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Peripheral neuropathy
Peripheral neuropathy
Peripheral neuropathy
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Peripheral neuropathy
Micrograph showing a vasculitic peripheral neuropathy; plastic embedded; Toluidine blue stain
SpecialtyNeurology
SymptomsShooting pain, numbness, tingling, tremors, bladder problems, unsteadiness

Peripheral neuropathy, often shortened to neuropathy, refers to damage or disease affecting the nerves.[1] Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerve fibers are affected. Neuropathies affecting motor, sensory, or autonomic nerve fibers result in different symptoms. More than one type of fiber may be affected simultaneously. Peripheral neuropathy may be acute (with sudden onset, rapid progress) or chronic (symptoms begin subtly and progress slowly), and may be reversible or permanent.

Common causes include systemic diseases (such as diabetes or leprosy), hyperglycemia-induced glycation,[2][3][4] vitamin deficiency, medication (e.g., chemotherapy, or commonly prescribed antibiotics including metronidazole and the fluoroquinolone class of antibiotics (such as ciprofloxacin, levofloxacin, moxifloxacin)), traumatic injury, ischemia, radiation therapy, excessive alcohol consumption, immune system disease, celiac disease, non-celiac gluten sensitivity, or viral infection. It can also be genetic (present from birth) or idiopathic (no known cause).[5][6][7][8] In conventional medical usage, the word neuropathy (neuro-, "nervous system" and -pathy, "disease of")[9] without modifier usually means peripheral neuropathy.

Neuropathy affecting just one nerve is called "mononeuropathy", and neuropathy involving nerves in roughly the same areas on both sides of the body is called "symmetrical polyneuropathy" or simply "polyneuropathy". When two or more (typically just a few, but sometimes many) separate nerves in disparate areas of the body are affected it is called "mononeuritis multiplex", "multifocal mononeuropathy", or "multiple mononeuropathy".[5][6][7]

Neuropathy may cause painful cramps, fasciculations (fine muscle twitching), muscle loss, bone degeneration, and changes in the skin, hair, and nails. Additionally, motor neuropathy may cause impaired balance and coordination or, most commonly, muscle weakness; sensory neuropathy may cause numbness to touch and vibration, reduced position sense causing poorer coordination and balance, reduced sensitivity to temperature change and pain, spontaneous tingling or burning pain, or allodynia (pain from normally nonpainful stimuli, such as light touch); and autonomic neuropathy may produce diverse symptoms, depending on the affected glands and organs, but common symptoms are poor bladder control, abnormal blood pressure or heart rate, and reduced ability to sweat normally.[5][6][7]

Classification

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Peripheral neuropathy may be classified according to the number and distribution of nerves affected (mononeuropathy, mononeuritis multiplex, or polyneuropathy), the type of nerve fiber predominantly affected (motor, sensory, autonomic), or the process affecting the nerves; e.g., inflammation (neuritis), compression (compression neuropathy), chemotherapy (chemotherapy-induced peripheral neuropathy). The affected nerves are found in an EMG (electromyography) / NCS (nerve conduction study) test and the classification is applied upon exam completion.[10]

Mononeuropathy

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See also: Compression neuropathy and Ulnar neuropathy

Mononeuropathy is a type of neuropathy that only affects a single nerve.[11] Diagnostically, it is important to distinguish it from polyneuropathy because when a single nerve is affected, it is more likely to be due to localized trauma or infection.[citation needed]

The most common cause of mononeuropathy is physical compression of the nerve, known as compression neuropathy. Carpal tunnel syndrome and axillary nerve palsy are examples. Direct injury to a nerve, interruption of its blood supply resulting in (ischemia), or inflammation also may cause mononeuropathy.[citation needed]

Polyneuropathy

[edit]
Main article: Polyneuropathy

"Polyneuropathy" is a pattern of nerve damage that is quite different from mononeuropathy, often more serious and affecting more areas of the body. The term "peripheral neuropathy" sometimes is used loosely to refer to polyneuropathy. In cases of polyneuropathy, many nerve cells in various parts of the body are affected, without regard to the nerve through which they pass; not all nerve cells are affected in any particular case. In distal axonopathy, one common pattern is that the cell bodies of neurons remain intact, but the axons are affected in proportion to their length; the longest axons are the most affected. Diabetic neuropathy is the most common cause of this pattern. In demyelinating polyneuropathies, the myelin sheath around axons is damaged, which affects axons' ability to conduct electrical impulses. The third and least common pattern directly affects the cell bodies of neurons. This affects the sensory neurons (known as sensory neuronopathy or dorsal root ganglionopathy).[12][13]

The effect of this is to cause symptoms in more than one part of the body, often symmetrically on the left and right sides. As for any neuropathy, the chief symptoms include motor symptoms such as weakness or clumsiness of movement; and sensory symptoms such as unusual or unpleasant sensations such as tingling or burning; reduced ability to feel sensations such as texture or temperature, and impaired balance when standing or walking. In many polyneuropathies, these symptoms occur first and most severely in the feet. Autonomic symptoms also may occur, such as dizziness on standing up, erectile dysfunction, and difficulty controlling urination.[citation needed]

Polyneuropathies usually are caused by processes that affect the body as a whole. Diabetes and impaired glucose tolerance are the most common causes. Hyperglycemia-induced formation of advanced glycation end products (AGEs) is related to diabetic neuropathy.[14] Other causes relate to the particular type of polyneuropathy, and there are many different causes of each type, including inflammatory diseases such as Lyme disease, vitamin deficiencies, blood disorders, and toxins (including alcohol and certain prescribed drugs).

Most types of polyneuropathy progress fairly slowly, over months or years, but rapidly progressive polyneuropathy also occurs. It is important to recognize that at one time it was thought that many of the cases of small fiber peripheral neuropathy with typical symptoms of tingling, pain, and loss of sensation in the feet and hands were due to glucose intolerance before a diagnosis of diabetes or pre-diabetes. However, in August 2015, the Mayo Clinic published a scientific study in the Journal of the Neurological Sciences showing "no significant increase in...symptoms...in the prediabetes group", and stated that "A search for alternate neuropathy causes is needed in patients with prediabetes."[15]

The treatment of polyneuropathies is aimed firstly at eliminating or controlling the cause, secondly at maintaining muscle strength and physical function, and thirdly at controlling symptoms such as neuropathic pain.[citation needed]

Mononeuritis multiplex

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Mononeuritis multiplex, occasionally termed polyneuritis multiplex, is simultaneous or sequential involvement of individual noncontiguous nerve trunks,[16] either partially or completely, evolving over days to years and typically presenting with acute or subacute loss of sensory and motor function of individual nerves. The pattern of involvement is asymmetric. However, as the disease progresses, deficit(s) becomes more confluent and symmetrical, making it difficult to differentiate from polyneuropathy.[17] Therefore, attention to the pattern of early symptoms is important.

Mononeuritis multiplex is sometimes associated with a deep, aching pain that worsens at night and frequently in the lower back, hip, or leg. In people with diabetes mellitus, mononeuritis multiplex typically is encountered as acute, unilateral, and severe thigh pain followed by anterior muscle weakness and loss of knee reflex.[medical citation needed]

Electrodiagnostic medicine studies will show multifocal sensory motor axonal neuropathy.[citation needed]

It is caused by, or associated with, several medical conditions:

Autonomic neuropathy

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Autonomic neuropathy is a form of polyneuropathy that affects the non-voluntary, non-sensory nervous system (i.e., the autonomic nervous system), affecting mostly the internal organs such as the bladder muscles, the cardiovascular system, the digestive tract, and the genital organs. These nerves are not under a person's conscious control and function automatically. Autonomic nerve fibers form large collections in the thorax, abdomen, and pelvis outside the spinal cord. They have connections with the spinal cord and ultimately the brain, however. Most commonly autonomic neuropathy is seen in persons with long-standing diabetes mellitus type 1 and 2. In most—but not all—cases, autonomic neuropathy occurs alongside other forms of neuropathy, such as sensory neuropathy.[citation needed]

Autonomic neuropathy is one cause of malfunction of the autonomic nervous system, but not the only one; some conditions affecting the brain or spinal cord also may cause autonomic dysfunction, such as multiple system atrophy, and therefore, may cause similar symptoms to autonomic neuropathy.[citation needed]

The signs and symptoms of autonomic neuropathy include the following:

Neuritis

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Neuritis is a general term for inflammation of a nerve[26] or the general inflammation of the peripheral nervous system. Symptoms depend on the nerves involved, but may include pain, paresthesia (pins-and-needles), paresis (weakness), hypoesthesia (numbness), anesthesia, paralysis, wasting, and disappearance of the reflexes.

Causes of neuritis include:

Types of neuritis include:

Signs and symptoms

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Those with diseases or dysfunctions of their nerves may have problems with normal nerve functions. Symptoms vary depending on the types of nerve fiber involved.[30] [citation needed] In terms of sensory function, symptoms commonly include loss of function ("negative") symptoms, including numbness, tremor, impairment of balance, and gait abnormality.[31] Gain of function (positive) symptoms include tingling, pain, itching, crawling, and pins-and-needles. Motor symptoms include loss of function ("negative") symptoms of weakness, tiredness, muscle atrophy, and gait abnormalities; and gain of function ("positive") symptoms of cramps, and muscle twitch (fasciculations).[32]

In the most common form, length-dependent peripheral neuropathy, pain, and parasthesia appear symmetrically and generally at the terminals of the longest nerve in the lower legs and feet. Sensory symptoms usually develop before motor symptoms such as weakness. Length-dependent peripheral neuropathy symptoms make a slow ascent of the lower limbs, while symptoms may never appear in the upper limbs; if they do, it will be around the time that leg symptoms reach the knee.[33] When the nerves of the autonomic nervous system are affected, symptoms may include constipation, dry mouth, difficulty urinating, and dizziness when standing.[32]

CAP-PRI scale for diagnosis

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A user-friendly, disease-specific, quality-of-life scale can be used to monitor how someone feels with the burden of chronic, sensorimotor polyneuropathy. This scale, called the Chronic, Acquired Polyneuropathy - Patient-reported Index (CAP-PRI), contains only 15 items and is completed by the person affected by polyneuropathy. The total score and individual item scores can be followed over time, with item scoring used by the patient and care provider to estimate the clinical status of some of the more common life domains and symptoms impacted by polyneuropathy.[34]

Causes

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The causes are grouped broadly as follows:

Diagnosis

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Peripheral neuropathy may first be considered when an individual reports symptoms of numbness, tingling, and pain in feet. After ruling out a lesion in the central nervous system as a cause, a diagnosis may be made on the basis of symptoms, laboratory and additional testing, clinical history, and a detailed examination.

During physical examination, specifically a neurological examination, those with generalized peripheral neuropathies most commonly have distal sensory or motor and sensory loss, although those with a pathology (problem) of the nerves may be perfectly normal; may show proximal weakness, as in some inflammatory neuropathies, such as Guillain–Barré syndrome; or may show focal sensory disturbance or weakness, such as in mononeuropathies. Classically, ankle jerk reflex is absent in peripheral neuropathy.

A physical examination will involve testing the deep ankle reflex as well as examining the feet for any ulceration. For large fiber neuropathy, an exam will usually show an abnormally decreased sensation to vibration, which is tested with a 128-Hz tuning fork, and diminished sensation of light touch when touched by a nylon monofilament.[33]

Diagnostic tests include electromyography (EMG) and nerve conduction studies (NCSs), which assess large myelinated nerve fibers.[33] Testing for small-fiber peripheral neuropathies often relates to the autonomic nervous system function of small thinly- and unmyelinated fibers. These tests include a sweat test and a tilt table test. Diagnosis of small fiber involvement in peripheral neuropathy may also involve a skin biopsy in which a 3 mm-thick section of skin is removed from the calf by a punch biopsy, and is used to measure the skin intraepidermal nerve fiber density (IENFD), the density of nerves in the outer layer of the skin.[31] Reduced density of the small nerves in the epidermis supports a diagnosis of small-fiber peripheral neuropathy.

In EMG testing, demyelinating neuropathy characteristically shows a reduction in conduction velocity and prolongation of distal and F-wave latencies, whereas axonal neuropathy shows a reduction in amplitude.[48]

Laboratory tests include blood tests for vitamin B12 levels, a complete blood count, measurement of thyroid stimulating hormone levels, a comprehensive metabolic panel screening for diabetes and pre-diabetes, and a serum immunofixation test, which tests for antibodies in the blood.[32]

Treatment

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The treatment of peripheral neuropathy varies based on its cause, and treating the underlying condition can help neuropathy treatment. When peripheral neuropathy results from diabetes mellitus or prediabetes, blood sugar management is key to treatment. In prediabetes, strict blood sugar control can significantly alter the course of neuropathy.[31] In peripheral neuropathy that stems from immune-mediated diseases, the underlying condition is treated with intravenous immunoglobulin or steroids. When peripheral neuropathy results from vitamin deficiencies or other disorders, those are treated as well.[31]

Medications

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A range of medications that act on the central nervous system have been used to treat neuropathic pain. Commonly used medications include tricyclic antidepressants (such as nortriptyline,[49] amitriptyline.[50] imapramine,[51] and desipramine,[52]) serotonin-norepinephrine reuptake inhibitor (SNRI) medications (duloxetine,[53] venlafaxine,[54] and milnacipran[55]) and antiepileptic medications (gabapentin,[56] pregabalin,[57] oxcarbazepine[58] zonisamide[59] levetiracetam,[60] lamotrigine,[61] topiramate,[62] phenytoin,[63] lacosamide,[64] sodium valproate[65] and carbamazepine[66]). Opioid and opiate medications (such as buprenorphine,[67] morphine,[68] methadone,[69] fentanyl,[70] hydromorphone,[71] tramadol[72] and oxycodone[73]) are also often used to treat neuropathic pain.

As is revealed in many of the Cochrane systematic reviews listed below, studies of these medications for the treatment of neuropathic pain are often methodologically flawed and the evidence is potentially subject to major bias. In general, the evidence does not support the usage of antiepileptic and antidepressant medications for the treatment of neuropathic pain. Better-designed clinical trials and further review from non-biased third parties are necessary to gauge just how useful for patients these medications truly are. Reviews of these systematic reviews are also necessary to assess their failings.

It is also often the case that the aforementioned medications are prescribed for neuropathic pain conditions for which they had not been explicitly tested for which controlled research is severely lacking; or even for which evidence suggests that these medications are not effective.[74][75][76] The NHS for example explicitly states that amitriptyline and gabapentin can be used for treating the pain of sciatica.[77] This is despite both the lack of high-quality evidence that demonstrates the efficacy of these medications for that symptom,[50][56] and also the prominence of generally moderate to high-quality evidence that reveals that antiepileptics in specific, including gabapentin, demonstrate no efficacy in treating it.[78]

Antidepressants

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In general, according to Cochrane's systematic reviews, antidepressants have shown to either be ineffective for the treatment of neuropathic pain or the evidence available is inconclusive.[49][52][79][80] Evidence also tends to be tainted by bias or issues with the methodology.[81][82]

Cochrane systematically reviewed the evidence for the antidepressants nortriptyline, desipramine, venlafaxine, and milnacipran and in all these cases found scant evidence to support their use for the treatment of neuropathic pain. All reviews were done between 2014 and 2015.[49][52][79][80]

A 2015 Cochrane systematic review of amitriptyline found no evidence supporting amitriptyline that did not possess inherent bias. The authors believe amitriptyline may have an effect in some patients but that the effect is overestimated.[81] A 2014 Cochrane systematic review of imipramine notes that the evidence suggesting benefit were "methodologically flawed and potentially subject to major bias."[82]

A 2017 Cochrane systematic review assessed the benefit of antidepressant medications for several types of chronic non-cancer pains (including neuropathic pain) in children and adolescents and the authors found the evidence inconclusive.[83]

Antiepileptics

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A 2017 Cochrane systematic review found that daily dosages between 1800–3600 mg of gabapentin could provide good pain relief for pain associated with diabetic neuropathy only. This relief occurred for roughly 30–40% of treated patients, while placebo had a 10–20% response. Three of the seven authors of the review had conflicts of interest declared.[56] In a 2019 Cochrane review of pregabalin the authors conclude that there is some evidence of efficacy in the treatment of pain deriving from post-herpetic neuralgia, diabetic neuropathy, and post-traumatic neuropathic pain only. They also warned that many patients treated will have no benefit. Two of the five authors declared receiving payments from pharmaceutical companies.[57]

A 2017 Cochrane systematic review found that oxcarbazepine had little evidence to support its use for treating diabetic neuropathy, radicular pain, and other neuropathies. The authors also call for better studies.[58] In a 2015 Cochrane systematic review the authors found a lack of evidence showing any effectiveness of zonisamide for treating pain deriving from any peripheral neuropathy.[59] A 2014 Cochrane review found that studies of levetiracetam showed no indication of its effectiveness at treating pain from any neuropathy. The authors also found that the evidence was possibly biased and that some patients experienced adverse events.[84]

A 2013 Cochrane systematic review concluded that there was high-quality evidence to suggest that lamotrigine is not effective for treating neuropathic pain, even at high dosages 200–400 mg.[85] A 2013 Cochrane systematic review of topiramate found that the included data had a strong likelihood of major bias; despite this, it found no effectiveness for the drug in treating the pain associated with diabetic neuropathy. It had not been tested for any other type of neuropathy.[62] Cochrane reviews from 2012 of clonazepam and phenytoin uncovered no evidence of sufficient quality to support their use in chronic neuropathic pain."[86][87]

A 2012 Cochrane systematic review of lacosamide found it very likely that the drug is ineffective for treating neuropathic pain. The authors caution against positive interpretations of the evidence.[88] For sodium valproate the authors of a 2011 Cochrane review found that "three studies no more than hint that sodium valproate may reduce pain in diabetic neuropathy". They discuss how there is a probable overestimate of the effect due to the inherent problems with the data and conclude that the evidence does not support its usage.[89] In a 2014 systematic review of carbamazepine the authors believe the drug benefits some people. No trials were considered greater than level III evidence; none lasted longer than 4 weeks and had poor reporting quality.[90]

A 2017 Cochrane systematic review aiming to assess the benefit of antiepileptic medications for several types of chronic non-cancer pains (including neuropathic pain) in children and adolescents found the evidence inconclusive. Two of the ten authors of this study declared receiving payments from pharmaceutical companies.[91]

Opioids

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A Cochrane review of buprenorphine, fentanyl, hydromorphone, and morphine, all dated between 2015 and 2017, and all for the treatment of neuropathic pain, found that there was insufficient evidence to comment on their efficacy. Conflicts of interest were declared by the authors in this review.[67][68][70][71] A 2017 Cochrane review of methadone found very low-quality evidence, three studies of limited quality, of its efficacy and safety. They could not formulate any conclusions about its relative efficacy and safety compared to a placebo.[69]

For tramadol, Cochrane found that there was only modest information about the benefits of its usage for neuropathic pain. Studies were small, had potential risks of bias and apparent benefits increased with risk of bias. Overall the evidence was of low or very low quality and the authors state that it "does not provide a reliable indication of the likely effect".[72] For oxycodone the authors found very low-quality evidence showing its usefulness in treating diabetic neuropathy and postherpetic neuralgia only. One of the four authors declared receiving payments from pharmaceutical companies.[73]

More generally, a large-scale 2013 review found opioids to be more effective for intermediate-term use than short-term use, but couldn't properly assess effectiveness for chronic use because of insufficient data. Most recent guidelines on the pharmacotherapy of neuropathic pain however are in agreement with the results of this review and recommend the use of opioids.[92] A 2017 Cochrane review examining mainly propoxyphene therapy as a treatment for many non-cancer pain syndromes (including neuropathic pain) concluded, "There was no evidence from randomised controlled trials to support or refute the use of opioids to treat chronic non-cancer pain in children and adolescents."[93]

Others

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A 2016 Cochrane review of paracetamol for the treatment of neuropathic pain concluded that its benefit alone or in combination with codeine or dihydrocodeine is unknown.[94]

Few studies have examined whether nonsteroidal anti-inflammatory drugs are effective in treating peripheral neuropathy.[95]

There is some evidence that symptomatic relief from the pain of peripheral neuropathy may be obtained by the application of topical capsaicin. Capsaicin is the factor that causes heat in chili peppers. However, the evidence suggesting that capsaicin applied to the skin reduces pain for peripheral neuropathy is of moderate to low quality and should be interpreted carefully before this treatment is used.[96]

Evidence supports the use of cannabinoids for some forms of neuropathic pain.[97] A 2018 Cochrane review of cannabis-based medicines for the treatment of chronic neuropathic pain included 16 studies. All of these studies included THC as a pharmacological component of the test group. The authors rated the quality of evidence as very low to moderate. The primary outcome was quoted as, "Cannabis-based medicines may increase the number of people achieving 50% or greater pain relief compared with placebo" but "the evidence for improvement in Patient Global Impression of Change (PGIC) with cannabis to be of very low quality". The authors also conclude, "The potential benefits of cannabis-based medicine... might be outweighed by their potential harms."[98]

A 2014 Cochrane review of topical lidocaine for the treatment of various peripheral neuropathies found its usage supported by a few low-quality studies. The authors state that no high-quality randomised control trials demonstrate its efficacy or safety profile.[99]

A 2015 (updated in 2022) Cochrane review of topical clonidine for the treatment of diabetic neuropathy included two studies of 8 and 12 weeks in length; both of which compared topical clonidine to placebo and both of which were funded by the same drug manufacturer. The review found that topical clonidine may provide some benefit versus placebo. However, the authors state that the included trials are potentially subject to significant bias and that the evidence is of low to moderate quality.[100]

A 2007 Cochrane review of aldose reductase inhibitors for the treatment of pain deriving from diabetic polyneuropathy found it no better than a placebo.[101]

Medical devices

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Transcutaneous electrical nerve stimulation (TENS) therapy is often used to treat various types of neuropathy. A 2010 review of three trials, for the treatment of diabetic neuropathy explicitly, involving a total of 78 patients found some improvement in pain scores after 4 and 6 but not 12 weeks of treatment and an overall improvement in neuropathic symptoms at 12 weeks.[102] Another 2010 review of four trials, for the treatment of diabetic neuropathy, found significant improvement in pain and overall symptoms, with 38% of patients in one trial becoming asymptomatic. The treatment remains effective even after prolonged use, but symptoms return to baseline within a month of cessation of treatment.[103]

These older reviews can be balanced with a more recent 2017 review of TENS for neuropathic pain by Cochrane which concluded that "This review is unable to state the effect of TENS versus sham TENS for pain relief due to the very low quality of the included evidence... The very low quality of evidence means we have very limited confidence in the effect estimate reported." A very low quality of evidence means, 'multiple sources of potential bias' with a 'small number and size of studies'.[104]

Surgery

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Main article: Nerve decompression

Peripheral neuropathy due to nerve compression is treatable with a nerve decompression.[105][106][107][108] When a nerve is subject to localized pressure or stretching, the vascular supply is interrupted leading to a cascade of physiological changes that causes nerve injury.[109] In a nerve decompression, a surgeon explores the entrapment site and removes tissue around the nerve to relieve pressure. Common sites of entrapment are spaces of anatomic narrowing such as osteofibrous tunnels (e.g. carpal tunnel in carpal tunnel syndrome).[110] In many cases the potential for nerve recovery (full or partial) after decompression is excellent, as chronic nerve compression is associated with low-grade nerve injury (Sunderland classification I-III) rather than high-grade nerve injury (Sunderland classification IV-V).[111] Nerve decompressions for properly selected patients are associated with a significant reduction in pain, in some cases the complete elimination of pain.[112][105][106]

In people with diabetic peripheral neuropathy, two reviews make a case for nerve decompression surgery as an effective means of pain relief and support claims for protection from foot ulceration.[113][114] There is less evidence for efficacy of surgery for non-diabetic peripheral neuropathy of the legs and feet. One uncontrolled study that did before/after comparisons with a minimum of one-year follow-up reported improvements in pain relief, impaired balance, and numbness. "There was no difference in outcomes between patients with diabetic versus idiopathic neuropathy in response to nerve decompression."[41] There are no placebo-controlled trials for idiopathic peripheral neuropathy in the published scientific literature.

Diet

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According to a review, strict gluten-free diet is an effective treatment when neuropathy is caused by gluten sensitivity, with or without the presence of digestive symptoms or intestinal injury.[8][clarification needed]

Counselling

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A 2015 review on the treatment of neuropathic pain with psychological therapy concluded that "There is insufficient evidence of the efficacy and safety of psychological interventions for chronic neuropathic pain. The two available studies show no benefit of treatment over either waiting list or placebo control groups."[115]

Alternative medicine

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A 2019 Cochrane review of the treatment of herbal medicinal products for people with neuropathic pain for at least three months concluded that "There was insufficient evidence to determine whether nutmeg or St John's wort has any meaningful efficacy in neuropathic pain conditions. The quality of the current evidence raises serious uncertainties about the estimates of effect observed, therefore, we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect."[116]

A 2017 Cochrane review on the usage of acupuncture as a treatment for neuropathic pain concludes, "Due to the limited data available, there is insufficient evidence to support or refute the use of acupuncture for neuropathic pain in general, or for any specific neuropathic pain condition when compared with sham acupuncture or other active therapies." Also, "Most studies included a small sample size (fewer than 50 participants per treatment arm) and all studies were at high risk of bias for blinding of participants and personnel." Also, the authors state, "we did not identify any study comparing acupuncture with treatment as usual."[117]

Alpha lipoic acid (ALA) with benfotiamine is a proposed pathogenic treatment for painful diabetic neuropathy only.[118] The results of two systematic reviews state that oral ALA produced no clinically significant benefit, intravenous ALA administered over three weeks may improve symptoms and that long-term treatment has not been investigated.[119]

Research

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A 2008 literature review concluded that "based on principles of evidence-based medicine and evaluations of methodology, there is only a 'possible' association of celiac disease and peripheral neuropathy due to lower levels of evidence and conflicting evidence. There is not yet convincing evidence of causality."[120]

A 2019 review concluded that "gluten neuropathy is a slowly progressive condition. About 25% of the patients will have evidence of enteropathy on biopsy (CD [celiac disease]) but the presence or absence of an enteropathy does not influence the positive effect of a strict gluten-free diet."[8]

Stem-cell therapy is also being examined as a possible means to repair peripheral nerve damage but efficacy has not yet been demonstrated.[121][122][123]

See also

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References

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Further reading

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[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Peripheral neuropathy

View on Grokipedia
from Grokipedia
Peripheral neuropathy is a disorder characterized by damage to the peripheral nervous system, which consists of nerves outside the brain and spinal cord that transmit signals between the central nervous system and the rest of the body. This condition disrupts nerve function, resulting in symptoms such as numbness, tingling, pain, and muscle weakness, primarily affecting the hands and feet but potentially involving other areas. It encompasses over 100 types and impacts approximately 2.4% of the global population, with prevalence increasing to 5-7% among individuals aged 45 and older. The peripheral nervous system includes sensory nerves (which carry information about touch, temperature, and ), motor nerves (which control muscle movement), and autonomic nerves (which regulate involuntary functions like and ). Damage can occur in these nerve types individually or in combination, leading to varied presentations; for instance, sensory neuropathy often causes prickling or burning sensations, while motor involvement results in cramps, twitching, or loss of coordination. may manifest as issues with , sweating, or gastrointestinal motility. Symptoms typically develop gradually and may worsen over time if untreated, though they are rarely life-threatening. Causes of peripheral neuropathy are diverse and can be broadly classified as acquired or inherited. Acquired forms, which account for the majority of cases, are most commonly linked to diabetes mellitus, affecting over 50% of individuals with the disease due to prolonged high blood sugar damaging nerves. Other significant causes include chronic alcohol misuse, vitamin B-12 deficiency, infections (such as or ), autoimmune disorders (like Guillain-Barré syndrome), exposure to toxins or , and trauma. Inherited neuropathies, such as Charcot-Marie-Tooth disease, result from genetic mutations affecting nerve structure or function. In up to 30% of cases, no clear cause is identified, termed idiopathic neuropathy. Diagnosis typically begins with a thorough and , followed by tests such as (EMG), nerve conduction studies, blood tests for underlying conditions, imaging (MRI or CT), or nerve biopsy to confirm nerve damage and identify the etiology. Treatment focuses on addressing the underlying cause where possible—for example, blood sugar control in or immunosuppressive therapy for autoimmune-related cases—and managing symptoms through medications like or for pain, for strength and balance, or assistive devices like braces. Lifestyle modifications, including exercise, a balanced diet, and avoidance of alcohol and toxins, play a crucial role in prevention and symptom alleviation. While there is no universal cure, early intervention can halt progression and improve .

Introduction

Definition

Peripheral neuropathy refers to damage or dysfunction of the peripheral nerves, which are the nerves located outside the and , leading to impaired sensory, motor, or autonomic function. The peripheral nervous system (PNS) consists of the (except the ) and spinal nerves that connect the (CNS)—comprising the and —to the rest of the body, transmitting sensory from the periphery to the CNS and motor commands from the CNS to muscles and glands. This distinguishes peripheral neuropathy from central nervous system disorders, as the PNS is responsible for voluntary and involuntary functions beyond the and . Common manifestations include numbness, tingling (), muscle weakness, or pain, often starting in the extremities such as the hands or feet and potentially progressing inward in a distal-to-proximal pattern known as a "stocking-glove" distribution. These symptoms arise from disrupted signaling, which can affect sensation, movement, or organ depending on the nerves involved. The condition affects approximately 2.4% of the global population, with rising to approximately 8% among older adults over age 55 due to age-related risks and comorbidities. The term "neuropathy" was first used in circa 1834, reflecting early 19th-century recognition of nerve diseases, while modern understanding advanced significantly in the through electrophysiologic techniques like nerve conduction studies that enabled precise assessment of nerve function. represents the most common form, involving multiple nerves symmetrically.

Epidemiology

Peripheral neuropathy affects approximately 2.4% of the global population, with rising to approximately 8% among individuals over 55 years of age. In the United States, incidence rates are estimated at approximately 250 cases per 100,000 person-years, reflecting a substantial burden on healthcare systems. Demographic patterns reveal higher among males compared to females, potentially due to differences in exposure to risk factors such as occupational hazards and metabolic conditions. Among individuals with , up to 50% develop peripheral neuropathy, making a leading contributor. Elevated rates are also observed in those with , where can exceed 60%, and in patients with alcohol use disorder, affecting 25-66% of chronic users. Geographic variations show higher reported rates in developed countries, driven by aging populations and increasing diabetes prevalence, whereas underdiagnosis is common in low-resource settings due to limited access to diagnostic tools. The increasing global prevalence of and , which are major risk factors, contributes to higher rates of peripheral neuropathy.

Classification

Mononeuropathy

Mononeuropathy refers to damage or dysfunction affecting a single peripheral , typically resulting from localized compression, trauma, or , which disrupts the 's ability to transmit sensory, motor, or autonomic signals. This focal involvement distinguishes it from more widespread forms of neuropathy, as the symptoms are confined to the specific distribution of the affected . This leads to focal sensory loss in the distribution of the affected nerve (for example, in median nerve palsy, sensory loss affects the thumb, index finger, middle finger, and lateral palm), and diagrams typically illustrate mononeuropathy as a localized patch in the affected nerve territory. Common examples include , which involves compression of the at the wrist, leading to symptoms in the thumb, index, middle, and part of the ring finger; peroneal neuropathy, often causing due to common peroneal near the ; and at the , affecting the and resulting in issues with the fourth and fifth fingers. Clinical features typically manifest as localized weakness, sensory loss such as numbness or , and or burning sensations within the nerve's territory, with motor deficits like or clumsiness in advanced cases. Risk factors for mononeuropathy often involve repetitive motions, direct trauma, or anatomical entrapment, with conditions like , , or occupational exposures increasing susceptibility. For instance, affects 1% to 5% of the general population, with a higher incidence in females and those aged 40 to 60. is generally favorable compared to diffuse neuropathies, as symptoms are often reversible with early intervention to relieve compression or address trauma, though delays can lead to permanent axonal damage.

Polyneuropathy

Polyneuropathy refers to a diffuse process involving symmetric damage to multiple peripheral nerves, typically in a length-dependent manner that results in symmetric distal sensory loss in a "stocking-glove" pattern, starting in the toes/feet and fingers/hands, progressing proximally with increasing severity. This pattern arises because longer axons are more vulnerable to metabolic, toxic, or degenerative insults that impair or energy supply. Diagrams typically illustrate polyneuropathy with graded shading darker distally in the limbs to represent the stocking-glove pattern. Polyneuropathy is the most common form of peripheral neuropathy, accounting for the majority of cases, and is often chronic and progressive, with estimates ranging from 1-3% in the general population and rising to approximately 7% in individuals over 65 years. Subtypes of polyneuropathy are classified based on the primary site of nerve pathology: axonal degeneration, which is the most prevalent and involves direct damage to nerve fibers (e.g., in diabetic ), or demyelinating processes, which affect the sheath insulating the nerves (e.g., in Guillain-Barré syndrome). Axonal polyneuropathies predominate in metabolic conditions like , where up to 50% of patients develop neuropathy within 10 years of , while demyelinating forms are often immune-mediated. Clinical patterns vary, including sensorimotor , which affects both sensory and motor functions with symptoms like numbness, tingling, and weakness; pure sensory polyneuropathy, characterized by isolated loss of sensation or pain; or motor-only polyneuropathy, featuring predominant without sensory involvement. Notable examples include (CIDP), a demyelinating subtype with a relapsing-remitting course over weeks to months, often leading to significant motor impairment if untreated. In some cases, polyneuropathy may involve autonomic nerves, resulting in symptoms such as or gastrointestinal dysfunction, particularly when small fibers are affected.

Mononeuritis multiplex

Mononeuritis multiplex, also known as multiple mononeuropathy, is a peripheral nerve disorder characterized by the patchy, asynchronous involvement of two or more noncontiguous peripheral nerves, resulting in multifocal sensory and motor deficits. This manifests as damage to individual nerve trunks in an irregular distribution, distinguishing it from more uniform patterns of . It is commonly associated with underlying conditions such as (including and ANCA-associated forms), diabetes mellitus, and infections like or cytomegalovirus reactivation. In patients with ANCA-associated vasculitis who develop neuropathic features, mononeuritis multiplex occurs in approximately 70-90% of cases. Other etiologies include , , and less frequently, paraneoplastic syndromes or immune-mediated reactions. Clinically, it presents with a stepwise progression of symptoms, featuring sudden-onset deficits in distinct nerve territories that lead to asymmetric sensory disturbances (such as , tingling, burning, or loss of sensation) and motor impairments (including , paralysis, or ). For instance, a may experience acute in one limb followed by sensory loss in an unrelated area weeks later, creating an irregular pattern of neurological involvement. Diagnosis poses challenges due to its mimicry of stroke-like focal events, requiring (EMG) and nerve conduction studies (NCS) to confirm multifocal axonal damage rather than demyelinating or symmetric processes. Blood tests for markers, glucose levels, or infectious agents, along with possible nerve biopsy, aid in identifying the . It differs from through its asymmetry and non-length-dependent distribution, and from isolated mononeuropathy by the multiplicity of affected nerves.

Autonomic neuropathy

Autonomic neuropathy refers to damage to the peripheral nerves of the autonomic nervous system, which regulates involuntary bodily functions including heart rate, blood pressure regulation, gastrointestinal motility, and thermoregulation through sweating. This form of neuropathy disrupts the transmission of signals from the brain to organs such as the heart, blood vessels, digestive tract, and sweat glands, leading to impaired automatic control of these systems. It manifests in two primary forms: pure autonomic neuropathy, a rare degenerative condition primarily affecting the autonomic nerves without significant somatic involvement, and mixed autonomic neuropathy, which often coexists with somatic peripheral neuropathy, as frequently observed in chronic conditions like diabetes mellitus. Characteristic symptoms include causing dizziness or fainting upon standing, resulting in delayed stomach emptying and , erectile dysfunction in males, and anhidrosis or abnormal sweating patterns. These manifestations arise from selective involvement of sympathetic and parasympathetic fibers, varying by the extent of nerve damage. The prevalence of autonomic neuropathy is notable in certain populations, affecting approximately 20% of individuals with , with rates increasing to 30-40% in those with long-standing ; it is even higher in hereditary , where autonomic involvement occurs in up to 80% of cases. Cardiovascular autonomic neuropathy, a common subtype, is associated with a five-fold increased of mortality due to heightened susceptibility to cardiac events and sudden death. This subtype often develops insidiously and can occur alongside other forms of , compounding overall neurological impairment.

Pathophysiology

Nerve damage mechanisms

Peripheral neuropathy arises from damage to peripheral nerves through several primary mechanisms, including axonal degeneration, demyelination, and mixed patterns. Axonal degeneration, often manifesting as , involves the breakdown of the distal to site due to loss of nutrient supply from the neuronal cell body, leading to fragmentation and clearance by macrophages. This process affects approximately 80% of symmetrical polyneuropathies and is characterized by cytoskeletal disruption and impaired . Demyelination, conversely, targets the sheath produced by Schwann cells, resulting in slowed or blocked conduction while sparing the initially; it accounts for about 20% of such neuropathies and is frequently immune-mediated. Mixed neuropathies combine these features, complicating classification and requiring targeted therapeutic approaches. Key pathological processes driving nerve damage include oxidative stress, inflammation, and ischemia. Oxidative stress promotes axonal degeneration by inducing calcium-dependent breakdown of the neuronal cytoskeleton, generating reactive oxygen species (ROS) that overwhelm cellular antioxidants. Inflammation, particularly in demyelinating forms, involves cytokine release from immune cells, which damages Schwann cells and myelin integrity. Ischemia contributes through reduced blood flow to vasa nervorum, causing nerve infarction and exacerbating Wallerian degeneration. At the molecular level, voltage-gated sodium channels play a critical role in neuronal hyperexcitability, a hallmark of neuropathic damage. Channels such as Nav1.7 and Nav1.8, expressed in sensory neurons, undergo gain-of-function alterations post-injury, shifting activation thresholds and increasing persistent sodium currents, which lower firing thresholds and promote ectopic firing. This hyperexcitability can lead to axonal overload and degeneration via excessive sodium influx and subsequent calcium dysregulation. Mitochondrial dysfunction further compounds energy failure in nerves, impairing ATP production through defects in the and elevating ROS, which triggers and deficits. Nerve damage progresses in distinct stages: acute phases, such as those following trauma, involve rapid and inflammatory responses within days to weeks, often resolving with regeneration if the proximal stump remains intact. Chronic stages, seen in metabolic conditions like , develop gradually over months to years through cumulative insults like hyperglycemia-induced , leading to persistent axonal loss and incomplete recovery. A key concept in these mechanisms is length-dependent vulnerability, where the longest axons—such as those innervating the distal extremities—face the highest metabolic demands and are most susceptible to degeneration due to their distance from the cell body, explaining the characteristic "stocking-glove" distribution in polyneuropathies.

Types of nerve fiber involvement

Peripheral nerve fibers are classified based on their diameter, myelination, and conduction velocity into groups A, B, and C, with further subdivisions influencing their functional roles in neuropathy. Group A fibers are myelinated and include A-alpha (Aα) fibers, which are large-diameter (12-20 μm) and conduct rapidly (70-120 m/s), primarily serving motor functions to skeletal muscles; A-beta (Aβ) fibers, also large (5-12 μm, 30-70 m/s), mediate touch, , and ; and A-delta (Aδ) fibers, small-diameter (1-5 μm, 4-36 m/s), involved in sharp and sensation. fibers are lightly myelinated preganglionic autonomic efferents (3 μm, 3-15 m/s), while fibers are unmyelinated postganglionic autonomic and sensory fibers (0.2-1.5 μm, 0.4-2.8 m/s) that transmit dull , warmth, and . In peripheral neuropathy, involvement patterns often distinguish between small-fiber and large-fiber types, reflecting selective damage to specific fiber classes. Small-fiber neuropathies predominantly affect Aδ and C fibers, leading to isolated sensory or autonomic dysfunction without motor deficits, as seen in conditions like idiopathic small-fiber neuropathy where these fibers degenerate distally in a length-dependent manner. In contrast, large-fiber neuropathies target Aα and Aβ fibers, resulting in motor weakness and loss of or vibration sense, exemplified by alcoholic neuropathy, which causes axonal degeneration of large myelinated fibers and contributes to gait due to impaired position sense. Autonomic involvement typically implicates B and C fibers, as in diabetic , where postganglionic C-fiber loss disrupts visceral regulation. Pathological changes vary by fiber type and neuropathy subtype, with axonal loss being common in small-fiber cases affecting unmyelinated C s, while demyelinating neuropathies more frequently involve loss of myelinated A s, reducing intraepidermal fiber density in biopsies. In axonal neuropathies, distal degeneration of unmyelinated s predominates, whereas demyelinating processes disrupt the sheath around large A s, slowing conduction. These changes are confirmed histologically, showing reduced densities of specific fiber types without widespread involvement. Selective fiber involvement underlies the diverse presentations of peripheral neuropathy, such as pure motor deficits in , where conduction block occurs almost exclusively in Aα motor fibers without sensory fiber damage. This selectivity explains why some neuropathies spare certain functions, like preserved touch in small-fiber predominant cases, highlighting the need for targeted diagnostics like nerve conduction studies for large fibers and skin biopsies for small fibers.

Signs and symptoms

Sensory symptoms

Sensory symptoms in peripheral neuropathy result from dysfunction or damage to fibers, leading to a range of abnormal perceptions and sensory deficits. These manifestations are broadly categorized into positive symptoms, which involve spontaneous or evoked abnormal sensations, and negative symptoms, which reflect a loss of normal sensory function. Positive symptoms commonly include , described as tingling, "pins and needles," or prickling sensations often starting in the extremities, along with burning pain and other unpleasant sensations. These symptoms, particularly paresthesia and dysesthesia, frequently worsen at night or during sleep due to reduced sensory distractions, lower temperatures, or positional factors, often disrupting sleep. refers to unpleasant abnormal sensations, such as random sharp, burning, stabbing, or crawling feelings, while occurs when typically non-painful stimuli, like light touch, provoke pain. These symptoms arise due to aberrant neural signaling and can be intermittent or persistent, varying in intensity. In contrast, negative symptoms involve diminished sensory processing, including (numbness or reduced perception of touch, vibration, or temperature), and , the complete absence of sensation in the affected regions. Such deficits contribute to risks like unnoticed injuries, as patients may not feel or pressure adequately. Sensory symptoms often exhibit distinct patterns depending on the type of peripheral neuropathy. In polyneuropathy, the most common form, they typically follow a distal symmetric distribution known as the "stocking-glove" pattern, beginning in the toes and fingers before advancing proximally along the limbs if untreated. In contrast, mononeuropathy results in focal sensory loss confined to the specific distribution of the single affected peripheral nerve (e.g., sensory deficits in the thumb, index finger, middle finger, radial half of the ring finger, and lateral palm in median nerve involvement). These patterns are commonly illustrated in neurological diagrams, with polyneuropathy depicted as graded shading darker distally in the limbs and mononeuropathy as a localized patch in the affected nerve territory. This distribution reflects the vulnerability of longer fibers. These disturbances are frequently linked to small-fiber damage, which selectively affects unmyelinated C-fibers and thinly myelinated A-delta fibers responsible for pain and temperature sensation. To quantify symptom severity, particularly for , the Neuropathic Pain Symptom Inventory (NPSI) is employed as a validated self-assessment tool that evaluates distinct pain qualities, such as burning, pressing, or evoked pain, across multiple subscales. Chronic sensory symptoms, especially pain, profoundly affect daily functioning, with reports of disrupted sleep, depressed mood, and diminished ; approximately one-third of patients with peripheral neuropathy experience .

Motor symptoms

Motor symptoms in peripheral neuropathy result from dysfunction of motor nerve fibers, which control voluntary muscle movements, leading to progressive impairment in muscle strength and coordination. The hallmark is , often starting distally in the extremities due to the length-dependent nature of many neuropathies. In polyneuropathies, lower limbs are typically affected first, with weakness manifesting as difficulty rising from a , climbing , or dorsiflexing the ankle, commonly resulting in —a condition where the front of the foot cannot be lifted, causing tripping or a high-stepping . Upper extremity involvement may include hand weakness or clumsiness, impairing tasks such as grasping objects, writing, or buttoning clothing. Accompanying distal leads to visible shrinking and wasting of muscles in the feet, calves, and hands, sometimes resulting in deformities like high arches or hammertoes. Additional features include muscle cramps, which are sudden, painful contractions often occurring at rest or during activity, and fasciculations, involuntary twitching of muscle fibers visible under the skin. In advanced stages, reduced deep tendon reflexes or complete areflexia develop, further diminishing and stability. Symptoms often progress gradually over months to years, evolving from mild fatigue and subtle weakness to profound paralysis in motor-predominant forms, such as , which can mimic through asymmetric, progressive weakness without sensory involvement. Functionally, these symptoms cause instability, frequent falls, and increased dependency in , often necessitating assistive devices like ankle-foot orthoses or canes to maintain mobility and prevent injuries. The risk of falls is notably elevated, contributing to complications such as fractures and reduced .

Autonomic symptoms

Autonomic symptoms in peripheral neuropathy result from dysfunction of the , which regulates involuntary bodily functions such as , digestion, and sweating, often due to damage to small unmyelinated nerve fibers. These symptoms can manifest independently or alongside other features of neuropathy and may significantly impair by disrupting . Cardiovascular involvement commonly presents as , characterized by a sustained drop in systolic of at least 20 Hg or diastolic of at least 10 Hg within three minutes of standing, leading to symptoms like , , fainting, and from inadequate adjustment. may also occur as a compensatory response to maintain during positional changes. In severe cases, this autonomic impairment heightens the risk of silent myocardial ischemia and sudden cardiac death, with studies showing a 3.5-fold increased in symptomatic individuals compared to those without autonomic involvement. Gastrointestinal symptoms arise from impaired motility and secretion due to vagal and enteric nerve damage, including with delayed gastric emptying that causes early satiety, , , , and . Alternating and , or , may also occur from disrupted colonic function. Genitourinary manifestations include bladder dysfunction, such as from atony or , increasing infection risk, and difficulties sensing bladder fullness. is prevalent, with affecting up to 75% of men with due to impaired and nerve signaling, alongside or reduced ; in women, vaginal dryness and decreased or orgasmic function are common. Sudomotor dysfunction leads to anhidrosis, or reduced sweating, particularly in distal extremities, resulting in and dry skin, though compensatory may occur proximally or during meals. This impairment of can exacerbate systemic risks in hot environments.

Causes

Metabolic causes

Metabolic causes of peripheral neuropathy encompass disorders that disrupt normal biochemical processes, leading to nerve damage through endogenous imbalances such as , , dysfunction, and deficiencies. mellitus stands as the predominant metabolic etiology, responsible for approximately 50% of all peripheral neuropathy cases worldwide. In individuals with , the lifetime risk of developing diabetic peripheral neuropathy reaches 50% to 66%, with prevalence escalating alongside disease duration—for example, exceeding 50% in patients after 10 years of diagnosis. The pathogenesis of diabetic neuropathy involves chronic activating several damaging pathways. A key mechanism is the , where elevated glucose is shunted to via , resulting in intracellular osmotic stress, depletion of antioxidants like myo-inositol, and subsequent oxidative damage to Schwann cells and axons. Complementing this, (AGEs) accumulate from non-enzymatic of proteins and lipids, binding to receptors on endothelial cells and neurons to provoke , microvascular ischemia, and further nerve fiber degeneration. Beyond diabetes, chronic kidney disease induces uremic neuropathy through the buildup of uremic toxins, manifesting as a primarily axonal that symmetrically affects sensory and motor nerves, with greater involvement in the lower limbs. This condition impacts up to 90% of patients on long-term dialysis and around 70% of those approaching end-stage renal disease, though symptoms often partially reverse following successful or intensified dialysis. Hypothyroidism contributes to peripheral neuropathy via metabolic slowdown and impaired energy metabolism, typically producing a reversible sensorimotor with mixed axonal loss and demyelinating features, often improving with thyroid hormone replacement therapy. Vitamin deficiencies also drive metabolic neuropathies by impairing essential enzymatic functions. leads to demyelination of large-diameter sensory and motor fibers in the peripheral nerves, frequently alongside subacute combined degeneration of the , exacerbated by elevated levels that promote and vascular injury. Similarly, thiamine (vitamin B1) deficiency, prevalent among chronic alcoholics due to poor nutrition and impaired absorption, causes dry beriberi—a symmetrical distal characterized by axonal degeneration, , and motor weakness that can be reversed with prompt thiamine supplementation. Deficiencies in vitamin B6 (pyridoxine), though uncommon and often linked to medications such as isoniazid that interfere with its metabolism, can result in peripheral neuropathy with sensory and motor symptoms. Vitamin E (tocopherol) deficiency, typically resulting from severe fat malabsorption syndromes or genetic disorders, leads to a large-fiber sensory-predominant axonal neuropathy often accompanied by spinocerebellar ataxia due to impaired antioxidant protection in neural tissues.

Inherited causes

Inherited peripheral neuropathies, also known as hereditary neuropathies, result from genetic mutations that affect the structure, function, or maintenance of peripheral nerves. These conditions are typically chronic and progressive, often presenting in childhood or early adulthood. Charcot-Marie-Tooth disease (CMT), the most common inherited neuropathy, affects approximately 1 in 2,500 individuals worldwide and is caused by mutations in genes such as PMP22, MPZ, or MFN2, leading to demyelination or axonal degeneration. Symptoms include distal , , , and foot deformities like high arches. Other inherited forms include hereditary neuropathy with liability to pressure palsies (HNPP) due to PMP22 deletions, causing episodic nerve palsies, and hereditary sensory and autonomic neuropathies (HSAN), which primarily affect sensory and autonomic fibers. Diagnosis involves , and management is supportive, focusing on symptom relief and rehabilitation. Inherited causes account for about 20-30% of chronic polyneuropathies in adults.

Toxic causes

Toxic causes of peripheral neuropathy encompass exposure to exogenous agents such as alcohol, chemotherapeutic drugs, industrial chemicals, and certain medications, which can induce nerve damage through various mechanisms including axonal degeneration and mitochondrial dysfunction. These neuropathies are typically dose-dependent, symmetrical, and length-dependent, often presenting with sensory symptoms like numbness and in a stocking-glove distribution. While some overlap exists with metabolic factors in cases like chronic , the primary here stems from direct toxic effects. Chronic alcohol consumption is a leading toxic cause, resulting in axonal sensorimotor that predominantly affects small sensory fibers. This condition manifests in 25-66% of heavy drinkers, with symptoms including painful dysesthesias, burning sensations, and gait due to direct from and its metabolites, compounded by . Chemotherapeutic agents frequently induce peripheral neuropathy as a , with platinum compounds like causing a dose-dependent sensory neuropathy that affects up to 30-40% of patients through DNA cross-linking and in dorsal root ganglia neurons. Symptoms include persistent and loss of vibration sense, often worsening after treatment cessation due to a "coasting" effect. Vinca alkaloids, such as , primarily produce a mixed sensory-motor neuropathy by disrupting microtubule-based , leading to weakness and areflexia in up to 96% of pediatric cases at higher doses. Other agents, including taxanes like paclitaxel, immunomodulators such as thalidomide, and proteasome inhibitors like bortezomib, also commonly cause sensory-predominant neuropathies that may feature sharp intermittent or lancinating pains alongside paresthesia and numbness. Industrial toxins, particularly , contribute to occupational neuropathies; lead exposure results in a motor-predominant axonal neuropathy characterized by and from impaired energy metabolism and accumulation. , common in contaminated water sources, induces a painful sensory neuropathy with burning paresthesias and , mediated by oxidative damage and axonal degeneration. Other medications linked to peripheral neuropathy include antibiotics such as metronidazole and nitrofurantoin; cardiovascular drugs like amiodarone; statins for hyperlipidemia; antitubercular agents like isoniazid; anticonvulsants such as phenytoin; dapsone for leprosy; and long-term metformin use, which can contribute via vitamin B12 deficiency. These agents often produce distal sensory neuropathies that may present with sharp intermittent pain, burning dysesthesias, or paresthesias, through mechanisms like mitochondrial toxicity or nutrient depletion. Additionally, excessive intake of vitamin B6 (pyridoxine) from supplements can cause toxic sensory neuropathy, characterized by paresthesia, numbness, and ataxia in a stocking-glove distribution, typically associated with chronic doses exceeding 200 mg/day due to a paradoxical functional deficiency of the active vitamin form. Certain antiretroviral drugs for , such as stavudine, cause distal symmetric sensory in approximately 31-50% of treated patients via mitochondrial toxicity from inhibition of gamma, presenting with burning foot and numbness. Most toxic neuropathies demonstrate partial reversibility upon prompt cessation of exposure, with axonal regeneration possible in milder cases, though high cumulative doses often lead to permanent deficits due to neuronal loss.

Other acquired causes

Acquired causes beyond metabolic and toxic include trauma and compression, which often result in focal or multifocal neuropathies. Traumatic injuries, such as nerve lacerations or stretch during accidents, can cause immediate or delayed nerve damage, leading to mononeuropathies like palsy from humeral fractures. Repetitive trauma or entrapment, as in , compresses nerves like the , producing sensory and motor deficits in the affected distribution. These are common, with affecting up to 3-6% of adults. Treatment may involve surgical decompression or conservative measures.

Infectious and inflammatory causes

Peripheral neuropathy can arise from various infectious agents that directly invade peripheral nerves or trigger secondary immune responses. Human immunodeficiency virus (HIV) infection often leads to distal sensory polyneuropathy, characterized by symmetric pain, paresthesia, and numbness in the feet and hands, primarily due to direct viral effects on sensory neurons and associated mitochondrial toxicity from antiretroviral therapies. Leprosy, caused by Mycobacterium leprae, is a major infectious cause in endemic regions, resulting in multibacillary forms that involve skin lesions and peripheral nerve damage through bacterial infiltration and granulomatous inflammation, leading to sensory loss, motor weakness, and deformities if untreated. Lyme disease, transmitted by Borrelia burgdorferi, can manifest as Bannwarth syndrome, an acute radiculoneuritis with severe radicular pain, facial palsy, and peripheral nerve involvement, typically occurring weeks after a tick bite in endemic areas. Inflammatory processes, often autoimmune-mediated, represent another key category of peripheral neuropathy etiologies. Guillain-Barré syndrome (GBS) is an acute inflammatory demyelinating polyneuropathy frequently triggered by preceding infections such as or respiratory viruses, involving molecular mimicry where antibodies against microbial antigens cross-react with peripheral nerve components like gangliosides, leading to rapid-onset ascending weakness and areflexia. The incidence of GBS is approximately 1-2 cases per 100,000 people annually worldwide, with higher rates in certain populations such as those over 50 years old. Chronic inflammatory demyelinating polyneuropathy (CIDP), a related but persistent condition, features relapsing or progressive sensorimotor deficits over months, responsive to immunomodulatory treatments like intravenous immunoglobulin (IVIG), and affects about 1-9 per 100,000 individuals, often without a clear infectious . Autoimmune mechanisms further contribute to inflammatory neuropathies, sometimes linked to systemic diseases or malignancies. Paraneoplastic neuropathies, such as sensory neuronopathy associated with anti-Hu antibodies, occur in patients with underlying cancers like small-cell lung carcinoma, where immune responses against tumor antigens mistakenly target dorsal root ganglia neurons, causing subacute, asymmetric sensory loss and . Vasculitic neuropathies, exemplified by those tied to or , involve immune-mediated vessel wall inflammation that compromises nerve blood supply, resulting in mononeuritis multiplex with painful, stepwise deficits in multiple nerve distributions. In post-infectious cases like GBS, molecular exemplifies how inflammatory cascades amplify nerve damage through and complement-mediated attacks on or axons.

Idiopathic causes

In up to 30% of peripheral neuropathy cases, no underlying cause can be identified, classifying them as idiopathic. These are often chronic, distal symmetric sensorimotor polyneuropathies, more common in older adults, and may involve small fiber damage leading to painful symptoms without motor involvement. requires exclusion of known etiologies through comprehensive testing, and management focuses on symptom control.

Diagnosis

Clinical evaluation

The clinical evaluation of peripheral neuropathy commences with a comprehensive history to characterize the disorder and identify potential etiologies. Patients are queried regarding the temporal profile of symptoms, including onset (acute if less than 4 weeks, subacute if 4–12 weeks, or chronic if exceeding 12 weeks) and progression pattern, as rapid subacute worsening may indicate inflammatory processes. A detailed exposure history encompasses occupational hazards, medications (e.g., agents like ), recreational substances such as alcohol, and environmental toxins (e.g., ), all of which can precipitate toxic neuropathies. Family history is scrutinized for hereditary conditions, such as , particularly if there is evidence of chronic distal weakness or foot deformities in relatives. Screening for associated systemic conditions is routine, including diabetes mellitus (via inquiries about glycemic control and ), autoimmune disorders, malignancies, or infectious risks, as these frequently underlie acquired neuropathies. Laboratory testing is an essential component of the clinical evaluation to identify treatable underlying causes. Routine initial tests include a , (assessing renal and liver function), fasting blood glucose or HbA1c (for ), serum with methylmalonic acid (for deficiency), , and or (for inflammation). Additional tests, such as for paraproteins or tests for infections (e.g., , Lyme), may be indicated based on history. The then systematically assesses neurological function to confirm peripheral nerve involvement and delineate its distribution and severity. Sensory evaluation targets both large and small fiber modalities: vibration sense is tested at the toes using a 128-Hz , with diminished perception indicating large-fiber dysfunction, while pinprick sensation (using a or similar) probes small-fiber integrity and may reveal or —pain elicited by light touch in symptomatic regions. Motor examination employs the Council (MRC) scale to grade strength from 0 (no ) to 5 (normal power against full resistance), often revealing distal weakness such as before proximal involvement. Deep tendon reflexes are elicited throughout, with distal areflexia (e.g., absent ankle jerks) being a hallmark of length-dependent axonopathies, whereas generalized may suggest demyelination. Characteristic neurologic patterns guide ; the classic stocking-glove distribution—symmetric sensory loss starting in the distal lower extremities and progressing proximally, then involving the hands—predominates in metabolic and toxic causes. Bedside screening tools, such as the , offer a validated, rapid assessment combining patient questionnaire and foot inspection to detect abnormalities like ulceration or deformity, especially in diabetic cohorts where it demonstrates high sensitivity for distal symmetric . Red flags warranting urgent specialist referral include acute symmetric weakness (suggestive of Guillain-Barré syndrome), multifocal asymmetry (indicative of or mononeuritis multiplex), or prominent autonomic features like , as these signal potentially treatable or progressive etiologies.

Electrophysiological tests

Electrodiagnostic testing, encompassing nerve conduction studies (NCS) and needle (EMG), plays a central role in confirming the presence of peripheral neuropathy and characterizing its underlying . These tests provide objective measures of nerve function by assessing electrical conduction along peripheral nerves and muscle electrical activity, helping to distinguish between axonal and demyelinating forms of the disorder. Nerve conduction studies involve stimulating peripheral nerves with electrical impulses and recording the resulting (CMAP) or action potential (SNAP). Key parameters include conduction velocity, which is typically greater than 40 m/s in healthy adults, reflecting the number of functioning axons, and distal latency, the time from stimulation to response onset. Reduced conduction velocity and prolonged distal latency suggest demyelination, as seen in conditions like (CIDP), while preserved velocity with decreased indicates axonal damage. For instance, in , NCS often reveals prolonged distal latency of the , confirming focal compression. Electromyography complements NCS by inserting a needle into muscles to evaluate spontaneous and voluntary electrical activity. Abnormal spontaneous activity, such as fibrillations and positive sharp waves, signifies active due to axonal loss, typically appearing 2-3 weeks after injury. In chronic phases, reinnervation manifests as action potentials (MUAPs) with increased and duration, reflecting collateral sprouting from surviving axons. These EMG patterns aid in localizing the and assessing its chronicity. Indications for these tests include differentiating neuropathy subtypes; for example, slowed conduction velocities and conduction blocks on NCS strongly support a of CIDP over axonal polyneuropathies like those caused by . They are particularly useful when clinical suggests large-fiber involvement, guiding further management. Despite their utility, electrophysiological tests have limitations. NCS and EMG primarily evaluate large myelinated fibers and thus often yield normal results in small-fiber neuropathy cases, where unmyelinated or thinly myelinated fibers are affected. Additionally, results are operator-dependent, requiring expertise for accurate stimulation, recording, and interpretation to avoid false positives or negatives.

Imaging and biopsy

Imaging techniques play a crucial role in evaluating structural abnormalities in peripheral neuropathy, particularly when identifying nerve entrapment or enlargement. Magnetic resonance imaging (MRI) is particularly effective for visualizing deep-seated nerves, such as the brachial plexus, where it can detect entrapment through findings like nerve flattening, proximal enlargement, and hyperintense signals on T2-weighted sequences. Ultrasound complements MRI by providing high-resolution assessment of superficial nerves, such as the median, ulnar, and peroneal nerves, through measurement of cross-sectional area (CSA), where enlargement (e.g., median nerve CSA >10-15 mm² at the wrist) indicates pathology like entrapment or inflammatory changes. Nerve biopsy, often of the sural nerve, serves as a gold standard for diagnosing specific etiologies like amyloidosis and vasculitis by revealing amyloid deposits or vascular inflammation in tissue samples. In cases of demyelinating neuropathies, biopsy may show characteristic onion-bulb formations, consisting of concentric layers of Schwann cell processes surrounding denuded axons. Skin punch biopsy offers a less invasive alternative for assessing small-fiber involvement, quantifying intraepidermal nerve fiber density via PGP 9.5 immunostaining, where a density below 5 fibers/mm indicates significant loss. These procedures are typically indicated when nerve conduction studies are normal yet clinical suspicion for inflammatory or infiltrative causes remains high, such as in rapidly progressive or asymmetric neuropathies. Risks of biopsy include wound infection, neuroma formation, and permanent in the lateral foot, occurring in approximately 5-10% of cases. punch biopsy has a lower risk profile, with primarily minor issues like bruising or scarring. The diagnostic yield is positive in about 40-60% of idiopathic cases, often identifying treatable etiologies like or .

Management

Pharmacological treatments

Pharmacological treatments for peripheral neuropathy primarily target relief and, in specific etiologies, address underlying disease processes to modify progression. First-line therapies focus on symptom management, with medications selected based on efficacy, tolerability, and patient-specific factors such as comorbidities. Guidelines from organizations like the American Academy of Neurology and the European Federation of Neurological Societies recommend starting with anticonvulsants or antidepressants for pain control, reserving opioids for refractory cases due to risks of dependence and side effects. Gabapentinoids, including (typically dosed at 900-3600 mg/day in divided doses) and (150-600 mg/day), are first-line options for due to their modulation of activity in the , reducing release and pain signaling. Clinical trials demonstrate that these agents provide at least 50% pain reduction in approximately 30-40% of patients, with (NNT) values of 4-7 for significant relief compared to . They are particularly effective in diabetic peripheral neuropathy and , with pregabalin showing faster onset in some studies. Common side effects include dizziness, affecting up to 30% of users with gabapentin, and or with pregabalin. Antidepressants also serve as first-line agents by influencing serotonin and norepinephrine , which modulates pain pathways. Tricyclic antidepressants (TCAs) like amitriptyline (25-150 mg/day at bedtime) are effective for various neuropathic pains, though their effects limit use in older adults. Serotonin-norepinephrine inhibitors (SNRIs), such as (60 mg/day), are FDA-approved specifically for diabetic peripheral , showing moderate efficacy in reducing pain intensity by 30-50% in randomized trials. TCAs and SNRIs have comparable NNT values of around 3-5 for 50% pain relief, but SNRIs may have a better tolerability profile. For severe, refractory pain, opioids such as or are considered second- or third-line options per CDC guidelines, which emphasize short-term use and monitoring for risk. (50-400 mg/day) provides dual action via mu-opioid agonism and serotonin-norepinephrine reuptake inhibition, while extended-release (100-500 mg/day), FDA-approved for diabetic , demonstrates efficacy in reducing pain scores by 30% or more in clinical studies, though with risks of and . These are reserved for cases unresponsive to non-opioid therapies due to potential for tolerance and overdose. In inflammatory subtypes like (CIDP), disease-modifying treatments include intravenous immunoglobulin (IVIG), corticosteroids, and . IVIG is administered as an induction dose of 2 g/kg over 2-5 days, followed by maintenance dosing of 1 g/kg every 3-6 weeks, leading to improvement in 60-80% of patients by suppressing autoimmune-mediated . Corticosteroids, such as oral (1 mg/kg/day initially, tapered over months) or pulsed dexamethasone, induce remission in up to 61% of responders, though long-term use requires monitoring for and . (plasmapheresis), typically 5-7 sessions over 2 weeks, removes autoantibodies and inflammatory factors, achieving improvement in about 60-70% of patients, particularly those unresponsive to other first-line therapies. For uremic neuropathy in end-stage renal disease, erythropoietin-stimulating agents (e.g., at 50-100 IU/kg thrice weekly) can improve conduction and symptoms by correcting and reducing uremic toxins, with studies showing modest electrophysiological benefits after 6 months. These targeted therapies are etiology-specific and often combined with for optimal outcomes.

Non-pharmacological interventions

Non-pharmacological interventions play a crucial role in managing peripheral neuropathy symptoms by focusing on symptom relief, functional improvement, and slowing disease progression through rehabilitative and lifestyle strategies. These approaches aim to enhance mobility, reduce , and prevent complications such as falls, often complementing other treatments. Evidence supports their use in various etiologies, including diabetic peripheral neuropathy, with benefits observed in balance, modulation, and overall . Physical therapy, including balance training and strengthening exercises, is recommended to address gait instability and reduce fall risk in individuals with peripheral neuropathy. Programs incorporating sensorimotor training, such as supervised sessions twice weekly for 12 weeks, have demonstrated significant improvements in balance, lower extremity strength, and walking speed, with effects sustained for up to six months. For example, , a low-impact exercise emphasizing controlled movements, has been shown to enhance postural control, single-leg stance duration, and functional mobility in people with peripheral neuropathy, potentially reducing fall incidence through better and coordination. These interventions can improve stability by 20-30% in key metrics like timed up-and-go tests, based on systematic reviews of exercise programs. Assistive devices provide targeted support for specific deficits, such as and . Ankle-foot orthoses (AFOs) are commonly prescribed to maintain foot alignment during , preventing excessive plantarflexion and improving balance in patients with peripheral neuropathy-related weakness. These devices enhance proprioceptive feedback and reduce energy expenditure while walking, thereby minimizing fall risk. (TENS) units offer a non-invasive option for , delivering low-level electrical currents to modulate activity. Clinical trials indicate mixed evidence, with some showing 26-50% pain intensity reduction on visual analog scales compared to sham treatments, though overall quality is low due to study limitations; benefits are more consistent in diabetic and postherpetic neuropathies when used daily at home. For refractory painful diabetic peripheral neuropathy, spinal cord stimulation (SCS) is an FDA-approved neuromodulation therapy as of 2023. Involves implanting a device to deliver electrical impulses to the , SCS has shown in clinical trials to reduce by at least 50% in over 70% of patients, with additional benefits in improving , mood, and potentially nerve function. It is recommended for cases unresponsive to conventional therapies, per updated guidelines. Lifestyle modifications are essential for mitigating progression, particularly in diabetic peripheral neuropathy. Tight glycemic control through diet, exercise, and monitoring can significantly slow neuropathy advancement; for instance, intensive insulin in reduced the relative risk of clinical neuropathy by 60% over five years in landmark trials. is advised to improve vascular health and nerve , as continued smoking exacerbates microvascular damage and pain sensitivity in diabetic neuropathy, while quitting correlates with reduced symptom severity over time. , targeting a 5-10% body weight reduction in individuals, supports better glycemic regulation and may stabilize neuropathy progression by alleviating inflammatory and metabolic stressors. Additional supportive tips for managing symptoms such as foot cramps, numbness, and burning sensations in the fingers and feet include avoiding excessive heat on hands and feet; wearing comfortable footwear; elevating feet when possible; staying well-hydrated such as drinking 2-3 liters of water daily; and avoiding alcohol and caffeine if possible to improve circulation and reduce irritation. These measures provide temporary relief but do not replace medical consultation. Managing stress supports overall control, and consuming vitamin B-rich foods (e.g., eggs, fish, nuts) or supplements if recommended by a doctor may aid nerve health. Acupuncture, involving needle insertion at specific points, provides moderate relief for , particularly in diabetic cases. Meta-analyses of randomized controlled trials report significant reductions in scores, with acupuncture yielding a mean difference of -1.62 points on a 0-10 visual analog scale compared to controls, translating to approximately 20-30% improvement in symptom intensity when combined with standard care. These effects are attributed to and mechanisms, with benefits observed in both short- and medium-term follow-up. Topical , derived from chili peppers, is applied as a cream or 8% patch for localized relief. The 8% patch, administered under supervision for 30-60 minutes every three months, depletes in sensory nerves, leading to desensitization and reduced transmission. Clinical supports its use in diabetic peripheral neuropathy, with trials showing moderate reduction lasting up to 12 weeks, though initial application may cause transient burning.

Surgical options

Surgical interventions for peripheral neuropathy are typically reserved for cases involving structural compression, trauma, or specific autonomic complications, rather than diffuse polyneuropathy. Decompression surgery aims to relieve pressure on entrapped nerves, such as in where the is compressed at the . release, performed via open or endoscopic techniques, demonstrates clinical success rates of 75-90% in alleviating symptoms, particularly in mild to moderate cases, with recurrence occurring in 4-25% of patients depending on the definition used. For other entrapment neuropathies, such as cubital tunnel syndrome affecting the , surgical decompression yields symptom resolution in approximately 88-90% of cases when managed arthroscopically or openly. In trauma-induced mononeuropathy, repair procedures, including direct suturing or for lacerations and defects, are employed to restore continuity and function. Autologous is commonly used for gaps up to 3 cm, with outcomes varying significantly based on timing; repairs performed within 3 months of , ideally less than 6 months, yield better sensory and motor recovery compared to delayed interventions exceeding 1 year. Overall, fewer than 50% of patients achieve good to excellent motor or sensory function following repair, influenced by factors like defect length and mechanism, such as where a 2-3 week delay allows zone-of-injury demarcation before . Indications for these surgeries include compression unresponsive to conservative measures or focal lesions like tumors causing neuropathy, where excision or decompression can preserve function; however, they are not suitable for widespread lacking a correctable structural cause. Common risks encompass in about 5-11% of cases, particularly in open procedures, and incomplete symptom relief in up to 20% of chronic entrapments due to formation or persistent damage. Post-surgical rehabilitation, including immobilization for 10-14 days followed by gradual mobilization, supports recovery but does not mitigate all risks.

Prognosis and prevention

Factors affecting outcomes

Early is a key positive factor in improving outcomes for peripheral neuropathy, as it allows for timely intervention to prevent irreversible nerve damage. For reversible causes, such as , prompt treatment can lead to significant recovery, with many patients experiencing substantial in neurological symptoms within months of supplementation initiation. Younger age also favors better prognosis, particularly in traumatic or inflammatory neuropathies, where regenerative capacity is higher compared to older individuals. Conversely, prolonged disease duration exceeding one year often results in axonal loss that becomes irreversible, limiting functional recovery due to the slow rate of regeneration. In diabetic peripheral neuropathy, poor glycemic control with HbA1c levels above 7% is associated with accelerated progression and worse outcomes, including increased severity of sensory and motor deficits. Comorbidities such as exacerbate neuropathy risk and impair recovery, promoting inflammation and metabolic stress on peripheral nerves independent of . Outcomes vary significantly by subtype; for Guillain-Barré syndrome (GBS), approximately 80% of patients achieve independent walking within six months, though full motor recovery occurs in about 60% by one year. In contrast, idiopathic axonal , while often considered benign, can lead to reduced and functional impairments due to gradual progression and limited response to . The Neuropathy Impairment Score (NIS) serves as a validated metric for tracking disease progression and treatment response, assessing , reflex loss, and sensory deficits to quantify impairment over time. Autonomic involvement in peripheral neuropathy elevates mortality risk by 2- to 3-fold, primarily through cardiovascular complications like silent ischemia and arrhythmias. Long-term, chronic pain affects approximately one-third of patients with peripheral neuropathy, significantly impacting , and can lead to with reduced mobility and over time. Adherence to management strategies can mitigate these risks but does not alter underlying prognostic factors.

Preventive strategies

Preventive strategies for peripheral neuropathy focus on modifiable risk factors to reduce incidence or delay onset, particularly in high-risk populations such as those with or occupational exposures. For individuals with , the primary preventive measure is tight glycemic control, which has been shown to significantly lower the risk of developing diabetic peripheral neuropathy. The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive insulin therapy, targeting near-normal blood glucose levels, reduced the risk of clinical neuropathy by 60% compared to conventional therapy in patients with . Similarly, in , achieving an HbA1c below 7% through lifestyle and pharmacological interventions can mitigate neuropathy progression. Annual comprehensive foot examinations, including monofilament testing for loss of protective sensation, are recommended by the to enable early detection and intervention in at-risk patients. Lifestyle modifications play a crucial role in prevention across various etiologies. Limiting alcohol intake is essential, as chronic consumption is a leading cause of alcoholic neuropathy; is advised to halt damage, though moderate limits of up to 14 units per week for men and 7 for women may reduce risk in non-dependent individuals. A balanced diet rich in (especially B12, benfotiamine for B1, and B6 if deficient) supports health and prevents deficiency-related neuropathy, with sources including whole grains, leafy greens, and fortified foods. Supplementation may be considered if dietary intake is inadequate. Evidence-based supplements such as alpha-lipoic acid (600 mg/day), acetyl-L-carnitine (1,500–3,000 mg/day), and certain B vitamins have demonstrated benefits primarily in symptom relief and potential support for nerve function in diabetic neuropathy, with alpha-lipoic acid having the strongest evidence from multiple randomized controlled trials and meta-analyses for reducing pain and improving nerve function. Acetyl-L-carnitine shows moderate evidence for pain relief and improved nerve conduction. Evidence for actual nerve regeneration is limited, with these supplements mainly aiding symptom management and potentially slowing progression. They should always be used under medical supervision due to possible interactions with medications or contraindications in certain conditions. For detailed discussion, see Pharmacological treatments. Regular , such as brisk walking for at least 150 minutes per week at moderate intensity, can delay the onset of by improving glycemic control and function. In occupational settings, ergonomic interventions prevent entrapment neuropathies like by minimizing repetitive strain and awkward postures. Using wrist supports or splints during tasks involving prolonged hand use maintains neutral wrist alignment and reduces compression. Adhering to (OSHA) guidelines on permissible exposure limits (PELs) for neurotoxic substances, such as lead and organic solvents, is vital to avoid toxic neuropathies; this includes proper ventilation, , and monitoring workplace air quality. Vaccination against varicella-zoster virus prevents shingles-related neuropathies. The recombinant zoster vaccine (Shingrix), recommended by the CDC for adults aged 50 years and older, is over 90% effective in preventing herpes zoster and its complication, postherpetic neuralgia, a form of peripheral neuropathy. Screening in high-risk groups, such as those with prediabetes, facilitates early identification of subclinical neuropathy. Monofilament testing detects loss of sensation in up to 30% of prediabetic individuals, allowing timely lifestyle interventions to avert progression to overt diabetes and neuropathy.

Research directions

Emerging therapies

Gene therapy targeting sodium channels, particularly Nav1.7 encoded by the SCN9A gene, represents a promising approach for managing pain in peripheral neuropathy. Preclinical studies since 2020 have demonstrated that silencing Nav1.7 expression in neurons via adeno-associated virus-delivered provides long-lasting analgesia in rodent models of neuropathic and inflammatory pain without affecting motor function. A 2023 review highlights how gain-of-function mutations in SCN9A contribute to , supporting as a strategy to restore normal channel function in peripheral neuropathies. More recent preclinical work in 2025 using vectorized for SCN9A knockdown has shown durable reduction in pain behaviors in models, underscoring the potential for non-opioid gene-based interventions. Stem cell therapies utilizing mesenchymal stem cells (MSCs) aim to promote regeneration in diabetic peripheral neuropathy. Phase II clinical trials, such as one evaluating intravenous MSC transfusion, have investigated improvements in clinical symptoms including and . A 2024 meta-analysis of studies reported significant enhancements in , with weighted mean differences of 2.2 m/s (95% CI: 1.6–2.8) for motor and 1.8 m/s (95% CI: 1.2–2.4) for sensory, corresponding to 30-50% improvements in function parameters in diabetic patients. These multipotent cells exert paracrine effects to support axonal regrowth and reduce , offering regenerative potential beyond symptomatic relief. Emerging anti-inflammatory therapies for (CIDP) include biologic agents targeting immune pathways, building on approvals of novel immunomodulators since 2022. Although anti-TNF agents like have shown mixed results in small pre-2022 pilot studies for CIDP, with some patients experiencing symptom stabilization, larger randomized controlled trials (RCTs) post-2022 have focused on other biologics such as FcRn inhibitors (e.g., nipocalimab) demonstrating delayed in ongoing phase II/III studies. These agents aim to reduce autoantibody-mediated damage, with current RCTs evaluating long-term and safety in CIDP cohorts unresponsive to standard intravenous immunoglobulin. Neuroprotective strategies, such as intravenous alpha-lipoic acid (ALA), target in peripheral neuropathy. Administered at 600 mg daily for three weeks, ALA has been approved in since the early 2010s for symptomatic diabetic , leading to clinically relevant reductions in pain scores and improvements in nerve function. ALA acts as a potent , scavenging and enhancing mitochondrial function to mitigate oxidative damage in peripheral nerves. Clinical data confirm its role in decreasing total symptom scores by up to 51% in responsive patients, positioning it as a supportive emerging option for oxidative stress-related neuropathies. Implantable devices like spinal cord stimulation (SCS) offer neuromodulation for refractory neuropathic pain. The U.S. Food and Drug Administration approved SCS systems in the 2020s specifically for painful diabetic peripheral neuropathy, including Abbott's Proclaim XR in 2023 and Medtronic's Intellis in 2022. Prospective studies report 50-70% pain relief in a majority of patients, with one trial showing over 50% reduction in numeric rating scale scores in 86% of participants at one year and sustained benefits in 55% at five years. By delivering electrical pulses to the spinal cord, SCS interrupts pain signal transmission, providing an opioid-sparing alternative for chronic cases.

Clinical trials and future prospects

Ongoing clinical trials for peripheral neuropathy encompass a range of interventions targeting relief, nerve regeneration, and prevention, particularly in diabetic and chemotherapy-induced cases. For instance, a phase 3 trial evaluating VM202 (Engensis), a delivering hepatocyte growth factor via plasmid DNA, completed in 2025 and aimed to assess safety and efficacy in reducing from diabetic peripheral neuropathy through bilateral intramuscular injections. Similarly, the EPPIC-Net platform trial is investigating multiple novel analgesics, including suzetrigine (VX-548), a selective NaV1.8 inhibitor, for painful diabetic peripheral neuropathy, focusing on reduction and quality-of-life improvements in a multi-arm adaptive ; suzetrigine received FDA approval in January 2025 for moderate-to-severe acute , with designation for diabetic peripheral neuropathy. In chemotherapy-induced peripheral neuropathy, the AIUR trial tests compression therapy using surgical gloves during administration to prevent onset, showing preliminary reductions in incidence rates in interim analyses. Non-pharmacological approaches are also advancing in trials, such as stimulation for small fiber neuropathy, where a -initiated study (NCT06287736) evaluates long-term pain relief and functional outcomes, with estimated completion in 2026. therapies represent another frontier; a of human studies reported significant improvements in following mesenchymal stem cell transplantation in diabetic peripheral neuropathy patients, with no major adverse events, supporting phase II expansions. Cryoneurolysis trials for diabetic foot neuropathy, like NCT06646731 starting in 2025, are exploring targeted nerve freezing to alleviate , with early data indicating up to 50% pain score reductions at 6 months. Future prospects hinge on regenerative and precision strategies to address underlying nerve damage rather than symptoms alone. Gene editing technologies, such as CRISPR-based approaches for inherited peripheral neuropathies, show promise in preclinical models by correcting mutations in genes like PMP22, with initial human trials anticipated by late 2020s. Peripheral , including next-generation selective inhibitors, could revolutionize treatment by minimizing central side effects, as evidenced by 2024 Yale studies demonstrating targeted pain blockade in models of neuropathy. A 2025 narrative review emphasizes multimodal therapies integrating , biologics, and pathway-specific drugs (e.g., targeting S100A4/TLR4/ in ), predicting personalized regimens based on neuropathy subtype and biomarkers to improve outcomes beyond current 30-50% response rates. Overall, these developments signal a shift toward disease-modifying treatments, contingent on larger, mechanism-driven trials to validate efficacy and safety.

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