Tools
Diabetic Peripheral Neuropathy
Introduction
Peripheral neuropathy encompasses a broad range of clinical pathologies potentially presenting with peripheral nervous system dysfunction.[1] Patients with peripheral neuropathy often present with varying degrees of numbness, tingling, aching, burning sensation, weakness of limbs, hyperalgesia, allodynia, and pain. This pain has been characterized as superficial, deep-seated, or severe, unremitting pain with exacerbation at night.[2] While metabolic disorders represent the predominant etiology of extremity pain caused by an underlying peripheral neuropathy clinical pathology, broad clinical consideration is given to many clinical conditions.
Although there are many possible causes of peripheral neuropathy, the most prevalent subtype, diabetic peripheral neuropathy (DPN), can lead to significant complications ranging from paresthesia to loss of limb and life.[2] Early assessment of symptoms of peripheral polyneuropathy helps avoid neuropathic foot ulcers to combat potential morbidity and mortality resulting from the pathophysiologic poor wound healing potential, which can lead to limb compromise, local to systemic infection, septicemia, and even death.[3][4][5] DPN is primarily diagnosed clinically through history and neurological assessment of small fiber sensation with temperature changes or pinpricks, large fiber sensation with vibrations, and ulceration risk with pressure testing using a 10 g monofilament. Neurology consultation and specialized testing, including nerve conduction studies and intraepidermal nerve fiber density testing, are only indicated for patients with atypical clinical features (eg, rapid symptom onset, severe neuromotor impairment, and asymmetrically abnormal sensation).[6]
The exact cause of DPN is not known. Proposed theories include metabolic, neurovascular, and autoimmune pathways have been proposed. Mechanical compression (eg, carpal tunnel), genetics, and social and lifestyle factors such as chronic alcohol consumption and smoking have all been implicated. Perpetually high blood serum glucose leads to insulin resistance, promoting oxidative stress, inflammation, and cell damage.[7] First, the distal sensory and autonomic nerve fibers are damaged; the damage continues with proximal progression, leading to a gradual loss of protective sensation in the skin and foot joints. DPN management consists of several strategies, including preventative measures (eg, patient education, proper foot care, correct shoe wear, and annual foot exam), glucose control, dietary modifications, weight loss, and pain control. Half of the diabetic peripheral neuropathies may be asymmetric.[6] If not recognized and preventative foot care is not implemented, patients have an increased risk of injury due to their insensate feet.[8][9]
Etiology
Register For Free And Read The Full Article
Search engine and full access to all medical articles- 10 free questions in your specialty
- Free CME/CE Activities
- Free daily question in your email
- Save favorite articles to your dashboard
- Emails offering discounts
Learn more about a Subscription to StatPearls Point-of-Care
Etiology
Metabolic disorders represent the most common clinical category of etiologies, causing extremity pain from underlying peripheral neuropathy conditions. Several causes of PN exist, but diabetes mellitus is the most common etiology. Other underlying etiologies include:
- Alcohol use disorder [10]
- Nutritional deficiencies (eg, low B12, high B6) [11]
- Guillain-Barre syndrome [12]
- Toxins (eg, chemotherapy) and overdose [13][14][15][16]
- Hereditary or genetic conditions (eg, Charcot Marie Tooth disease, amyloidosis, porphyria) [17][18][19][20][21][22]
- Infection (eg, HIV)[23][24][25]
- Inflammatory conditions (eg, lupus and rheumatoid arthritis) [26][27]][28]
- Hypothyroidism [29][30][31][32]
- Malignancy
- Trauma [33][34]
Diabetic Peripheral Neuropathy Risk Factors
Risk factors for DPN include:
- Advanced age
- Hypertension
- Peripheral vascular disease
- Smoking
- Dyslipidemia
- Poor glucose control
- Long-standing diabetes
- Obesity
- Excessive alcohol consumption
- Positive HLA-DR3/4 genotype
Epidemiology
At the time a patient is diagnosed with diabetes, the literature estimates that 10% to 20% of these patients are concomitantly diagnosed with DPN; however, studies analyzing patients with long-standing diabetes mellitus report that DPN has a higher prevalence in those patients. After 5 years, 26% have peripheral neuropathy, and 41% of patients with diabetes have neuropathy at 10 years. The literature reports that 50% to 66% of patients with diabetes mellitus will eventually develop DPN during their lifetime.[35] DPN can occur in both type 1 and type 2 diabetes, but the prevalence is higher in individuals with type 2 diabetes due to the longer duration and higher rates of comorbidities.[36] Diabetes mellitus is also the most common cause of Charcot neuroarthropathy, with an incidence of 0.1% to 0.4% and as high as 29% in patients with peripheral neuropathy.[37]
About half of patients with DPN can clinically present with asymmetric sensory changes.[38][39] Obesity and genetic factors increase the risk of developing diabetes. Peripheral and autonomic neuropathies are some of the leading causes of morbidity in diabetes mellitus. At 5 years, the risk of death for patients with a diabetic foot ulcer is 2.5 times as high as the risk of death for a patient with diabetes who does not have a foot ulcer. The rate of emergency department visits for diabetic foot ulcers and associated infection exceeds the rates for congestive heart failure, renal disease, depression, and most forms of cancer.[40][41][42]
Pathophysiology
DPN encompasses sensory, motor, and autonomic neuropathy. Increased serum glucose leads to insulin resistance, dyslipidemia, and oxidative stress of the endoplasmic reticulum and mitochondria. These processes contribute to accumulating reactive oxygen species (ROS), inflammation, and cellular damage. The infiltrated macrophages inside peripheral nerve cells trigger cytokine and chemokine production, promoting inflammation and nerve fiber damage.[7] In addition, implicated causes of peripheral nerve damage include advanced glycosylation end products and disturbance of hexosamine, protein kinase C, and polymerase pathways. Neurovascular impairment with poor repair processes and endothelial dysfunction also have been implicated.[39]
Toxicokinetics
Transient hyperglycemia is often tolerated by normal compensatory physiological function and homeostatic mechanisms of blood sugar control. However, serum glucose can have toxic effects such as neuropathy in chronically elevated states. For patients diagnosed early with type 1 diabetes, tight glucose control can reduce the risk of diabetic peripheral neuropathy by 78%.[36] In contrast, typically, with a later diagnosis of long-standing hyperglycemia or type 2 diabetes, tight glucose control only reduces the risk by 5% to 9%.[36][43]
History and Physical
Because peripheral neuropathy is so common in patients with diabetes, the American Diabetes Association (ADA) recommends clinicians evaluate patients with type 2 diabetes when they are diagnosed; in patients with type 1 diabetes, clinicians should assess for peripheral neuropathy 5 years after diagnosis and then annually. Peripheral neuropathy is primarily diagnosed clinically through history and neurological assessment of small fiber sensation with temperature changes or pinpricks, large fiber sensation with vibrations, and ulceration risk with pressure testing using a 10 g monofilament.[6]
Clinical History
Clinicians should perform a complete medical history, including diabetes, obesity, dyslipidemia, and hypertension. Furthermore, a review of systems and medications captures most of the underlying causes of DPN. Other risk factors for peripheral neuropathy should also be noted (eg, older age and diabetes control). Characteristic symptoms of peripheral neuropathy include burning, numbness, or tingling in the feet that worsens at night.[6] Patients with pedal paresthesias and dysesthesia often describe a nonspecific constellation of symptoms resulting in difficulty with ambulation and other basic activities of daily living (ADL). Clinical features of peripheral neuropathy and distal sensory peripheral neuropathy are present in about 80% of DPN patients, often described as a "stocking-glove distribution," which can take several years to develop.[44]
Physical Examination
A lower extremity neurological physical exam should include muscle strength, reflex, and sensation evaluation, including light touch with a monofilament, vibratory sensation, and proprioception. A dermatological exam demonstrating dry/cracked skin may point to autonomic neuropathy, while pedal deformities (eg, hammertoes) suggest motor neuropathy.[44]
Small fiber sensation is assessed with temperature changes or pinprick testing. A patient's risk for developing ulcers is evaluated by determining the individual's ability to feel pressure. Since the protective sensation is lost after sensory impairment, the standard Semmes-Weinstein 5.07 monofilament 10 g of pressure protective sensation test may be accurately sensed even after developing a neurotrophic ulcer.[6]
Large fibers are assessed through vibratory sensation.[6] Simply timing the duration that a vibrating 128 Hz tuning fork is felt at the dorsal hallux interphalangeal joint, normally 18 seconds in most individuals, can be used to detect sensory deficits earlier and quantify severity. Decreased light touch sensation or loss of ankle reflexes tend to occur earlier in the disease process. In contrast, the detectable loss of protective sensation tends to occur later in the disease, sometimes even after a neuropathic ulcer develops. Needle electromyography (EMG) and nerve conduction velocity testing can be both painful and expensive and mainly test the large myelinated fibers. Epidermal nerve fiber density testing can be performed to evaluate the small unmyelinated fibers.[45]
Autonomic Symptoms
Autonomic neuropathy is also prevalent in diabetes and can affect the gastrointestinal, cardiovascular, and genitourinary organs. Common symptoms in each organ system include:
- GI: Abdominal discomfort, dysphagia, nausea, fecal incontinence, constipation, diarrhea
- Cardiac: Hypotension, sinus tachycardia, variable heart rate, syncope
- Bladder: Weak urinary stream, straining to void, incomplete emptying of bladder,
- Skin: Heat intolerance, gustatory sweating, extreme diaphoresis
- Nervous: Carpal tunnel syndrome, radiculopathy, lumbosacral, cervical neuropathy, and impairment of cranial nerves III, IV, VI, and VII
Evaluation
Neurology consultation and specialized testing, including nerve conduction studies and intraepidermal nerve fiber density testing, are only indicated for patients with atypical clinical features (eg, rapid symptom onset, severe neuromotor impairment, and asymmetrically abnormal sensation).[6] Electromyography and nerve conduction studies are suggested for severe or rapidly progressive symptoms or motor weakness.
Intraepidermal nerve fiber density is the preferred test for small fiber neuropathy evaluation. Intraepidermal nerve fiber density measurement by skin biopsy can be considered in patients with idiopathic cases. The number and morphology of axons within the epidermis can be evaluated, and intraepidermal nerve fiber density is compared to age-dependent normal values.[46][47]
Minor symptoms may not need laboratory workup. Persistent unexplained symptoms may warrant laboratory investigation, including serum glucose, hemoglobin A1c, complete blood count, erythrocyte sedimentation rate, rapid plasma reagin, serum electrophoresis, and vitamin B1, B6, and B12 levels.
Treatment / Management
DPN management consists of several strategies, including preventative measures (eg, patient education, proper foot care, correct shoe wear, and annual foot exam), glucose control, dietary modifications, weight loss, and pain control. Many patients with neuropathy have mild to moderate numbness symptoms yet retain protective sensation in their feet. Patients may only need reassurance and education regarding the cause of the numbness. Periodic follow-up is essential. Peripheral arterial disease and radiculopathy should be ruled out. With improved glycemic control, paresthesias and dysesthesias may diminish within one year. In 2022, the Current Pain and Headache Reports proposed a treatment algorithm for painful diabetic neuropathy.[48] The algorithm is divided into conservative, pharmacologic, and interventional therapies, subcategorized as first, second, and third-line treatment.(A1)
Conservative Therapy
- First-line therapy: Physical therapy
- Weight-bearing exercises
- Tai chi massage therapy
- Second-line therapy: Health management
- Optimization of glucose
- Properly manage comorbidities
- Weight loss
- Healthy diet
- Third-line therapy: Minimally invasive treatment
- Acupuncture
- Transcutaneous electrical nerve stimulation (TENS)
Pharmacological Therapy
- First-line agents
- Gabapentinoids (eg, pregabalin and gabapentin)
- Duloxetine
- Second-line agents
- Serotonin and norepinephrine reuptake inhibitors (eg, venlafaxine)
- Tricyclic antidepressants (eg, amitriptyline)
- Tapentadol
- Capsaicin patch 8%
- Lidocaine patch 5%
- Third- and Fourth-line agents
- Tramadol
- Opioid
- Intravenous agents (eg, lidocaine, ketamine)
Interventional Therapy
- First-line therapy: Dorsal column spinal cord stimulation
- Typically 10 kHz
- Tonic waveforms
- Second-line therapy: Other neuromodulation options
- Burst spinal cord stimulation
- Dorsal root ganglion spinal cord stimulation
- Peripheral nerve stimulation
- Third-line therapy: Intrathecal drug delivery system
- Intrathecal morphine, fentanyl, or hydromorphone
- Intrathecal ziconatide
DPN can affect other body areas, including the digestive, endocrine, and vascular systems. Diabetic gastroparesis may be managed with erythromycin and metoclopramide.[49][50] Tegaserod is a newer agent but is only available on an emergency basis because of serious adverse cardiac effects.[51] Erectile dysfunction is managed with phosphodiesterase inhibitors, but not everyone has a response. A penile prosthesis may be of benefit.[52] Orthostatic hypotension may be managed by increased salt and fluid intake and compression stockings. If that fails, steroids may be required. Glycopyrrolate is used to manage sweating but often does not work.[53](B3)
Alternative Therapies
Some patients may also benefit from supplements, but studies are scarce. Omega-3 polyunsaturated fatty acid oral supplements (ie, fish oil) have perhaps the best evidence in attenuating sensory loss and reducing the incidence of peripheral neuropathy.[54] One randomized controlled trial reported a significant increase in corneal nerve fiber length in patients with dry eye disease compared to placebo.[55] Several studies have linked vitamin D deficiency with an increased risk for diabetic peripheral neuropathy, diabetic ulcer, and cardiovascular autonomic neuropathy.[56] In addition, a single high-dose intramuscular injection of vitamin D supplementation 600,000 IU has significantly improved patients' quality of life and perception of foot problems.[57] There is moderate evidence that alpha lipoic acid supplementation decreases pain with little to no adverse effects.[58][59][60] (A1)
Additionally, although classified as a medical food, the prescription containing L-methyl folate, pyridoxal 5'-phosphate, and methylcobalamin for the dietary management of endothelial dysfunction has significantly improved nerve fiber density and monofilament sensation.[61] Scant evidence shows that supplementation with vitamins C and E prevents diabetic complications. There is no evidence that taking vitamin B12 oral supplements improves DPN.[62] Depleting substance P with topical capsaicin cream may help some patients who can tolerate the initially increased burning.[63][64][65] For patients with painful diabetic peripheral neuropathy, a capsaicin 8% patch in serial treatments can provide modest improvements in pain and sleep quality.[66][67](A1)
Differential Diagnosis
Differential diagnoses of DPN include the following:
- Alcohol-associated neuropathy
- Nutritional linked neuropathy
- Uremic neuropathy
- Vasculitic linked neuropathy
- Vitamin B12 deficiency
- Toxic metal neuropathy
Staging
While numerous classifications have attempted to categorize different types of diabetic neuropathies, most experts agree that a classification based on the clinical manifestation is the most appropriate.[68] The following classification of diabetic neuropathies described initially by Thomas is the most accepted today:
- Rapidly reversible
- hyperglycemic neuropathy
- Generalized symmetrical polyneuropathies
- Chronic sensorimotor
- Acute sensory
- Autonomic
- Prediabetic or impaired glucose tolerance neuropathy
- Focal and multifocal neuropathies
- Cranial
- Thoracolumbar radiculoneuropathy
- Focal limb
- Proximal motor (eg, amyotrophy)
- Superimposed chronic inflammatory demyelinating neuropathy [69]
The most common type of DPN is generalized symmetrical sensorimotor polyneuropathy.[70] The staging of diabetic neuropathy was described by Dyck and divided into 4 stages:[71]
- Stage 0: no neuropathy
- Stage 1: asymptomatic neuropathy
- Stage 2: symptomatic neuropathy
- Stage 3: disabling neuropathy
Prognosis
Poorly treated diabetics have higher morbidity and complication rates associated with DPN than well-controlled diabetics. DPN often leads to skin breakdown, infection, ulceration, and eventually to amputation. Further, the treatment of DPN is not satisfactory, and adverse cardiac events are common. Less than a third of patients achieve reasonable pain control. For most patients with DPN, the quality of life is poor.
Complications
Common complications of DPN include the following:
- Amputations of the toes, foot, or leg
- Infections of the foot
- Falls secondary to dizziness
- Diarrhea, failure to thrive, and dehydration
- Pain
- Cardiovascular neuropathy can cause death
Deterrence and Patient Education
Preventative strategies are an essential aspect of DPN management. According to the American Diabetes Association, people with diabetes should have a complete foot examination annually and a visual examination of the feet at each visit, usually every 3 to 4 months. Patients should be educated on monitoring blood sugar levels and self-examining their feet daily to look for ulcers, wounds, or broken skin. They should also follow a diet plan and take medications on time, as advised by the doctor. Clinicians should make patients aware of the contributing role of alcohol and smoking in peripheral neuropathy and recommend a plan to quit as needed. Moreover, abnormally fitting shoes should not be worn by the patient.
Pearls and Other Issues
The lower extremities are especially prone to the repetitive microtrauma-induced complications of polyneuropathy. There is an increased propensity to develop not only recurrent neuropathic ulcers but also Charcot neuroarthropathy and, to a lesser extent, motor neuropathy. Additionally, as patients age, their nails become dystrophic, and the risk of subungual ulcerations, gangrene, and osteomyelitis increases with decreased protective sensation. Periodic pedal-focused examinations are essential. Professional foot care and therapeutic shoes and insoles have helped reduce the lower limb amputation rates in patients with diabetes mellitus.
Enhancing Healthcare Team Outcomes
Diabetic neuropathy affects many organ systems and is best managed by an interprofessional team. Because there is no cure for the disorder, the key is prevention. All people with diabetes should have a dietary consult and receive education on what foods they should eat and what to avoid. The diet should be realistic and focused on lowering blood glucose levels. The patients should also enter a rehabilitation program or some exercise. Losing weight makes it easier to control blood sugars and lowers blood pressure and lipids. A podiatry consult is vital as protection of the foot is necessary. Further, all people with diabetes should be informed about avoiding trauma and undergoing any invasive procedure on the feet without prior clearance from the endocrinologist. In addition, the patient should be told to avoid cold or hot temperatures.
A nurse proficient in diabetes management should educate the patient about all aspects of diabetes and the importance of euglycemia. Patients should be taught how to monitor their blood glucose and use portable glucose monitors. The pharmacist should offer education about the medications, their benefits, and their adverse effects.
Compliance with medication therapy to treat diabetes is vital. Finally, patients who develop neuropathy also tend to have nephropathy and retinopathy; hence, all people with diabetes should be referred to a nephrologist and ophthalmologist. There should be open communication between the interprofessional team so that all patients are provided with the available standard of care with minimal morbidity. Foot and nail care nurses monitor patients, provide education, and inform the team of the patient's condition. Pharmacists educate patients about the use of medications and the importance of compliance.[72][73]
Outcomes
In general, patients with diabetes mellitus who are not compliant with treatment or undertreated usually tend to have a poorer outcome than patients who undergo treatment. The neuropathy frequently results in skin breakdown, ulceration, and, eventually, an infection. Amputation of the toes and limbs is not uncommon. However, the actual treatment of diabetic neuropathy is not perfect, and often, most treatments do not work. Complete relief from symptoms of neuropathy is rare. Overall, the mortality rates are highest in patients with diabetes mellitus with autonomic neuropathy, especially those who have cardiac dysfunction. The overall mortality rates are 15% to 30% over 10 years, but there is also significant morbidity from limb amputation. Other symptoms that make the quality of life poor include syncopal attacks, diarrhea, constipation, and continuous pain.[70][74]
References
Wang Y, Li W, Peng W, Zhou J, Liu Z. Acupuncture for postherpetic neuralgia: Systematic review and meta-analysis. Medicine. 2018 Aug:97(34):e11986. doi: 10.1097/MD.0000000000011986. Epub [PubMed PMID: 30142834]
Level 1 (high-level) evidenceÇakici N, Fakkel TM, van Neck JW, Verhagen AP, Coert JH. Systematic review of treatments for diabetic peripheral neuropathy. Diabetic medicine : a journal of the British Diabetic Association. 2016 Nov:33(11):1466-1476. doi: 10.1111/dme.13083. Epub 2016 Feb 21 [PubMed PMID: 26822889]
Level 1 (high-level) evidenceDewanjee S, Das S, Das AK, Bhattacharjee N, Dihingia A, Dua TK, Kalita J, Manna P. Molecular mechanism of diabetic neuropathy and its pharmacotherapeutic targets. European journal of pharmacology. 2018 Aug 15:833():472-523. doi: 10.1016/j.ejphar.2018.06.034. Epub 2018 Jun 30 [PubMed PMID: 29966615]
Alavi A, Sibbald RG, Mayer D, Goodman L, Botros M, Armstrong DG, Woo K, Boeni T, Ayello EA, Kirsner RS. Diabetic foot ulcers: Part I. Pathophysiology and prevention. Journal of the American Academy of Dermatology. 2014 Jan:70(1):1.e1-18; quiz 19-20. doi: 10.1016/j.jaad.2013.06.055. Epub [PubMed PMID: 24355275]
Vinik AI, Casellini C, Névoret ML. Alternative Quantitative Tools in the Assessment of Diabetic Peripheral and Autonomic Neuropathy. International review of neurobiology. 2016:127():235-85. doi: 10.1016/bs.irn.2016.03.010. Epub 2016 Apr 13 [PubMed PMID: 27133153]
Level 3 (low-level) evidenceElafros MA, Andersen H, Bennett DL, Savelieff MG, Viswanathan V, Callaghan BC, Feldman EL. Towards prevention of diabetic peripheral neuropathy: clinical presentation, pathogenesis, and new treatments. The Lancet. Neurology. 2022 Oct:21(10):922-936. doi: 10.1016/S1474-4422(22)00188-0. Epub [PubMed PMID: 36115364]
Baum P, Toyka KV, Blüher M, Kosacka J, Nowicki M. Inflammatory Mechanisms in the Pathophysiology of Diabetic Peripheral Neuropathy (DN)-New Aspects. International journal of molecular sciences. 2021 Oct 7:22(19):. doi: 10.3390/ijms221910835. Epub 2021 Oct 7 [PubMed PMID: 34639176]
Vinik AI, Casellini C, Parson HK, Colberg SR, Nevoret ML. Cardiac Autonomic Neuropathy in Diabetes: A Predictor of Cardiometabolic Events. Frontiers in neuroscience. 2018:12():591. doi: 10.3389/fnins.2018.00591. Epub 2018 Aug 27 [PubMed PMID: 30210276]
Level 3 (low-level) evidenceSloan G, Shillo P, Selvarajah D, Wu J, Wilkinson ID, Tracey I, Anand P, Tesfaye S. A new look at painful diabetic neuropathy. Diabetes research and clinical practice. 2018 Oct:144():177-191. doi: 10.1016/j.diabres.2018.08.020. Epub 2018 Sep 7 [PubMed PMID: 30201394]
Julian T, Glascow N, Syeed R, Zis P. Alcohol-related peripheral neuropathy: a systematic review and meta-analysis. Journal of neurology. 2019 Dec:266(12):2907-2919. doi: 10.1007/s00415-018-9123-1. Epub 2018 Nov 22 [PubMed PMID: 30467601]
Level 1 (high-level) evidenceGwathmey KG, Grogan J. Nutritional neuropathies. Muscle & nerve. 2020 Jul:62(1):13-29. doi: 10.1002/mus.26783. Epub 2019 Dec 26 [PubMed PMID: 31837157]
Willison HJ, Jacobs BC, van Doorn PA. Guillain-Barré syndrome. Lancet (London, England). 2016 Aug 13:388(10045):717-27. doi: 10.1016/S0140-6736(16)00339-1. Epub 2016 Mar 2 [PubMed PMID: 26948435]
Freund PR, Wright T, Margolin EA. Toxic Optic Neuropathy From Quinine Overdose. Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society. 2020 Jun:40(2):258-261. doi: 10.1097/WNO.0000000000000865. Epub [PubMed PMID: 31842144]
Guala A, Folgori G, Silvestri M, Barbaglia M, Danesino C. Vitamin B6 Neonatal Toxicity. Case reports in pediatrics. 2022:2022():3171351. doi: 10.1155/2022/3171351. Epub 2022 Dec 6 [PubMed PMID: 36524152]
Level 3 (low-level) evidenceMalet L, Dayot L, Moussy M, de la Gastine B, Goutelle S. [Peripheral neuropathy with hypervitaminosis B6 caused by self-medication]. La Revue de medecine interne. 2020 Feb:41(2):126-129. doi: 10.1016/j.revmed.2019.11.003. Epub 2019 Nov 30 [PubMed PMID: 31796339]
Ko JU, Seo H, Lee GJ, Park D. Bilateral sciatic neuropathy with severe rhabdomyolysis following venlafaxine overdose: A case report. Medicine. 2018 Sep:97(37):e12220. doi: 10.1097/MD.0000000000012220. Epub [PubMed PMID: 30212953]
Level 3 (low-level) evidenceLy KI, Blakeley JO. The Diagnosis and Management of Neurofibromatosis Type 1. The Medical clinics of North America. 2019 Nov:103(6):1035-1054. doi: 10.1016/j.mcna.2019.07.004. Epub [PubMed PMID: 31582003]
Jani-Acsadi A, Ounpuu S, Pierz K, Acsadi G. Pediatric Charcot-Marie-Tooth disease. Pediatric clinics of North America. 2015 Jun:62(3):767-86. doi: 10.1016/j.pcl.2015.03.012. Epub 2015 Apr 15 [PubMed PMID: 26022174]
Freeman R. Autonomic Peripheral Neuropathy. Continuum (Minneapolis, Minn.). 2020 Feb:26(1):58-71. doi: 10.1212/CON.0000000000000825. Epub [PubMed PMID: 31996622]
Kaku M, Berk JL. Neuropathy Associated with Systemic Amyloidosis. Seminars in neurology. 2019 Oct:39(5):578-588. doi: 10.1055/s-0039-1688994. Epub 2019 Oct 22 [PubMed PMID: 31639841]
Gandhi Mehta RK, Caress JB, Rudnick SR, Bonkovsky HL. Porphyric neuropathy. Muscle & nerve. 2021 Aug:64(2):140-152. doi: 10.1002/mus.27232. Epub 2021 Mar 31 [PubMed PMID: 33786855]
Gerischer LM, Scheibe F, Nümann A, Köhnlein M, Stölzel U, Meisel A. Acute porphyrias - A neurological perspective. Brain and behavior. 2021 Nov:11(11):e2389. doi: 10.1002/brb3.2389. Epub 2021 Oct 17 [PubMed PMID: 34661997]
Level 3 (low-level) evidenceAbrams RMC, Simpson DM, Navis A, Jette N, Zhou L, Shin SC. Small fiber neuropathy associated with SARS-CoV-2 infection. Muscle & nerve. 2022 Apr:65(4):440-443. doi: 10.1002/mus.27458. Epub 2021 Nov 22 [PubMed PMID: 34766365]
Saif DS, Ibrahem RA, Eltabl MA. Prevalence of peripheral neuropathy and myopathy in patients post-COVID-19 infection. International journal of rheumatic diseases. 2022 Nov:25(11):1246-1253. doi: 10.1111/1756-185X.14409. Epub 2022 Aug 1 [PubMed PMID: 35915515]
Benstead TJ, Chalk CH, Parks NE. Treatment for cryoglobulinemic and non-cryoglobulinemic peripheral neuropathy associated with hepatitis C virus infection. The Cochrane database of systematic reviews. 2014 Dec 20:(12):CD010404. doi: 10.1002/14651858.CD010404.pub2. Epub 2014 Dec 20 [PubMed PMID: 25525951]
Level 1 (high-level) evidenceFerro JM, Oliveira Santos M. Neurology of inflammatory bowel disease. Journal of the neurological sciences. 2021 May 15:424():117426. doi: 10.1016/j.jns.2021.117426. Epub 2021 Mar 27 [PubMed PMID: 33810878]
García-Cabo C, Morís G. Peripheral neuropathy: an underreported neurologic manifestation of inflammatory bowel disease. European journal of internal medicine. 2015 Sep:26(7):468-75. doi: 10.1016/j.ejim.2015.07.013. Epub 2015 Jul 23 [PubMed PMID: 26211733]
Seeliger T, Prenzler NK, Gingele S, Seeliger B, Körner S, Thiele T, Bönig L, Sühs KW, Witte T, Stangel M, Skripuletz T. Neuro-Sjögren: Peripheral Neuropathy With Limb Weakness in Sjögren's Syndrome. Frontiers in immunology. 2019:10():1600. doi: 10.3389/fimmu.2019.01600. Epub 2019 Jul 11 [PubMed PMID: 31354737]
Seretny M, Currie GL, Sena ES, Ramnarine S, Grant R, MacLeod MR, Colvin LA, Fallon M. Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis. Pain. 2014 Dec:155(12):2461-2470. doi: 10.1016/j.pain.2014.09.020. Epub 2014 Sep 23 [PubMed PMID: 25261162]
Level 1 (high-level) evidenceSałat K. Chemotherapy-induced peripheral neuropathy-part 2: focus on the prevention of oxaliplatin-induced neurotoxicity. Pharmacological reports : PR. 2020 Jun:72(3):508-527. doi: 10.1007/s43440-020-00106-1. Epub 2020 Apr 28 [PubMed PMID: 32347537]
Staff NP, Grisold A, Grisold W, Windebank AJ. Chemotherapy-induced peripheral neuropathy: A current review. Annals of neurology. 2017 Jun:81(6):772-781. doi: 10.1002/ana.24951. Epub 2017 Jun 5 [PubMed PMID: 28486769]
Zajączkowska R, Kocot-Kępska M, Leppert W, Wrzosek A, Mika J, Wordliczek J. Mechanisms of Chemotherapy-Induced Peripheral Neuropathy. International journal of molecular sciences. 2019 Mar 22:20(6):. doi: 10.3390/ijms20061451. Epub 2019 Mar 22 [PubMed PMID: 30909387]
Taylor CA, Braza D, Rice JB, Dillingham T. The incidence of peripheral nerve injury in extremity trauma. American journal of physical medicine & rehabilitation. 2008 May:87(5):381-5. doi: 10.1097/PHM.0b013e31815e6370. Epub [PubMed PMID: 18334923]
Level 2 (mid-level) evidenceNoland SS, Bishop AT, Spinner RJ, Shin AY. Adult Traumatic Brachial Plexus Injuries. The Journal of the American Academy of Orthopaedic Surgeons. 2019 Oct 1:27(19):705-716. doi: 10.5435/JAAOS-D-18-00433. Epub [PubMed PMID: 30707114]
Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, Wilson DM, O'Brien PC, Melton LJ 3rd, Service FJ. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology. 1993 Apr:43(4):817-24 [PubMed PMID: 8469345]
Level 2 (mid-level) evidencePop-Busui R, Boulton AJ, Feldman EL, Bril V, Freeman R, Malik RA, Sosenko JM, Ziegler D. Diabetic Neuropathy: A Position Statement by the American Diabetes Association. Diabetes care. 2017 Jan:40(1):136-154. doi: 10.2337/dc16-2042. Epub [PubMed PMID: 27999003]
Hjelm LR. Diabetes Mellitus: An Overview in Relationship to Charcot Neuroarthropathy. Clinics in podiatric medicine and surgery. 2022 Oct:39(4):535-542. doi: 10.1016/j.cpm.2022.05.001. Epub 2022 Aug 6 [PubMed PMID: 36180186]
Level 3 (low-level) evidenceDjibril AM, Mossi EK, Djagadou AK, Balaka A, Tchamdja T, Moukaila R. [Epidemiological, diagnostic, therapeutic and evolutionary features of diabetic foot: a study conducted at the Medico-surgical Clinic, University Hospital Sylvanus Olympio in Lomé]. The Pan African medical journal. 2018:30():4. doi: 10.11604/pamj.2018.30.4.14765. Epub 2018 May 3 [PubMed PMID: 30123407]
Level 2 (mid-level) evidenceGhotaslou R, Memar MY, Alizadeh N. Classification, microbiology and treatment of diabetic foot infections. Journal of wound care. 2018 Jul 2:27(7):434-441. doi: 10.12968/jowc.2018.27.7.434. Epub [PubMed PMID: 30016139]
Schröder K, Szendroedi J, Benthin A, Gontscharuk V, Ackermann P, Völker M, Steingrube N, Nowotny B, Ziegler D, Müssig K, Geerling G, Kuß O, Roden M, Guthoff R, GDS Cohort. German Diabetes Study - Baseline data of retinal layer thickness measured by SD-OCT in early diabetes mellitus. Acta ophthalmologica. 2019 Mar:97(2):e303-e307. doi: 10.1111/aos.13851. Epub 2018 Sep 21 [PubMed PMID: 30238609]
Moţăţăianu A, Maier S, Bajko Z, Voidazan S, Bălaşa R, Stoian A. Cardiac autonomic neuropathy in type 1 and type 2 diabetes patients. BMC neurology. 2018 Aug 27:18(1):126. doi: 10.1186/s12883-018-1125-1. Epub 2018 Aug 27 [PubMed PMID: 30149797]
Doria M, Viadé J, Palomera E, Pérez R, Lladó M, Costa E, Huguet T, Reverter JL, Serra-Prat M, Franch-Nadal J, Mauricio D. Short-term foot complications in Charcot neuroarthropathy: A retrospective study in tertiary care centres in Spain. Endocrinologia, diabetes y nutricion. 2018 Nov:65(9):479-485. doi: 10.1016/j.endinu.2018.06.004. Epub 2018 Aug 11 [PubMed PMID: 30108031]
Level 2 (mid-level) evidenceGiri B, Dey S, Das T, Sarkar M, Banerjee J, Dash SK. Chronic hyperglycemia mediated physiological alteration and metabolic distortion leads to organ dysfunction, infection, cancer progression and other pathophysiological consequences: An update on glucose toxicity. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2018 Nov:107():306-328. doi: 10.1016/j.biopha.2018.07.157. Epub 2018 Aug 8 [PubMed PMID: 30098549]
Sloan G, Selvarajah D, Tesfaye S. Pathogenesis, diagnosis and clinical management of diabetic sensorimotor peripheral neuropathy. Nature reviews. Endocrinology. 2021 Jul:17(7):400-420. doi: 10.1038/s41574-021-00496-z. Epub 2021 May 28 [PubMed PMID: 34050323]
Sène D. Small fiber neuropathy: Diagnosis, causes, and treatment. Joint bone spine. 2018 Oct:85(5):553-559. doi: 10.1016/j.jbspin.2017.11.002. Epub 2017 Nov 16 [PubMed PMID: 29154979]
Chedid V, Brandler J, Vijayvargiya P, Park SY, Szarka LA, Camilleri M. Characterization of Upper Gastrointestinal Symptoms, Gastric Motor Functions, and Associations in Patients with Diabetes at a Referral Center. The American journal of gastroenterology. 2019 Jan:114(1):143-154. doi: 10.1038/s41395-018-0234-1. Epub [PubMed PMID: 30166634]
Petropoulos IN, Ponirakis G, Khan A, Almuhannadi H, Gad H, Malik RA. Diagnosing Diabetic Neuropathy: Something Old, Something New. Diabetes & metabolism journal. 2018 Aug:42(4):255-269. doi: 10.4093/dmj.2018.0056. Epub [PubMed PMID: 30136449]
D'Souza RS, Barman R, Joseph A, Abd-Elsayed A. Evidence-Based Treatment of Painful Diabetic Neuropathy: a Systematic Review. Current pain and headache reports. 2022 Aug:26(8):583-594. doi: 10.1007/s11916-022-01061-7. Epub 2022 Jun 18 [PubMed PMID: 35716275]
Level 1 (high-level) evidenceShakhatreh M, Jehangir A, Malik Z, Parkman HP. Metoclopramide for the treatment of diabetic gastroparesis. Expert review of gastroenterology & hepatology. 2019 Aug:13(8):711-721. doi: 10.1080/17474124.2019.1645594. Epub 2019 Jul 30 [PubMed PMID: 31314613]
Frazee LA, Mauro LS. Erythromycin in the Treatment of Diabetic Gastroparesis. American journal of therapeutics. 1994 Dec:1(4):287-295 [PubMed PMID: 11835102]
Stevens JE, Jones KL, Rayner CK, Horowitz M. Pathophysiology and pharmacotherapy of gastroparesis: current and future perspectives. Expert opinion on pharmacotherapy. 2013 Jun:14(9):1171-86. doi: 10.1517/14656566.2013.795948. Epub 2013 May 11 [PubMed PMID: 23663133]
Level 3 (low-level) evidenceMobley DF, Khera M, Baum N. Recent advances in the treatment of erectile dysfunction. Postgraduate medical journal. 2017 Nov:93(1105):679-685. doi: 10.1136/postgradmedj-2016-134073. Epub 2017 Jul 27 [PubMed PMID: 28751439]
Level 3 (low-level) evidencePalma JA, Kaufmann H. Management of Orthostatic Hypotension. Continuum (Minneapolis, Minn.). 2020 Feb:26(1):154-177. doi: 10.1212/CON.0000000000000816. Epub [PubMed PMID: 31996627]
Zhang AC, De Silva MEH, MacIsaac RJ, Roberts L, Kamel J, Craig JP, Busija L, Downie LE. Omega-3 polyunsaturated fatty acid oral supplements for improving peripheral nerve health: a systematic review and meta-analysis. Nutrition reviews. 2020 Apr 1:78(4):323-341. doi: 10.1093/nutrit/nuz054. Epub [PubMed PMID: 31532492]
Level 1 (high-level) evidenceChinnery HR, Naranjo Golborne C, Downie LE. Omega-3 supplementation is neuroprotective to corneal nerves in dry eye disease: a pilot study. Ophthalmic & physiological optics : the journal of the British College of Ophthalmic Opticians (Optometrists). 2017 Jul:37(4):473-481. doi: 10.1111/opo.12365. Epub 2017 Mar 12 [PubMed PMID: 28295445]
Level 3 (low-level) evidencePutz Z, Tordai D, Hajdú N, Vági OE, Kempler M, Békeffy M, Körei AE, Istenes I, Horváth V, Stoian AP, Rizzo M, Papanas N, Kempler P. Vitamin D in the Prevention and Treatment of Diabetic Neuropathy. Clinical therapeutics. 2022 May:44(5):813-823. doi: 10.1016/j.clinthera.2022.03.012. Epub 2022 Apr 12 [PubMed PMID: 35428527]
Alam U, Fawwad A, Shaheen F, Tahir B, Basit A, Malik RA. Improvement in Neuropathy Specific Quality of Life in Patients with Diabetes after Vitamin D Supplementation. Journal of diabetes research. 2017:2017():7928083. doi: 10.1155/2017/7928083. Epub 2017 Dec 28 [PubMed PMID: 29445752]
Level 2 (mid-level) evidenceEsposito C, Ugo Garzarella E, Santarcangelo C, Di Minno A, Dacrema M, Sacchi R, Piccinocchi G, Piccinocchi R, Daglia M. Safety and efficacy of alpha-lipoic acid oral supplementation in the reduction of pain with unknown etiology: A monocentric, randomized, double-blind, placebo-controlled clinical trial. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2021 Dec:144():112308. doi: 10.1016/j.biopha.2021.112308. Epub 2021 Oct 12 [PubMed PMID: 34649217]
Level 1 (high-level) evidenceJeffrey S, Samraj PI, Raj BS. The Role of Alpha-lipoic Acid Supplementation in the Prevention of Diabetes Complications: A Comprehensive Review of Clinical Trials. Current diabetes reviews. 2021:17(9):e011821190404. doi: 10.2174/1573399817666210118145550. Epub [PubMed PMID: 33461470]
. Retraction. Alpha-lipoic acid supplementation and diabetes. Nutrition reviews. 2012 Aug:70(8):482. doi: 10.1111/j.1753-4887.2012.00507.x. Epub 2012 Jun 15 [PubMed PMID: 22835141]
Fonseca VA, Lavery LA, Thethi TK, Daoud Y, DeSouza C, Ovalle F, Denham DS, Bottiglieri T, Sheehan P, Rosenstock J. Metanx in type 2 diabetes with peripheral neuropathy: a randomized trial. The American journal of medicine. 2013 Feb:126(2):141-9. doi: 10.1016/j.amjmed.2012.06.022. Epub 2012 Dec 5 [PubMed PMID: 23218892]
Level 1 (high-level) evidenceJayabalan B, Low LL. Vitamin B supplementation for diabetic peripheral neuropathy. Singapore medical journal. 2016 Feb:57(2):55-9. doi: 10.11622/smedj.2016027. Epub [PubMed PMID: 26892473]
Krishnasamy S, Abell TL. Diabetic Gastroparesis: Principles and Current Trends in Management. Diabetes therapy : research, treatment and education of diabetes and related disorders. 2018 Jul:9(Suppl 1):1-42. doi: 10.1007/s13300-018-0454-9. Epub 2018 Jun 22 [PubMed PMID: 29934758]
Garcia-Klepzig JL, Sánchez-Ríos JP, Manu C, Ahluwalia R, Lüdemann C, Meloni M, Lacopi E, De Buruaga VR, Bouillet B, Vouillarmet J, Lázaro-Martínez JL, Van Acker K. Perception of diabetic foot ulcers among general practitioners in four European countries: knowledge, skills and urgency. Journal of wound care. 2018 May 2:27(5):310-319. doi: 10.12968/jowc.2018.27.5.310. Epub [PubMed PMID: 29738299]
Iqbal Z, Azmi S, Yadav R, Ferdousi M, Kumar M, Cuthbertson DJ, Lim J, Malik RA, Alam U. Diabetic Peripheral Neuropathy: Epidemiology, Diagnosis, and Pharmacotherapy. Clinical therapeutics. 2018 Jun:40(6):828-849. doi: 10.1016/j.clinthera.2018.04.001. Epub 2018 Apr 30 [PubMed PMID: 29709457]
Simpson DM, Robinson-Papp J, Van J, Stoker M, Jacobs H, Snijder RJ, Schregardus DS, Long SK, Lambourg B, Katz N. Capsaicin 8% Patch in Painful Diabetic Peripheral Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Study. The journal of pain. 2017 Jan:18(1):42-53. doi: 10.1016/j.jpain.2016.09.008. Epub 2016 Oct 13 [PubMed PMID: 27746370]
Level 1 (high-level) evidenceVinik AI, Perrot S, Vinik EJ, Pazdera L, Jacobs H, Stoker M, Long SK, Snijder RJ, van der Stoep M, Ortega E, Katz N. Capsaicin 8% patch repeat treatment plus standard of care (SOC) versus SOC alone in painful diabetic peripheral neuropathy: a randomised, 52-week, open-label, safety study. BMC neurology. 2016 Dec 6:16(1):251 [PubMed PMID: 27919222]
Level 1 (high-level) evidenceBoulton AJ. Diabetic neuropathy: classification, measurement and treatment. Current opinion in endocrinology, diabetes, and obesity. 2007 Apr:14(2):141-5 [PubMed PMID: 17940432]
Level 3 (low-level) evidenceThomas PK. Classification, differential diagnosis, and staging of diabetic peripheral neuropathy. Diabetes. 1997 Sep:46 Suppl 2():S54-7 [PubMed PMID: 9285500]
Zafeiri M, Tsioutis C, Kleinaki Z, Manolopoulos P, Ioannidis I, Dimitriadis G. Clinical Characteristics of Patients with co-Existent Diabetic Peripheral Neuropathy and Depression: A Systematic Review. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association. 2021 Feb:129(2):77-85. doi: 10.1055/a-0741-6937. Epub 2018 Sep 26 [PubMed PMID: 30257266]
Level 1 (high-level) evidenceDyck PJ. Detection, characterization, and staging of polyneuropathy: assessed in diabetics. Muscle & nerve. 1988 Jan:11(1):21-32 [PubMed PMID: 3277049]
Ferraresi R, Casini A, Caminiti M, Losurdo F, Clerici G. [Multidisciplinary approach to diabetic foot: a challenge of expertises]. Giornale italiano di cardiologia (2006). 2018 Sep:19(9):495-503. doi: 10.1714/2951.29668. Epub [PubMed PMID: 30087510]
Jiménez S, Rubio JA, Álvarez J, Lázaro-Martínez JL. Analysis of recurrent ulcerations at a multidisciplinary diabetic Foot unit after implementation of a comprehensive Foot care program. Endocrinologia, diabetes y nutricion. 2018 Oct:65(8):438.e1-438.e10. doi: 10.1016/j.endinu.2018.03.012. Epub 2018 Jun 15 [PubMed PMID: 29914816]
Edwards RA, Bonfanti G, Grugni R, Manca L, Parsons B, Alexander J. Predicting Responses to Pregabalin for Painful Diabetic Peripheral Neuropathy Based on Trajectory-Focused Patient Profiles Derived from the First 4 Weeks of Treatment. Advances in therapy. 2018 Oct:35(10):1585-1597. doi: 10.1007/s12325-018-0780-3. Epub 2018 Sep 11 [PubMed PMID: 30206821]
Level 3 (low-level) evidence