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EsaMervaala
MariAuranen

Polyneuropathies

Essentials

  • Usually symmetrical disease of (sensory and motor) peripheral nerves and/or the autonomic nerve system
  • The aetiology includes an agent causing damage to the peripheral nerves.
    • The most common causes of polyneuropathy are diabetes and alcohol, as well as vitamin B12 deficiency. Other causes are more rare.
  • When the aetiology is clear, the patient can be treated in the primary care clinic. If the cause remains unclear and the symptoms are rapidly progressing, referral to a specialty hospital is required.
  • In elderly people, especially in persons over 75 years of age, the degenaration of neurofibrils of peripheral nerves often causes symptoms of polyneuropathy. In such cases, further investigations are often not required, but instead it is advisable to focus on symptomatic treatment and on ensuring that mobility is preserved.
  • ENMG (electroneuromyography) is an essential diagnostic tool which can also be used for monitoring disease progress.
  • The type of neuropathy (axonal, demyelinating or mixed; sensory, motor or sensorimotor) may give hints about its aetiology.
  • Treatment is directed at the basic cause: successful treatment of an aetiological factor may halt the progress of polyneuropathy. Symptomatic medications, especially drugs for neuropathic pain are often needed.

Symptoms and signs

  • The most typical initial symptom is glove and stocking type sensory loss distally in limbs, often beginning from lower extremities.
  • As symptoms progress, neuralgias develop; often these are at their worst in the evening and during the night.
  • Sensory loss in feet easily leads to balance difficulties and impaired walking ability.
  • Typical signs include weakening of reflexes, especially in lower extremities, and the impairment of, at first, vibration sense and later other types of tactile senses (touch, sharp pain, postural sensation). Additionally, paraesthesias, sensation of pain through non-painful stimulus (allodynia) and hyperalgesia occur. Also muscular atrophy may develop.

Diagnosis

  • Diagnosis can be confirmed with ENMG Clinical Neurophysiology in Diagnostics. This will also provide information on the type and severity of the polyneuropathy.
  • In the diagnostics of small fibre neuropathy, examination of thresholds for hot and cold stimuli (QST = quantitative sensory testing) as well as punch biopsy of the skin to quantify the number of small nerve fibres are used.
  • The following tests can be performed in primary care: HbA1c, Basic blood count with platelet count, vitamin B12-TC2 (transcobalamin-bound), phosphatidylethanol, TSH, and plasma creatinine.
  • If the aetiology cannot be determined on the basis of the history Peripheral Neuropathies: Examination of the Patient and the initial tests, a neurologist should be consulted. Neurological consultation is also recommended in demyelinating neuropathy.
  • Further investigations are planned according to the type of neuropathy, and the extent of diagnostic investigations is considered individually for each patient. The aetiology will reman unknown in a large share of cases despite extensive examinations.
  • Further blood tests include, among others, serum protein fractions, coealiac screen test and anti-Borrelia antibodies.
  • Molecular genetic testing is available for targeted diagnostics of hereditary polyneuropathies (see Hereditary neuropathies below).
  • A suspicion of polyneuropathy that is associated with a storage disease and/or is rapidly progressing is an indication to proceed to nerve (n. suralis) and muscle biopsy.
  • In about 25% of patients in all age groups and in about 45% of patients over 55 years the aetiology remains unclear.

Toxic neuropathies

Alcohol polyneuropathy

  • The most common toxic neuropathy
  • Clinically confirmed in ca. 20% of alcoholics; in addition, ca. 30% are subclinical (i.e. abnormalities revealed only with ENMG)
  • Acute polyneuropathy develops during heavy drinking binges in the distal parts of the extremities, often first in the legs. Symptoms include severe hyperalgesia, erythema and occasional oedema, which may prevent walking.
  • Typical finding on ENMG is sensorimotor polyneuropathy. In mild cases, sensory symptoms (burning feet and painful paraesthesia) dominate, while more severe conditions include also motor impairment.
  • In chronic polyneuropathy, disease progression and recovery are slow.
  • Treatment consists of alcohol abstinence and vitamin B substitution Neurological Disorders and Alcohol.

Polyneuropathy caused by solvents and heavy metals

  • Solvents such as hexane in glues, MBK (methyl butyl ketone) in paints and shellacs, and acrylamide used for coating paper can cause polyneuropathy as a result of occupational exposure, and occasionally deliberate sniffing. Other causes are carbon disulphide and organophosphates.
  • Exposure to arsenic, lead, thallium, mercury, and gold can produce clinical polyneuropathy.

Drug-induced polyneuropathy

  • Many cytotoxic drugs (especially cisplatin, vincristine and taxanes) may cause peripheral neuropathy.
  • Polyneuropathies caused by nitrofurantoin and isoniazid are relatively common problems.
  • Disulfiram may cause a neuropathy which may be attributed to alcohol abuse.
  • Pyridoxine (vitamin B6) in large doses may cause polyneuropathy (sensory symptoms dominate). This may lead to diagnostic problems as vitamin B supplements have been prescribed for polyneuropathy patients without taking regard into the specific aetiology.
  • Other possible causes include statins, chloramphenicol, metronidazole and amiodarone.

Metabolic neuropathies

Diabetic neuropathy

Uraemic polyneuropathy

  • Common complication of renal failure that occurs in approximately 25% of the patients. Haemodialysis has a clearly resolving effect.
  • This condition differs from other metabolic neuropathies in that motor and sensory impairment are equally severe (i.e. sensory symptoms are not dominant).

Polyneuropathy associated with vitamin deficiency

  • Vitamin B12 deficiency (pernicious anaemia) is the most commonly encountered condition.
  • It is better to determine the biologically active form of vitamin B12 (B12-TC2) than the total concentration of vitamin B12.
  • Remember to ask about the patient's diet and consider the possibility of vitamin B12 deficiency e.g. if the patient follows a vegan diet.
  • B12 therapy partially resolves the symptoms in about a year's time.
  • Pellagra, which is caused by nicotine acid or tryptophan deficiency, has been found among alcoholics in Western countries. In addition, deficiency of pyridoxine (B6), thiamine (B1) or tocopherol (E) can on rare occasions cause polyneuropathy. Neuropathy following gastroplasty can be caused by a vitamin deficiency.
  • Coeliac disease may be associated with axonal polyneuropathy that is usually predominantly sensory.

Polyneuropathy associated with hypothyroidism

  • Sensory polyneuropathy is the most common peripheral nerve disorder associated with hypothyroidism.
  • Medication for hypothyroidism may completely resolve clinical neuropathy.

Polyneuropathy associated with acute porphyria

  • Clinical presentations include acute abdominal pain, psychiatric symptoms, and peripheral neuropathy.
  • The patient typically has an acute flaccid motor paralysis and absence of tendon reflexes.

Paraneoplastic polyneuropathy

  • In males, the condition is usually associated with lung cancer, in females, with breast cancer.
  • If subacute sensory axonal polyneuropathy is detected, look for signs of cancer.
  • In paraneoplastic neuropathies the protein concentration in the cerebrospinal fluid is often increased.
  • Motor neuropathy may occur in paraproteinaemias, leukaemias and myelomas.

Hereditary neuropathies

  • Hereditary neuropathies are among the most common hereditary neurological diseases.
  • Prevalence 1:2 500
  • Investigation of the family history is essential.
  • A major proportion of these neuropathies are inherited in an autosomal dominant manner.
  • Molecular genetic methods may be used in the majority of hereditary neuropathies.
  • Besides the diseases mentioned below there are other, rare sensory-motor or sensory neuropathies, e.g hereditary gelsolin amyloidosis that is part of the Finnish disease heritage.

Hereditary motor and sensory neuropathy (CMT diseases) Ascorbic Acid for the Treatment of Charcot-Marie-Tooth Disease

  • Type 1: demyelinating Charcot-Marie-Tooth disease (CMT1)
    • Muscle weakness accentuated in the peroneal region, distal muscle atrophy, and prominent plantar arch since childhood
    • The symptoms are of varying severity.
    • ENMG shows strongly dimished motor nerve conduction velocities.
    • The mode of inheritance is autosomal dominant; usually caused by duplication of the PMP22 gene.
  • Type 2: axonal Charcot-Marie-Tooth disease (CMT2)
    • Muscle weakness develops often later than in Type 1.
    • Deformities of the feet are also typical.
    • ENMG reveals axonal damage and chronic denervation.
      • There are a number of underlying genes; in Finland e.g. CHCHD10 and GDAP1 gene defect.
    • Diseases to be considered in differential diagnostics include e.g. distal myopathies and particularly tibial muscle dystrophy; in these conditions the nerve conduction velocities are normal Hereditary Myopathies.

Brittle nerve -syndrome

  • Recurrent pareses and paraesthesias caused by the brittleness of the myelin sheath
  • Reduced nerve conduction velocities especially in the areas of nerve entrapment
  • Autosomal dominant heritability; usually caused by deletion of the PMP22 gene

Polyneuropathies associated with immunological disorders

Acute polyradiculitis = Guillain-Barré-syndrome

  • Ascending muscle weakness and numbness develop acutely within a few days to a few weeks. If this condition is suspected, the patient must be referred to a hospital immediately as an emergency case Guillain-Barré Syndrome (Polyradiculitis).

Chronic inflammatory polyneuropathy

  • There are several types of chronic inflammatory polyneuropathies, demyelinating and axonal, with motor or sensory predominance. Diagnosis is based on ENMG and on laboratory and CSF tests as well as on imaging, done in specialist care.

Multifocal motor neuropathy

  • Multifocal motor neuropathy (MMN) is a rare immune-mediated disease usually manifesting itself as progressive and asymmetric muscle weakness in the extremities.
  • Diagnosis is primarily based on a typical clinical picture and on ENMG findings.
  • Factors supporting the diagnosis include an increased CSF protein concentration and serum anti-ganglioside antibodies.
  • Conduction block phenomenon is considered as the cornerstone in the ENMG findings; this refers to blocked conduction of nerve impulses outside the typical nerve entrapment sites due to demyelinating nerve damage.
  • In some cases it is difficult to differentiate MMN from a motor neuron disease.
  • The patients are referred to a neurologist. Regular intravenous immunoglobulin therapy (IVIG) usually alleviates symptoms Intravenous Immunoglobulin for Multifocal Motor Neuropathy.

Neuropathy associated with HIV infection

  • The initial symptoms in 10-30% of HIV patients originate either from the central or the peripheral nervous system.
  • Neuropathies of various kinds found in association with HIV infection and AIDS include:
    • Distal, painful sensory polyneuropathy
    • Multiple mononeuropathies
    • Progressive polyradiculitis (Guillain-Barré)
    • Chronic disorders of the Guillain-Barré-type.
  • In addition, many other viruses (cytomegalo, herpes, hepatitis B and C) may cause neuropathies.

Neuropathy in Lyme borreliosis

  • See Lyme Borreliosis (LB).
  • The most common symptom is painful meningoradiculitis.
  • Neuropathy is usually a subacute, sensorimotor polyneuropathy.
  • Facial paralysis, also in bilateral form, is the most common mononeuropathy Peripheral Facial Paralysis. Also other cranial nerves or peripheral nerves may be affected (e.g. peroneal paresis).

Polyneuropathy associated with paraproteinaemias

  • Benign paraproteinaemia or myeloma may be associated with a sensorimotor polyneuropathy caused by protein binding in the peripheral nerve.
  • If this condition causes significant symptoms, the treatment consists of immunosuppression (glucocorticoids or cytostatic drugs) or, in severe cases, plasmapheresis.

Polyneuropathies associated with vasculitis and systemic diseases

  • Neuropathies caused by vasculites often present with unilateral symptoms mainly in the lower limbs.
  • SLE can be associated with many types of neuropathies, a Guillain-Barré-resembling or a distal sensorimotor polyneuropathy.
  • In addition to mononeuropathies, Sjögren's syndrome can be associated with a distal sensorimotor polyneuropathy or sensory and small-fibre neuropathy.
  • MCTD (mixed connective tissue disease) or sarcoidosis can also be associated with neuropathies.

Treatment, prognosis and follow-up of polyneuropathies Immunosuppressive Treatment for Multifocal Motor Neuropathy, Corticosteroids for Chronic Inflammatory Demyelinating Polyradiculoneuropathy, Intravenous Immunoglobulin (Ivig) for Chronic Inflammatory Demyelinating Polyradiculoneuropathy (Cidp), Azathioprine, Interferon Beta-1a or Methotrexate for Chronic Inflammatory Demyelinating Polyradiculoneuropathy, Plasma Exchange for Chronic Inflammatory Demyelinating Polyradiculoneuropathy, Immunotherapy for Igm Anti-Myelin-Associated Glycoprotein Paraprotein-Associated Peripheral Neuropathies

  • The aetiology is of crucial importance in the treatment and prognosis. Treatment is directed at the basic cause.
  • Symptomatic medication to treat neuropathic pain (see Chronic Pain)
  • ENMG controls to monitor even progressive polyneuropathy should not be ordered too frequently because changes in ENMG develop after changes in clinical symptoms. The recommended interval between the studies is approximately 6 months.

Treatment of neuropathic pain Venlafaxine in the Treatment of Neuropathic Pain

  • In nociceptive pain, which is caused by damage in the tissue sensing the pain, the nerves themselves are healthy. Treatment directed at the cause relieves the pain, often with anti-inflammatory analgesics alleviates the pain.
  • Neuropathic pain indicates damage in the nerve tissue itself.
    • Aches, hyperalgesia, pain interfering with sleep: amitriptyline or nortriptyline, initially 10-25 mg per day (in the evening), increased over 2-3 weeks to up to 100 mg per day.
    • Alternative medications include pregabalin, gabapentin, and pain-relieving antidepressants of the SNRI class (e.g. venlafaxine and duloxetine).
    • Pain resembling electric shocks or shooting pain: carbamazepine up to 200 mg × 2-3 (dose increase 100 mg per 3 days)
  • See also Chronic pain Chronic Pain.

References

  • Hanewinckel R, van Oijen M, Ikram MA et al. The epidemiology and risk factors of chronic polyneuropathy. Eur J Epidemiol 2016;31(1):5-20. [PubMed]
  • Barrell K, Smith AG. Peripheral Neuropathy. Med Clin North Am 2019;103(2):383-397. [PubMed]
  • Freeman R. Autonomic Peripheral Neuropathy. Continuum (Minneap Minn) 2020;26(1):58-71. [PubMed]
  • Kaur D, Tiwana H, Stino A et al. Autonomic neuropathies. Muscle Nerve 2021;63(1):10-21. [PubMed]

Evidence Summaries ⬆