Diabetic neuropathy (DN) is a group of syndromes resulting from the disturbances in nerve function caused by diabetes mellitus1
Subtypes of diabetic neuropathy2
- Symmetric and diffuse
- Diabetic sensorimotor polyneuropathy
- Small fiber neuropathy
- Autonomic neuropathy
- Treatment-induced diabetic neuropathy
- Diabetic cachexia
- Asymmetric and focal
- Carpal tunnel syndrome
- Ulnar neuropathy at the elbow
- Fibular neuropathy
- Diabetic lumbosacral radiculoplexus neuropathy
- Diabetic cervical radiculoplexus neuropathy
- Thoracic radiculopathy
- Cranial neuropathy
Epidemiology including risk factors and primary prevention
The primary risk factor for DN is the hyperglycemia of poorly controlled diabetes mellitus, and strict glycemic control may retard its progression.1 Recent observation shows even those with good glycemic control (HbA1c of less than 5.4%) are at risk. Though treatment of hyperglycemia in type 1 DM can decrease the incidence of neuropathy by up to 60 to 70%, glucose control in type 2 DM results in only a mild reduction (5-7%).3 Though Type 2 DM is much more common than type 1 DM it has a lower lifetime incidence of neuropathy (45%) as compared with type 1 DM (54-59%).3 Diabetic polyneuropathy (DPN) with its lifetime prevalence of approximately 50% is the most common diabetic complication. DPN causes disability due to foot ulceration leading to amputation, gait disturbance, and fall-related injury. Neuropathic pain is present in approximately 20 to 30% of patients with DPN. The total annual medical cost for diabetes is $6,632 per patient which increases to twofold ($12,492) in DPN and fourfold ($30,755) in severe painful peripheral neuropathy.3 In 2012, about 27% of healthcare costs of diabetes can be attributed to DPN in United States.3
DN is likely caused by DM-related metabolic or vascular disturbances that are interrelated or synergistic. These mechanisms lead to axonal loss via retrograde injury, as well as peripheral nerve segmental demyelination4. Long-term hyperglycemia inhibits uptake of myo-inositol and other essential molecules within the nerve, leading to the slowing of nerve conduction. The excess glucose is converted into sorbitol, which is then metabolized into fructose, both of these can cause osmotic stress on individual neurons when they accumulate.1 Excessive glucose also leads to: (i) the formation of advanced glycation end-products (AGEs) that results from the non-enzymatic glycosylation of proteins, nucleotides, or lipids; (ii) the aberrant activation of protein kinase C (PKC); (iii) the glucose shunt through the hexosamine pathway; as well as (iv) the formation of oxidative and nitrosative stress associated with an impaired anti-oxidative defense.5 The diabetic state lowers the NAD+/NADH ratio in retina and nerve through increased flux through the polyol pathway and the elevated activity of sorbitol dehydrogenase.6
The increased intracellular glucose concentration along with impaired growth factor support by insulin causes a metabolic imbalance in adult sensory neurons. The energy sensing pathway of AMP activated protein kinase (AMPK)/sirtuin (SIRT)/peroxisome proliferator-activated receptor-γ coactivator α (PGC-1α) signaling axis is damaged. This leads to nutrient stress, and loss of insulin dependent growth factor support; this causes suppression of mitochondrial oxidative phosphorylation and shift to anaerobic glycolysis.6 All these leased to diminishment of collateral sprouting and axon regeneration in diabetic neuropathy.
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
Generalized symmetric polyneuropathy is a length-dependent process initially producing sensory disturbances of the distal limbs in a stocking glove distribution. When involving large myelinated A-Type α- and β-Fibers it presents with numbness, tingling, deep-seated gnawing or aching pain, weakness, ataxia with poor balance, and falling. Exam shows impaired reflexes, loss of proprioception and perception of vibration, wasting of small muscles of hands and feet,and weakness in the feet. Clinical implications are Impaired sense of pressure and balance; susceptibility to falls, traumatic fractures, and Charcot’s arthropathy.7
When involving small myelinated and unmyelinated A-Type δ-Fibers and small unmyelinated A-Type δ-Fibers and C-Type fibers results in burning pain with sensation of stabbing and electric shocks, allodynia, hyperalgesia, and hyperesthesia. Exam shows impaired sensation of warm and cold temperatures and of pinprick; normal strength, reflexes, and nerve conduction. Impaired nociception results in susceptibility to foot ulcers, and increased risk of amputation.7
Autonomic neuropathy predominantly disrupts the cardiovascular, genitourinary, and gastrointestinal systems. Common presentations include orthostatic hypotension, absence of fluctuations in heart rate, erectile dysfunction, cardiac arrhythmias, sudomotor dysfunction, and bowel and bladder disturbances.8
Diabetic lumbosacral radiculoplexus neuropathy may present insidiously or suddenly and often begins with unilateral proximal lower limb pain, followed by intense proximal weakness. While it can evolve into a widespread paralytic disorder affecting the lower limbs, it carries a favorable prognosis, with the majority of affected patients reporting resolution of pain and weakness after several years.1,9
Diabetic cachexia can rarely occur after rapid glycemic control. This results in severe neuropathic pain with marked weight loss and sensorimotor polyneuropathy. Usually there is an improvement of the symptoms over several months.2
Treatment-induced neuropathy in diabetes (TIND) is an iatrogenic small-fiber neuropathy presenting with acute onset of neuropathic pain and/or autonomic dysfunction within 8 weeks of significant glycemic control specified as a decrease in glycosylated HbA1c of more than 2% points over 3 months. TIND was first recognized soon after the introduction of insulin and named “insulin neuritis”.2
Specific secondary or associated conditions and complications
Loss of pedal sensation from DN may result in skin wounds and ulceration. The concomitant vascular and immunologic disorders make these wounds susceptible to infection that may progress to osteomyelitis or gangrene. There are many other secondary complications including autonomic dysfunction, erectile dysfunction, gastroparesis, and neuropathic arthropathies (Charcot joints). DN may also contribute to common entrapment neuropathies, such as carpal tunnel syndrome.
2. ESSENTIALS OF ASSESSMENT
DN may produce painful positive symptoms like squeezing, throbbing, freezing, burning, or lancinating sensations. Non-painful positive symptoms include a feeling of stiffness and thickness. Negative symptoms include numbness. History should also assess for gait disturbances, skin lesions, hypotensive symptoms, sexual dysfunction, changes in bowel or bladder function, and progressive weakness.
Distal symmetric polyneuropathy generally presents insidiously and involves the distal lower limbs in a symmetric pattern. Neurogenic or vascular claudication and other length-dependent neuropathies may mimic DN. Diabetic distal symmetric polyneuropathy generally presents insidiously and involves the distal lower limbs in a symmetric pattern, while diabetic lumbosacral radiculoplexus neuropathy has an abrupt, painful onset, is generally accompanied by weight loss, and often is a presenting finding in newly diagnosed diabetics. It is characterized by sharp, burning, and asymmetric pain that more often presents proximally in the hip and thigh before later spreading distally.1,9
Gait and skin evaluations are mandatory. Proprioceptive deficits should be exposed with Romberg, tandem gait, and one-leg stand tests. Examinations with a 128 Hz tuning fork and a 10-g monofilament test carry sensitivities of 62.5 and 62.8%, respectively, and specificities of 95.3 and 92.9%, respectively. Vibratory sensation is often the first sensory finding in DN, and pinprick and light touch examinations may also suggest a pattern of sensory deficit. Ankle deep tendon reflexes and strength should be documented. A skin examination should detect erythema, callouses, and ulcers, and inspection should also look for bony irregularities and muscle atrophy. Diabetic distal symmetric polyneuropathy shows sensory loss in all modalities with progression to weakness and atrophy in a distal to proximal distribution. Examination in small fiber neuropathy can show allodynia and loss of sensation to various modalities. Warm, dry skin and orthostasis may signify underlying autonomic neuropathy.
Diabetic lumbosacral radiculoplexus neuropathy generally presents with proximal deficits; motor findings are greater than sensory findings. Physical examination should be documented and serially monitored to accurately assess disease progression.1
History should emphasize mobility, transfers, and other activities of daily living. Functional independence measures and the 36-item short form health survey may assist in functional assessments.
Basic laboratory evaluation of polyneuropathy includes: complete blood count, erythrocyte sedimentation rate, vitamin B12, folate, comprehensive metabolic panel (including fasting blood glucose and both renal and liver function tests), thyroid function tests, and serum protein immunofixation electrophoresis. An important cause of vitamin B12 deficiency is iatrogenic, linked to cumulative doses of metformin3. Depending on the results of these studies and the patient’s history, other studies may include: methylmalonic acid with or without homocysteine, drug and toxin screens, urinalysis, and urine protein electrophoresis with immunofixation. Whether these routine studies need to be performed in known diabetics or prediabetics is unclear. Prediabetics can be identified with a fasting glucose, HbA1c, or glucose tolerance test.10
Magnetic resonance imaging of the lumbar spine and arterial studies may identify spinal or vascular etiologies of symptoms that mimic DN. Plain films may diagnose and follow the progression of neuroarthropathies, such as Charcot foot. When osteomyelitis is suspected, advanced imaging may assist in confirming the diagnosis.11
Supplemental assessment tools
Electrodiagnostic studies, including electromyography (EMG) and nerve conduction studies, may facilitate the diagnosis, monitor progression, and investigate other pathologies within the differential diagnosis of DN. In diabetic distal symmetrical polyneuropathy, conduction slowing is evidenced by prolonged latencies for distal and late responses and decreased conduction velocities. Axonal loss shows small motor and sensory amplitudes. Fibrillation potentials and positive sharp waves on needle EMG examination reveal active axonal loss. Large amplitude motor unit action potentials indicate a chronic component to the individuals with DN Diabetic amyotrophy often shows evidence of axonal loss in the affected nerve distribution. Small fiber neuropathies frequently have normal standard electrodiagnostic studies, and skin biopsy may be useful in this diagnosis. This involves a 3 mm diameter punch biopsy usually taken from the lower extremity with measurement of intraepidermal nerve fiber density, which has 88% sensitivity. Autonomic neuropathy can be diagnosed with specialized neurophysiologic methods including sympathetic skin response and R-R variability testing on electrocardiogram.1,3,12
Corneal confocal microscopy is a non-invasive quantitative method of detecting corneal innervation in the subbasal plexus. It has been found to be reduced early in the disease, and to be more sensitive in assessing nerve repair than other standard measures such as IENFD and NCS.13
Early predictions of outcomes
Pain, falls and foot ulcers are costly and debilitating conditions, and are important factors in patient outcomes. The presence of DPN increases the risk of falls in diabetics two to three times as compared to those without neuropathy. The increased risk of falls has been shown to occur 3 to 5 years before their diagnosis. Those with neuropathy have a 15% increased risk of developing ulcers and 6 to 43% of these ulcers will result in an amputation.3 If autonomic neuropathy is diagnosed in a diabetic individual, the chance of death increases by 25-50% over 10 years.1,14
It is important to ensure that the living environment of a patient with DN is accessible. Proper lighting at night and avoidance of throw rugs should be encouraged in order to minimize fall risk.
3. REHABILITATION MANAGEMENT AND TREATMENTS
Available or current treatment guidelines
Ultimate goals of treatment are maintenance of function, quality of life, and limb preservation. So far no disease modifying drugs have been identified for DPN. Optimized glycemic control decreases the incidence of neuropathy in type 1 DM, and was noted to show improved NCS findings and vibration sense.2 There is strong evidence that anticonvulsants are beneficial, particularly pregabalin. There is moderate evidence supporting antidepressants (tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors), capsicin, isosorbide dinitrate spray, and opioids (dextromethorphan, morphine sulfate, tramadol, and oxycodone) to treat the pain associated with DN. Medication selection generally depends on their roles in treating comorbid conditions, contraindications, and on their interactions with other medications. Patients with neuropathic pain refractory to the above treatments may be candidates for spinal cord stimulators. There is moderate evidence that percutaneous electrical nerve stimulation is beneficial.1,15
In animal models and human trials, aerobic exercise has been shown to improve symptoms of neuropathy and facilitate re-growth of cutaneous small-diameter fibers. Similarly reduction in periods of seated, awake inactivity produces metabolic benefits similar to exercise.16
At different disease stages
Evaluations and treatments must be tailored to the specific complications and functional needs of each patient.
Coordination of care
The physiatrist coordinates diagnostic and treatment plans among orthotists, prosthetists, podiatrists, physical and occupational therapists, and surgical specialists. 
Patient & family education
The patient and family must be educated about the relationship between glycemic control and the course of diabetic neuropathies. Patients and their caretakers should be encouraged to perform daily foot inspections and bring any skin lesions to the attention of their physician. They must be educated on the complications of DN and effective methods of prevention. Routine podiatry visits must be recommended for nail care.
Function should be monitored subjectively by the patient. Skin lesions must be carefully observed to resolution. For pain and other subjective neuropathic complaints, the Visual Analogue Scale, Neuropathic Pain Scale, Mcgill Pain Questionaire, and the Leeds Assessment of Neuropathic Symptoms and Signs may also assist in assessing treatment efficacy
Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
The importance of glycemic control cannot be overstated, and patients should be continually educated about this. As vibratory sensation is lost early in DN, an examination of this should be performed if DN is suspected and serially monitored. Physiatrists must coordinate effectively with primary care and other involved physicians, providing education as appropriate for prevention and treatment techniques.
4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE
Cutting edge concepts and practice
Alpha lipoic acid (ALA) 600 milligrams per day was found to be most successful antioxidant in clinical trials and has been approved for the treatment of DPN in Europe. 
Aldose reductase treatment showed initial promise in the treatment of DPN in several studies; but a Cochrane review of 32 randomized controlled trials, showed no statistical difference between aldose reductase inhibitors and placebo.
Multiple pre-clinical and clinical studies demonstrate a pathogenic role for inflammation, especially cytokine and chemokine production, which can be playing significant role in development of charcot arthropathy, impaired wound healing in DN. Targeting low-grade inflammation via modulation of the IKKβ/NF-κB pathway could interfere with several critical pathways involved in the pathogenesis of DN and of the DN associated pain . One review article suggests DN in type 2 DM patients have increased serum TNF-α level than type 2 diabetic patients without peripheral neuropathy and healthy controls. 
A recent randomized controlled trial of fulranumab, a monoclonal antibody directed against nerve growth factor (NGF), revealed some efficacy in the reduction of daily pain when administered at 10 mg subcutaneously every 4 weeks. This study was discontinued by the Food and Drug Administration (FDA) because of the possibility that anti-NGF antibodies could be associated with increased risk of osteoarthritis or osteonecrosis. 
5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE
Gaps in the evidence-based knowledge
Etiologies for DN remain controversial. Several novel theories for the pathogenesis of DN are currently in development. Neurotrophic factors, such as vascular endothelial growth factor, nerve growth factor, and insulin-like growth factor, promote the maintenance and regeneration of neurons, and low levels in diabetics may lead to neuronal apoptosis. 
The relationship between prediabetes and neuropathy remains unproven, as does the relationship between chronic inflammatory demyelinating polyneuropathy and DN.
So far there have been no preventive, or disease modifying therapy recognized to prevent the development or progression of diabetic neuropathy. Early detection and diagnosis remains the mainstay of treatment. 
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- Aaron Izenberg, Bruce A. Perkins, Vera Bril. Diabetic Neuropathies. Semin Neurol 2015;35:424–430.
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- Matti D. Allen,Timothy J. Doherty, Charles L. Rice, Kurt Kimpinski. Physiology in Medicine: neuromuscular consequences of diabetic neuropathy. J Appl Physiol (1985) 2016;121(1):1-6.
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Original Version of the Topic
Jarron I. Tilghman, MD, Kevin Komes, MD, Michael Khadavi, MD, Ebby Varghese, MD. Diabetic neuropathy. 07/25/2012.
Eathar A. Saad, MD
Nothing to Disclose
Neel Chandel, MD
Nothing to Disclose