Peripheral neuropathy

Peripheral neuropathy
Micrograph showing a vasculitic peripheral neuropathy; plastic embedded; Toluidine blue stain
Classification and external resources
ICD-10	G64, G90.0
ICD-9	356.0, 356.8
DiseasesDB	9850
MedlinePlus	000593
Patient UK	Peripheral neuropathy
MeSH	D010523

Peripheral neuropathy (PN) is damage to or disease affecting nerves, which may impair sensation, movement, gland or organ function, or other aspects of health, depending on the type of nerve affected. Common causes include systemic diseases (such as diabetes or leprosy), vitamin deficiency, medication (e.g., chemotherapy), traumatic injury, radiation therapy, excessive alcohol consumption, immune system disease or viral infection. It can also be genetic (present from birth) or idiopathic (no known cause).^[1][2][3] In conventional medical usage, the word neuropathy (neuro-, "nervous system" and -pathy, "disease of")^[4] without modifier usually means peripheral neuropathy.

Neuropathy affecting just one nerve is called "mononeuropathy" and neuropathy involving multiple 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."^[1][2][3]

Peripheral neuropathy may be chronic (a long term condition where symptoms begin subtly and progress slowly) or acute (sudden onset, rapid progress, and slow resolution). Acute neuropathies demand urgent diagnosis. Motor nerves (that control muscles), sensory nerves, or autonomic nerves (that control automatic functions such as heart rate, body temperature, and breathing), may be affected. More than one type of nerve may be affected at the same time. Peripheral neuropathies may be classified according to the type of nerve predominantly involved, or by the underlying cause. Where the cause is unknown it is described as idiopathic neuropathy.^[1][2][3]

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 skin allodynia (severe 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.^[1][2][3]

Classification

Peripheral neuropathy may be classified according to the number and distribution of nerves affected (mononeuropathy, mononeuritis multiplex, or polyneuropathy), the type of nerve cell predominantly affected (motor, sensory, autonomic), or the process affecting the nerves; e.g., inflammation (neuritis), compression (compression neuropathy), chemotherapy (chemotherapy-induced peripheral neuropathy).

Mononeuropathy

Mononeuropathy is a type of neuropathy that only affects a single nerve.^[5] Diagnostically, it is useful to distinguish it from polyneuropathy because the limitation in scope makes it more likely that the cause is a 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 of this. The "pins-and-needles" sensation of one's "foot falling asleep" (paresthesia) is caused by a compression mononeuropathy, albeit, a temporary one that may be resolved merely by moving around and adjusting to a more appropriate position. Direct injury to a nerve, interruption of its blood supply (ischemia), or inflammation also may cause mononeuropathy.

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 also may cause pain, which is characterized as 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:

• diabetes mellitus
• vasculitides: polyarteritis nodosa, granulomatosis with polyangiitis, and Churg–Strauss syndrome
• immune-mediated diseases, such as rheumatoid arthritis, lupus erythematosus (SLE)
• infections: leprosy, lyme disease, HIV
• sarcoidosis, amyloidosis
• cryoglobulinemia
• reactions to exposure to chemical agents, including trichloroethylene and dapsone
• rarely, following the sting of certain jellyfish, such as the sea nettle

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. 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 neurones directly. This usually picks out either the motor neurones (known as motor neurone disease) or the sensory neurones (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 weakness or clumsiness of movement (motor); unusual or unpleasant sensations such as tingling or burning; reduction in the ability to feel texture, temperature, etc.; and impaired balance when standing or walking (sensory). 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. 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 glucose levels in the blood may spike to nerve-damaging levels after eating even though fasting blood sugar levels and average blood glucose levels may still remain below normal levels (currently they typically are considered below 100 mg/dL for fasting blood plasma and 6.0% for HGBA1c, the test commonly used to measure average blood glucose levels over an extended period). Studies have shown that many of the cases of peripheral small fiber neuropathy with typical symptoms of tingling, pain, and loss of sensation in the feet and hands are due to glucose intolerance before a diagnosis of diabetes or pre-diabetes. Such damage often is reversible, particularly in the early stages, with changes in diet, exercise, and weight loss.

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.

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:

• Urinary bladder conditions: bladder incontinence or urine retention
• Gastrointestinal tract: dysphagia, abdominal pain, nausea, vomiting, malabsorption, fecal incontinence, gastroparesis, diarrhoea, constipation
• Cardiovascular system: disturbances of heart rate (tachycardia, bradycardia), orthostatic hypotension, inadequate increase of heart rate on exertion
• Respiratory system: impairments in the signals associated with regulation of breathing and gas exchange (central sleep apnea, hypopnea, bradypnea).^[6]
• Other areas: hypoglycemia unawareness, genital impotence, sweat disturbances

Neuritis

Neuritis is a general term for inflammation of a nerve^[7] 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:

• Physical injury
• Infection
  • Diphtheria
  • Herpes zoster (shingles)
  • Leprosy
  • Lyme disease
• Chemical injury such as chemotherapy
• Radiation therapy
• Underlying conditions including:  :
  • Alcoholism
  • Autoimmune disease, especially multiple sclerosis and Guillain-Barre syndrome
  • Beriberi (vitamin B1 deficiency)
  • Cancer
  • Celiac disease^[8]
  • Diabetes (Diabetic neuropathy)
  • Hypothyroidism
  • Porphyria
  • Vitamin B12 deficiency
  • Vitamin B6 excess^[9]

Types of neuritis include:

• Brachial neuritis
• Cranial neuritis such as Bell's palsy
• Optic neuritis
• Vestibular neuritis
• Wartenberg's migratory sensory neuropathy

Signs and symptoms

Those with diseases or dysfunctions of their nerves may present with problems in any of the normal nerve functions.

In terms of sensory function, there commonly are loss of function (negative) symptoms, which include numbness, tremor, and gait abnormality.

Gain of function (positive) symptoms include tingling, pain, itching, crawling, and pins-and-needles. Pain may become intense enough to require use of opioid (narcotic) drugs (i.e., morphine, oxycodone).

Motor symptoms include loss of function (negative) symptoms of weakness, tiredness, heaviness, and gait abnormalities; and gain of function (positive) symptoms of cramps, tremor, and muscle twitch (fasciculations).

Other symptoms include myalgia (muscle pain), cramps and autonomic dysfunction.

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.

Causes

The causes are grouped broadly as follows:

• Genetic diseases: Friedreich's ataxia, Charcot-Marie-Tooth disease,^[10] hereditary neuropathy with liability to pressure palsy
• Metabolic and endocrine diseases: diabetes mellitus,^[11] chronic renal failure, porphyria, amyloidosis, liver failure, hypothyroidism
• Toxic causes: drugs (vincristine, metronidazole, phenytoin, nitrofurantoin, isoniazid, ethyl alcohol, statins^[12][13]), organic herbicides TCDD dioxin, organic metals, heavy metals, excess intake of vitamin B₆ (pyridoxine). Peripheral neuropathies also may result from long term (more than 21 days) treatment with Linezolid (Zyvox).
• Adverse effects of fluoroquinolones: irreversible neuropathy is a serious adverse reaction of fluoroquinolone drugs^[14]
• Inflammatory diseases: Guillain-Barré syndrome, systemic lupus erythematosus, leprosy, multiple sclerosis, Sjögren's syndrome, Lyme disease, sarcoidosis,^[15]
• Vitamin deficiency states: Vitamin B₁₂ (Methylcobalamin), vitamin A, vitamin E, vitamin B₁ (thiamin)
• Physical trauma: compression, pinching, cutting, projectile injuries (for example, gunshot wound), strokes including prolonged occlusion of blood flow, electric discharge, including lightning strikes
• Effect of chemotherapy - see Chemotherapy-induced peripheral neuropathy^[16]
• Others: electric shock, HIV,^[17] malignant disease, radiation, shingles

Treatment

Many treatment strategies for peripheral neuropathy are symptomatic. Some current research in animal models has shown that neurotrophin-3 may oppose the demyelination present in some peripheral neuropathies.^[18]

A range of drugs that act on the central nervous system, such as drugs originally intended as antidepressants and antiepileptic drugs, have been found to be useful in managing neuropathic pain. Commonly used treatments include using a tricyclic antidepressant (such as amitriptyline) and antiepileptic therapies such as gabapentin or sodium valproate. These have the advantage that besides being effective in many cases, they are relatively low in cost.

A great deal of research has been conducted between 2005 and 2010 resulting in indications that synthetic cannabinoids and inhaled cannabis are effective treatments for a range of neuropathic disorders.^[19] Research has demonstrated that the synthetic oral cannabinoid Nabilone is an effective adjunct treatment option for neuropathic conditions, especially for people who are resistant, intolerant, or allergic to common medications.^[20] Oral opiate derivatives were found to be more effective than cannabis for most people.^[21] Smoked cannabis has been found to provide relief from HIV-associated sensory neuropathy.^[22] Smoked cannabis also was found to relieve neuropathy associated with CRPS type I, spinal cord injury, peripheral neuropathy, and nerve injury.^[23]

Pregabalin is an anticonvulsant drug used for neuropathic pain. It also has been found effective for generalized anxiety disorder. It was designed as a more potent successor to gabapentin, but is significantly more expensive, especially now that the patent on gabapentin has expired and gabapentin is available as a generic drug. Pregabalin is marketed by Pfizer under the trade name Lyrica.

Duloxetine, a serotonin-norepinephrine reuptake inhibitor, also is being used to reduce neuropathic pain.

Transcutaneous electrical nerve stimulation therapy may be effective and safe in the treatment of diabetic peripheral neuropathy. A recent review of three trials involving 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.^[24] A second review of four trials 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.^[25]

Neuropathy has been reported to make winter weather more perilous for older adults.^[26] Often, people with neuropathy who live in areas with defined winters (such as the northern United States) report that their symptoms were much less severe after moving to places with an undefined winter, such as Florida or California.

Sometimes symptomatic relief for the pain of peripheral neuropathy is obtained by application of topical capsacin. Capsacin is the factor that causes heat in chili peppers. Relief up to 12 weeks is noted with high concentrations of capsacin applied cutaneously. Local anesthesia often is used to counteract the initial discomfort of the capsacin. More information is available in this review by the National Institute of Health.^[27]

References

Further reading

• Latov, Norman (2007). Peripheral Neuropathy: When the Numbness, Weakness, and Pain Won't Stop. New York: American Academy of Neurology Press Demos Medical. ISBN 1-932603-59-X. 
• Committee on Standards and Practice Parameters, American Society of Anesthesiologists (2000). "Practice advisory for the prevention of perioperative peripheral neuropathies: an updated report by the American Society of Anesthesiologists Task Force on prevention of perioperative peripheral neuropathies". Anesthesiology 92 (4): 1168–82. doi:10.1097/00000542-200004000-00036. PMID 10754638. 

Pathology: Medical conditions and ICD code (Disease / Disorder / Syndrome / Sequence, Symptom / Sign, Injury, etc.) (A/B, 001–139) Infectious disease/Infection: Bacterial disease G+ G- Viral disease Parasitic disease Protozoan infection Helminthiasis Ectoparasitic infestation Mycosis Zoonosis (C/D, 140–239 & 279–289) Cancer (C00–D48, 140–239) Neoplasm Myeloid hematologic (D50–D77, 280–289) Anemia Coagulopathy Lymphoid immune (D80–D89, 279) Immunodeficiency Immunoproliferative disorder Hypersensitivity (E, 240–278) Endocrine disease Nutrition disorder Inborn error of metabolism (F, 290–319) Mental disorder (G, 320–359) Nervous system disease CNS PNS Neuromuscular disease (H, 360–389) Eye disease Ear disease (I, 390–459) Cardiovascular disease Heart disease Vascular disease (J, 460–519) Respiratory disease Obstructive lung disease Restrictive lung disease Pneumonia (K, 520–579) Oral and maxillofacial pathology Tooth disease salivary gland disease tongue disease Digestive disease Esophageal Stomach Enteropathy Liver Pancreatic (L, 680–709) Skin disease skin appendages Nail disease Hair disease Sweat gland disease (M, 710–739) Musculoskeletal disorders: Myopathy Arthropathy Osteochondropathy Osteopathy Chondropathy (N, 580–629) Urologic disease Nephropathy Urinary bladder disease Male genital disease Breast disease Female genital disease (O, 630–679) Complications of pregnancy Obstetric labor complication Puerperal disorder (P, 760–779) Fetal disease (Q, 740–759) Congenital disorder Congenital abnormality (R, 780–799) Syndromes Medical signs Eponymous (S/T, 800–999) Bone fracture Joint dislocation Sprain Strain Subluxation Head injury Chest trauma Poisoning

Nervous system pathology, PNS, somatic (G50–G64, 350–357)   Nerve, nerve root, plexus Cranial nerve disease V Trigeminal neuralgia Anesthesia dolorosa VII Facial nerve paralysis Bell's palsy Melkersson–Rosenthal syndrome Parry–Romberg syndrome Central seven XI Accessory nerve disorder Radiculopathy, plexopathy brachial plexus Brachial plexus lesion Thoracic outlet syndrome Phantom limb Mono- neuropathy Upper limb median nerve: Carpal tunnel syndrome Ape hand deformity ulnar nerve: Ulnar nerve entrapment Froment's sign Guyon's canal syndrome Ulnar claw radial nerve: Radial neuropathy Wrist drop Cheiralgia paresthetica long thoracic nerve: Winged scapula Lower limb lateral cutaneous nerve of thigh: Meralgia paraesthetica tibial nerve: Tarsal tunnel syndrome plantar nerve: Morton's neuroma superior gluteal nerve: Trendelenburg's sign sciatic nerve: Piriformis syndrome General Causalgia Mononeuritis multiplex Neuropathy Neuralgia/Neuritis Nerve compression syndrome   Polyneuropathies/Polyradiculoneuropathy HMSN Charcot–Marie–Tooth disease Dejerine–Sottas disease Refsum's disease Hereditary spastic paraplegia Hereditary neuropathy with liability to pressure palsy Familial amyloid neuropathy Autoimmune/demyelinating Guillain–Barré syndrome Chronic inflammatory demyelinating polyneuropathy Other Alcoholic polyneuropathy Index of the peripheral nervous system Description Anatomy Nerves cranial trigeminal cervical brachial lumbosacral plexus somatosensory spinal autonomic Physiology reflexes proteins neurotransmitters transporters Development neurotrophins Disease Autonomic Congenital Injury Neoplasms and cancer Other Symptoms and signs eponymous Treatment Procedures Local anesthetics

Autonomic diseases, Dysautonomia, autonomic- neuropathy (G90, 337) HSAN I II III/Familial dysautonomia IV/Congenital insensitivity to pain with anhidrosis V Orthostatic intolerance Postural orthostatic tachycardia syndrome Orthostatic hypotension Other Horner's syndrome Multiple system atrophy Pure autonomic failure Autonomic dysreflexia Index of the peripheral nervous system Description Anatomy Nerves cranial trigeminal cervical brachial lumbosacral plexus somatosensory spinal autonomic Physiology reflexes proteins neurotransmitters transporters Development neurotrophins Disease Autonomic Congenital Injury Neoplasms and cancer Other Symptoms and signs eponymous Treatment Procedures Local anesthetics

Neuropathic pain and fibromyalgia pharmacotherapies Monoaminergics SNRIs (e.g., duloxetine, milnacipran) TCAs (e.g., amitriptyline, nortriptyline, dosulepin) Tapentadol Tramadol Ion channel blockers Anticonvulsants (e.g., gabapentin, pregabalin, carbamazepine, oxcarbazepine, lamotrigine) Lacosamide Local anesthetics (e.g., lidocaine) Mexiletine TCAs (e.g., amitriptyline, nortriptyline, desipramine) Ziconotide Others Alpha lipoic acid Benfotiamine Botulinum toxin A Bupropion Cannabinoids (e.g., cannabis, dronabinol, nabilone) NMDAR antagonists (e.g., ketamine, dextromethorphan, methadone) Opioids (e.g., hydrocodone, morphine, oxycodone, methadone, buprenorphine, tramadol, tapentadol) Sodium oxybate (GHB)