Overview of acquired peripheral neuropathies in children

INTRODUCTION — Peripheral neuropathy is defined as a disorder of the peripheral nerves. It typically is characterized by weakness, sensory loss (numbness), and/or positive sensory symptoms such as paresthesia, pain, or burning sensations. Most peripheral nerve disorders in children are hereditary (figure 1). However, many systemic illnesses, drugs, and toxins can also injure the peripheral nervous system in children (table 1).

An overview of acquired peripheral neuropathies is presented here.

Hereditary peripheral neuropathies and specific disorders that affect the peripheral nerves are discussed separately.

●(See "Overview of hereditary neuropathies".)

●(See "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis".)

●(See "Hereditary sensory and autonomic neuropathies".)

●(See "Neuropathies associated with hereditary disorders".)

CLINICAL FEATURES — Most peripheral nerve disorders have a gradual and slowly progressive course. However, trauma, toxic exposure, or inflammatory conditions may lead to acute presentations.

Most peripheral neuropathies manifest with bilateral, symmetric, predominantly distal involvement, though focal neuropathies do occur in children from various causes such as trauma. The severity of diffuse nerve injuries is related directly to axon length; thus, longer axons are affected first, resulting in symptoms that typically have an earlier presentation and are more prominent in the distal lower extremities.

Most neuropathies have combined sensory and motor involvement. However, some disorders have only motor or sensory abnormalities. The most common motor symptom is weakness. It may present as clumsiness, difficulty with running or climbing stairs, or impaired fine motor skills such as writing, buttoning clothes, opening jars, or tying shoes. Ataxia, or balance difficulty, is another motor symptom associated with neuropathy. Sensory symptoms may include numbness or positive sensory symptoms such as paresthesia, pain, or burning sensations.

Autonomic neuropathy may occur in isolation or may accompany a more widespread neuropathy. Autonomic symptoms such as abnormal sweating, cardiac arrhythmias, hypotension, or bowel and bladder dysfunction may accompany peripheral neuropathy. The central nervous system may be involved in some disorders, but this occurs more often with hereditary neurodegenerative diseases.

DIAGNOSIS — The diagnosis of a peripheral neuropathy is made by clinical examination, often supported by electrodiagnostic studies (EDX).

Clinical examination — The characterization of a peripheral nerve disorder involves a careful history and neurologic examination. A complete history includes perinatal and developmental history in addition to history of neurologic symptoms. For younger children unable to cooperate with a detailed examination, assessment includes observation of a child's activity and behavior. A general physical examination may also be performed to assess for abnormal findings associated with systemic disorders. (See "Detailed neurologic assessment of infants and children".)

The evaluation sometimes benefits from examination of family members to detect an inherited condition.

Electrodiagnostic evaluation — Evaluation of a suspected neuropathy in childhood is often augmented by EDX, which consist of nerve conduction studies (NCS) and needle electromyography (EMG) [1,2]. The abbreviation "EMG" is often used to refer to both NCS and EMG collectively, as these are two parts of a complete electrodiagnostic evaluation. NCS may be performed on a variety of upper and lower extremity motor and sensory nerves. (See "Overview of nerve conduction studies" and "Overview of electromyography".)

Sensory NCS are commonly performed on the median, ulnar, sural, superficial fibular (previously known as the superficial peroneal), and medial plantar nerves in children. The medial plantar study is especially useful in infants as the sural nerve response is often difficult to obtain in this age group. Motor NCS are commonly performed on the median, ulnar, tibial, and fibular (previously known as peroneal) nerves in children of all ages. The needle EMG can be performed on any muscle accessible via the needle electrode. For evaluations of potential neuropathies, examination of distal muscles is often most useful. For a child who may not tolerate a comprehensive needle examination, high-yield muscles may be examined first, in case the study needs to be terminated prematurely.

EDX can help distinguish if the symptoms are caused by a radiculopathy, plexopathy, motor neuron disease, nerve disorder (neuropathy), disorder of the neuromuscular junction, or muscle disorder (myopathy) [3]. EDX also can help differentiate whether a neuropathy is axonal or demyelinating in character.

Demyelinating disorders may be associated with the following electrodiagnostic findings:

●Slow nerve conduction velocities.

●Temporal dispersion of compound motor action potentials upon proximal stimulation.

●Conduction block (decreased amplitude of muscle compound action potentials on proximal compared with distal nerve stimulation).

●Marked prolongation of distal latencies.

●Prolonged F response latencies or absent F responses. It is worth noting that fibular (peroneal) F responses may sometimes be difficult to elicit in normal individuals; thus, absent F responses in isolation may be difficult to interpret. (See "Overview of nerve conduction studies", section on 'F wave'.)

●Normal or subtly abnormal needle EMG studies (reduced recruitment patterns in isolation may sometimes be seen).

By contrast, axonal neuropathies are characterized by reduced amplitudes of compound motor action potentials (on both distal and proximal stimulations) and/or sensory nerve action potentials with relative preservation of nerve conduction velocities and distal latencies. Chronic axonal neuropathies are also characterized by reinnervation patterns on needle EMG examination; denervating features are seen in both neurogenic and myopathic diseases.

However, effects on either conduction velocities or amplitudes are not exclusive to demyelinating versus axonal neuropathies, respectively. As an example, axonal neuropathies that affect the fastest firing axons may lead to a mild reduction in conduction velocity. Some neuropathies also have mixed physiology, with both demyelinating and axonal features. These studies should be performed and interpreted by a trained neurophysiologist with experience in the pediatric population.

Determining if the neuropathy affects sensory or motor nerves and is primarily a disorder of demyelination or axonal degeneration can assist in generating a differential diagnosis of the primary disease or toxic exposure. Further testing may be required to establish the cause.

INFLAMMATORY NEUROPATHIES — Inflammatory neuropathies include Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP).

Guillain-Barré syndrome — GBS presents as an acute monophasic paralyzing illness known as acute inflammatory demyelinating polyneuropathy (AIDP) that is often, though not always, linked to an antecedent infection. GBS was considered a single disorder, but it is now known to be a heterogeneous syndrome with several variant forms in both children and adults [4]. Additional demyelinating forms of GBS are Miller-Fisher syndrome and polyneuritis cranialis. Axonal forms of GBS are now well-recognized; these are acute motor axonal neuropathy (AMAN) and acute motor-sensory axonal neuropathy (AMSAN) and tend to occur more frequently in East Asia compared with other regions [5-7]. Particular aspects of GBS in children include the frequent occurrence of pain as a significant symptom along with weakness, the frequent occurrence of conduction block on electrophysiological testing, and the excellent long-term prognosis in most patients [8-14]. When spine magnetic resonance imaging (MRI) with gadolinium contrast is performed, nerve root enhancement is frequently present, and this test modality can supplement the more traditional electrophysiological studies and cerebrospinal fluid analysis [15-17].

GBS is discussed in detail separately. (See "Guillain-Barré syndrome in children: Epidemiology, clinical features, and diagnosis" and "Guillain-Barré syndrome in adults: Treatment and prognosis" and "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis".)

Chronic inflammatory demyelinating polyneuropathy — CIDP is an acquired chronic paralyzing disorder of peripheral nerves and nerve roots. It is generally distinguished from GBS by the duration of illness, with symptoms in CIDP progressive for at least eight weeks. There is a temporal continuum between AIDP, the demyelinating form of GBS, and CIDP. Although the incidence of CIDP is unknown, it is thought to be the most common acquired treatable polyneuropathy in children [18].

The classic form of CIDP is fairly symmetric, and motor involvement is greater than sensory. Weakness is present in both proximal and distal muscles. Most patients also have sensory involvement and globally diminished or absent reflexes. Cranial nerve and bulbar involvement occur in a minority. A relapsing-remitting course is most common in children, with some patients experiencing a prolonged monophasic course [19].

There are several ways of confirming a diagnosis of CIDP. Increased cerebrospinal fluid protein without pleocytosis (cytoalbuminologic dissociation) is present in over 90 percent of patients with CIDP and is an important diagnostic finding [20]. While the initial diagnosis of CIDP is clinical, documentation of peripheral nerve demyelination is important. This was traditionally obtained by either electrodiagnostic testing or by nerve biopsy, with support from cytoalbuminologic dissociation; nerve biopsies are not commonly performed any longer. Nerve root abnormalities on spine MRI are also supportive, along with the cerebrospinal fluid abnormalities mentioned above.

The mainstays of treatment for CIDP are intravenous immune globulin (IVIG), glucocorticoids, and plasma exchange. These treatments have traditionally been regarded as being equally efficacious. A retrospective study of childhood CIDP suggested that the response to treatment was more favorable with IVIG and glucocorticoids than with plasma exchange, but very few children received plasma exchange as a first-line treatment [19]. Plasma exchange and cyclosporine may be effective treatment options in some cases of CIDP that are refractory to IVIG therapy [21]. The long-term prognosis of CIDP is generally favorable, but a minority of patients experience persistent disabilities despite treatment.

CIDP is discussed in detail separately. (See "Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis" and "Chronic inflammatory demyelinating polyneuropathy: Treatment and prognosis".)

INFECTIONS — Peripheral neuropathies are associated with a variety of infections. With the exception of Lyme disease, these conditions are rare in the United States.

Lyme disease — Lyme disease is a multisystem inflammatory disease caused by spirochetes, known collectively as Borrelia burgdorferi, which are spread by the bite of infected Ixodes ticks. Adults with Lyme disease can develop a painful radiculitis manifested by neuropathic symptoms such as numbness, tingling, and burning. This radiculoneuropathy may affect the limbs (upper greater than lower extremity) or trunk. (See "Nervous system Lyme disease", section on 'Radiculoneuritis (Bannwarth syndrome)'.)

In contrast with their prevalence in affected adults, meningoradiculitis and peripheral neuropathy occur rarely in children [22]. Another study found that persistent facial palsy occurred in 13 percent of children diagnosed with Lyme neuroborreliosis [23]. Facial palsies due to Lyme disease closely resemble Bell's palsy, and it is important to consider both possibilities. Chronic peripheral neuropathy, which occurs in adults, has not been reported in children. With appropriate treatment, prognosis for recovery is good. (See "Lyme disease: Clinical manifestations in children".)

Chagas disease — Chagas disease (American trypanosomiasis) is caused by infection with the protozoan parasite Trypanosoma cruzi. It can be asymptomatic or can result in acute and chronic disease. The typical features of acute symptomatic infection are fever, swollen face or eyelids (Romaña sign), peripheral edema, conjunctivitis, hepatosplenomegaly, and lymphadenopathy. Myocarditis and meningoencephalitis also can develop. (See "Chagas disease: Acute and congenital Trypanosoma cruzi infection".)

A sensorimotor peripheral neuropathy with predominantly sensory symptomatology has been reported in the chronic phase of Chagas disease [24-26]. In addition, autonomic neuropathy (blunting of autonomic responses) is fairly common in chronic Chagas disease, with subtle changes on testing even in children [27,28]. However, peripheral neuropathy is a known side effect of benznidazole [29] and nifurtimox [30] (more commonly with the latter), and both are used to treat Chagas disease. Therefore, it is difficult to ascertain whether the neuropathy is related to Chagas disease itself or to its treatment. (See "Chagas disease: Antitrypanosomal drug therapy" and "Chagas disease: Acute and congenital Trypanosoma cruzi infection".)

In a study of 511 patients with chronic Chagas disease and with other causes of neurologic impairment excluded, 10 percent had signs and symptoms of mixed peripheral neuropathy [31]. Electrophysiologic features seen in approximately 30 percent included reduced number of functional motor units in the thenar, hypothenar, soleus, and/or extensor digitorum brevis muscles; slow sensory and motor nerve conduction velocities; low sensory action potential amplitude; impairment of neuromuscular transmission; and reduction in single motor unit action potentials with increased polyphasic activity.

Diphtheria — Diphtheria is an acute respiratory or cutaneous illness caused by Corynebacterium diphtheriae, a pleomorphic gram-positive bacillus. Toxigenic strains of C. diphtheriae produce respiratory disease that typically consists of pseudomembranous pharyngitis. A generalized motor-sensory demyelinating polyneuropathy caused by the exotoxin produced by C. diphtheriae is a common complication of severe infection. (See "Epidemiology and pathophysiology of diphtheria" and "Clinical manifestations, diagnosis, and treatment of diphtheria".)

The clinical course of diphtheritic polyneuropathy was described in 50 adults in Riga, Latvia [32]. Neurologic complications occurred in 15 percent of patients hospitalized with diphtheria, usually in those with severe pharyngeal infection. Neurologic signs typically developed in two phases. Bulbar symptoms occurred first in 49 of 50 patients at a median of 10 (range 2 to 50) days after onset of pharyngitis. Bulbar function typically improved after approximately 30 days then deteriorated in 19 of the patients. Limb symptoms affected 45 patients, beginning at 37 (range 12 to 63) days. Achilles tendon reflexes were lost in 78 percent of patients with neuropathy, and 48 percent were unable to walk unaided. Early treatment with antitoxin was associated with a good prognosis, although chronic disability occurred in some patients.

Leprosy — Leprosy (Hansen disease) is a chronic disease caused by Mycobacterium leprae. It involves mainly the skin, mucosa of the upper respiratory tract, and peripheral nerves. Most cases in the United States occur in immigrants from areas in which leprosy is endemic, especially Southeast Asia and Mexico. The disease is classified on the basis of the skin, motor, and sensory changes and biopsy findings as indeterminate, tuberculoid, borderline, and lepromatous. (See "Leprosy: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Classification and terminology'.)

Peripheral neuropathy is caused by bacterial invasion of the Schwann cells in the peripheral nerves. Both segmental demyelination and axonal degeneration occur. Motor and sensory nerve conduction is slow in both clinically involved and unaffected nerves [33]. Nerve biopsy shows loss of axons and myelin with swollen Schwann cells that contain the organism.

Sensory and/or motor loss generally will occur in the distribution of nerves in the vicinity of a tuberculoid lesion, whereas nerve damage may become more generalized later in the disease in individuals who fall into the borderline lepromatous (BL) and lepromatous (LL) disease categories at the end of the spectrum. Sensory loss usually involves the distal extremities first. Nerves commonly involved include the ulnar and median (claw hand), the common peroneal (foot drop), the posterior tibial (claw toes and plantar insensitivity), facial, radial cutaneous, and great auricular. The pattern of neuropathy often fits within the realm of mononeuropathy multiplex [34]. Although relatively uncommon today, advanced cases may demonstrate loss of eyebrows and lashes, nasal septal perforation with collapsed nose, and hoarseness (laryngeal involvement).

Rabies — Rabies virus is endemic in wildlife in the United States. Important sources of infection for humans and domestic animals include raccoons, skunks, foxes, coyotes, and bats [35]. The virus is present in saliva; transmission occurs by bites or contamination of skin lesions or mucosa. (See "Clinical manifestations and diagnosis of rabies", section on 'Transmission'.)

Infection with rabies virus results in an acute rapidly progressive illness characterized by encephalitis, anxiety, dysphagia, and seizures. Some patients develop paralysis and/or focal neurologic signs. (See "Clinical manifestations and diagnosis of rabies", section on 'Clinical manifestations'.)

Peripheral neuropathy, with weakness and loss of deep tendon reflexes, occurs in approximately 20 percent of children with paralysis caused by rabies [36]. The neuropathy is caused by axonal degeneration with segmental demyelination [37]. Some patients develop an ascending paralysis with bulbar dysfunction similar to that of Guillain-Barré syndrome [38]. The disease nearly always is fatal once symptoms have developed [39].

Rabies diagnosis, treatment, and prophylaxis are discussed in greater detail separately. (See "Clinical manifestations and diagnosis of rabies" and "Rabies immune globulin and vaccine".)

RHEUMATOLOGIC DISEASES — Peripheral neuropathy can be seen in many rheumatologic diseases.

Eosinophilic granulomatosis with polyangiitis — Eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss) is a multisystem disorder characterized by allergic rhinitis, asthma, and prominent peripheral blood eosinophilia [40]. The most common organ involved is the lung, followed by the skin. EGPA, however, can affect any organ system, including the cardiovascular, gastrointestinal, and central and peripheral nervous systems. The disorder is rare, but approximately 20 percent of cases occur in children [41]. (See "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)".)

Neurologic involvement is common in EGPA and typically manifests as a peripheral neuropathy [42,43]. In one series of 47 affected patients, peripheral neuropathy was present in 25 [42]. This included multiple mononeuropathy in 17, distal symmetric polyneuropathy in 7, and asymmetric polyneuropathy in 1.

Immunoglobulin A vasculitis (Henoch-Schönlein purpura) — Immunoglobulin A vasculitis (IgAV; Henoch-Schönlein purpura [HSP]) is a systemic vasculitis with a prominent cutaneous component. The clinical manifestations include a classic tetrad that can occur in any order and at any time over a period of several days to several weeks: rash, arthralgias, abdominal pain, and renal disease. (See "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis".)

Peripheral neuropathy is rare in children with IgAV (HSP) [44]. Acute mononeuropathy can affect the femoral or sciatic nerve. The pathogenesis is not known, although suggested mechanisms include immune disease, mechanical compression, or metabolic disturbance. In most cases, IgAV (HSP) resolves completely, including neurologic signs. However, recurrences are possible.

Inflammatory bowel disease — Inflammatory bowel disease is comprised of two major disorders: ulcerative colitis and Crohn disease. These disorders have distinct pathologic and clinical characteristics, but their pathogenesis remains poorly understood. (See "Management of mild to moderate ulcerative colitis in children and adolescents" and "Clinical manifestations and complications of inflammatory bowel disease in children and adolescents".)

Neurologic involvement is uncommon in inflammatory bowel disease, occurring in 3 percent of 638 patients with ulcerative colitis or Crohn disease [45]. In this series, peripheral neuropathy occurred in six patients with ulcerative colitis and none with Crohn disease.

Peripheral neuropathy may occur in adolescent males with long-standing Crohn disease. Extraintestinal manifestations often include large joint arthritis and uveitis. Affected patients often have a family history of collagen vascular disease.

Peripheral neuropathy is a rare primary manifestation of Crohn disease [46-48]. It usually occurs in affected patients who have vitamin B12 deficiency due to malabsorption [49] or have been treated with metronidazole [50].

Juvenile idiopathic arthritis — Peripheral neuropathy is a rare feature of juvenile idiopathic arthritis [51,52]. The mechanism may be vasculitis involving the vaso nervorum that results in an axonal neuropathy with secondary demyelination [51]. (See "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis".)

Polyarteritis nodosa — Polyarteritis nodosa is a systemic necrotizing vasculitis that typically affects the small and medium-sized muscular arteries. A mononeuropathy multiplex (or asymmetric polyneuropathy) with motor and sensory deficits is one of the most common findings in patients with polyarteritis nodosa [53-55]. With time, additional nerve branches may be affected, possibly resulting in the appearance of a distal polyneuropathy. Cranial nerves are less commonly involved. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults".)

Nerve conduction studies in affected patients show slowed conduction. Pathologic examination of peripheral nerve demonstrates arteritis with nerve infarction and demyelination [53].

Sarcoidosis — Sarcoidosis is a multisystem disorder of unknown etiology characterized by the accumulation of T lymphocytes, mononuclear phagocytes, and noncaseating granulomas in involved tissues. The lungs are affected in approximately 90 percent of patients and account for most of the morbidity and mortality. Other tissues commonly involved include the skin, eyes, and lymph nodes. (See "Pathology and pathogenesis of sarcoidosis".)

Approximately 5 percent of adults with sarcoidosis have neurologic involvement, which can on occasion be the presenting symptom. The protean manifestations of central nervous system involvement usually occur in the early phase of the disease, whereas peripheral nerve and skeletal muscle involvement characteristically are seen in the more chronic stages. Neurologic involvement is uncommon in children with sarcoidosis, and peripheral neuropathy has not been described.

Sjögren's disease — Sjögren's disease is a chronic inflammatory disorder characterized primarily by diminished lacrimal and salivary gland secretions resulting in symptoms of dry eyes and dry mouth, the so-called "sicca complex." Like many connective tissue diseases, Sjögren's disease is thought to be an autoimmune disorder. (See "Clinical manifestations of Sjögren's disease: Exocrine gland disease" and "Clinical manifestations of Sjögren’s disease: Extraglandular disease".)

Neurologic disease is common in Sjögren's disease, occurring in 25 to 60 percent of patients [56]. In one series, 33 of 50 (66 percent) affected patients had neurologic abnormalities. Both the central and peripheral nervous systems were involved in 19, only peripheral in 9, and only central in 5 [57]. The incidence of peripheral neuropathy in affected children is not known [58].

The neuropathy is highly variable and may present in various forms, including cranial, distal sensory, distal sensory-motor, or pure sensory neuropathy [59]. It may be difficult to differentiate this disorder from Guillain-Barré syndrome or chronic inflammatory demyelinating polyradiculoneuropathy [60].

A peripheral "glove and stocking" neuropathy affects as many as 10 percent of adult patients with Sjögren's disease. It usually is a symmetric, sensorimotor polyneuropathy in which the sensory features (eg, dysesthesias) predominate. The patient thus presents with anesthesia and dysesthesias of the extremities. The course generally is slowly progressive, although some patients may benefit from steroids.

Other neuropathies may be found, usually in subjects who already have a peripheral neuropathy. These include the trigeminal nerve, the most common cranial nerve defect; other cranial nerves VII, VIII, III, IV, or VI; and autonomic nerves.

Confirmation of peripheral nerve involvement requires nerve conduction studies and sural nerve biopsy. Biopsy of affected nerves shows axonal degeneration and a perivascular inflammatory infiltrate, suggesting an underlying vasculitic cause [61]. Antibodies to extractable nuclear antigens (anti-Ro/SSA, anti-La/SSB, anti-Sm, and anti-RNP) often are negative. Additional tests of ocular or salivary gland involvement often are required to confirm the diagnosis [62].

Systemic lupus erythematosus — Systemic lupus erythematosus (SLE) is a chronic inflammatory disease of unknown cause which can affect the skin, joints, kidneys, lungs, nervous system, serous membranes and/or other organs of the body. Distinct immunologic abnormalities, especially the production of numerous antinuclear antibodies, are another prominent feature. (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis".)

Peripheral neuropathy affects 2 to 27 percent of patients with SLE [63,64]. Peripheral neuropathy is rare in affected children [65,66]. Pathologic findings include vasculitis and axonal degeneration [67]. Findings in mixed connective tissue disease are similar to those in SLE.

Granulomatosis with polyangiitis — Granulomatosis with polyangiitis is a systemic vasculitis of the medium and small arteries as well as the venules, arterioles, and occasionally large arteries. "Classic" granulomatosis with polyangiitis is a form of systemic vasculitis that primarily involves the upper and lower respiratory tracts and the kidneys. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis".)

Peripheral neuropathy is common in this disorder, occurring in 17 and 43 percent of adult patients in two series [68,69]. Patients typically had distal symmetrical polyneuropathy or mononeuropathy multiplex. In a series of 23 children with the disease, 9 percent had neurologic disease that was predominantly peripheral neuropathy [70].

OTHER SYSTEMIC DISORDERS — Patients with endocrine abnormalities (eg, diabetes mellitus, hypothyroidism), disorders of the gastrointestinal tract (eg, celiac disease), and enzyme deficiencies (eg, porphyria) may develop peripheral neuropathies. Peripheral neuropathy associated with malignancy may be caused by the underlying illness or its treatment.

Diabetes mellitus — Peripheral neuropathy is a common complication of diabetes. The mechanism is uncertain but is thought to be mediated by the effects of hyperglycemia on the peripheral nerve (table 2) [71]. (See "Pathogenesis of diabetic polyneuropathy", section on 'Pathophysiology'.)

Diabetic polyneuropathy primarily is a symmetrical sensory neuropathy, initially affecting the distal lower extremities (see "Screening for diabetic polyneuropathy"). With disease progression, sensory loss ascends and, when reaching approximately mid-calf, becomes clinically apparent in the hands. This gradual evolution causes the typical "stocking-glove" sensory loss. This pattern reflects preferential damage according to axon length; the longest axons are affected first. Motor involvement with frank weakness occurs in the same pattern but only later and in more severe cases. Autonomic dysfunction also is common in diabetic children [72].

Neuropathy may be present at the time of diagnosis. Abnormalities were detected in 25 percent of children at their initial presentation by measurement of reduced nerve conduction velocities [73]. Nerve conduction studies have detected evidence for neuropathy in 32 percent of children and adolescents in another study [74], while assessment of the thermal threshold for heat and cold at the wrist and foot and the vibration threshold at the great toe and medial malleolus was abnormal in 28 percent at baseline [75]. These studies suggest that about a quarter of children and adolescents with diabetes have clinical or subclinical signs of nerve injury.

Most patients with established disease are affected, although most abnormalities are subclinical [74]. In one report, electrophysiologic studies were performed on median, peroneal, and sural nerves in 75 patients 7 to 20 years of age with diabetes longer than three years' duration [76]. Measurements of motor and sensory conduction velocity and sensory nerve action potential were abnormal in 57 percent. However, only three patients had signs or symptoms of neuropathy.

Hypothyroidism — Hypothyroidism may result in abnormalities of the peripheral and central nervous system, although the latter is more likely to be affected. In one study, clinical and electrophysiologic measurements were performed in 23 patients, 17 to 64 years of age, with hypothyroidism [77]. Abnormalities of the peripheral nervous system occurred in 52 percent, including entrapment neuropathy, axonal neuropathy, and myopathy. Central nervous system abnormalities occurred in 78 percent. (See "Neurologic manifestations of hypothyroidism", section on 'Peripheral neuropathy'.)

Celiac disease — Celiac disease is a malabsorption disorder in which there is abnormal small intestinal mucosa that improves morphologically when treated with a gluten-free diet and relapses when gluten is reintroduced.

A number of reports have described an association of celiac disease with neurologic disorders, including cerebellar ataxia, progressive myoclonic ataxia, peripheral neuropathy, myopathy, and seizures. These complications have generally been reported in adults. However, the diagnosis of celiac disease was frequently based only upon anti-gliadin antibodies (which lack specificity for celiac disease) and not all studies have detected these associations, making the relationship to celiac disease unclear.

In children with celiac disease, clinically apparent neurologic disorders are uncommon, and the evidence supporting the association with celiac disease is weak. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children", section on 'Non-gastrointestinal manifestations'.)

Peripheral neuropathy has been reported multiple times in children with celiac disease but likely occurs at a low frequency [78-80]. Nevertheless, there are case reports suggesting the existence of a reversible neuropathy related to celiac disease [81].

Porphyria — The porphyrias are genetic or acquired deficiencies in the activity of enzymes in the heme biosynthetic pathway. Peripheral neuropathy is a common feature of acute intermittent porphyria, although it also occurs in hereditary coproporphyria, and variegate porphyria.

Muscle weakness often begins proximally in the legs but may involve the arms or the distal extremities. Reflexes are lost. Motor neuropathy also may involve the cranial nerves or lead to bulbar paralysis, respiratory impairment, and death. Some patients develop sensory, patchy neuropathy. Autonomic dysfunction may lead to colicky abdominal pain, diarrhea or constipation, and bladder dysfunction. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis" and "Hereditary coproporphyria" and "Variegate porphyria".)

Malignancy — Peripheral neuropathy is an uncommon paraneoplastic complication of lymphoma in adults that has been reported in a few cases in children [82,83].

The neuropathy may be acute or chronic and can present as sensory or sensorimotor abnormalities. Sensory symptoms include paresthesias, dysesthesias, pain, or sensory ataxia [84]. Acute motor neuropathy may resemble Guillain-Barré with distal ascending weakness. Chronic neuropathy typically presents as distal weakness with loss of reflexes and may be relapsing.

The neuropathy is thought to be immune mediated, resulting in axonal degeneration. Malignant infiltration of peripheral nerves also may occur. Segmental demyelination is seen in the relapsing form.

Chemotherapeutic agents also can cause peripheral neuropathy (table 1). Neuropathy associated with malignancy thus may be caused by the treatment as well as the underlying disease. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy".)

Organ failure — Peripheral neuropathy may be associated with organ failure, such as renal or hepatic failure, or with critical illness.

Renal failure — Dysfunction of the peripheral nervous system induced by uremia commonly occurs in patients with end-stage kidney disease [85]. Peripheral polyneuropathy generally develops only in advanced renal failure and is an indication to initiate dialysis. However, patients already being dialyzed adequately are also at some risk, although the neural dysfunction is often subclinical and detectable only by electrophysiologic studies.

Uremic peripheral neuropathy is a distal, symmetrical, mixed sensorimotor neuropathy. It occurs more commonly in males and is independent of the underlying disease. As with other neuropathies, symptoms are more prominent in the lower extremities. The sensory symptoms (paresthesias, burning sensations, and pain) tend to precede the motor symptoms.

The initial finding is loss of position and vibration sense in the toes and decreased deep tendon reflexes, beginning with the Achilles reflex. Clinical involvement of the hands typically is delayed until the sensory defects have moved to or above the knees. Electrophysiologic studies are the most sensitive way to detect uremic neuropathy [86]. Uremic neuropathy is rare in younger individuals, but at least one adolescent case has been reported [87]. (See "Uremic polyneuropathy".)

Liver transplantation — Neurologic complications commonly occur after liver transplantation and predominantly affect the central nervous system. Some cases are attributed to immunosuppressive therapy.

In a series of 427 consecutive orthotopic liver transplantations in 391 patients, 19 percent developed neurologic complications, of which encephalopathy comprised 59 percent [88]. Other complications included seizures, peripheral neuropathy, stroke, and central nervous system infections. Encephalopathy occurred with similar frequency in adults and children, although only 1 of 16 cases of brachial plexus and peripheral nerve injuries occurred in children. Mortality rate was higher in children with than without neurologic complications (50 versus 7 percent).

Bone marrow transplantation — An inflammatory neuropathy may occur after bone marrow transplantation. [89,90]. The disorder was associated with graft-versus-host disease and improved as graft-versus-host disease resolved [89].

Critical illness polyneuropathy — Critical illness polyneuropathy occurs in patients with multiple organ failure who receive prolonged intensive care treatment. This condition occurs predominantly in adults, but children also may be affected. The disorder is associated with multiple organ dysfunction, prolonged mechanical ventilation, and sepsis [91]. Critical illness polyneuropathy has been reported in children but appears to be rare [92]. (See "Neuromuscular weakness related to critical illness".)

Affected patients have flaccid paralysis and areflexia [92]. The diagnosis should be considered in a flaccid child who is difficult to wean from ventilator support [93].

Nerve conduction studies show a generalized axonal neuropathy, and electromyography may show varied abnormalities. Often, evidence of ongoing denervation (fibrillation potentials and positive sharp waves) is seen in conjunction with normal-appearing motor units. Occasionally, electromyography shows myopathic changes; this observation correlates with pathologic studies that demonstrate a myopathy. Cerebrospinal fluid is normal. Motor function returns slowly over several months.

Peripheral neuropathy with myopathy may occur after prolonged neuromuscular blockade with nondepolarizing neuromuscular blocking agents including vecuronium, atracurium, and pancuronium [94,95]. Affected patients developed pronounced weakness without sensory loss [94]. The condition delayed weaning from the ventilator and recovery of strength took several months.

MEDICATIONS — Peripheral neuropathy is a side effect of many medications (table 1). The most common associations are listed here.

Antibiotics — Antibiotic agents have been associated with peripheral nerve disorders [96]. These agents include penicillin, sulfonamide, chloramphenicol, metronidazole, and isoniazid. Symptoms consist of paresthesias, motor weakness, and/or sensory abnormalities.

Antiretroviral agents — Treatment of HIV with antiretroviral agents (eg, zidovudine, stavudine, lamivudine) may result in toxic neuropathies. These disorders are characterized predominantly by sensory symptoms that include spontaneous or evoked pain and follow a subacute or chronic course [97]. Pathologic features include degeneration of long axons in distal regions, loss of unmyelinated fibers, and infiltration of macrophages in peripheral nerves and dorsal root ganglia. The mechanism is thought to be interference with mitochondrial DNA synthesis and mitochondrial toxicity [97,98].

Chemotherapeutic agents — Peripheral neuropathy is an important complication of chemotherapeutic agents, including vincristine, cisplatin, cytarabine, bortezomib, thalidomide, and paclitaxel [99,100]. In some cases, this toxicity may limit the use of these drugs. However, retrospective data suggest that most children with chemotherapy-induced peripheral neuropathy have a favorable outcome, with clinical improvement during the maintenance phase or after completion of therapy [99]. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy".)

Phenytoin — Peripheral neuropathy associated with the use of phenytoin has been well described. In one report, nerve conduction studies were abnormal in 15 of 21 children with epilepsy receiving long-term phenytoin therapy [101]. The most frequent abnormalities were slowed motor conduction velocity of the ulnar and posterior tibial nerves and slowed sensory conduction velocity of the sural nerve. The total dose and duration of therapy with phenytoin correlated with reduced motor conduction velocity in the posterior tibial nerve.

Thalidomide — Thalidomide, which inhibits tumor necrosis factor and angiogenesis, has been used in disorders including Crohn disease, graft-versus-host-disease, HIV complications, and multiple myeloma [102]. In addition to its sedative and embryopathic effects, thalidomide can cause an irreversible toxic peripheral neuropathy. This neuropathy has been documented in children [103]. The risk in children appears to increase with cumulative dosage and duration of therapy [104], though the severity of the neuropathy appears to plateau in some children despite ongoing therapy [105]. Regular clinical and neurophysiologic monitoring for neuropathy is warranted for children receiving thalidomide.

VITAMIN DEFICIENCY OR EXCESS — Vitamin deficiency or excess may result in peripheral neuropathy. Symptoms usually resolve with correction of the deficiency or elimination of the excess vitamin.

Some vitamin deficiencies have genetic origins, and thus the presence of a neuropathy in the setting of a vitamin deficiency may require genetic testing. (See "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis", section on 'Differential diagnosis'.)

●Vitamin B1 (thiamine) deficiency – Thiamine, formerly known as vitamin B1, serves as a catalyst in the conversion of pyruvate to acetyl CoA and is involved in many other cellular metabolic activities. Thiamine has a role in the initiation of nerve impulse propagation that is independent of its coenzyme functions. (See "Overview of water-soluble vitamins".)

B1 deficiency typically is seen in areas where polished rice is a major portion of the diet. Breastfed infants of thiamine-deficient mothers may develop encephalopathy, seizures, diarrhea, and cardiomyopathy [106].

Thiamine deficiency results in beriberi, a fulminant cardiac syndrome with cardiomegaly, tachycardia, a loud, piercing cry, cyanosis, dyspnea, and vomiting, and neurologic abnormalities, including altered sensorium, hoarseness caused by laryngeal nerve paralysis and considered a classic sign, and peripheral neuropathy. The latter may be obscured by the central nervous system and systemic symptoms. If the deficiency is prolonged, a patchy, demyelinating neuropathy may develop.

●Vitamin B2 (riboflavin) deficiency – Riboflavin is an essential component of coenzymes involved in multiple cellular metabolic pathways, including the energy-producing respiratory pathways. Deficiency occurs most often in patients with malabsorption syndromes, anorexia nervosa, inborn errors in riboflavin synthesis, and long-term use of phenobarbital (which may impair riboflavin function), and in those who avoid dairy products (a good source of riboflavin). It also may occur in regions where access to food is limited. (See "Overview of water-soluble vitamins".)

Signs of significant B2 deficiency include sore throat, hyperemia of pharyngeal mucous membranes, edema of mucous membranes, cheilitis, stomatitis, glossitis, normocytic-normochromic anemia, and seborrheic dermatitis [107]. Because riboflavin deficiency usually is accompanied by deficiencies of other water-soluble vitamins that can cause similar symptoms, it is uncertain whether these result from riboflavin deficiency alone. Sensory and sensory-motor neuropathy due to nutritional deficiency of thiamine and riboflavin comprised 10 percent of a series of 358 cases of peripheral neuropathy in Nigerians [108].

●Vitamin B6 (pyridoxine) deficiency – Pyridoxine plays a role in amino acid metabolism, gluconeogenesis, conversion of tryptophan to niacin, sphingolipid biosynthesis, neurotransmitter synthesis, immune function, and steroid hormone modulation. (See "Overview of water-soluble vitamins".)

Dietary pyridoxine deficiency is rare. Clinical features include seborrheic dermatitis, glossitis and stomatitis. A microcytic hypochromic anemia is common. Peripheral neuropathy may occur in adolescents although not in younger children [109]. The latter develop encephalopathy with seizures.

The neuropathy was investigated in an experimental model of rats fed a diet deficient in B6 [110]. The deficient rats developed abnormal walking patterns, which resolved with B6 supplementation. Morphometric analysis of the sciatic and posterior tibial nerves in the deficient animals showed a normal total number of myelinated nerve fibers, significantly decreased nerve fiber density, and increased axon-to-myelin ratio compared with controls.

Isoniazid, used to treat tuberculosis, inhibits pyridoxine [111]. As a result, pyridoxine supplementation may be needed to prevent neuropathy in these patients. (See "Isoniazid: An overview", section on 'Neurologic reactions'.)

●Vitamin B6 (pyridoxine) toxicity – Excessive doses of pyridoxine may cause peripheral neuropathy [112,113]. A few cases of peripheral neuropathy, dermatoses, photosensitivity, dizziness, and nausea have been reported with long-term use of large doses of pyridoxine [112]. Cases of acute intoxication typically present with paresthesias, generalized sensory loss, and autonomic dysfunction, without weakness [113]. The clinical picture is similar to that of animal models of pyridoxine toxicity and may be caused by a sensory ganglion neuronopathy [114]. In a patient treated with isoniazid and high-dose pyridoxine who developed a severe sensory neuropathy, sural nerve biopsy showed loss of large myelinated fibers [115].

●Vitamin B12 (cobalamin) deficiency — Deficiency of cobalamin (vitamin B12), a cofactor for DNA synthesis, can occur in exclusively breastfed infants of vegetarian mothers [116,117] or genetic disorders, such as defective cobalamin ileal transport [118]. Deficiency of cobalamin produces megaloblastic anemia and neurologic changes. (See "Treatment of vitamin B12 and folate deficiencies".)

Symptoms of neuropathy associated with B12 deficiency include areflexia and loss of vibration and position sense, but they are difficult to detect in young children. Affected infants develop irritability, anorexia, and failure to thrive, with developmental regression and poor brain growth [119]. Lethargy and coma can occur in severe cases [120]. In general, central nervous system abnormalities and peripheral neuropathy accompany anemia or macrocytosis, although neurologic disease can occur without hematologic findings [121].

●Vitamin E (tocopherol) deficiency – Vitamin E is a generic term for a group of fat-soluble compounds, of which alpha-tocopherol is most important. These compounds function as free radical scavengers at the cellular level. Vitamin E deficiency is uncommon in humans except in unusual circumstances because of the abundance of tocopherols in our diet. Deficiency may occur in patients with fat malabsorption and steatorrhea and in those with certain genetic disorders, including abetalipoproteinemia. (See "Overview of vitamin A".)

The major features of vitamin E deficiency are skeletal myopathy, spinocerebellar ataxia, and pigmented retinopathy with loss of vision [122]. Sensory-motor neuropathy occurs late in the course of vitamin E deficiency and is manifested by loss of vibration and position sense, loss of reflexes, and generalized weakness. Pathologic findings on nerve biopsy include accumulation of lipofuscin in peripheral Schwann cell cytoplasm and selective loss of large myelinated fibers [123,124].

The progressive course of the neurologic disorder in vitamin E deficiency was described in a series of children with either chronic forms of intrahepatic neonatal cholestasis or extrahepatic biliary atresia [61]. All patients had normal neurologic function before reaching one year of age. Among those with vitamin E deficiency, neurologic abnormalities occurred in one-half between one and three years of age and in all after three years. Areflexia was the first abnormality noted and occurred before the patients reached four years of age; truncal and limb ataxia, peripheral neuropathy, and ophthalmoplegia developed when they were between three and six years. Most of children became disabled by neurologic dysfunction by the time they were 8 to 10 years of age.

TOXINS — Toxins that cause peripheral neuropathy include heavy metals and industrial or environmental substances (table 1). These toxins primarily affect the axon with secondary myelin involvement. Chronic exposure is usually required, although abnormalities can occur after acute exposure. The diagnosis is confirmed by identification of the toxic substance in blood, urine, or body tissues (eg, hair or nails).

●Arsenic – Toxic exposure to arsenic may result from environmental sources such as contaminated water or accidental ingestion of pesticides, particularly ant poison. Chronic exposure is rare and usually is the result of deliberate poisoning. Arsenic exposure and toxicity are discussed in detail separately. (See "Arsenic exposure and chronic poisoning".)

Clinical features of arsenic poisoning include changes in skin pigmentation, palmar and plantar hyperkeratosis, and white striae of the nails (Mees lines or transverse leukonychia). Systemic signs include anemia, gastrointestinal symptoms (vomiting, bloody diarrhea, and abdominal pain), and liver disease. Peripheral neuropathy typically develops after one to three weeks and is characterized by a distal motor-sensory neuropathy (see "Arsenic exposure and chronic poisoning", section on 'Neurologic'). Paresthesia and numbness occur in the fingers and toes and ascend proximally. Autonomic symptoms, such as sweating, tachycardia, and hypotension, occur early.

Treatment and prevention of arsenic poisoning are reviewed separately. (See "Arsenic exposure and chronic poisoning", section on 'Management' and "Arsenic exposure and chronic poisoning", section on 'Neurologic'.)

●Lead – Lead toxicity can occur after acute or chronic exposure. The characteristic neurologic manifestations of lead poisoning range from developmental delay and loss of milestones to encephalopathy (see "Childhood lead poisoning: Clinical manifestations and diagnosis"). Neuropathy occurs infrequently, and sensory symptoms are minimal.

Neuropathy, when it occurs, usually presents in children as distal ankle weakness with foot drop. In contrast, the arms are more likely to be affected in adults, who often develop wrist drop. The peripheral neuropathy is caused by axonal degeneration of the large myelinated fibers [125].

●Mercury – Toxicity may occur from exposure to either organic (eg, eating contaminated fish) or inorganic (eg, antiseptic solutions, occupational exposures) mercury. The principal organ systems affected by mercury poisoning are the central nervous system and the kidneys. (See "Mercury toxicity".)

Peripheral motor neuropathy, characterized by weakness and areflexia, may result from acute toxicity. Sensory findings may include distal paresthesias. Residual neurologic deficits may persist many years after the initial exposure [126].

●N-hexane (glue sniffing) – N-hexane is a neurotoxin that causes giant axonal changes [127]. Products such as solvents, glues, spray paints, coatings, and silicones contain n-hexane, a petroleum distillate and aliphatic hydrocarbon. Toxicity can result from industrial exposure [128] or addictive inhalation [129]. (See "Inhalant misuse in children and adolescents".)

Peripheral neuropathy caused by n-hexane presents as distal weakness and muscle atrophy, mainly in the hands and feet. Sensory symptoms are minimal and consist of numbness [130]. Other solvents such as 2,5-hexanedione and methyl n-butyl ketone cause a similar neuropathy. After elimination of the exposure, recovery is slow and may be incomplete.

●Organophosphorus esters – Poisoning from organophosphorus esters can occur through their use in insecticides. However, insecticide exposure causes symptoms in less than 10 percent of cases and rarely results in peripheral neuropathy [131].

Acute intoxication results from inhibition of acetylcholinesterase. Muscarinic effects include salivation, lacrimation, bronchoconstriction, sweating, abdominal cramps, diarrhea, constricted pupils, mental confusion, and muscle cramps with fasciculations. Nicotinic effects may be seen in the subacute phase, with muscle weakness affecting both proximal muscles and respiratory muscles secondary to postsynaptic neuromuscular block.

A specific syndrome known as organophosphorus-induced delayed polyneuropathy (OPIDP) may occur after industrial exposure or contamination of foods, drinks, or cooking oil with tri-ortho-cresyl phosphate, used in the manufacture of plastics and as a high-temperature lubricant [132,133]. Leg cramps and burning dysesthesias of the feet and hands develop approximately three weeks after exposure. Distal weakness, foot drop, spasticity, hyperreflexia, and ataxia typically occur. There is no treatment for this condition.

●Thallium – Thallium is used in rodenticides and insecticides in some countries, despite recommendation against its use by the World Health Organization [134]. Intoxication can occur through inhalation, ingestion, or introduction through the skin. Clinical features include alopecia, black deposits at the base of hairs, glossitis, and Mees lines (white lines in the fingernails). Abdominal pain with nausea and vomiting occur in the acute phase.

A painful, rapidly progressive, and usually ascending peripheral neuropathy typically begins two to five days after acute exposure and dominates the clinical picture in the second or third week [134]. Motor findings include distal weakness primarily affecting the lower extremities. Sensory findings include paresthesias and pain of the lower extremities and numbness of the fingers and toes. Nerve fibers show axonal degeneration and demyelination.

Other neurologic abnormalities include tremor, ataxia, seizures, and coma. Optic nerve atrophy may result in visual changes.

Treatment consists of oral ferric hexacyanoferrate (Prussian blue), which binds thallium and prevents reabsorption. Chelating agents are not effective. Thallium poisoning case-fatality rates range from 0 to 40 percent [135].

SUMMARY

●Clinical features – Peripheral neuropathies typically develop with bilateral, symmetric, predominantly distal involvement. Combined sensory and motor involvement is most common, but motor or sensory abnormalities may predominate in some cases, and autonomic symptoms may also occur. (See 'Clinical features' above.)

Peripheral nerve disorders typically have a gradual and slowly progressive course. However, acute presentation may occur with toxic exposure or inflammatory conditions. Many systemic illnesses, drugs, and toxins affect the peripheral nervous system (table 1).

●Diagnosis – The diagnosis of a peripheral nerve disorder requires a careful neurologic examination and typically involves a nerve conduction study (NCS) with electromyography (EMG) that includes a needle examination of select muscles.

Electrodiagnostic studies (EDX) can help distinguish if the symptoms are caused by a radiculopathy, plexopathy, motor neuron disease, nerve disorder (neuropathy), disorder of the neuromuscular junction, or muscle disorder (myopathy). EDX can also help differentiate whether a neuropathy is axonal or demyelinating in character. (See 'Diagnosis' above.)

●Inflammatory neuropathies – Inflammatory neuropathies include Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP). GBS typically presents as an acute monophasic paralyzing illness often linked to an antecedent infection. CIDP is a chronic paralyzing illness. (See 'Inflammatory neuropathies' above.)

●Systemic disorders

•Infections – Peripheral neuropathies are associated with a variety of infections, including Lyme disease, Chagas disease, diphtheria, leprosy, and rabies. With the exception of Lyme disease, these conditions are rare in the United States. (See 'Infections' above.)

•Rheumatologic diseases – Peripheral neuropathy can be seen in many rheumatologic diseases, including the following (see 'Rheumatologic diseases' above):

-Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)

-Immunoglobulin A vasculitis (IgAV; Henoch-Schönlein purpura [HSP])

-Inflammatory bowel disease (ulcerative colitis and Crohn disease)

-Juvenile idiopathic arthritis

-Polyarteritis nodosa

-Sarcoidosis

-Sjögren's disease

-Systemic lupus erythematosus

-Granulomatosis with polyangiitis

•Other systemic disorders – Patients with endocrine abnormalities (eg, diabetes mellitus, hypothyroidism), disorders of the gastrointestinal tract (eg, celiac disease), and enzyme deficiencies (eg, porphyria) may develop peripheral neuropathies. Peripheral neuropathy associated with malignancy may be caused by the underlying illness or its treatment. (See 'Other systemic disorders' above.)

Peripheral neuropathy may be associated with organ failure, such as renal or hepatic failure, or with critical illness. (See 'Organ failure' above.)

●Medications – Peripheral neuropathy is a side effect of many medications (table 1). The most common associations involve antibiotics, antiretroviral agents, chemotherapeutic agents, phenytoin, and thalidomide. (See 'Medications' above.)

●Vitamin deficiency or excess – Vitamin deficiency or excess may result in peripheral neuropathy. Symptoms usually resolve with correction of the deficiency or elimination of the excess vitamin. (See 'Vitamin deficiency or excess' above.)

●Toxins – Toxins that cause peripheral neuropathy include heavy metals and industrial or environmental substances such as arsenic, lead, mercury, n-hexane, organophosphorus esters, and thallium (table 1). These toxins primarily affect the axon with secondary myelin involvement. Chronic exposure is usually required, although abnormalities can occur after acute exposure. (See 'Toxins' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert Cruse, DO, who contributed to earlier versions of this topic review.