Metabolic Neuropathy Clinical Presentation

Updated: Jul 20, 2021
  • Author: Emad R Noor, MBChB; Chief Editor: Nicholas Lorenzo, MD, CPE, MHCM, FAAPL  more...
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Symptoms in metabolic neuropathy can reflect sensory, motor, or autonomic involvement.

  • Patients usually complain of tingling and numbness (ie, paresthesias) and painful dysesthesias, worse at night. Motor and autonomic complaints are less common. Classifying the involvement of peripheral nerves is useful. Classification of metabolic neuropathy by topographic involvement, modified from Thomas and Tomlinson, [16]  is as follows:

    • Symmetric polyneuropathies

      • Sensory or sensorimotor polyneuropathy

      • Autonomic neuropathy

    • Focal and multifocal neuropathies

      • Entrapment neuropathies

      • Cranial neuropathy

      • Radiculopathy/plexopathy

      • Asymmetric lower limb motor neuropathy

    • Mixed forms

    • Symptoms of metabolic neuropathy according to this classification are as follows:

      • In symmetric polyneuropathy, initial symptoms begin insidiously and are most prominent distally in the lower extremities. Sensory disturbances exhibit a typical "length related pattern," with involvement of the toes that advances to the feet and legs.

      • The upper limbs are affected more rarely; however, when upper limbs are involved, symptoms develop in the same pattern, with involvement of the fingers spreading to the hands and forearms in a glovelike pattern.

      • In advanced stages, sensory symptoms may involve the anterior part of abdomen and trunk (hence the term "trunk neuropathy"), leading sometimes to the erroneous diagnosis of myelopathy. In extreme cases, the vertex of the head may be affected.

  • Sensory symptoms

    • Symptoms in most patients are mild in severity. However, when pain becomes severe, it presents with lancinating paresthesias and burning sensations that are typically worse at night.

    • Involvement of nerves by entrapment is common in metabolic neuropathies. Sensory symptoms such as pain and paresthesias along the distribution of the nerve and worsening at night are typical manifestations. The nerves most commonly involved are the median nerve (carpal tunnel syndrome [CTS]), ulnar nerve, and median and lateral plantar nerves (tarsal tunnel syndrome [TTS]). Multifocal sensory symptoms also suggest mononeuritis multiplex.

    • Pain described as "aching of the whole arm" is not uncommon in CTS. In TTS, paresthesias in the feet and pain are worse when walking. The presence of an entrapment neuropathy in children younger than 10 years is almost always suggestive of a rare metabolic disorder such as mucopolysaccharidosis or mucolipidosis or of hereditary neuropathy with liability to pressure palsy.

    • Metabolic neuropathy can cause injury to both large and small nerve fibers. Involvement of large fibers can cause alteration in vibration and proprioception and a sensory ataxia. Involvement of small fibers produces alteration in temperature perception or autonomic function. Small-fiber involvement can cause alteration in pain and temperature, leading to the so-called "pseudosyringomyelia."

  • Motor symptoms

    • Mild distal weakness is a common complaint, but patients also may experience proximal leg weakness, which is often asymmetric.

    • Asymmetric motor involvement in lower limbs is more common in patients with diabetes and is termed "amyotrophy."

    • Motor weakness can be asymmetric and focal, suggesting the diagnosis of plexopathy; when painful, it suggests the presence of radiculoplexopathy.

    • Involvement of cranial nerves can cause signs and symptoms such as diplopia, facial drooping, lacrimation, dysgeusia, and facial pain.

  • Autonomic symptoms: Clinical manifestations of autonomic neuropathy, modified from Thomas and Tomlinson [16] , are as follows:

    • Pupillary and lacrimal gland dysfunction

      • Miosis

      • Disturbance of dilatation

      • Argyll Robertson pupil

    • Cardiovascular disturbances

      • Tachyarrhythmias and bradyarrhythmias

      • Postural hypotension

      • Asymptomatic myocardial infarction

      • Sudden death

    • Thermoregulatory disorders

      • Distal anhydrosis

      • Gustatory sweating

      • Abnormal vasomotor responses to temperature changes

    • Alimentary tract disorders

      • Esophageal atony

      • Gastric and duodenal atony

      • Gallbladder atony

      • Diarrhea, constipation

      • Colonic atony

      • Anal sphincter weakness

    • Genitourinary disturbances

      • Bladder atony

      • Retrograde ejaculation

      • Impotence

      • Female sexual dysfunction

      • Disturbances of respiratory control

      • Charcot's neuroarthropathy [17]

      • Neuroendocrine dysfunction [18]



In the general examination, checking for signs of autonomic dysfunction as described above is important if metabolic diseases are present. Also, determination of skin color changes is key; look for signs of adrenal insufficiency or the syndrome of polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS). For signs of diabetic neuropathy, refer to the article Diabetic Neuropathy.

Sensory findings

Symmetric distal sensory loss suggests polyneuropathy.

Asymmetric hypoesthesia in distal territories of multiple nerves suggests mononeuritis multiplex.

Allodynia is the perception that a sensory stimulus is painful.

Signs of entrapment include Tinel sign, in which percussion around the site of the median nerve in the wrist produces paresthesias in the first 4 digits, and Phalen sign, in which sustained flexion of the wrist causes paresthesias in the digits. These signs also may be triggered with percussion of the ulnar nerve at the wrist or elbow, at the fibular head (peroneal nerve entrapment), or at the posterior part of the internal malleolus (tibial nerve entrapment).

Altered perception of pain and temperature with a pseudosyringomyelia state suggests involvement of small fibers. Some patients experience loss of visceral pain sensation, which may manifest as painless myocardial infarction or loss of testicular sensation.

Foot ulceration is one of the most severe complications of diabetic neuropathy; it can lead to gangrene and result in the need for amputation.

Damage to large sensory fibers leads to loss of touch-pressure sensitivity, vibration and joint position sense, and tendon reflexes, with a resulting sensory ataxia. Patients may have postural instability, with sensory ataxia that is more prominent in lower limbs and with eyes closed (Romberg sign).

Motor findings

Mild distal weakness may be noted in patients with sensory polyneuropathy. If any metabolic condition is accompanied by moderately severe to severe subacute weakness, consider other diagnoses, including chronic inflammatory demyelinating polyneuropathy (CIDP). This entity is more common in patients with diabetes than in the general population.

Asymmetric motor neuropathy, which is subacute painful asymmetric lower limb (rarely upper limb) weakness, is another motor abnormality that has received several names, including motor neuropathy, diabetic myelopathy, diabetic amyotrophy, femoral neuropathy, Burns-Garland syndrome, diabetic polyradiculopathy, proximal diabetic neuropathy and, perhaps the most adequate, diabetic lumbosacral plexus neuropathy.

Double-crush phenomenon: Simultaneous compromise of nerve roots and peripheral nerves by entrapment can be found in metabolic diseases.

Cranial neuropathies

The most common finding in patients with diabetes is an isolated third nerve palsy without pupillary involvement. Less common is compromise of the sixth or seventh cranial nerve. These neuropathies are usually not painful and occur most commonly in elderly patients. Diabetes may involve the optic nerve and retina, causing diabetic retinopathy, which leads to blindness.

Peripheral neuropathies

Table 1. Symptoms and Signs of Peripheral Neuropathy* (Open Table in a new window)

Small-Fiber Sensory

Large-Fiber Sensory


Burning pain

Loss of vibration

Heart rate changes

Cutaneous allodynia

Proprioception loss

Postural blood pressure change


Loss of reflexes

Abnormal sweating

Lancinating pain

Slowed NCVs


Loss pain/temperature

Sensory ataxia


Foot ulcers


Abnormal ejaculation

Visceral pain loss



* Modified from Apfel, 1999. [19]


Uremic polyneuropathy is usually subacute, sensorimotor, distal, and more prominent in the lower extremities. It commonly is associated with muscle cramps and the restless leg syndrome.

The earliest finding in uremic neuropathy is loss of ankle jerks or elevation of the vibratory sensation threshold. Assessing neuropathic changes in uremia is challenging because they also may be related to other factors, such as diabetes, vasculitis, or nutritional impairment.

The most common mononeuropathy in chronic renal failure is CTS, but mononeuropathies of ulnar or femoral nerves may be caused by compression by fistulas or dialysis catheters. Multiple cranial nerve neuropathies also have been reported in uremia. Pardoxical heat sensation seems to be a common and early sign in uremic sensory neuropathy. [20]

Thyroid neuropathy

Entrapment neuropathy of the median nerve is the most common neuropathy associated with hypothyroidism. Compromise of the eighth nerve causing deafness is not uncommon. Multiple cranial nerve involvement is rare.

Polyneuropathy is usually subacute, sensory, and occurs in 31-65% of patients. Subclinical hypothyroidism also may present with peripheral nerve involvement.

Sensory complaints include painful dysesthesias in the hands and feet and radiating lancinating pains, occasionally suggesting nerve root compression. Examination findings may reveal distal glove-and-stocking sensory loss and ataxia.

Weakness is a common complaint, but it usually is related to myopathic involvement.

Hyporeflexia and delayed relaxation phase of the ankle jerk are common. Transient swelling on percussion of the skin (mounding phenomenon) may be observed.

Occasionally, hyperthyroidism may be associated with polyneuropathy. [21]

Neuropathy in chronic liver disease

Nonalcoholic chronic liver disease may be associated with an asymptomatic or mild sensory-motor demyelinating polyneuropathy in approximately 45-50% of patients.

Peripheral neuropathy also has been reported in primary biliary cirrhosis and following acute viral hepatitis.

Acute motor peripheral neuropathy similar to that of Guillain-Barré syndrome and associated with liver disease also has been documented.

Polyneuropathy in chronic obstructive pulmonary disease (COPD)

Several controversial reports describe mild polyneuropathy associated with COPD. Treatment of patients who have COPD with drugs that may affect peripheral nerves secondarily may help explain this association. A study done in 2010 compared COPD patients and healthy controls. All study participants were evaluated with standard motor and sensory nerve conduction studies. Peripheral neuropathy was found in 15% of COPD patients. [22]

Miscellaneous: Acromegaly and amyloidosis are associated more often with entrapment neuropathies and less commonly with peripheral neuropathy. Monoclonal gammopathies, such as cryoglobulinemia, monoclonal gammopathy of undetermined significance (MGUS), and myelin-associated glycoprotein (MAG)–associated gammopathy, can present with peripheral neuropathy.

Clinical features of MGUS

It is associated with the presence of monoclonal proteins in the serum. [23]

Amyloidosis, osteosclerotic myeloma, or related disorders are absent.

MGUS presents as a symmetric sensorimotor polyneuropathy that begins insidiously and progresses slowly over months or years.

It occurs especially in the fifth, sixth, and seventh decades of life.

Males are affected more commonly than females.

Paresthesias, ataxia, and pain may be prominent.

Cranial nerves are not affected.

Amyloid neuropathy (nonfamilial)

Progressive involvement of small-diameter fibers with loss of pain and temperature sensation is typical of amyloid neuropathy, but occasionally patients can develop large-fiber neuropathy as well.

It presents commonly as CTS or as a painful peripheral neuropathy. Initial symptoms of neuropathy are sensory, with more extensive involvement of the lower extremities. With time, motor symptoms develop and are more prominent in the lower limbs.

Occasionally, amyloid neuropathy may manifest as autonomic dysfunction with severe orthostatic hypotension, syncopal episodes, or sexual impotence.

In patients whose amyloidosis begins with neuropathy, the clue to the diagnosis may be involvement of the heart, bowel, or kidneys.

Porphyric neuropathy

Disorders of porphyrin metabolism are a rare cause of peripheral neuropathy. Only hepatic porphyrias are associated with neurologic disease.

Acute intermittent porphyria may be associated with attacks of acute motor neuropathy with mild sensory symptoms very similar to Guillain-Barré syndrome.

Attacks are precipitated by drugs like phenytoin and phenobarbital and may be accompanied by abdominal pain, confusion, and seizures.

Diabetic neuropathy and nutritional neuropathy

Diabetic neuropathy and nutritional neuropathy are discussed in detail in the following articles: Diabetic Neuropathy and Nutritional Neuropathy.



See the list below:

  • Common causes of metabolic neuropathy include the following:

  • Rare causes of metabolic neuropathy include the following:

    • Hyperthyroidism

    • Porphyria

    • Mitochondrial disorders

    • Adrenal insufficiency (rare reports of autonomic involvement)

    • Disorders of lipid or glycolipid metabolism (eg, Refsum disease, Fabry disease, abetalipoproteinemia, hypobetalipoproteinemia, Tangier disease)

    • Leukodystrophies with peripheral nerve involvement (adrenomyeloneuropathy, adrenoleukodystrophy, Krabbe disease)

  • Risk factors for metabolic neuropathy include the following:

    • Uncontrolled metabolic status

    • Hypertension, obesity, and smoking (for diabetic neuropathy)

    • Thalidomide has been found useful in treating multiple myeloma, whether in refractory forms, in first diagnosis patients, [24] during the induced-remission phase before autologous transplantation, or as maintenance therapy for responders. However, the most feared side effect is peripheral neuropathy, which inevitably causes even effective therapy to be suspended.



Patients with metabolic neuropathy can develop autonomic dysfunction and are at high risk to develop asymptomatic myocardial infarction and sudden death.

Patients with diabetes who have neuropathy can develop foot ulcers.