
Key words: Diabetes, Peripheral, Neuropathies
Diabetic peripheral neuropathy is defined as the presence of symptoms and signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes1. It manifests in the somatic, sensory and or autonomic parts of the peripheral nervous system2. The sensory phenotype is divided into: small, large or mixed fiber types. Symptoms of neuropathy are very common, and subclinical neuropathy is more common than clinical neuropathy3. Neuropathy may remain undetected, and progress over time leading to serious complications. With the rising global burden of diabetes, peripheral neuropathy, and other diabetes complications are expected to be on the increase. This would negatively affect their quality of life and mortality. The most common clinical presentation of diabetic peripheral neuropathy is distal symmetrical polyneuropathy4.
This review focuses on the common neuropathies encountered in clinical practice. We also bring to fore the rarely thought about neuropathies commonly misdiagnosed as other conditions. A good knowledge of these neuropathies would go a long way in improving the patient care offered by the diabetes clinician.
2. Anatomic Considerations
Small fiber neuropathies manifest with painful paresthesias most commonly over the lower limb. The pain may be dull, aching, burning, lancinating or cramp-like. Paresthesias may manifest as a sensation of coldness, numbness or tingling. There may be associated diminution of pain and temperature perception in the lower limbs in a glove and stocking distribution. Features of large fiber neuropathy include loss of ankle jerk, impaired position, and vibration sense, sensory ataxia Mixed small and large fiber neuropathy is the most common variety of painful diabetic neuropathy5.
3. Acute Painful Neuropathy
First described by Archer et al.6 in 1983, is a distinct and common variant of distal symmetrical polyneuropathy that presents with abrupt onset of severe sensory symptoms with little or no sensory and motor signs. It usually follows a period of change in glycemic control. It usually starts with rapid weight loss over a short period followed by severe, unremitting pain mostly in the feet. Optimizing glycaemic control eventually leads to weight gain and remission of symptoms7.
4. Chronic Sensorimotor Distal Symmetrical Polyneuropathy
Chronic sensorimotor distal symmetrical polyneuropathy (DSPN) is the most common form of diabetic neuropathy. It is present in more than 10% of patients at the diagnosis of type 2 diabetes with an insidious onset. More than 80% of patients with clinical diabetic neuropathy have a distal symmetrical form of the disorder8.
Symptoms may be positive or negative. Positive symptoms include feelings of pins and needles, tingling, burning, and neuropathic pain. Negative symptoms include numbness, impaired tactile, thermal and pain sensation. Positive symptoms, probably due to neural hyperexcitability, includepins and needles and pain which may be of varying qualities (burning, aching or lancinating). These negative and positive sensory symptoms may coexist. Symptoms begin distally in the toes and the feet and gradually extend proximally to involve the hands and fingers. This pattern of spread or progression reflects the dying-back nature of underlying nerve damage9.
5. Painful Small Fiber Neuropathy
It is a variant of distal sensorimotor polyneuropathy in which the small myelinated fibers are affected alone or out of proportion to large nerve fibers. Key complaints are burning or stabbing pain in the feet which may be spontaneous10. This form of neuropathy is usually distressing and debilitating, impairing patient’s quality of life.
6. Focal limb neuropathies
Most persons with diabetes and upper limb neuropathic symptoms and signs will either have a mononeuropathy or multiple mononeuropathies. This adds to the disability already imposed by the polyneuropathy that is almost always present. Ulnar neuropathies in people with diabetes are often insidious and are mainly motor with limited sensory symptoms and signs. Such focal neuropathies can easily go undetected because their symptoms are thought to be due to a polyneuropathy11. When sensory or motor symptoms are more prominent in the hands than feet, carpal tunnel syndromes or ulnar neuropathies should be suspected and excluded.
7. Cranial Neuropathies (Diabetic Ophthalmoplegia)
Oculomotor nerve palsies are the most common cranial neuropathy observed in diabetic patients. It occurs in rarely occurs in children. It affects mostly middle age adults. The pupillary function is spared. It has been attributed to ischemia occurring centrally within the third nerve, preserving the peripherally located parasympathetic pupil- constrictor fibers. This is in contrast to compressive lesions of the oculomotor nerve, such as an aneurysm of the posterior communicating artery, in which the pupillary fibers are affected12. Sixth nerve palsies also occur, but rarely. It is unclear whether seventh nerve palsies occur more frequently in people with diabetes than in the general population.
8. Compression Neuropathies
Compression or entrapment neuropathies are more common in people with diabetes. They include carpal tunnel syndrome (CTS), ulnar neuropathy at the elbow (UNE), meralgia paraesthetica (entrapment of the lateral femoral cutaneous nerve of the thigh) at the inguinal ligament or peroneal neuropathy at the fibular head13. Nerve conduction studies should be carried to conform compressive median or ulnar mononeuropathies and to screen for associated axonal injury. Those found to have pure demyelinating neuropathy usually respond well to positional splints while those with active demyelination are treated with carpal tunnel decompression which as nearly as effective for diabetic patients as for normoglycemic controls14.
9. Diabetic Truncal Radiculoneuropathy
It occurs in the setting of long-standing diabetes with other complications, especially polyneuropathy. Most of the affected individuals are in the 5th or 6th decade of life with a variable duration of diabetes15. It presents gradually with painful paresthesias in variable size patches unilaterally or bilaterally in the lower anterior chest or upper abdomen with nocturnal worsening. Associated involvement of motor nerve fibers can lead to bulging of the abdominal wall in the paraesthetic areas, best appreciated when the patient is standing.
10. Chronic Inflammatory Demyelinating Polyneuropathy
Patients with DM seem to develop clinical and electrophysiologic characteristics in keeping with CIDP. This condition tends to occur more frequently in people with diabetes than in non-diabetics. The rapid onset and progression of the neuropathy, demyelinating features on nerve conduction studies and an excellent response toimmunomodulatory treatments distinguish this entity from the far more frequent chronic diabetic sensorimotor polyneuropathy16. Treatment should be instituted promptly to prevent ongoing demyelination and the secondary axonal loss that would result in permanent disability.
11. Hypoglycemic Neuropathy
It is a distal symmetrical predominantly sensory neuropathy occurring on a background of recurrent episodic symptoms secondary to hypoglycemia. Hypoglycemia causes effects in both the central and peripheral nervous systems. Energy depletion plays a key role in the pathogenesis of hypoglycemia induced neuropathy17. Ischemia also plays a role. The electrophysiological findings are suggestive of a primary axonal neuropathy with evidence of secondary demyelination. The pathologic changes in hypoglycemic neuropathy may include axonal neuropathy, anterior horn cells destruction in cervical spinal cord with normal dorsal and ventral roots and dorsal root ganglia, or even a normal nerve18. There is a need to exclude the presence of an insulinoma as the literature on humans developing a hypoglycemic neuropathy is small and related to the presence of an insulinoma.
12. Impaired Glucose Tolerance Neuropathy
This occurs in persons with normal fasting glucose and glycosylated hemoglobin values. However, they have impaired glucose tolerance (IGT) on oral glucose tolerance testing. This form of diabetic neuropathy manifests as a predominantly sensory neuropathy. Small fiber neuropathic changes occur more commonly in persons with IGT than the normal population19. This neuropathy is clinically similar to early diabetic neuropathy with a predilection for small fiber damage leading to distressing pain and autonomic symptoms.
13. Diabetic Autonomic Neuropathy
Autonomic nerve involvement is probably the most undiagnosed complication. Diabetic autonomic neuropathy (DAN) may present in multiple organ systems in undiagnosed patients and can result in significant morbidity and mortality. Autonomic dysfunction may already exist at the time of type 2 DM diagnosis, and its prevalence in the diabetic population rises with time. In type 1 DM, hypoglycemia unawareness is the most common symptom20. Autonomic nerve fibers are invariably involved in chronic sensorimotor polyneuropathy, frequently subclinical in the early stages of the polyneuropathy, although it may be detected using sensitive methods to measure and quantify autonomic function. When symptomatic, this may result in impaired sweating and some skin vasomotor changes. However, the autonomic nervous system may become widely involved and dominate the clinical picture. In most patients, the symptoms are not severe, but some have devastating diabetic autonomic neuropathy. The neuropathy may affect all or selected organs or systems innervated by the autonomic nervous system. Thus one or more of the following may develop gastroparesis, diarrhea, constipation, orthostatic hypotension, bladder dysfunction, and erectile dysfunction. About 40% of diabetic men develop erectile dysfunction which may occur in the absence of, or in association with, other manifestations of diabetic autonomic neuropathy21. The clinical examination of the autonomic nervous system is limited. A resting tachycardia and a fixed heart rate of deep breathing or when the patient goes from lying to standing indicate vagal parasympathetic dysfunction. The simple bedside measurement of lyingstanding blood pressure change is an important test for sympathetic vasoconstrictor dysfunction.
It is important for clinicians to be knowledgeable about the various neuropathic complications of DM. Autonomic involvement which is a leading cause of mortality in these patients may mistake for other disease complications. Prompt diagnosis and recognition of these with the institution of appropriate treatment measures would go a long way towards reducing morbidity and mortality outcomes.
1. Boulton AJM, Malik RA, Arezzo JC, Sosenko JM. Diabetic somatic neuropathies Diabetes Care. 2005; 27(6)1458- 1486.
2. Boulton AJM, Vinik AJ, Arezzo JC, Bril V, Feldman EL, Freeman R, et al. Diabetic neuropathies. Diabetes Care. 2005; 28(4):956-962.
3. Eastman RC. Neuropathy in Diabetes. In Diabetes in America, Harris MI, Ed. National Diabetes Information, Clearinghouse, 2nd Edition. 1995, 339-360.
4. Kasznicki J. Advanves in the diagnosis and management of diabetic distal symmetric polyneuropathy. Archives of Medical Science. 2014; 10(2):345-354.
5. Vinik AI, Mehrabian A. Diabetic neuropathies. Medical Clinics North America. 2004; 88(4):947-99.
6. Archer AG, Watkins PJ, Thomas PK, Sharma AK, Payan J. The natural history of acute painful neuropathy in diabetes mellitus. Journal of Neurology, Neurosurgery and Psychiatry. 1983; 46(6):491-9.
7. Thomas PK. Classification, differential diagnosis and staging of diabetic peripheral neuropathy. Diabetes. 1997; 46(2):S54-7.
8. De Freitas MRG. Diabetic neuropathy I-Epidemiology, classification, clinical and electrophysiologic aspects. A study of 210 cases. Rev Brasileira Neurol. 1992; 28:69-73.
9. Boulton AJM, Amstrong WD, Scarpello JH, Ward JD. The natural history of painful diabetic neuropathy: a 4-year study. Postgraduate Medical Journal.1983;59(695):556-9.
10. Vital C, Vital A, Dupont M, Gin H, Rouanet-Larriviere M, Lacut JY. Acute painful diabetic neuropathy: two patients with recent IDDM. Journal of the Peripheral Nervous System. 1996; 2(2):151-154.
11. Dyck PJ, Dyck PJB, Englestad J. Pathologic alterations of nerve. Peripheral Neuropathy. 2005; 1:733-829.
12. Said G. Focal and multifocal diabetic neuropathies. Arquivos de neuro-psychiatria. 2007; 65(4B):1272-1278.
13. Asbury AK, Aldredge H, Hershberg R, Fischer CM. Oculomotor palsy in diabetes mellitus: a clinicopathological study. Brain. 2016; 93(3):555-566.
14. Thomsen NO, Cederlund R, Rosén I, Björk J, Dahlin LB. Clinical outcomes of surgical release among diabetic patients with carpal tunnel syndrome: prospective follow-up with matched controls. The Journal of Hand Surgery. 2009; 34(7):1177-1187.
15. Pourmand R. Diabetic neuropathy. Neurology Clinics. 1997; 15(3):569-76.
16. Krendel DA, Costigan DA, Hopkins LC. Successful treatment of neuropathies in patients with diabetes mellitus. Archives of Neurology. 1995; 52(11):1053-1061.
17. Hsu YC, Zhan HL, Yang CP. Clinical and experimental evidence of hypoglycemic neuropathy. Diabetes Res Open Journal. 2015; 1(5):131-135.
18. Tom MI, Richardson JC. Hypoglycemia from islet cell tumour of pancreas with amyotrophy and cerebrospinal nerve cell changes: A case report. Journal of Neuropathology and Experimental Neurology. 1951; 10(1):57-66.
19. Boulton AJM, Malik RA. Neuropathy of Impaired Glucose Tolerance and Its Measurement Diabetes Care. 2010; 1(33):207-209.
20. Vinik AI, Maser RE, Freeman R. Diabetic Autonomic Neuropathy (Technical Review). Diabetes Care. 2003; 26(5):1553-1579.
21. Toyry JP, Niskanem JK, Mantyscari MJ, Lansimies EA, Uusitupa MIJ. Occurrence, predictors and clinical significance of autonomic neuropathy in NIDDM: ten year follow-up from diagnosis. Diabetes. 1996; 45(3):308-315.