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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 15  |  Issue : 3  |  Page : 189-199

Approach to diabetic neuropathy


1 Department of Endocrinology, Diabetes and Metabolism, Christian Medical College and Hospital, Vellore, India; Non communicable Diseases Unit, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia
2 Department of Family Medicine, Christian Medical College and Hospital, Vellore, India
3 Department of Endocrinology, Diabetes and Metabolism, Christian Medical College and Hospital, Vellore, India

Date of Web Publication7-Aug-2017

Correspondence Address:
Nitin Kapoor
Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore - 632 004, Tamil Nadu, India

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cmi.cmi_38_17

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  Abstract 


Neuropathy is the most common symptomatic complication of diabetes mellitus(DM) and accounts for a large share of morbidity and hospitalization associated with the disease. The symptoms of neuropathy in diabetes may present with somatic, autonomic, motor or sensory symptoms. Symmetric distal sensory polyneuropathy is the most common form, affecting the distal lower extremities and hands in a “glove and stocking” pattern. Cardiac autonomic neuropathy can, in particular, contribute to 6% of sudden deaths(painless myocardial infarction) among those with long-standing diabetes. Neuropathy whether sensory, motor, or autonomic may lead to the formation of fissures or calluses which lead to ulceration. Tight glycemic control is the only strategy which has demonstrated to show prevention and progress of diabetic peripheral neuropathy and autonomic neuropathy. Early treatment of diabetic neuropathy should, therefore, include tight glycemic control. All patients should be screened for diabetic neuropathy starting at diagnosis of type2 DM and 5years after diagnosis of type1 DM and at least annually thereafter. An annual comprehensive foot examination is a must for all patients with diabetes and consists of examination of foot and footwear, neuropathy screening, vascular assessment, and musculoskeletal assessment of feet. This would help in identification of risk factor predictive of ulcers and amputation.

Keywords: Diabetes mellitus, diabetic neuropathy, peripheral neuropathy


How to cite this article:
Kapoor N, David K, Saravanan B. Approach to diabetic neuropathy. Curr Med Issues 2017;15:189-99

How to cite this URL:
Kapoor N, David K, Saravanan B. Approach to diabetic neuropathy. Curr Med Issues [serial online] 2017 [cited 2019 Mar 19];15:189-99. Available from: http://www.cmijournal.org/text.asp?2017/15/3/189/212366



Case Scenario

A 58-year-old female who had poorly controlled type. 2 diabetes mellitus for 12 years presented in the outpatient clinic with a history of fever and swelling of the left foot for 2 days. She had recently returned from a vacation to a distant pilgrimage center. On examination of the foot, a glass piece was found embedded in the plantar aspect of the left foot, and the surrounding region showed signs of severe inflammation. The remarkable aspect of this case was that she had never experienced any pain in the foot.

What do you think was the cause of the loss of sensation and infection in the foot?

How could it have been prevented?


  Introduction Top


Diabetes is a systemic disease, the incidence of which is rising all over the world. The most common symptomatic complication of diabetes is peripheral neuropathy. It is a microvascular disease that accounts for the most number of hospitalizations among those with diabetes and is the most common cause of nontraumatic amputations and foot ulcers[Figure1].[1],[2] It is also one of the important causes of mortality(through silent myocardial infarction) among diabetics.
Figure1:(a) Incidence of diabetic neuropathy among those with diabetes for>20years.(b) Neuropathy, ulceration and amputation.

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It is estimated that about 90% of patients with diabetes for more than 20years will develop diabetic neuropathy[Figure1]. What is worrying is that in approximately 40% of these patients, the diabetic neuropathy may be asymptomatic.[3] It is important therefore for the physician to actively seek evidence of neuropathy and to make the patient aware of the risk of developing this complication.

Clinical Pearl

When should diabetic patients be tested for neuropathy?All patients with diabetes should be screened for diabetic neuropathy

  • Type 2 diabetes mellitus – starting at the time of the first diagnosis
  • Type 1 diabetes mellitus – starting at 5 years after the diagnosis and at least once a year thereafter.


The costly sequelae of neuropathy-like foot ulceration and amputation are preventable with early detection. The pain associated with neuropathy severely impairs the quality of life, physical activity, and productivity of patients.

The important goals as primary care physicians are:

  • To screen and diagnose neuropathy at an early stage
  • To initiate strict glycemic control which is the main disease modifying option available for neuropathy [4]
  • Initiate evidence-based management of painful neuropathy and to provide good quality of life to these patients
  • Prevent neuropathy-related sequelae like amputation.



  Definition Top


Diabetic peripheral neuropathy may be defined as the “presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after exclusion of other causes”[Box1].[5]



The important thing to note in this definition is any patient with symptoms is also termed to have neuropathy even when signs are absent and vice-versa. It is not essential to have both signs and symptoms before terming it neuropathy; therefore, examination for neuropathy must be done in all long-standing diabetic patients to detect loss of sensation even when symptoms are absent. The risk factors for developing diabetic neuropathy are summarized in [Box 2].




  Classification Top


Diabetic neuropathy can be classified into symmetrical and asymmetrical neuropathies[Table1]. Of these, symmetric distal sensory polyneuropathy is the most common form[Figure2]. This affects distal lower extremities and hands in a “glove and stocking” pattern.
Table 1: Classification of diabetic neuropathy

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Figure2: “Glove and stocking” neuropathy.

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Diabetic neuropathy may also be classified according to the type of nerve fiber[Table2] involved into:
Table 2: Features of small and large fiber neuropathy

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  1. Small fiber neuropathy and
  2. Large fiber neuropathy.



  Clinical Signs and Symptoms Top


The symptoms of neuropathy in diabetes may present with somatic, autonomic, motor, or sensory symptoms [Table3].
Table 3: Symptoms and signs in diabetic neuropathy

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Somatic sensory symptoms

Diabetic neuropathy can involve both the upper and lower limbs. Symmetric distal sensory polyneuropathy is the most common form. This affects distal lower extremities and hands in a “glove and stocking” pattern[Figure2]. Large fiber neuropathy(A delta fibers) is more common and leads to symptoms such as electrical tingling sensation or sensation of a band around the ankles or feet. The patient may have a sense of imbalance, especially at night with prominent gait instability. Small fiber neuropathy(A alpha and C fibers) is less common and results in burning or stabbing paresthesias, which are more severe at night.

Autonomic symptoms

There is a high prevalence of autonomic neuropathy among diabetics(50%–60%)[5],[6] and is associated with significant mortality and morbidity. Cardiac autonomic neuropathy can, in particular, contribute to 6% of sudden deaths(painless myocardial infarction) among those with long-standing diabetes. It is important therefore to ask questions to elicit history of autonomic dysfunction and perform appropriate investigations.

Some of the simple questions that can uncover a hidden underlying autonomic neuropathy are:

  • Cardiac autonomic neuropathy-Do you feel dizzy when you get up from a lying position(orthostatic hypotension)? Check for resting tachycardia
  • Gastroparesis-Do you feel full after eating less than what you normally eat?
  • Cystopathy-Decreased/increased urinary frequency and sensation of incomplete voiding after passing urine
  • Gustatory sweating-Is there sweating over the face while eating?
  • Erectile dysfunction.


Clinical Pearl

Screening for signs and symptoms (e.g., orthostasis, resting and tachycardia) of cardiovascular autonomic neuropathy should be considered with more advanced disease.


  Pathogenesis Top


There are many hypotheses for the pathogenesis of diabetic neuropathy. The chronic, more insidious neuropathy is predominantly due to persistent hyperglycemia while the acute, usually self-limiting neuropathy may be due to vascular causes.

Hyperglycemia results in accumulation of advanced glycosylated end products and activation of other pathways ultimately leading to oxidative stress, axonal loss, and demyelination resulting in nerve dysfunction.[7] Excess glucose also gets converted into sorbitol by the enzyme aldose reductase. Sorbitol decreases levels of myoinositol nerve growth factor which leads to diabetic neuropathy[Figure3]. Optimal glucose control is, therefore, the primary preventive measure.
Figure3: Pathogenesis of diabetic neuropathy.

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An understanding of the underlying pathophysiology of diabetic neuropathy does help in understanding the treatment options available as many of the medications available address the factors involved.


  Screening Tests to Be Done for Assessing Peripheral Neuropathy Top


The following are recommended as screening assessments for peripheral neuropathy.[8]

  1. Inspection of the feet and the footwear
  2. Small fiber function: Pin prick test and temperature test
  3. Large fiber function: Vibration perception, monofilament test, and ankle reflexes
  4. Loss of protective sensation test: monofilament test
  5. Musculoskeletal assessment for deformity
  6. Vascular assessment of the feet
  7. Examination of the footwear used, especially at the sites of ulcer.


Quantification of diabetic neuropathy

An objective measurement or quantification of diabetic neuropathy can help in assessing progress/worsening and response to treatment. Small fiber neuropathy can be quantified using a nylon monofilament while large fiber neuropathy is quantified by assessing vibration sensation.

Assessment of sensation using a nylon Semmes–Weinstein monofilament

Semmes-Weinstein Monofilament is a nylon filament which is available in standard thicknesses. The commonly used ones are(from thin to thick) the 2g(purple), 4g(red), and 10g(orange). The ten areas of the foot tested are illustrated in [Figure4](9 on the plantar aspect and one on the dorsal aspect).
Figure4: Assessment of sensation using a nylon Semmes–Weinstein monofilament.[11] (Adapted from Mahesh DM, Paul T, Thomas N. Peripheral neuropathy. A Practical Guide to Diabetes Mellitus. 7th ed. Jaypee; New Delhi. 2016. p. 171-189.)

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Quantification of diabetic neuropathy using the semmes-weinstein monofilament

  1. Show the Semmes-Weinstein monofilament to the patient. Touch it first to the patient's forehead or sternum so that the sensation is understood.
  2. Instruct the patient to say “yes” every time the monofilament stimulus is perceived.
  3. With the patient's eyes closed, apply the monofilament to the one of the 10 regions. Use a smooth motion-touch the skin with the filament, bend the filament for a full second, then lift from the skin. Perform this stimulus 4 times per foot in an arrhythmic manner so the patient does not anticipate when the stimulus is to be applied. [Figure 4]
  4. If the individual can perceive 6 out of the 10 touches, sensation is assumed to the normal. The 2 gram filament is used first; proceed to the thicker filaments (4 and then 10 gm) if sensation is not perceived.
  5. If the 10 gm filament is not perceived, then there is definitely a loss of protective sensation.
  6. Note the filament perceived and the number of regions perceived for future reference. It is advisable to perform this test at least once a year.[9]


Tests for vibration sense

Testing for large fiber neuropathy is done by assessing the perception of vibration sense using a tuning fork(128Hz).{Figure 4}

Rapid screening for diabetic neuropathy using the 128-Hz vibration tuning fork(modified from the Canadian Diabetes Association guidelines)

  1. Strike the tuning fork against the palm of your hand hard enough that it will vibrate for approximately 40 s
  2. Apply the base of the tuning fork to the patient's forehead or sternum and ensure that the vibration sensation (not just the touch sensation) is understood
  3. With the patient's eyes closed, apply the tuning fork to the bony prominence situated at the dorsum of the first toe just proximal to the nail bed. Ask if the vibration sensation is perceived. [Figure 5]
  4. Ask the patient to tell you when the vibration stimulus is stopped and then dampen the tuning fork with your other hand
  5. Repeat this on other toes and bony prominences at the ankle like the medial and lateral malleolus.[10]


Quantification of vibration perception

The perception of vibration can be objective assessed and quantified using a biothesiometer. This is an instrument that can be used for the assessment of vibration in a graded manner using various grades of electric current. If there is neuropathy, the recording is usually more than 15 mV when it is mild, more than 25 mV if it is moderate, and more than 40 mV when it is severe[Figure6].
Figure5: Tuning fork test for vibration sense.

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Figure6: (a) Biothesiometer.(b) Using a biothesiometer.

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  Sequelae of Diabetic Peripheral Neuropathy Top


Neuropathy, whether sensory, motor, or autonomic may lead to the formation of fissures or calluses which lead to ulceration. Abnormal pressure over bony prominences is the likely cause of skin breakdown in patients with diabetes. The pressure can be long-standing(as with an ill-fitted shoe) or sudden(stepping over a sharp rock or glass piece). Loss of sensation prevents the patient from being warned of abnormal pressures. This may result in the formation of blisters in feet and skin breakdown. The venous edema which often accompanies autonomic neuropathy causes swelling of the foot and tightness of footwear. Thickened hypertrophic nails can contribute to increased pressure. This commonly results in skin breakdown and ulcer formation.

Fissure and foot ulcer

Autonomic neuropathy coupled with loss of sensation in the predisposes to formation of fissures and foot ulcers. Autonomic neuropathy results in decreased sweating and dryness in the feet which may result in the formation of fissures[Figure7]. Afissure can get infected and lead to the formation of a foot ulcer.
Figure7: Development of fissures in foot.

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Callus

Long-standing abnormal pressure over bony prominences can result in the formation of a region of thickened skin called callus. The callus may develop a hematoma following an injury which can get infected, resulting in abscess, and ulcer formation[Figure8].
Figure8: Development of callus and foot ulcer.

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The common foot deformities seen are hammer toe and claw feet both due to motor neuropathy. Extreme deformity in a neuropathic foot can result in an acute condition termed as Charcot foot [Figure 9]. Charcot foot or “rocker bottom feet” is characterized by acute swelling of the foot with warmth and erythema, bounding pulses and ulcers without much pain.
Figure9: Charcot's foot with a healing foot ulcer.

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  Management of Diabetic Neuropathy Top


Treatment of diabetic neuropathy consists of three components:

  1. Glycemic control
  2. Pain control
  3. Foot care.[9]


Glycemic control

Tight glycemic control is the only strategy which has demonstrated to show prevention and progress of diabetic peripheral neuropathy and autonomic neuropathy. Early treatment of diabetic neuropathy should, therefore, include tight glycemic control.

In the Diabetes Control and Complications Trial, intensive therapy slowed the onset of neuropathy by 70% and the progression of early neuropathy by 57%.[11] In the UK Prospective Diabetes Study, glucose control was associated with improved vibratory sensation.[12]

Treatment should also aim at control of blood pressure, dyslipidemia, and lifestyle modifications such as exercise and cessation of smoking and alcohol.

Clinical Pearl

Tight glycemic control is the only strategy convincingly shown to prevent or delay the development of diabetic peripheral neuropathy and cardiac autonomic neuropathy in patients with type 1 diabetes and to slow the progression of neuropathy in some patients with type 2 diabetes.

Pain control–symptomatic treatment of painful neuropathy

Pain and paresthesia are distressing symptoms, and optimal management significantly improves the quality of life of the individual. The options available for symptomatic treatment of paresthesia and dysesthesia(discussed below) raise the threshold for pain and provide some degree of comfort. The drugs used to treat pain in diabetic neuropathy are summarized in [Table1].

Agents available for symptomatic treatment of neuropathy

The medications used for the symptomatic treatment of diabetic neuropathy are discussed below and summarized in [Table4].[5]
Table 4: Medications used to treat symptomatic diabetic neuropathy (modified from Canadian Diabetic Association guidelines)

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  Tricyclic Antidepressants(Eg. Amitriptyline) Top


It is probably the most cost-effective and powerful agent in therapy of painful neuropathy. Dose: it is started in the doses of 25mg and increased by increments of 25mg usually up to 150mg. Other norepinephrine reuptake inhibitors, such as desipramine and nortriptyline, have also been shown to be beneficial.

Caution: Prostatic hypertrophy–It can worsen symptoms; Cardiac arrhythmias–can be worsened, so a check electrocardiogram is recommended; narrow-angle glaucoma (in the view of the anticholinergic effect). Anticholinergic effects, orthostatic hypotension and erectile dysfunction limit their usage. They can be used in renal failure.


  Anticonvulsants Top


Anticonvulsants have a major impact on pain relief in neuropathy if used in optimal doses. However, sodium phenytoin should be avoided since it may worsen hyperglycemia.

  1. Carbamazepine is the other drug commonly used in the symptomatic management of paresthesia. In higher doses, it can cause ataxia. It rarely causes Stevens-Johnson syndrome
  2. Gabapentin: Gabapentin has been shown to improve sleep, which may be impaired in a patient with chronic pain
  3. Pregabalin: This agent has been found to be marginally superior to gabapentin Pregabalin and gabapentin have a similar mechanism of action in that they bind to a subunit of the voltage-sensitive calcium channel and thereby decreasing calcium influx at nerve terminals modulating neurotransmitter release. Dizziness, somnolence, and peripheral edema are frequently reported adverse effects.
  4. Topiramate has shown promising results in trials with an effect on causing growth of intraepidermal nerve fibers and is used in a dose of 25–50 mg/day.


Fluoxetine has some impact on neuropathic pain. However, more recently duloxetine has been found to be more effective. Duloxetine hydrochloride is a selective and potent norepinephrine and serotonin reuptake inhibitor in the brain and spinal cord that has been approved in the treatment of painful neuropathy.

Besides the above list of drugs, analgesics, nonsteroidal anti-inflammatory drugs(NSAIDs), and opioids are also used in addition to treat symptomatic painful neuropathy; however, no advantage of NSAIDs over paracetamol has been noted.

Deep-seated pain–treatment options

Deep-seated, poorly localized pain is experienced by some individuals with diabetic neuropathy. The following options may be used in the management of this type of pain.

  • Opioid derivatives: Tramadol is an effective semi-synthetic opioid. In combination with acetaminophen, it is effective in curbing deep pain and is less addictive than other opioid derivatives[Table1]
  • Transcutaneous electrical nerve stimulation: it is effective in therapy of deep-seated pain
  • Local application of capsaicin ointment: in randomized trials, it is found to be useful as an adjuvant therapy [Table1].


Other medications for diabetic neuropathy

There are several medications that have been used, with varying levels of success, in the treatment of diabetic neuropathy by targeting different aspects of the pathogenesis pathway[Figure10] described earlier. Many of these agents enlisted below are new, and some are in different phases of clinical trials.
Figure10: Agents used in treatment of diabetic neuropathy.

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  • Ruboxistaurin–This is a protein kinase C inhibitor. However, it was not found to be clinically effective
  • Alpha lipoic acid–This is an antioxidant which reduces oxidative stress on the neurons that lead to nerve damage. This agent was not found to be very effective in the oral formulation in the management of neuropathy
  • High-myoinositol diets–A diet rich in myoinositol MI(legumes and nuts) has been tried
  • Recombinant nerve growth factor
  • Topical nitric oxide
  • Aldose reductase inhibitors.


Foot care

Care of the foot and the use of appropriate footwear is an important part of diabetes care. Tight or ill-fitting footwear can result in abnormal pressures over bony prominences, especially in those with foot deformities. The loss of sensation prevents the patient from appreciating injury due to these pressures which leads to blister formation and skin breakdown over time. Fissure and callus formation in the feet leading on to foot ulcers must be prevented as these may lead to significant disability. Educating the individual regarding prevention of these complications of neuropathy is therefore vital[Box3].



Patient education

Every patient with neuropathy must be educated to take care of their feet. This can be done either by the physician or a trained nurse. Some of the general instructions for individuals with diabetic neuropathy are enlisted below.


  Foot Care and Foot Wear Top


The majority of diabetic foot related complications resulting in amputation can be prevented by early detection and appropriate treatment of the ulcers by the primary care giver. Individuals with Diabetic foot ulcers (DFU) are demonstrating increased incidence of hospitalization due to infection, and amputations. DFUs contribute up to 83% of major and 96% of minor amputations among all amputations associated with a foot wound of any type. Diabetic foot ulcer may be present in a pre-existing Charcot's foot [Figure 4]. So it should be the primary focus of the physicians to perform routine foot examination for all the diabetic patients.

“Foot problems can be prevented by Simple foot care and Proper foot wear

Foot care in Small fiber neuropathy (loss of pain and temperature sensation)

  • Daily foot inspection-Use a mirror to inspect the soles of the feet
  • Microcellular rubber (MCR) footwear – distributes weight evenly, has optimal hardness, has elastic recoil which maintains shape of foot while walking
  • Shoes should fit well
  • Socks - Avoid tight socks, wrinkles in socks. Cotton/wool is preferred
  • Avoid exposure to heat
  • Creams may be used to prevent drying and cracking of skin
  • After bathing, feet should be dried thoroughly
  • Nails should be cut transversely.


Foot care in Large fiber neuropathy

  • Gait and strength training: diabetic patients with large fiber neuropathy have an increased predisposition to falls due to ataxia, incoordination, weakness, and muscle wasting. Improving muscle strength by high-intensity strength training, coordination, and balance techniques helps to reduce falls and resultant fractures
  • Advise use of MCR footwear.


Callus and fissure care

  • After shower or bath, soak foot for 10 min to soften the callus.
  • Rub pumice stone over the callus (in one direction)
  • Apply 6% salicylic acid to the callus.
  • If callus is thick, it may need to be trimmed with scalpel by a trained nurse/doctor
  • Remember to look for cause of the callus– examine the footwear and make changes if necessary.


Toenail care

  • Soak feet 10 min before cutting the nail– this will soften
  • Trim the nail straight across– then file the corners
  • Leave toenail about 2–3 mm long to avoid cutting close to the nail bed.
  • For Thick toenails: file the nail down with an emery board.


Foot wear

The most important aspect of diabetic foot care is selection of appropriate foot wear, which protects the neuropathic feet from uneven plantar pressure, trauma and further preventing amputation. Microcellular rubber (MCR) is the most common material used to relieve plantar pressure and can be prescribed for all diabetic patients. Modifications can be made in the insole, outsole, and shoes upper portion in order to relieve pressure in the areas which are at risk for ulceration.

Wound care

Assessing the diabetic wound is important for planning further management. Description of ulcer characteristic such as size, depth, location, appearance and odour should be periodically monitored to assess the wound healing. Wound care involves daily 0.9% saline dressing, appropriate offloading, good glycemic control and infection prevention.

Small fiber neuropathy(loss of pain and temperature sensation)

  • Daily foot inspection-Use a mirror to inspect the soles of the feet
  • Microcellular rubber(MCR) footwear–distributes weight evenly, has optimal hardness, has elastic recoil which maintains shape of foot while walking
  • Shoes should fit well
  • Socks-Avoid tight socks, wrinkles in socks. Cotton/wool is preferred
  • Avoid exposure to heat
  • Creams may be used to prevent drying and cracking of skin
  • After bathing, feet should be dried thoroughly
  • Nails should be cut transversely.


Large fiber neuropathy

  • Gait and strength training: diabetic patients with large fiber neuropathy have an increased predisposition to falls due to ataxia, incoordination, weakness, and muscle wasting. Improving muscle strength by high-intensity strength training, coordination, and balance techniques helps to reduce falls and resultant fractures
  • MCR footwear.


Callus and fissure care

  • After shower or bath(soak foot for 10min.)
  • Rub pumice stone over the callus(in one direction)
  • Apply 6% salicylic acid to the callus.
  • If callus is thick, it may need to be trimmed with scalpel by a trained nurse/doctor
  • Remember to look for cause of the callus–examine the footwear and make changes if necessary.


Toenail care

  • Soak feet 10min before cutting the nail–this will soften nails
  • Trim the nail straight across–then file the corners
  • Leave toenail about 2–3mm long to avoid cutting close to the nail bed
  • Thick toenails: file the nail down with an emery board.



  Conclusions Top


  • All patients should be screened for diabetic neuropathy starting at the diagnosis of type2 diabetes mellitus(DM) and 5years after the diagnosis of type1 DM and at least annually thereafter
  • The clinical assessment should include a detailed history and 10g monofilament testing and at least one of the following tests: pinprick test, temperature test, and tests for vibration sensation
  • Symptoms and signs of autonomic neuropathy should be assessed in patients with microvascular and neuropathy complications [8]
  • Tight glycemic control is the only strategy which has demonstrated to show prevention and progress of diabetic peripheral neuropathy and autonomic neuropathy
  • An annual comprehensive foot examination is a must for all patients with diabetes and consists of examination of foot and footwear, neuropathy screening, vascular assessment, and musculoskeletal assessment of feet. This would help in the identification of risk factor predictive of ulcers and amputation.


Financial support and sponsorship

Nil.

Conflicts of interets

There are no conflicts of interest.



 
  References Top

1.
FeldmanEL, StevensMJ, RussellJW, GreeneDA. Somatosensory neuropathy. In: PorteD, SherwinRS, BaronA, editors. Ellenberg and Rifkin's Diabetes Mellitus. 6thed. NewYork, USA: McGraw Hill; 2002. p.771-88.  Back to cited text no. 1
    
2.
Vinik AI, Erbas T, Pfeifer MA, Feldman EL, Stevens MJ, Russell JW. Diabetic autonomic neuropathy. In: Porte D, Sherwin RS, Baron A, eds. Ellenberg & Rifkin's Diabetes Mellitus. 6th ed. New York: McGraw Hill. 2003;789-804.  Back to cited text no. 2
    
3.
HermanWH, KennedyL. Underdiagnosis of peripheral neuropathy in type2 diabetes. Diabetes Care 2005;28:1480-1.  Back to cited text no. 3
    
4.
The effect of intensive diabetes therapy on the development and progression of neuropathy. The Diabetes Control and Complications Trial Research Group. Ann Intern Med 1995;122:561-8.  Back to cited text no. 4
    
5.
BoultonAJ, VinikAI, ArezzoJC, BrilV, FeldmanEL, FreemanR, etal. Diabetic neuropathies: A statement by the American Diabetes Association. Diabetes Care 2005;28:956-62.  Back to cited text no. 5
    
6.
NanaiahA, ChowdhurySD, JeyaramanK, ThomasN. Prevalence of cardiac autonomic neuropathy in Asian Indian patients with fibrocalculous pancreatic diabetes. Indian J Endocrinol Metab 2012;16:749-53.  Back to cited text no. 6
    
7.
BrownleeM. The pathobiology of diabetic complications: A unifying mechanism. Diabetes 2005;54:1615-25.  Back to cited text no. 7
    
8.
Microvascular Complications and Foot Care. American Diabetes Association. Standards of medical care in diabetes – 2017. Diabetes Care 2017;40(Suppl. 1):S88-98.  Back to cited text no. 8
    
9.
Mahesh DM, Paul T, Thomas N. Peripheral neuropathy. A Practical Guide to Diabetes Mellitus. 7th ed. Jaypee; New Delhi. 2016. p. 171-89.  Back to cited text no. 9
    
10.
Canadian Diabetes Association. Clinical Practice Guidelines. Available from: http://www.guidelines.diabetes.ca/Browse/Appendices/Appendix8. [Last accessed on 2016 Jun 10].  Back to cited text no. 10
    
11.
Diabetes Control and Complications Trial Research Group, NathanDM, GenuthS, LachinJ, ClearyP, CroffordO, etal. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. NEngl J Med 1993;329:977-86.  Back to cited text no. 11
    
12.
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type diabetes(UKPDS). UK Prospective Diabetes Study(UKPDS) Group. Lancet 1998;352:837-53.  Back to cited text no. 12
    


    Figures

  [Figure1], [Figure2], [Figure3], [Figure4], [Figure 5], [Figure6], [Figure7], [Figure8], [Figure 9], [Figure10]
 
 
    Tables

  [Table1], [Table2], [Table3], [Table4]



 

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Abstract
Introduction
Definition
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Sequelae of Diab...
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Anticonvulsants
Foot Care and Fo...
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