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Wednesday, March 27, 2024

Peripheral neuropathy

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Peripheral_neuropathy
 
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. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerves are affected. Neuropathies affecting motor, sensory, or autonomic nerves result in different symptoms. More than one type of nerve 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, 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). In conventional medical usage, the word neuropathy (neuro-, "nervous system" and -pathy, "disease of") 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".

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.

Classification

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 completion of the exam.

Mononeuropathy

See also: Compression neuropathy and Ulnar neuropathy

Mononeuropathy is a type of neuropathy that only affects a single nerve. 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.

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.

Polyneuropathy

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 the ability of the axons to conduct electrical impulses. The third and least common pattern affects the cell bodies of neurons directly. This affects the sensory neurons (known as sensory neuronopathy or dorsal root ganglionopathy).

The effect of this is to cause symptoms in more than one part of the body, often symmetrically on 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.

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. 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."

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.

Mononeuritis multiplex

Mononeuritis multiplex, occasionally termed polyneuritis multiplex, is simultaneous or sequential involvement of individual noncontiguous nerve trunks, 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. Therefore, attention to the pattern of early symptoms is important.

Mononeuritis multiplex is sometimes associated with a deep, aching pain that is worse 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.

Electrodiagnostic medicine studies will show multifocal sensory motor axonal neuropathy.

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

Autonomic neuropathy

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.

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.

The signs and symptoms of autonomic neuropathy include the following:

Neuritis

Neuritis is a general term for inflammation of a nerve 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

Those with diseases or dysfunctions of their nerves may present with problems in any of the normal nerve functions. Symptoms vary depending on the types of nerve fiber involved. In terms of sensory function, symptoms commonly include loss of function ("negative") symptoms, including numbness, tremor, impairment of balance, and gait abnormality. 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).

In the most common form, length-dependent peripheral neuropathy, pain and parasthesia appears symmetrically and generally at the terminals of the longest nerves, which are in the lower legs and feet. Sensory symptoms generally 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. When the nerves of the autonomic nervous system are affected, symptoms may include constipation, dry mouth, difficulty urinating, and dizziness when standing.

CAP-PRI scale for diagnosis

A user-friendly, disease-specific, quality-of-life scale can be used to monitor how someone is doing living 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 clinical status of some of the more common life domains and symptoms impacted by polyneuropathy.

Causes

The causes are grouped broadly as follows:

Diagnosis

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, 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 decreased sensation of light touch when touched by a nylon monofilament.

Diagnostic tests include electromyography (EMG) and nerve conduction studies (NCSs), which assess large myelinated nerve fibers. 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. 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.

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.

Treatment

The treatment of peripheral neuropathy varies based on the cause of the condition, and treating the underlying condition can aid in the management of neuropathy. When peripheral neuropathy results from diabetes mellitus or prediabetes, blood sugar management is key to treatment. In prediabetes in particular, strict blood sugar control can significantly alter the course of neuropathy. 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.

Medications

A range of medications that act on the central nervous system have been used to symptomatically treat neuropathic pain. Commonly used medications include tricyclic antidepressants (such as nortriptyline, amitriptyline. imapramine, and desipramine,) serotonin-norepinephrine reuptake inhibitor (SNRI) medications (duloxetine, venlafaxine, and milnacipran) and antiepileptic medications (gabapentin, pregabalin, oxcarbazepine zonisamide levetiracetam, lamotrigine, topiramate, clonazepam, phenytoin, lacosamide, sodium valproate and carbamazepine). Opioid and opiate medications (such as buprenorphine, morphine, methadone, fentanyl, hydromorphone, tramadol and oxycodone) 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 for 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 on or for which controlled research is severely lacking; or even for which evidence suggests that these medications are not effective. The NHS for example explicitly state that amitriptyline and gabapentin can be used for treating the pain of sciatica. This is despite both the lack of high quality evidence that demonstrates efficacy of these medications for that symptom, 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.

Antidepressants

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. Evidence also tends to be tainted by bias or issues with the methodology.

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.

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

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.

Antiepileptics

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. 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.

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. In a 2015 Cochrane systematic review the authors found a lack of evidence showing any effectiveness of zonisamide for the treatment of pain deriving from any peripheral neuropathy. A 2014 Cochrane review found that studies of levetiracetam showed no indication for 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.

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. A 2013 Cochrane systematic review of topimirate 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. Cochrane reviews from 2012 of clonazepam and phenytoin uncovered no evidence of sufficient quality to support their use in chronic neuropathic pain."

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. 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 effect due to the inherent problems with the data and conclude that the evidence does not support its usage. In a 2014 systematic review of carbamazepine the authors believe the drug to be of benefit for some people. No trials were considered greater than level III evidence; none were longer than 4 weeks in length or were deemed as having good reporting quality.

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.

Opioids

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. 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.

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". 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.

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. 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."

Others

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.

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

There is some evidence that symptomatic relief from the pain of peripheral neuropathy may be obtained by 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 using this treatment option.

Evidence supports the use of cannabinoids for some forms of neuropathic pain. 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."

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 there are no high quality randomised control trials demonstrating its efficacy or safety profile.

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.

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

Medical devices

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. 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.

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'.

Surgery

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. There is less evidence for efficacy of surgery for non-diabetic peripheral neuropathy of the legs and feet. One uncontrolled study did before/after comparisons with a minimum of one-year follow-up and reported improvements for pain relief, impaired balance and numbness. "There was no difference in outcomes between patients with diabetic versus idiopathic neuropathy in response to nerve decompression." There are no placebo-controlled trials for idiopathic peripheral neuropathy in the published scientific literature.

Diet

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.

Counselling

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."

Alternative medicine

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."

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."

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

Research

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."

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."

Stem-cell therapy is also being looked at as a possible means to repair peripheral nerve damage, however efficacy has not yet been demonstrated.

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Nerve

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Nerve
 
Nerve
Nerves (yellow) in the arm

A nerve is an enclosed, cable-like bundle of nerve fibers (called axons) in the peripheral nervous system.

Nerves have historically been considered the basic units of the peripheral nervous system. A nerve provides a common pathway for the electrochemical nerve impulses called action potentials that are transmitted along each of the axons to peripheral organs or, in the case of sensory nerves, from the periphery back to the central nervous system. Each axon, within the nerve, is an extension of an individual neuron, along with other supportive cells such as some Schwann cells that coat the axons in myelin.

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Nerve cell and organization

Within a nerve, each axon is surrounded by a layer of connective tissue called the endoneurium. The axons are bundled together into groups called fascicles, and each fascicle is wrapped in a layer of connective tissue called the perineurium. Finally, the entire nerve is wrapped in a layer of connective tissue called the epineurium. Nerve cells (often called neurons) are further classified as sensory, motor, or mixed nerves.

In the central nervous system, the analogous structures are known as nerve tracts.

Structure

Cross-section of a nerve

Each nerve is covered on the outside by a dense sheath of connective tissue, the epineurium. Beneath this is a layer of fat cells, the perineurium, which forms a complete sleeve around a bundle of axons. Perineurial septae extend into the nerve and subdivide it into several bundles of fibres. Surrounding each such fibre is the endoneurium. This forms an unbroken tube from the surface of the spinal cord to the level where the axon synapses with its muscle fibres, or ends in sensory receptors. The endoneurium consists of an inner sleeve of material called the glycocalyx and an outer, delicate, meshwork of collagen fibres. Nerves are bundled and often travel along with blood vessels, since the neurons of a nerve have fairly high energy requirements.

Within the endoneurium, the individual nerve fibres are surrounded by a low-protein liquid called endoneurial fluid. This acts in a similar way to the cerebrospinal fluid in the central nervous system and constitutes a blood-nerve barrier similar to the blood–brain barrier. Molecules are thereby prevented from crossing the blood into the endoneurial fluid. During the development of nerve edema from nerve irritation (or injury), the amount of endoneurial fluid may increase at the site of irritation. This increase in fluid can be visualized using magnetic resonance neurography, and thus MR neurography can identify nerve irritation and/or injury.

Categories

Nerves are categorized into three groups based on the direction that signals are conducted:

Nerves can be categorized into two groups based on where they connect to the central nervous system:

Terminology

Main article: Anatomical terms of neuroanatomy

Specific terms are used to describe nerves and their actions. A nerve that supplies information to the brain from an area of the body, or controls an action of the body is said to innervate that section of the body or organ. Other terms relate to whether the nerve affects the same side ("ipsilateral") or opposite side ("contralateral") of the body, to the part of the brain that supplies it.

Development

Nerve growth normally ends in adolescence, but can be re-stimulated with a molecular mechanism known as "Notch signaling".

Regeneration

If the axons of a neuron are damaged, as long as the cell body of the neuron is not damaged, the axons can regenerate and remake the synaptic connections with neurons with the help of guidepost cells. This is also referred to as neuroregeneration.

The nerve begins the process by destroying the nerve distal to the site of injury allowing Schwann cells, basal lamina, and the neurilemma near the injury to begin producing a regeneration tube. Nerve growth factors are produced causing many nerve sprouts to bud. When one of the growth processes finds the regeneration tube, it begins to grow rapidly towards its original destination guided the entire time by the regeneration tube. Nerve regeneration is very slow and can take up to several months to complete. While this process does repair some nerves, there will still be some functional deficit as the repairs are not perfect.

Function

A nerve conveys information in the form of electrochemical impulses (as nerve impulses known as action potentials) carried by the individual neurons that make up the nerve. These impulses are extremely fast, with some myelinated neurons conducting at speeds up to 120 m/s. The impulses travel from one neuron to another by crossing a synapse, where the message is converted from electrical to chemical and then back to electrical.

Nerves can be categorized into two groups based on function:

  • An afferent nerve fiber conducts sensory information from a sensory neuron to the central nervous system, where the information is then processed. Bundles of fibres or axons, in the peripheral nervous system are called nerves, and bundles of afferent fibers are known as sensory nerves.
  • An efferent nerve fiber conducts signals from a motor neuron in the central nervous system to muscles. Bundles of these fibres are known as efferent nerves.

Nervous system

Main article: Nervous system

The nervous system is the part of an animal that coordinates its actions by transmitting signals to and from different parts of its body. In vertebrates it consists of two main parts, the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS consists of the brain, brainstem and spinal cord. The PNS consists mainly of nerves, which are enclosed bundles of the long fibers or axons, that connect the CNS to all remaining body parts.

Nerves that transmit signals from the CNS are called motor or efferent nerves, while those nerves that transmit information from the body to the CNS are called sensory or afferent. Spinal nerves serve both functions and are called mixed nerves. The PNS is divided into three separate subsystems, the somatic, autonomic, and enteric nervous systems. Somatic nerves mediate voluntary movement.

The autonomic nervous system is further subdivided into the sympathetic and the parasympathetic nervous systems. The sympathetic nervous system is activated in cases of emergencies to mobilize energy, while the parasympathetic nervous system is activated when organisms are in a relaxed state. The enteric nervous system functions to control the gastrointestinal system. Both autonomic and enteric nervous systems function involuntarily. Nerves that exit from the cranium are called cranial nerves while those exiting from the spinal cord are called spinal nerves.

Clinical significance

Micrograph demonstrating perineural invasion of prostate cancer. H&E stain.

Cancer can spread by invading the spaces around nerves. This is particularly common in head and neck cancer, prostate cancer and colorectal cancer.

Nerves can be damaged by physical injury as well as conditions like carpal tunnel syndrome (CTS) and repetitive strain injury. Autoimmune diseases such as Guillain–Barré syndrome, neurodegenerative diseases, polyneuropathy, infection, neuritis, diabetes, or failure of the blood vessels surrounding the nerve all cause nerve damage, which can vary in severity.

Multiple sclerosis is a disease associated with extensive nerve damage. It occurs when the macrophages of an individual's own immune system damage the myelin sheaths that insulate the axon of the nerve.

A pinched nerve occurs when pressure is placed on a nerve, usually from swelling due to an injury, or pregnancy and can result in pain, weakness, numbness or paralysis, an example being CTS. Symptoms can be felt in areas far from the actual site of damage, a phenomenon called referred pain. Referred pain can happen when the damage causes altered signalling to other areas.

Neurologists usually diagnose disorders of nerves by a physical examination, including the testing of reflexes, walking and other directed movements, muscle weakness, proprioception, and the sense of touch. This initial exam can be followed with tests such as nerve conduction study, electromyography (EMG), and computed tomography (CT).

Other animals

A neuron is called identified if it has properties that distinguish it from every other neuron in the same animal—properties such as location, neurotransmitter, gene expression pattern, and connectivity—and if every individual organism belonging to the same species has exactly one neuron with the same set of properties. In vertebrate nervous systems, very few neurons are "identified" in this sense. Researchers believe humans have none—but in simpler nervous systems, some or all neurons may be thus unique.

In vertebrates, the best known identified neurons are the gigantic Mauthner cells of fish. Every fish has two Mauthner cells, located in the bottom part of the brainstem, one on the left side and one on the right. Each Mauthner cell has an axon that crosses over, innervating (stimulating) neurons at the same brain level and then travelling down through the spinal cord, making numerous connections as it goes. The synapses generated by a Mauthner cell are so powerful that a single action potential gives rise to a major behavioral response: within milliseconds the fish curves its body into a C-shape, then straightens, thereby propelling itself rapidly forward. Functionally this is a fast escape response, triggered most easily by a strong sound wave or pressure wave impinging on the lateral line organ of the fish. Mauthner cells are not the only identified neurons in fish—there are about 20 more types, including pairs of "Mauthner cell analogs" in each spinal segmental nucleus. Although a Mauthner cell is capable of bringing about an escape response all by itself, in the context of ordinary behavior other types of cells usually contribute to shaping the amplitude and direction of the response.

Mauthner cells have been described as command neurons. A command neuron is a special type of identified neuron, defined as a neuron that is capable of driving a specific behavior all by itself. Such neurons appear most commonly in the fast escape systems of various species—the squid giant axon and squid giant synapse, used for pioneering experiments in neurophysiology because of their enormous size, both participate in the fast escape circuit of the squid. The concept of a command neuron has, however, become controversial, because of studies showing that some neurons that initially appeared to fit the description were really only capable of evoking a response in a limited set of circumstances.

In organisms of radial symmetry, nerve nets serve for the nervous system. There is no brain or centralised head region, and instead there are interconnected neurons spread out in nerve nets. These are found in Cnidaria, Ctenophora and Echinodermata.

History

Further information: History of neurology and neurosurgery

Herophilos (335–280 BC) described the functions of the optic nerve in sight and the oculomotor nerve in eye movement. Analysis of the nerves in the cranium enabled him to differentiate between blood vessels and nerves (Ancient Greek: νεῦρον (neûron) "string, plant fiber, nerve").

Modern research has not confirmed William Cullen's 1785 hypothesis associating mental states with physical nerves, although popular or lay medicine may still invoke "nerves" in diagnosing or blaming any sort of psychological worry or hesitancy, as in the common traditional phrases "my poor nerves", "high-strung", and "nervous breakdown".

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Motor neuron

From Wikipedia, the free encyclopedia

Motor neurons begin to develop early in embryonic development, and motor function continues to develop well into childhood. In the neural tube cells are specified to either the rostral-caudal axis or ventral-dorsal axis. The axons of motor neurons begin to appear in the fourth week of development from the ventral region of the ventral-dorsal axis (the basal plate). This homeodomain is known as the motor neural progenitor domain (pMN). Transcription factors here include Pax6, OLIG2, Nkx-6.1, and Nkx-6.2, which are regulated by sonic hedgehog (Shh). The OLIG2 gene being the most important due to its role in promoting Ngn2 expression, a gene that causes cell cycle exiting as well as promoting further transcription factors associated with motor neuron development.

Further specification of motor neurons occurs when retinoic acid, fibroblast growth factor, Wnts, and TGFb, are integrated into the various Hox transcription factors. There are 13 Hox transcription factors and along with the signals, determine whether a motor neuron will be more rostral or caudal in character. In the spinal column, Hox 4-11 sort motor neurons to one of the five motor columns.

Motor columns of spinal cord 
Motor column Location in spinal cord Target
Median motor column Present entire length Axial muscles
Hypaxial motor column Thoracic region Body wall muscles
Preganglionic motor column Thoracic region Sympathetic ganglion
Lateral motor column Brachial and lumbar region (both regions are further divided into medial and lateral domains) Muscles of the limbs
Phrenic motor column Cervical region Diaphragm

Anatomy and physiology

Spinal cord tracts
Location of lower motor neurons in spinal cord

Upper motor neurons

Upper motor neurons originate in the motor cortex located in the precentral gyrus. The cells that make up the primary motor cortex are Betz cells, which are giant pyramidal cells. The axons of these cells descend from the cortex to form the corticospinal tract. Corticomotorneurons project from the primary cortex directly onto motor neurons in the ventral horn of the spinal cord. Their axons synapse on the spinal motor neurons of multiple muscles as well as on spinal interneurons. They are unique to primates and it has been suggested that their function is the adaptive control of the hands including the relatively independent control of individual fingers. Corticomotorneurons have so far only been found in the primary motor cortex and not in secondary motor areas.

Nerve tracts

Nerve tracts are bundles of axons as white matter, that carry action potentials to their effectors. In the spinal cord these descending tracts carry impulses from different regions. These tracts also serve as the place of origin for lower motor neurons. There are seven major descending motor tracts to be found in the spinal cord:

Lower motor neurons

Lower motor neurons are those that originate in the spinal cord and directly or indirectly innervate effector targets. The target of these neurons varies, but in the somatic nervous system the target will be some sort of muscle fiber. There are three primary categories of lower motor neurons, which can be further divided in sub-categories.

According to their targets, motor neurons are classified into three broad categories:

  • Somatic motor neurons
  • Special visceral motor neurons
  • General visceral motor neurons

Somatic motor neurons

Somatic motor neurons originate in the central nervous system, project their axons to skeletal muscles (such as the muscles of the limbs, abdominal, and intercostal muscles), which are involved in locomotion. The three types of these neurons are the alpha efferent neurons, beta efferent neurons, and gamma efferent neurons. They are called efferent to indicate the flow of information from the central nervous system (CNS) to the periphery.

  • Alpha motor neurons innervate extrafusal muscle fibers, which are the main force-generating component of a muscle. Their cell bodies are in the ventral horn of the spinal cord and they are sometimes called ventral horn cells. A single motor neuron may synapse with 150 muscle fibers on average. The motor neuron and all of the muscle fibers to which it connects is a motor unit. Motor units are split up into 3 categories:
    • Slow (S) motor units stimulate small muscle fibers, which contract very slowly and provide small amounts of energy but are very resistant to fatigue, so they are used to sustain muscular contraction, such as keeping the body upright. They gain their energy via oxidative means and hence require oxygen. They are also called red fibers.
    • Fast fatiguing (FF) motor units stimulate larger muscle groups, which apply large amounts of force but fatigue very quickly. They are used for tasks that require large brief bursts of energy, such as jumping or running. They gain their energy via glycolytic means and hence do not require oxygen. They are called white fibers.
    • Fast fatigue-resistant motor units stimulate moderate-sized muscles groups that do not react as fast as the FF motor units, but can be sustained much longer (as implied by the name) and provide more force than S motor units. These use both oxidative and glycolytic means to gain energy.

In addition to voluntary skeletal muscle contraction, alpha motor neurons also contribute to muscle tone, the continuous force generated by noncontracting muscle to oppose stretching. When a muscle is stretched, sensory neurons within the muscle spindle detect the degree of stretch and send a signal to the CNS. The CNS activates alpha motor neurons in the spinal cord, which cause extrafusal muscle fibers to contract and thereby resist further stretching. This process is also called the stretch reflex.

  • Beta motor neurons innervate intrafusal muscle fibers of muscle spindles, with collaterals to extrafusal fibres. There are two types of beta motor neurons: Slow Contracting- These innervate extrafusal fibers. Fast Contracting- These innervate intrafusal fibers.
  • Gamma motor neurons innervate intrafusal muscle fibers found within the muscle spindle. They regulate the sensitivity of the spindle to muscle stretching. With activation of gamma neurons, intrafusal muscle fibers contract so that only a small stretch is required to activate spindle sensory neurons and the stretch reflex. There are two types of gamma motor neurons: Dynamic- These focus on Bag1 fibers and enhance dynamic sensitivity. Static- These focus on Bag2 fibers and enhance stretch sensitivity.
  • Regulatory factors of lower motor neurons
    • Size Principle – this relates to the soma of the motor neuron. This restricts larger neurons to receive a larger excitatory signal in order to stimulate the muscle fibers it innervates. By reducing unnecessary muscle fiber recruitment, the body is able to optimize energy consumption.
    • Persistent Inward Current (PIC) – recent animal study research has shown that constant flow of ions such as calcium and sodium through channels in the soma and dendrites influence the synaptic input. An alternate way to think of this is that the post-synaptic neuron is being primed before receiving an impulse.
    • After Hyper-polarization (AHP) – A trend has been identified that shows slow motor neurons to have more intense AHPs for a longer duration. One way to remember this is that slow muscle fibers can contract for longer, so it makes sense that their corresponding motor neurons fire at a slower rate.

Special visceral motor neurons

These are also known as branchial motor neurons, which are involved in facial expression, mastication, phonation, and swallowing. Associated cranial nerves are the oculomotor, abducens, trochlear, and hypoglossal nerves.

Branch of NS Position Neurotransmitter
Somatic n/a Acetylcholine
Parasympathetic Preganglionic Acetylcholine
Parasympathetic Ganglionic Acetylcholine
Sympathetic Preganglionic Acetylcholine
Sympathetic Ganglionic Norepinephrine*
*Except fibers to sweat glands and certain blood vessels
Motor neuron neurotransmitters

General visceral motor neurons

These motor neurons indirectly innervate cardiac muscle and smooth muscles of the viscera ( the muscles of the arteries): they synapse onto neurons located in ganglia of the autonomic nervous system (sympathetic and parasympathetic), located in the peripheral nervous system (PNS), which themselves directly innervate visceral muscles (and also some gland cells).

In consequence, the motor command of skeletal and branchial muscles is monosynaptic involving only one motor neuron, either somatic or branchial, which synapses onto the muscle. Comparatively, the command of visceral muscles is disynaptic involving two neurons: the general visceral motor neuron, located in the CNS, synapses onto a ganglionic neuron, located in the PNS, which synapses onto the muscle.

All vertebrate motor neurons are cholinergic, that is, they release the neurotransmitter acetylcholine. Parasympathetic ganglionic neurons are also cholinergic, whereas most sympathetic ganglionic neurons are noradrenergic, that is, they release the neurotransmitter noradrenaline. (see Table)

Neuromuscular junctions

A single motor neuron may innervate many muscle fibres and a muscle fibre can undergo many action potentials in the time taken for a single muscle twitch. As a result, if an action potential arrives before a twitch has completed, the twitches can superimpose on one another, either through summation or a tetanic contraction. In summation, the muscle is stimulated repetitively such that additional action potentials coming from the somatic nervous system arrive before the end of the twitch. The twitches thus superimpose on one another, leading to a force greater than that of a single twitch. A tetanic contraction is caused by constant, very high frequency stimulation - the action potentials come at such a rapid rate that individual twitches are indistinguishable, and tension rises smoothly eventually reaching a plateau.

The interface between a motor neuron and muscle fiber is a specialized synapse called the neuromuscular junction. Upon adequate stimulation, the motor neuron releases a flood of acetylcholine (Ach) neurotransmitters from the axon terminals from synaptic vesicles bind with the plasma membrane. The acetylcholine molecules bind to postsynaptic receptors found within the motor end plate. Once two acetylcholine receptors have been bound, an ion channel is opened and sodium ions are allowed to flow into the cell. The influx of sodium into the cell causes depolarization and triggers a muscle action potential. T tubules of the sarcolemma are then stimulated to elicit calcium ion release from the sarcoplasmic reticulum. It is this chemical release that causes the target muscle fiber to contract.

In invertebrates, depending on the neurotransmitter released and the type of receptor it binds, the response in the muscle fiber could be either excitatory or inhibitory. For vertebrates, however, the response of a muscle fiber to a neurotransmitter can only be excitatory, in other words, contractile. Muscle relaxation and inhibition of muscle contraction in vertebrates is obtained only by inhibition of the motor neuron itself. This is how muscle relaxants work by acting on the motor neurons that innervate muscles (by decreasing their electrophysiological activity) or on cholinergic neuromuscular junctions, rather than on the muscles themselves.

Synaptic input to motor neurons

Motor neurons receive synaptic input from premotor neurons. Premotor neurons can be 1) spinal interneurons that have cell bodies in the spinal cord, 2) sensory neurons that convey information from the periphery and synapse directly onto motoneurons, 3) descending neurons that convey information from the brain and brainstem. The synapses can be excitatory, inhibitory, electrical, or neuromodulatory. For any given motor neuron, determining the relative contribution of different input sources is difficult, but advances in connectomics have made it possible for fruit fly motor neurons. In the fly, motor neurons controlling the legs and wings are found in the ventral nerve cord, homologous to the spinal cord. Fly motor neurons vary by over 100X in the total number of input synapses. However, each motor neuron gets similar fractions of its synapses from each premotor source: ~70% from neurons within the VNC, ~10% from descending neurons, ~3% from sensory neurons, and ~6% from VNC neurons that also send a process up to the brain. The remaining 10% of synapses come from neuronal fragments that are unidentified by current image segmentation algorithms and require additional manual segmentation to measure.
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