Peripheral neuropathy can be encountered by clinicians in a multitude of clinical settings: the patient with Guillain-Barré syndrome who presents to the ED, the patient with suspected carpal tunnel syndrome being referred to orthopedic surgery, the patient with diabetes seeing a primary care provider for new-onset paresthesias in the feet, or the patient following up with the oncology team about adverse medication reactions to chemotherapy (Figure 1). Given the number of systemic conditions with which peripheral neuropathy is associated, clinicians in all specialties need to understand the basic diagnostic principles of the condition.
Peripheral neuropathy is a common condition with diverse causes and varied clinical presentation. Due to its heterogeneous nature and the numerous ways to classify and define the condition, few epidemiologic studies have examined peripheral neuropathy as a whole.1 Available research suggests the prevalence of peripheral neuropathy is 2% to 8%.1-3 However, the actual prevalence of peripheral neuropathy may be greater. For example, Gregg and colleagues found that of the US population age 40 years and older, 14.8% had peripheral neuropathy; this number increased to 28.5% in those with diabetes.4 Differences between study results may exist based on the population examined and inclusion criteria.
CLASSIFICATIONS AND CAUSES
Peripheral neuropathy can be classified in many different ways and commonly is categorized based on the distribution of affected nerves. Although in the broadest sense, peripheral neuropathy refers to any disorder of the peripheral nervous system including plexopathy and radiculopathy, these generally are considered discrete entities from peripheral neuropathy.
This article focuses on disorders distal to the plexus. Table 1 identifies different distribution patterns of peripheral neuropathy and describes clinical features of each. Of these patterns, distal symmetric polyneuropathy (DSPN) is the most common.5 Diabetes is the most common cause of DSPN and the most common cause of peripheral neuropathy in the developed world.6,7 Other common causes of DSPN include vitamin B12 deficiency, alcohol use, inherited conditions, chemotherapy, chronic kidney disease, paraproteinemia, and thyroid disease.5,8 Of the mononeuropathies, carpal tunnel syndrome (median neuropathy at the wrist) is the most common, followed by cubital tunnel syndrome (ulnar neuropathy from compression at the elbow).5,6 Peripheral neuropathy also can be categorized by the type of nerve fiber affected (motor, sensory, autonomic), pathology (axonal versus demyelinating), and cause. Table 2 outlines some common and atypical causes of peripheral neuropathy.
Because peripheral neuropathy is associated with many conditions, treatment must be tailored to the underlying cause of the disorder. Some patients require aggressive immune therapy; others may be treated symptomatically. Unfortunately, determining the underlying cause of peripheral neuropathy can present a diagnostic challenge, and no clear universal diagnostic algorithm exists. Also, a patient's peripheral neuropathy can be multifactorial with multiple contributing causes, as in a patient with alcohol abuse and vitamin deficiencies, or a patient with diabetic polyneuropathy who develops carpal tunnel syndrome.9
HISTORY AND PHYSICAL EXAMINATION
A thorough history and physical examination will help clinicians classify the pattern of the patient's neuropathy, develop a reasonable differential diagnosis, and order appropriate diagnostic tests. Asymmetrical signs or symptoms are inconsistent with DSPN (Table 3) but may indicate another pattern of peripheral neuropathy such as mononeuropathy or mononeuropathy multiplex (Table 4).10
Sensory abnormalities alone do not necessarily indicate a diagnosis of peripheral neuropathy because central nervous system disorders, especially myelopathy, can cause sensory complaints. Literature shows that symptoms alone have relatively poor diagnostic accuracy in predicting polyneuropathy; signs are a better predictor.10 Additionally, multiple neuropathic symptoms are more accurate in predicting the presence of polyneuropathy than a single symptom, and multiple abnormalities on examination are more sensitive than a single abnormality.10 One study of patients with diabetes found that absent ankle reflexes were the most sensitive sign to detect neuropathy, and vibratory impairment was the most specific.11 Clinicians should look for multiple symptoms and signs to best support the diagnosis. Additional considerations about the history and physical examination include:
- Pay attention to family history. Because hereditary neuropathies are an important cause of peripheral neuropathy, obtain a comprehensive family history when working up a patient with peripheral neuropathy.7
- Be sure to inquire about toxin exposure and medications. Did the patient recently start a new medication that can be neurotoxic or does the patient have a history of significant alcohol use (Table 2)?
- What other significant medical history does the patient have? Pay special attention to conditions listed in Table 2. A patient may have a significant condition that has not been diagnosed, so be sure to look for findings on history and examination that may raise concern for one of these disorders.
- Clarify the onset and progression of the neuropathy. Was the onset acute (less than 4 weeks ago), subacute (4 to 12 weeks ago), or chronic (more than 12 weeks ago)?12 Has it rapidly progressed? Most neuropathies are chronic and develop over months or years, but those with more acute development may represent serious disease such as vasculitis or Guillain-Barré syndrome (GBS).6 In most patients with DSPN, symptoms start in the feet and move up the legs. Once symptoms reach the knee, patients also may notice symptoms in the hands. Symptoms developing in the hands and feet at the same time may raise concern for coexisting carpel tunnel syndrome or another pattern of neuropathy.13
- Perform an appropriate physical examination. Evaluate the patient's mental status, reflexes, cranial nerves, sensation, and motor system including gait. When doing a sensory examination, test different modalities such as light touch, pain sensation, temperature, vibration, and proprioception. Additionally, stay alert for signs of autonomic dysfunction and any signs that may point to underlying systemic disease that may be causing the neuropathy. The extent of physical examination required outside of the neurologic examination depends on patient presentation and the other diagnoses being considered.
- Rule out a central cause for sensory or motor abnormalities. Diseases of the central nervous system such as stroke, multiple sclerosis, and brain and spinal cord tumors also can cause sensory and motor symptoms that can mimic peripheral neuropathy, so stay alert for physical examination findings such as hyperreflexia or increased tone that may steer the differential toward a central process.14 In patients with evidence of lower and upper motor neuron dysfunction without sensory loss, consider the diagnosis of amyotrophic lateral sclerosis.15
Screening for peripheral neuropathy is prudent in asymptomatic patients at increased risk for peripheral neuropathy secondary to a systemic disease. Because only 10% to 15% of patients with diabetic neuropathy are symptomatic, annual screening for peripheral neuropathy is recommended for patients with diabetes.13 Multiple methods of screening exist, but the combination of testing vibration with a tuning fork and light touch with a monofilament is considered efficient, sensitive, and specific.13
Because the treatment for peripheral neuropathy must be tailored to the underlying cause, determining the cause is important when a patient presents with history and physical examination findings suggestive of peripheral neuropathy. No agreed-upon algorithm exists for evaluating the condition, and the cost of workup can be significant. Notably, substantial variation exists within and between provider types when working up DSPN.16 One study identified more than 400 patterns of testing in the initial evaluation of peripheral neuropathy.3 The study also found that Medicare expenditures in patients being evaluated for peripheral neuropathy rose substantially during the diagnostic period, with almost one-quarter of patients in the study receiving high-cost, low-yield MRIs.3 Another study found that 51% of patients underwent unnecessary investigations during evaluation of their chronic polyneuropathy.17 Considerations for various diagnostic studies used in the evaluation of peripheral neuropathy are discussed below.
Details of electrodiagnostic studies (such as nerve conduction studies and needle electromyography [EMG]) and their interpretation are beyond the scope of this article, but studies typically take 30 to 60 minutes to complete and can be uncomfortable for patients.12,18 These studies are very operator-dependent and should be performed by someone (such as a neurologist) with adequate experience interpreting the results. Although state laws vary regarding who may perform EMGs, this procedure typically is not in the scope of practice for physician assistants.
Although electrodiagnostic studies are considered sensitive and specific in defining polyneuropathy, fewer than half of all patients with suspected DSPN undergo them.19 These studies are limited in their ability to detect small-fiber neuropathy.10,14 The American Academy of Neurology (AAN) definition of DSPN states that the highest likelihood of polyneuropathy occurs with a combination of signs, symptoms, and abnormal electrodiagnostic studies, and a modest likelihood of polyneuropathy occurs with multiple signs and symptoms (when electrodiagnostic studies are not available).10
Given the sensitivity and specificity of electrodiagnostic studies, some clinicians and researchers favor routinely performing EMGs or nerve conduction studies in most patients with suspected DSPN and using the results to help guide further diagnostic studies.6,12,19-21 Not only can electrodiagnostic studies help establish the distribution pattern and involvement of motor and sensory fibers, they also can determine if the underlying pathophysiology is demyelinating or axonal and can differentiate peripheral neuropathy from myopathy or a neuromuscular junction defect.6,22 This information can help determine the underlying cause of the peripheral neuropathy.6 In some patients, such as those with multifocal motor neuropathy or chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), electrodiagnostic studies are crucial to making the diagnosis.18 In patients with mononeuropathies, electrodiagnostic studies are key in localizing the site of injury, and may reveal that a suspected mononeuropathy is actually due to mononeuropathy multiplex or associated with a more generalized neuropathy.6 Likewise, what appears on examination to be a DSPN may actually be revealed via electrodiagnostic studies to be mononeuropathy multiplex.12
Conversely, some research suggests that electrodiagnostic testing may be less helpful in diagnosing peripheral neuropathy or leading to management changes.8,17 One study found that inexpensive and simple blood tests for diabetes, thyroid dysfunction, and vitamin B12 deficiency allowed neurologists to identify a new cause for a patient's DSPN about 15% of the time; more expensive testing such as electrodiagnostic studies and MRIs rarely led to a change in management.8 Other studies suggest that electrodiagnostic testing results in diagnosis and management changes more frequently.19,21 Thus, even among neurologists, no universal approach exists to using EMGs and nerve conduction studies in the workup of peripheral neuropathy. Some clinicians prefer to order targeted laboratory studies first and then consider further testing if no underlying condition is found and the patient's symptoms persists.2,14 Although the role of EMGs and nerve conduction studies in patients with chronic neuropathy is not agreed on, clinicians seem to concur that they are vital in patients with acute neuropathies, motor-predominant neuropathies, asymmetrical or non-length-dependent neuropathies, mononeuropathy and mononeuropathy multiplex, genetic neuropathies, and severe or disabling neuropathies.12,13,18,23 When electrodiagnostic studies are performed, they should be considered an extension of the clinical assessment and do not replace a proper history and physical examination.18
Laboratory studies and imaging
No specific routine laboratory test can diagnose peripheral neuropathy, but tests can help screen patients with suspected peripheral neuropathy for a specific cause. The AAN recommends that screening laboratory tests be considered for all patients with polyneuropathy.7 Based on their evidence-based review, the tests that provide the highest yield of abnormality in evaluating DSPN are blood glucose, serum B12 with metabolites, and serum protein immunofixation electrophoresis.7 Specifically, in patients with DSPN, blood glucose was elevated in 11%, serum protein electrophoresis was abnormal in 9%, and B12 was low in 3.6%.7 Though the etiological role of impaired glucose tolerance in peripheral neuropathy is unclear, other tests for prediabetes, such as glucose tolerance tests, may be considered if blood glucose testing is not clearly abnormal.7
Serum protein immunofixation electrophoresis testing can help identify monoclonal gammopathies, which are more common in patients with polyneuropathy; abnormalities on a serum protein electrophoresis warrant further evaluation and possible referral to a hematologist.7,13,20 Clinical judgment will help guide when other laboratory tests are appropriate based on patient presentation (Table 5).
Routine cerebrospinal fluid (CSF) analysis with lumbar puncture generally has low diagnostic yield in patients with peripheral neuropathy, with the exception of those with suspected infectious neuropathy, neoplasm, or demyelinating polyneuropathy such as GBS or CIDP.6,7,20 Imaging of the brain and spinal cord typically is not needed in the diagnosis of isolated peripheral neuropathy. Although MRIs rarely lead to management changes when evaluating patients with DSPN, one study found that 23.2% of patients received an MRI of the brain and/or spinal cord during the workup of their peripheral neuropathy.3,8 Imaging of the brain or spinal cord should be considered in patients with physical examination findings consistent with central nervous system damage. Imaging such as skeletal radiographic surveys; chest radiography; or CT or MRI of the chest, abdomen, and pelvis may be useful in patients with suspected malignancy.6
New genetic information continues to shape the possible genetic tests available in hereditary neuropathy. Of the hereditary neuropathies, the demyelinating form of Charcot-Marie-Tooth (CMT) disease is most prevalent, and most patients with this condition have a duplication of the PMP22 gene (CMT1A).7 CMT2 (axonal CMT) is most commonly caused by MFN2 mutations.7 The AAN recommends genetic testing to accurately diagnose hereditary neuropathies, with initial genetic testing guided by clinical phenotype and inheritance pattern as well as electrodiagnostic features.7 Genetic testing can be expensive and picking the correct genetic test may not be straightforward: phenotypes can vary within the same family and different genetic mutations can present with a similar phenotype.7 Therefore, it is reasonable to refer patients with suspected hereditary neuropathy to a neurologist who can perform electrodiagnostic testing and the indicated genetic testing based on clinical features and electrodiagnostic results.
Autonomic testing, nerve biopsy, and skin biopsy
According to the AAN evidence-based review, autonomic testing should be considered as part of the evaluation of patients with polyneuropathy, particularly patients with suspected autonomic neuropathy or distal small-fiber sensory polyneuropathy.24 Some conditions associated with autonomic neuropathy include diabetes, GBS, alcohol abuse, and amyloidosis.14 The multiple ways to test for autonomic function include tilt-table testing, heart rate variability testing, thermoregulatory sweat testing, and skin vasomotor reflex testing.24
Nerve biopsy should not be performed as part of the standard workup for peripheral neuropathy but may be useful in certain clinical situations, such as in patients with suspected amyloid neuropathy, vasculitis, or atypical forms of CIDP.24 The sural nerve is the most common site to use.6 Nerve biopsy also may be helpful in patients with tumors, other inflammatory disorders such as sarcoidosis, infectious disease such as leprosy, or when CMT cannot be confirmed by other methods such as genetic testing.6,24 Skin biopsy is increasingly being used when evaluating peripheral neuropathy. Skin biopsy typically involves taking a punch biopsy from the leg and is particularly useful in diagnosing small-fiber sensory neuropathy.24
PUTTING IT ALL TOGETHER
Although researchers and clinicians have varying approaches to the order of diagnostic testing when working up a patient with peripheral neuropathy, most methods emphasize the importance of the history and physical examination in considering studies ordered. Use data gathered from the history and physical examination to localize the dysfunction to the peripheral nerves, categorize the distribution of the peripheral neuropathy, and assess which nerve fibers are likely affected. Also, review other etiologic clues discovered during the history and physical examination; these will be key in shaping the differential diagnosis and appropriate workup.15 For example, although most neuropathies are mixed, a purely motor neuropathy may raise concern for multifocal motor neuropathy.12
Neurologists play an important role in diagnosing and treating patients with peripheral neuropathy.8 However, it may not be feasible for every patient to be referred to a neurologist given expense and travel considerations. Clinicians must be alert in looking for alarm signs that warrant immediate referral to a neurologist. Neurologists are best equipped to carry out special testing such as EMGs and nerve conduction studies, genetic testing, nerve and skin biopsies, and specific antinerve antibodies. For patients with mild, sensory-predominant, length-dependent peripheral neuropathy, specialty consultation may not be required.13 Situations that warrant referral to a neurologist or neuromuscular specialist include:5,13
- Symptoms are motor or autonomic predominant
- Symptoms are rapidly progressive or acute/subacute in onset
- Peripheral neuropathy is severe and affects the patient's activities of daily living
- Hereditary neuropathy is suspected
- Non-length-dependent, asymmetric, or multifocal pattern
- Cause is unclear or clinical uncertainly exists about appropriate treatment.
These recommendations are not meant to deter referral to neurology in other appropriate situations based on a clinician's clinical acumen. Concern for diagnoses such as GBS, vasculitis, or other acute neuropathies requires urgent evaluation and treatment. If a patient presents with DSPN and does not meet any criteria for immediate referral to neurology, ordering targeted laboratory examinations and diagnostic testing may be reasonable based on patient presentation.
In the event of a nonurgent referral to neurology, consider some first-line screening laboratory tests as discussed previously if the patient cannot be seen quickly. Remember that laboratory results cannot be interpreted in isolation, and a patient can have more than one cause of peripheral neuropathy. For example, up to 10% of patients with diabetes may have an alternative cause contributing to neurologic deficits.13 In particular, consider an alternative cause of peripheral neuropathy in patients with diabetes when the patient has no evidence of retinopathy or nephropathy.13 When the cause of peripheral neuropathy is unclear, particularly when the question of the cause may affect treatment, refer the patient to neurology for further evaluation. About 25% of the time, no clear cause is discovered after thorough evaluation of chronic polyneuropathy; most of these idiopathic chronic neuropathies are mild with predominant sensory involvement.6,25 Some of these patients may have small-fiber peripheral neuropathy.6 When initial laboratory testing is normal, follow the patient and treat symptomatically in the absence of red flags or progression.20 However, patients with progression or any concern for a serious diagnosis should be referred to neurology.
Because many conditions cause peripheral neuropathy, no one approach to diagnosis will work for every patient. Ordering every possible test is seldom the right course of action.21 The extent of diagnostic testing required should be driven by the data gathered from a thorough history and physical examination, and clinicians should rule out findings that suggest an underlying central cause. Finally, clinicians should recognize situations where referral to neurology or more urgent evaluation is warranted.
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