For most patients with distal symmetric polyneuropathy the sensory symptoms overshadow the motor symptoms. Initial tests to order include full blood count (FBC); erythrocyte sedimentation rate (ESR), fasting glucose level and cholesterol panel; thyroid-stimulating hormone (TSH); vitamin B12 levels with metabolites; hepatitis, HIV, Lyme, and syphilis serologies; antinuclear antibodies; and serum and urine protein electrophoresis with immunofixation. Electrodiagnostic testing should be considered in the initial work-up particularly if the aetiology is unknown.

Historical considerations

  • Numbness, impaired co-ordination, and balance problems reflect sensory nerve fibre disease. Balance is worst in situations where vision is impaired, such as shampooing the hair in the shower or in low-light conditions.

  • Dysaesthesias may include tingling, burning, aching, swelling, tightness, formication, and/or electric shocks in the distal lower extremities. These symptoms typically present symmetrically in the toes or feet. Over time the sensory symptoms ascend proximally up the legs. If the symptoms extend to the knee level, the patient may report tingling or numbness in the fingertips.

  • Motor symptoms include weakness, which is usually distal. In severe polyneuropathies, the patient may develop bilateral foot drop.

  • Dizziness upon standing, erectile dysfunction, urinary hesitancy, constipation or diarrhoea, early satiety, and sweating disturbances suggest an autonomic neuropathy.

  • Past medical history requires careful review because polyneuropathies are common manifestations of systemic illness. Patients with underlying systemic diseases, such as diabetes, renal failure, and amyloidosis, can be presumed to have their polyneuropathy caused by the underlying condition, usually as a later manifestation. It may be reasonable to perform a brief workup of other treatable neuropathies which may present comorbidly.[31]

  • A family history of high foot arches or hammertoes increases the possibility of Charcot-Marie-Tooth neuropathy.

  • Asking about the patient's occupation and hobbies may reveal an exposure to a known neurotoxin.

  • Medicines and supplements need to be carefully reviewed because many pharmaceutical drugs (particularly chemotherapeutic agents) may cause a polyneuropathy.

  • Most polyneuropathies develop chronically. Rapidly progressive polyneuropathies have a much shorter list of diagnostic possibilities. Polyneuropathies evolving over hours to days include toxin induced neuropathies (e.g., diphtheria, arsenic), Guillain-Barre syndrome (GBS), and porphyric neuropathy. Immune-mediated neuropathies, paraneoplastic neuropathies, nutritional and toxic neuropathies may present subacutely (weeks-to-months).

Physical examination

General physical findings:

  • Erythema in sun-exposed areas suggests systemic lupus erythematosus (SLE)

  • Purpuric rashes and ulcers suggest a vasculitic neuropathy

  • Transverse white (Mee) lines in the nails may occur in arsenic or thallium poisoning

  • Pes cavus and hammer toes may be seen in association with Charcot-Marie-Tooth neuropathy. Consider inspecting the feet of relatives of the patient if they are also present at the appointment.

  • Atrophy of the distal musculature, particularly the calf and shin, causing a 'stork' or 'champagne bottle' appearance, might be seen in Charcot-Marie-Tooth neuropathy.

Neurological examination findings:

  • Atrophy of the intrinsic foot muscles and distal weakness.

  • Impaired temperature and pinprick sensation distally suggests loss of small-diameter sensory fibres.

  • Impaired vibratory sensation and proprioception distally suggests loss of large-diameter sensory fibres.

  • Symmetrically reduced or absent reflexes distally. Asymmetrical reflexes should raise concern for a radiculopathy or multifocal neuropathy (e.g., vasculitic neuropathy). Brisk reflexes may suggest a myelopathy. Asymptomatic older patients may have absent ankle jerks and increased sensory thresholds for warmth, vibration and cooling.

  • Trophic skin changes include dry cracked skin, decreased or increased sweating, loss of hair, rubor, callus formation, and ulceration especially in the setting of impaired sensation.[32] Use of sweat detection pads is not recommended.[33]

  • An abnormal Semmes-Weinstein 5.07/10g monofilament test may increase suspicion for a large fibre neuropathy in diabetic patients, but this should not be used as the sole method for establishing a diagnosis.[34]

Laboratory tests

The history, physical examination, and electrodiagnostic testing should direct laboratory testing. Unfortunately, the physician is often faced with a generic distal sensorimotor polyneuropathy and an unrevealing medical history. There are different approaches to the testing algorithm in this situation.[35][36][37][38][39]

Initial testing:

  • FBC, ESR, TSH.

  • Fasting glucose level and cholesterol panel.

  • Vitamin B12 levels with metabolites.

  • Serum protein electrophoresis with immunofixation, if there is suspicion for monoclonal gammopathy.

  • Hepatitis B and C, HIV, Lyme, and syphilis serologies.

  • Antinuclear antibodies (including SS-A and SS-B), extractable nuclear antibodies.

  • Nerve conduction studies and needle electromyography.

Subsequent testing:

  • If a fasting glucose level is normal, consider a 2-hour oral glucose tolerance test. Impaired glucose tolerance has been implicated as a cause of distal polyneuropathies.

  • In cases of a low or borderline-low B12 level, a methylmalonic acid level should be checked. An elevation of the methylmalonic acid level suggests impairment of B12-dependent metabolic pathways. The sensitivity of methylmalonic acid testing is increased in combination with elevated homocysteine.[22]

  • In cases of gastrointestinal malabsorption, vitamin E and copper levels may be helpful.

  • Measurement of serum pyridoxal phosphate is used to assess for vitamin B6 deficiency or toxicity.

  • In patients with an exposure history, checking heavy metal levels is advisable.

  • Commercial testing for some of the genetic neuropathies (Charcot-Marie-Tooth neuropathy) is available. The diagnostic yield is higher for the demyelinating than axonal genetic polyneuropathies.

  • Cerebrospinal fluid (CSF) analysis may be helpful in the evaluation of suspected inflammatory and/or rapidly progressive neuropathies. In GBS and chronic inflammatory demyelinating polyradiculoneuropathy, CSF is typically acellular with increased levels of protein (albuminocytologic dissociation).

  • Very long chain fatty acids (in suspected adrenomyeloneuropathy) and serum lactate and pyruvate (in suspected mitochondrial neuropathy).

  • Serum antibodies to anti-nerve and antiganglioside antigens may be found in paraneoplastic and other immune-mediated neuropathies. Commercially available tests include anti-Hu (ANNA-1), anti-Ri (ANNA-2), anti-CV2/CRMP5, and anti-Yo (PCA-1) antibodies to investigate paraneoplastic neuropathies. Tests for anti-MAG/SGPG, sulfatide, GM-1, GD1b, and GQ1b antibodies may help in the investigation of other immune-mediated neuropathies. Testing for these antibodies is generally reserved for unexplained severe or rapidly progressive polyneuropathies.

  • Anti-Ro (SS-A) and anti-La (SS-B) antibodies in suspected Sjögren's syndrome (dry eyes, dry mouth, angular cheilitis) or SLE (arthritis, butterfly rash, hepatomegaly, splenomegaly).

  • Urine protein electrophoresis with immunofixation may be considered in addition to serum protein electrophoresis in the workup of a monoclonal gammopathy.[40]

  • Autonomic testing can be used to diagnose autonomic neuropathy. Cardiovagal, adrenergic, and postganglionic sudomotor function can be assessed.[41]

Electrodiagnostic testing

Nerve conduction studies and electromyography help to confirm the clinical diagnosis and determine whether the neuropathy is primarily axonal or demyelinating. They provide important information including degree of demyelination present, pattern of nerve involvement, neuropathy chronicity and severity. These tests should be considered in the initial diagnostic work-up particularly when the cause of the neuropathy is unknown.

If the electrodiagnostic study reveals a demyelinating polyneuropathy, specific aetiologies should be considered. These include GBS, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), monoclonal gammopathies, and certain hereditary neuropathies.

Skin and nerve

Skin biopsy is increasingly used to aid the diagnosis of polyneuropathy, particularly small-fibre polyneuropathy (i.e., confirm decreased density of intra-epidermal sensory fibres), because morbidity is lower compared with nerve biopsy. It is particularly useful in the setting of convincing symptoms and normal electrodiagnostic testing, which is typical of isolated small-fibre disease.[36] Skin biopsy can also help to distinguish between multifocal and length-dependent neuropathies.

Nerve biopsies are generally reserved for rapidly progressive and asymmetric polyneuropathies. Vasculitis, sarcoidosis, giant axonal neuropathy, leprosy, Tangier's disease, tumour infiltration, and amyloidosis may be diagnosed by nerve biopsy. It can be useful in atypical CIDP. A sensory nerve (usually the sural) is biopsied to prevent unnecessary morbidity. Concurrent biopsy of nerve and muscle may be of benefit in selected scenarios.[42] Nerve biopsy has a very low diagnostic yield in typical distal symmetric polyneuropathy and is usually not indicated in the evaluation of such cases.

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