Peripheral polyneuropathy: evaluation and differential diagnosis

Author(s): Karen Barr, MD

Originally published:07/17/2013

Last updated:07/17/2013



Disease of multiple peripheral nerves. It may involve the cell body, axon, myelin sheath, or a combination of all nerve segments.


There are many causes of polyneuropathy. A rehabilitation medicine physician may diagnose a peripheral polyneuropathy, determine the cause, extent, severeity, prognosis, and treatment options. A thorough history and physical exam determines the key features of the condition and electrodiagnostic testing, including nerve conduction studies, together with electromyography, confirms and further characterizes the disease. Further investigation may include serologic tests, genetic testing, and nerve biopsy, among other tools. A comprehensive list of all of the causes of peripheral neuropathy is much beyond the scope of this article. However, some broad categories with commonly occuring examples are listed below.

Systemic disease: Common causes include diabetes mellitus, renal disease, and liver disease.

Vitamin deficiencies: A result of poor nutrition and poor absorption: examples are B-12, thiamine, vitamin D, and vitamin E deficiency.

Toxins: Medications (chemotherapies), alcohol, heavy metals and hexacarbons.

Infectious diseases: HIV, Lyme disease, and leprosy.

Autoimmune conditions: Rheumatologic disease, vasculitis, Sjogren’s syndrome, sarcoidosis, and Crohn’s disease. Autoimmune dysfunction is also the cause of inflammatory polyradiculoneuropathies such as AIDP (acute inflammatory demyelinating polyneuropathy, also called Guillain-Barre syndrome) and CIDP (chronic inflammatory demyelinating polyneuropathy)

Endocrine: Hypothyroidism

Paraneoplastic: Either as an isolated problem, or part of widespread neurological dysfunction that includes both the central nervous system and peripheral nerve. The most common cancer in which paraneopastic neuropathy is seen is small cell lung cancer. Others to consider include lymphoma and multiple myeloma.

Monoclonal gammopathy: Paraproteinemias, including monoclonal proteins and amyloidosis, are not uncommon, e.g., POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin abnormalities). This cause may account for as many as 10% of patients with peripheral neuropathy.

Inherited: The most common inherited neuropathy is hereditary motor sensory neuropathy, type 1 (HMSN-1, also known as Charcot Marie Tooth disease, or CMT) but other, much less common inherited diseases also cause neuropathy.

Idiopathic: For about 20-25% of patients with a peripheral neuropathy in a referral population, the cause of the neuropathy will not be found, despite a careful search.1

Epidemiology including risk factors and primary prevention

About 2% of the general population has a peripheral neuropathy.1 The epidemiology is specific to the cause of the neuropathy.


Most peripheral polyneuropathies involove degeneration of distal axons. This is caused by dysfunction within the cell body or within the axonal transport system that causes a dying back of the most distal parts of the nerves. These are the classic, symmetric, length-dependent patterns of disease one most commonly thinks of with the term polyneuropathy. “Neuronopathy” or “ganglionopathy” occurs when the cell body is the primary source of pathology. Common causes of cell body dysfunction include polio and amyotrophic lateral sclerosis, autoimmune conditions such as Sjogren’s, some chemotherapies, and some paraneoplastic syndromes. Because they are not length-dependent, the distrubution of symptoms is different, and symptoms are often very profound when compared to the more classically seen length-dependent axonopathies. Sometimes it is the myelin sheath, rather than the axon, that is dysfunctional. This often manifests as demyelination along the node of Ranvier at multiple sites on the nerve. Common neuropathies that involve the myelin more than the nerve axon include AIDP and HMSN-1. Some neuropathies involve both the myelin sheath and the axon even in the early stages; these include diabetic neuropathy and the neuropathy related to kidney disease. In later stages of disease and with most severly diseased nerves, all parts of the nerve are affected. For example, with significant axonal death, the myelin will not remain intact, and in cases of severe demyelination, axonal injury also occurs.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Because there are so many causes of peripheral neuropathy, it is difficult to generalize the disease course. Acquired demyelinating neuropathies likely have the most improved rates of recovery once adequately treated, whereas those with axonal loss or non-acquired causes such as hereditary causes are not likely to recover and will progress.

Specific secondary or associated conditions and complications

There is an increased risk for falls.2 Other risks include insensate skin, neurogenic bladder, gastrointestinal dysfunction and even cardiovascular complications that can occur, particularly in neuropathies that affect the autonomic nervous system. Those with acute to subacute decline, such as Guillain-Barre syndrome, warrant respiratory and often cardiac monitoring early in the course.



The diagnosis of peripheral neuropathy relies heavily on pattern recognition. Here are some key questions to consider.

1. Onset sudden or gradual and/or painful? Many length-dependent neuropathies have an insidious onset, and symptoms slowly worsen with time. A rapid onset of symptoms leads to a different differential diagnosis such as AIDP, vasculitis, or paraneoplastic syndrome.

2. Health changes prior to the time of onset of symptoms. Two common examples are critical illness neuropathy that begins during a prolonged ICU illness, and a neuropathy that comes on after starting a new medication.

3. Clarification of symptoms, including location, and whether or not there is involvement of any combination of motor, sensory, or autonomic nerve involvement. Most polyneuropathies have sensory complaints greater than motor weakness, and symptoms are more severe distally than proximally. If another pattern is seen, such as profound weakness early in the disease course, or weakness that is both proximal and distal, less common causes of neuropathy such as CMT or CIDP should be considered.

4. Concurrrent medical conditions. This history should include the type of condition, if it is well or poorly controlled, and the medications being used to treat it.

5. Risk factors and habits such as alcohol use, tobacco use, toxin exposures.

6. Family medical history: hereditary peripheral neuropathies, autoimmune conditions, diabetes, or inherited kidney disease.

Physical examination

The neurological exam includes:

1. Limb inspection: in a polyneuropathy, distal muscle atrophy and skin changes such as hair loss, nail changes, and shiny, thin skin are often evident. Altered biomechanic and decreased sensation may lead to skin breakdown or callus in the feet, so the feet should be closely examined.

2. Strength: is weakness symmetric, distal, proximal, or a combination? For some neuropathies, strength may be normal (pure sensory neuropathy), decreased distally (length-dependent neuropathy that affects both sensory and motor nerves) or cause both proximal and distal weakness (non-length-dependent neuropathy like AIDP).

3. Sensation: light touch, pin prick, vibration, joint position sense. Findings depend on neuropathy type. Loss of vibration and proprioception is often an early finding.

4. Reflexes: Symmetrically decreased or absent in a polyneuropathy. Brisk reflexes would suggest an alternative diagnosis which could mimic a neuropathy, such as cervical spinal cord compression.

5. Balance: single leg stance, Romberg, tandem gait.

6. Examination for competing diagnoses: Searching for multilevel radiculopathy may be informative, such as performing a straight leg raise or Spurling maneuver. Focused tests such as Tinel’s or Phalen’s signs looking for entrapment neuropathies. A vascular examination searching for evidence of claudication. Skin exam looking for hair loss, rashes, ulcers. Musculoskeletal examination for other causes of limb pain.

7.Gait: Observation of gait while a patient is focused on the task with toe and heel walking, if possible, looking for foot drop, steppage, ataxia, Trendelenburg patterns.

Functional assessment

Function may range from normal to total dependence, including ventilator dependence as in AIDP or critical illness neuropathy. Common impairments include balance and gait disturbances, falls, and increased fatiguability. Assessment for orthotics, gait aids, and wheelchairs may be necessary. Evaluation of the home environment and need for equipment such as shower chairs and grab bars in the bathroom, railings on stairs, and other adaptions is important. Acitivities of daily living deficits include impaired hand function, resulting in difficulty with fasteners, handwriting, eating, caregiving and homemaking. Sleep disturbances, depression, and loss of social roles require exploration.

Laboratory studies

Lab studies should be guided by the most likely diagnoses.

1. glucose tolerance test. Hb A1c is not a good screening test for this. About 25% of polyneuropathies of unknown cause are found to be from pre-diabetic patients with poor glucose tolerance, but not frank diabetes.

2. B-12 levels, but also its metabolite, methylmalonic acid with or without homocysteine, to capture borderline cases

3. Serum protein electrophoresis (SPEP) and immunoelectropheresis.

4. Other tests include heavy metal testing, inflammatory markers such as sedimentation rate, c-reactive protein, rheumatologic studies, and potentially genetic testing when available.3

Supplemental assessment tools

Large fiber polyneuropathy can usually be diagnosed by electrodiagnostic testing. The pattern of nerve involvement will point toward possible causes of the neuropathy, and assist in determining further testing and treatment options.

Is the pattern of involvement:

1. primarily motor or sensory?

2. symmetric or asymmetric?

3. proximal, distal, or diffuse?

4. primary axonal and/or demyelinating?

  • axonal: low amplitude responses without significant prolongation of distal latencies or slowing of conduction velocity, unless the axonal loss is very severe (less than 20 or 30% of normal values).
  • demyelinating: prolonged distal latency and slow conduction velocity. Conduction block and temporal dispersion indicate segmental demyelination. Proximal conduction studies such as F waves, H-reflex, and blink reflexes are often helpful.

A two-limb study typically answers the above questions and would include testing unilateral sural, median sensory and fibular,tibial, and ulnar motor studies if the examination is symmetric clinically. If the neuropathy is severe, or leg edema is severe and lower extremity studies are unobtainable, then proximal upper extremity studies may be useful. More extensive testing of the nerves of the hand may also be useful to rule out common compressive neuropathies such as carpal tunnel syndrome, which may coexist with a polyneuropathy. A third limb could be tested if asymmetry is present clinically and multifocal conditions are suspected.

Needle EMG should be performed to assess for signs of motor axon loss, degree of denervation, and pattern of involvment. This helps rule out competing diagnoses, such as the polyradiculopathy, myopathy, or other conditions that mimic polyneuropathy, especially in motor neuropathies.

Nerve biopsy: useful to help diagnose certain neuropathies. In amyloid neuropathy, nerve biopsy may reveals deposits. The diagnosis of leprosy may depend on nerve biopsy if there is not much skin involvment. Vasculitic neuropathies can often be confirmed by nerve biopsy. Inflammatory changes can confirm the diagnosis of CIDP by nerve biopsy. If genetic testing is not confirmatory, hereditary neuropathies can be evaluated by nerve biopsy. Most acquired, distal, symetric, length-dependent peripheral neuropathies do not require nerve biopsy since findings are not specific.5

Skin biopsy: diagnosis of small fiber neuropathies.

Autonomic testing: evaluate for suspected autonomic dysfunction.

Early predictions of outcomes

Outcome is dependent on the process that is causing the neuropathy. For example in Guillain-Barre syndrome, 14% of patients have severe persistent disability at one year, with those having an aggressive, fast onset of symptoms, and more extensive and axonal nerve involvement having worse prognosis.6 The presence of critical illness neuropathy increases hospital mortality and can lead to chronic disability.7 In general, neuropathies that show extensive axonal loss have a poor prognosis for full recovery.


See Part 2.


See Part 2.



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3.England JD, Gronseth G, Franklin GT, et al. Practice parameter evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence-based review). Mucle and Nerve. 2009;72:116-125.

4 Kuntzer T, Antoine JC, Steck AJ. Clinical features and pathophysiological basis of sensory neuronopathies. Muscle and Nerve. 2004:255-268.

5 Said, G .Indications and usefulness of nerve biopsy. Archives of Neurology. 2002;59(10):1532-1539.

6.Rajabally YA, Uncinic A. Outcomes and predictors in Guillain-Barre syndrome. J Neurol Neurosurg Psychiatry. 2012;83(7):711-718.

7.Latronico N, Bolton CF. Critical illness polyneuropathy and myopathy. Lancet Neurol. 2011; 10(10): 931-941.


Dumitru D. Electrodiagnostic Medicine. Philadelphia, PA: Hanley and Belfus; 1995.

Overell JR. Peripheral neuropathy: pattern recognition for the pragmatist. Pract Neurol. 2011; 11:62-70.

Author Disclosure

Karen Barr, MD
Nothing to Disclose

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