Aetiology

There are many causes of polyneuropathy, including neurological syndromes, systemic diseases, nutritional deficiencies, toxins/drugs, and genetic disorders. Additionally, several other neurological conditions can mimic the signs and symptoms of polyneuropathy.

Systemic diseases

Endocrine neuropathy

  • Diabetic polyneuropathy develops in approximately 50% of diabetic patients and is the most common cause of polyneuropathy in the world.[5] Risk factors include smoking, hypertension, older age, longer duration of diabetes, and greater degree of hyperglycaemia.

  • Impaired glucose tolerance without diabetes, also termed pre-diabetes 7.8 to 11.0 mmol/L (140 to 199 mg/dL) serum glucose level 2 hours after a 75 g oral glucose load) may also be associated with a polyneuropathy.[13][14]

  • Hypothyroidism and acromegaly may be associated with sensorimotor polyneuropathies.

Infectious neuropathy

  • HIV polyneuropathy may be caused by the infection or by dideoxynucleoside antiretrovirals. Low CD4 lymphocyte counts and high viral loads may increase the risk.[15][16]

  • Hepatitis C viral infection, diphtheria, and leprosy may cause polyneuropathy. Lyme disease may cause a variety of peripheral nerve disorders; axonal neuropathy may be a manifestation of late-stage neurological Lyme disease.[17][18][19] Diphtheria is notable for causing a post-infectious acute demyelinating condition by interfering with myelin synthesis; diphtheria toxin is also used to demyelinate nerves in the research laboratory setting.[20]

Immune-mediated

  • Guillain-Barre syndrome (GBS) refers to a rapidly progressive, often predominantly motor, polyneuropathy. It often occurs within 1 to 3 weeks of a respiratory or gastrointestinal illness. There are demyelinating and, less commonly, axonal variants. GBS can mimic other disorders and can present atypically.[21] One variant, Miller Fisher syndrome, presents with areflexia, ophthalmoplegia, and ataxia; it may be preceded by infection with Campylobacter jejuni or Haemophilus influenzae, and patients may have anti-GQ1b IgG antibodies.[22]

  • Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated neuropathy in which weakness is usually the prominent presenting symptom. It develops subacutely over the course of weeks to months. By convention, the symptoms must have progressed or relapsed for longer than eight weeks.[23] CIDP may occur with other medical diseases, such as monoclonal gammopathies, HIV, diabetes mellitus, central nervous system demyelination, or inflammatory bowel disease.

  • Connective tissue disorders, such as Sjögren's syndrome and systemic lupus erythematosus (SLE), are associated with polyneuropathy, which may be the initial presenting symptom.

  • Coeliac disease and gluten sensitivity are associated predominantly with sensorimotor axonal peripheral neuropathy.[24][25]

Monoclonal gammopathy

  • A minority of patients with monoclonal gammopathies (such as multiple myeloma, monoclonal gammopathy of undetermined significance, heavy chain disease, plasmacytoma, and Waldenstrom's macroglobulinaemia) develop a symmetric sensorimotor polyneuropathy. Patients with IgM gammopathies usually have more sensory ataxia and nerve demyelination than patients with IgA and IgG gammopathies. Approximately 50% of patients with IgM gammopathy demonstrate anti-MAG/SGPG antibodies, which are closely associated with demyelinating polyneuropathy.[26]

  • Familial and primary amyloidosis are associated with slowly progressive distal sensorimotor polyneuropathies.[27] Often, the small-diameter sensory and autonomic fibres are particularly affected.

Critical illness polyneuropathy

  • Patients with sepsis and multiple organ failure may develop a rapidly progressive polyneuropathy. Critical illness polyneuropathy is often first suspected when there is difficulty weaning a patient from ventilatory support. Critical illness myopathy may also be present.

Renal failure

  • Uraemic polyneuropathy is usually only seen in patients with serum creatinine levels of 442 micromol/L (5 mg/dL) or higher. Usually the polyneuropathy is slowly progressive, although rapidly progressive uraemic polyneuropathies have been described.

Paraneoplastic

  • A sensorimotor polyneuropathy which is most commonly associated with small cell lung cancer (including anti-Hu [ANNA-1] antibodies associated with small cell lung cancer).[28] May also be associated with lymphomas and other haematological malignancies, and breast, cervical, and ovarian cancer.

Nutritional deficiencies

Thiamine deficiency

  • The polyneuropathy is often associated with severe burning dysaesthesias. Progression is usually subacute or chronic, but in severe cases, the symptoms may progress over a few days. Alcohol-use disorder and prior bariatric surgery are risk factors.

Pyridoxine (vitamin B6) deficiency

  • Occurs with certain medicines (isoniazid and hydralazine), chronic peritoneal dialysis, or alcohol-use disorder; manifestations include polyneuropathy.

  • Toxicity may develop with excess iatrogenic repletion or over the counter supplementation.

Vitamin B12 deficiency

  • The polyneuropathy is usually associated with a myelopathy, the most severe form of which is subacute combined degeneration of the spinal cord. Patients may present with upper extremity symptoms.

  • Risk factors include chronic gastrointestinal (GI) illness and GI surgery, both of which are associated with malabsorption; advancing age; pregnancy; adherence to a vegan diet; long term use of certain medications, such as metformin, proton-pump inhibitors, and anticonvulsants.[29][30][31][32][33]

  • Pernicious anaemia is an autoimmune disorder affecting the gastric mucosa with impaired absorption of dietary cobalamin (vitamin B12) resulting in B12 deficiency.[34]

Other nutritional deficiencies

  • Vitamin E and copper deficiency have been associated with polyneuropathies.

Toxin or drug induced

  • Ethanol-polyneuropathy, associated with alcohol-use disorder may be caused by direct toxicity of ethanol on the nerve and/or concomitant nutritional deficiencies.

  • Pharmaceutical drugs may cause polyneuropathy. Chemotherapeutic agents used to treat malignancy, especially vinca alkaloids, platinum analogues, and taxols, are commonly responsible. Other pharmaceutical agents implicated include antibiotics such as dapsone, isoniazid, nitrofurantoin, and fluoroquinolones.[35][36] Amiodarone, colchicine, phenytoin, statin medicines, and thalidomide may also cause polyneuropathy.

  • Heavy metals that can cause polyneuropathy include arsenic, lead, thallium, and mercury. Other toxins include acrylamide, carbon disulfide, methylbutyl ketone, and triorthocresyl phosphate.

Genetic

  • Charcot-Marie-Tooth neuropathy refers to a large heterogenous group of hereditary polyneuropathies. Inheritance may be autosomal dominant, autosomal recessive, or X chromosome-linked. Axonal and demyelinating forms exist.

  • Hereditary amyloidosis with transthyretin (hATTR) mutations affects the peripheral nerves, and the heart and kidneys. Early recognition is important because of the increasing availability of treatment options.[37][38]

  • Adrenomyeloneuropathy, Fabry's disease, Refsum's disease, and Tangier's disease may also be associated with polyneuropathies.

  • Acute intermittent porphyria causes a predominantly motor peripheral neuropathy with marked upper extremity involvement.

Idiopathic

An idiopathic (or cryptogenic) polyneuropathy is a diagnosis of exclusion. Despite thorough investigations, 20% to 50% of patients with polyneuropathies presenting to academic centres fall into this category.[12][39][40] Patients are usually over 40 years of age and the polyneuropathy typically progresses very slowly.

Neurological mimics

Neurological conditions that can mimic the signs and symptoms of polyneuropathy include cauda equina syndrome, mononeuritis multiplex, multiple lumbosacral radiculopathies, or lumbosacral plexopathies.

  • Cauda equina can occur as a result of spinal trauma, vertebral compression fracture, disk herniation, spinal stenosis, primary or metastatic spinal tumour, or infection. The nerve root damage may be acute, subacute, or chronic and usually occurs due to direct compression, infiltration, or compromise of the vascular supply.

  • Mononeuritis multiplex is a multifocal neuropathy with a distinctive clinical presentation of progressive motor and sensory deficits in the distribution of specific peripheral nerves. It is most often a result of vasculitis, which may be either systemic or isolated to the nerves. Less commonly, it results from hypersensitivity reactions to drugs or infections, sarcoidosis, direct infiltration by tumour, or as a consequence of direct viral or bacterial infection of the nerves.

  • Radiculopathies can cause sensorimotor deficits and lower motor neuron signs in a dermatomal/myotomal pattern, typically due to degenerative disk disease or spinal osteophytes. When they occur in multiple adjacent and bilateral spinal levels, adjacent dermatomal/myotomal deficits appear confluent and can mimic polyneuropathy.

  • Plexopathies (i.e., lesions of the lumbosacral plexus) present similarly to unilateral adjacent radiculopathies. More rarely they may occur bilaterally. Notable aetiologies include diabetic neuralgic amyotrophy and compression/invasion by tumour, sarcoidosis, abscess/infection, or haematoma in the retroperitoneal space.

Use of this content is subject to our disclaimer