Introduction
Peripheral neuropathy is among the most common neurologic problems encountered by primary care clinicians, as it affects up to 8% of adults over the age of 55. Despite its frequency, however, peripheral neuropathy can be challenging to recognize and evaluate because of its many diverse forms and presentations. Distal symmetric polyneuropathy (DSP) is the most common form and is often encountered in the primary care setting as the most common systemic complication of diabetes mellitus.
The clinical presentation of neuropathy can include weakness, sensory abnormalities, and autonomic dysfunction. Accordingly, the primary care clinician must be comfortable using the neurologic examination—including assessment of motor function, multiple sensory modalities, and the deep tendon reflexes—to recognize and characterize neuropathy. Although the causes of peripheral neuropathy are numerous and diverse, careful review of the medical and family history coupled with limited, select laboratory testing can often efficiently lead to an etiologic diagnosis.
One-quarter to one-half of patients will remain idiopathic even after thorough workup, and at least one-fifth of patients will carry two or more risk factors. Therefore sound clinical reasoning is required in deciding how far to direct a workup in newly diagnosed patients. Moreover, the recommended testing can vary dramatically for other phenotypes of neuropathy (e.g., mononeuropathy multiplex). It is essential that one’s clinical approach to evaluating a patient with suspected neuropathy can identify these divergent patterns. In this chapter, we focus largely on the presentation and evaluation of DSP, but we also offer suggestions for recognizing and evaluating other presentations.
Disease-modifying therapies for neuropathy are limited at present. Most patients still benefit from counseling on lifestyle changes that can help them to avoid foot injuries and ulcerations and prevent falls. Many patients also require symptomatic treatment for neuropathic pain, including such options as gabapentinoids, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and sodium-channel blocking anticonvulsants.
Clinical Presentation
Peripheral nerves consist of sensory, motor, and autonomic fibers. There are accordingly numerous complaints that can prompt the clinician to consider neuropathy ( Table 19.1 ). Patients usually present with sensory signs or symptoms before motor or autonomic symptoms prevail. Sensory nerve fibers can be broadly divided into large-diameter fibers that mediate vibratory sensation and proprioception and small-diameter fibers that mediate pain and temperature sensation. Symptoms of neuropathy will vary based on the relative involvement of large fibers and small fibers; most, but not all, neuropathies affect both fiber types, often resulting in both negative (i.e., loss of sensation) and positive symptoms (e.g., pain, tingling). Neuropathic pain occurs in one-third of patients with peripheral neuropathy. Positive sensory symptoms include paresthesias—described as tingling, pins and needles, or feeling as if a limb is “asleep”—and dysesthesia—described as stabbing, bee stinging, burning, or sharp shooting sensations. Some patients will describe hyperesthesia, an accentuated sensation of tactile stimulation, or allodynia, the perception of normally nonpainful stimuli as painful. Patients with allodynia may describe intolerance to bedsheets overlying their feet or pain brought on by the breeze from a window fan. Patients with neuropathic pain often report that the pain is worst at night when they are trying to fall asleep. By contrast, pain on the soles of the feet that is worst with the first steps out of bed in the morning should prompt consideration of plantar fasciitis, an important entity in the differential diagnosis of painful neuropathy.
| Symptoms | Signs on Examination | |
|---|---|---|
| Motor | WeaknessCramps |
|
| Large fiber sensory |
|
|
| Small fiber sensory |
| Loss of pain and/or temperature sensation |
| Autonomic |
|
|
While patients do not often complain about negative sensory symptoms, it is important to recognize imbalance due to sensory loss and evaluate fall risk. On average, an increase in falls can be detected in patients with peripheral neuropathy 3 years before diagnosis. Patients usually cannot differentiate between motor and sensory symptoms when they describe gait dysfunction. It is not uncommon for patients to describe weakness when, in fact, a loss of proprioception is the primary deficit responsible.
Autonomic symptoms are often underrecognized but are common and can have a great impact on quality of life. The most common autonomic symptoms include manifestations of sweating and vasomotor dysfunction, such as coldness, burning, or flushing in the feet. Dry mouth, dry eyes, and dry skin are also common. Orthostatic intolerance, gastroparesis, constipation, diarrhea, neurogenic bladder, and sexual dysfunction can all occur and can be associated with disability and reduced quality of life. However, these are all potential targets for symptom management. Patients do not often intuitively connect these symptoms with their neuropathy, so asking about and identifying these symptoms proactively is critical. This will provide an opportunity to intervene and improve patients’ quality of life.
Rarely, autonomic symptoms may be the most prominent or only symptoms indicating neuropathy ( Table 19.2 ). This narrows the differential diagnosis of the underlying cause somewhat. Autonomic neuropathy is particularly common in patients with polyneuropathy associated with diabetes and can occur independently from sensorimotor neuropathy. Patients may occasionally present with pure parasympathetic failure, leading to vagal denervation of the heart with a resultant rise in resting heart rate and loss of heart rate variability or even exercise intolerance. Autonomic dysfunction in diabetic patients has been consistently associated with an increased risk of mortality; patients are at risk for arrhythmia, left ventricular dysfunction, and silent myocardial infarction.
| Differential for Autonomic Neuropathy | Differential for Acute Neuropathy |
|---|---|
|
|
| Differential for Mononeuropathy Multiplex | Differential for Motor-Predominant Neuropathy |
|---|---|
|
|
In taking a history from a patient, delineating the pace of progression is critical. When symptoms of neuropathy develop acutely, over days to a few weeks, the differential diagnosis is narrowed significantly ( Table 19.2 ). Hyperacute onset of symptoms (e.g., sudden wrist drop) in the absence of compression or trauma raises concern for a vasculitic process and merits urgent evaluation. Conversely, patients may not recognize longstanding symptoms or signs as being related to their presenting complaint. Asking about childhood clumsiness or poor athleticism, high arches, or ill-fitting shoes may reveal unrecognized signs of a chronic and perhaps hereditary neuropathy.
Cervical myelopathy and lumbosacral radiculopathy/lumbar spinal stenosis are two important considerations in the differential diagnosis of patients presenting with numbness, weakness, and/or gait dysfunction. The presence of neck pain, low back pain, radiating limb pain, and/or significant bowel or bladder dysfunction should prompt consideration of these alternatives, as these would be atypical of distal symmetric polyneuropathy.
Examining Patients with Suspected Neuropathy
Characterizing the Distribution of the Neuropathy
The examination of patients with symptoms that are concerning for peripheral neuropathy should focus on defining the anatomic distribution of findings and the extent of motor signs, sensory impairment, and absence of reflexes. The differential diagnosis for the causative process will vary based on these classifications. In a length-dependent process such as DSP, there is diffuse involvement of multiple nerves with symptoms and signs affecting the most distal segments first. This leads to the so-called stocking/glove distribution of findings. Symptoms or signs in the legs usually reach the knees or just above before symptoms or signs occur in the fingers. A non–length-dependent pattern and/or asymmetry may indicate a secondary process for which the differential diagnosis is different and the required workup changes.
Other common patterns include mononeuropathy, such as median neuropathy at the wrist (i.e., carpal tunnel syndrome), and radiculopathy, which is commonly caused by degenerative disease in the cervical or lumbosacral spine. Signs and symptoms will be restricted to the distribution of a single nerve, myotome, or dermatome in such cases.
The presence of multiple concurrent mononeuropathies—termed mononeuropathy multiplex—may suggest a vasculitic etiology ( Table 19.2 ). This can be seen in diabetes or systemic vasculitis, but sometimes patients develop peripheral nervous system vasculitis in isolation or before systemic involvement is evident. Other nonvasculitic acquired conditions (e.g., amyloidosis) or inherited conditions (e.g., hereditary neuropathy with liability to pressure palsies) can cause mononeuropathy multiplex, but due to the relatively rapid and progressive course and potentially irreversible neurologic disability, it is important to suspect and investigate for a vasculitic process early on. Usually, patients present with rather acute onset of pain in a single peripheral nerve or nerve root distribution followed by weakness shortly afterwards. If multiple nerves become affected over time, symptoms and exam findings become more confluent and can be challenging to distinguish from a length-dependent polyneuropathy. Even in such cases, a subacute onset, slight asymmetry of exam findings, and/or subtle non–length-dependent findings can serve as a clue and should not be ignored.
Modalities to Examine
In a patient with suspected neuropathy, examination should at least include assessment of motor function, sensory function, and the deep tendon reflexes. In addition to testing for specific muscle weakness, the motor examination should also identify the presence of muscle atrophy that can be seen in chronic neuropathy affecting motor fibers. Distal calf and extensor digitorum brevis muscle atrophy, hammertoes, and pes cavus (high-arched feet) are characteristics of a longstanding neuropathy, often seen in hereditary neuropathies ( Figure 19.1 ). When motor deficits are comparable to or greater than sensory deficits, demyelinating disorders such as chronic inflammatory demyelinating polyneuropathy (CIDP) or hereditary neuropathies must be considered ( Table 19.2 ). CIDP should also be considered if non–length-dependent motor or sensory deficits are identified, such as prominent proximal weakness.
The sensory examination should test both large fiber modalities (vibration and/or proprioception) and small fiber modalities (pain and/or temperature). Proprioceptive deficits can manifest as sensory ataxia, mimicking cerebellar dysfunction. The Romberg sign is an effective screening tool for sensory ataxia. The patient stands with their feet directly together and then closes their eyes; the patient must rely on sensory information alone to maintain balance. If the patient is steady with eyes open but sways and takes a step to steady themself with eyes closed, the test is positive.
Deep tendon reflexes may be diminished in a length-dependent pattern, with unobtainable ankle reflexes. Diffuse areflexia should prompt investigation for CIDP or hereditary neuropathy. Asymmetric reflexes—for example, if only one ankle reflex is absent—may suggest a superimposed mononeuropathy or radiculopathy. Accentuated deep tendon reflexes or extensor plantar responses are not seen in neuropathy; this finding would instead suggest a central nervous system disorder such as cervical myelopathy or vitamin B12 deficiency.
Isolated small fiber neuropathy is less common than typical DSP. Pain and allodynia are particularly common in patients with small fiber neuropathy. However, the only detectable exam abnormalities will be loss of pain and/or temperature sensation. Large fiber function will be normal, and reflexes will be preserved.
Screening for Neuropathy in Asymptomatic Patients
History alone may be insufficient to exclude a neuropathy in high-risk patients, such as those with diabetes. Many patients have only mild negative symptoms that go unnoticed but still put them at risk for injuries or foot ulcers. The lifetime risk of foot ulcers in patients with diabetic neuropathy, for example, is 15%–25%. The American Diabetes Association recommends that patients with diabetes be screened for signs of neuropathy annually. The highest yield bedside screening tests for large fiber sensory dysfunction are use of a 10-g Semmes-Weinstein monofilament or testing vibratory sensation with a 128-Hz tuning fork. The monofilament is pressed against the skin and designed to buckle when 10-g of force is applied, allowing for a consistent and quantifiable stimulus. Single modality testing can miss up to 25%–50% of patients with diabetic neuropathy, however. The combination of both tests is about 90% sensitive and 85%–89% specific for peripheral neuropathy in diabetic patients. Testing of pinprick sensation should also be considered, as such patients with isolated small fiber neuropathy will not be identified if only monofilament and vibratory sensation testing are carried out.
Finally, it is important to note that some aspects of the neurologic examination are expected to change with normal aging. In particular, many older adults will have reduced vibration sense in the toes and reduced or absent Achilles tendon reflexes. These patients often have no symptoms of neuropathy and no signs of neuropathy on electrodiagnostic testing. This emphasizes that these screening tests on examination are only the beginning of the diagnostic process; the findings still need to be put into the context of the patient’s history and eventual workup.
Identifying a Phenotype
After a history has been taken and the suggested neurologic examination has been performed, the information that was gathered can be used holistically to (1) ensure that peripheral neuropathy remains the most likely diagnostic category and (2) classify a specific phenotype for the neuropathy. Realistically, a trained neurologist may be best suited for this exercise. However, careful attention from a primary care provider can go a long way toward triaging those cases that truly require the expertise of a neurologist. When the history and examination reveal symmetric, length-dependent signs and symptoms suggesting DSP, the differential diagnosis includes either lumbosacral radiculopathy or myelopathy (process affecting the spinal cord). We have already provided some pearls in the history of exam that can identify these mimics. Low back pain, pain radiating into the legs, or bladder or bowel dysfunction may suggest radiculopathy. Hyperreflexia, spasticity, or sensory deficits in the trunk occur in myelopathy.
When it comes to classifying a neuropathy phenotype, a simple paradigm utilizing just four questions can be used:
- 1.
What is the time course?
- 2.
Are symptoms and signs on examination symmetric?
- 3.
Are symptoms and signs on examination length-dependent?
- 4.
Which modalities (e.g., motor, large fiber sensory, small fiber sensory, autonomic) are involved?
DSP is a chronic process leading to symmetric, length-dependent, sensory-predominant (large and small fiber) deficits. This pattern can be readily identified in the primary care setting. Our tips for diagnosis and management that follow will largely focus on this phenotype. If the answers to any of these questions deviate from the prototype of DSP, then the workup and management may need to change. This is where involvement of a neurologist, or at the very least some additional diagnostic testing (usually nerve conduction studies and/or electromyography), can be of higher yield.
Diagnosing Neuropathy
Symptoms alone (e.g., burning feet) have poor diagnostic accuracy for neuropathy. Neurologic examination findings such as distal sensory loss or absent ankle jerks are more sensitive and specific. In one cohort, the presence of two out of three suggestive symptoms, abnormal temperature sensation, or diminished ankle reflexes was 87% sensitive and 91% specific for neuropathy. Neuroimaging is not routinely indicated in patients with neuropathy. Spinal imaging, however, should be considered when the neurologic examination suggests a concurrent myelopathy or when the diagnosis of neuropathy is not firmly established and lumbosacral radiculopathy remains in the differential diagnosis.
The most reliable diagnosis of neuropathy rests on the combination of symptoms, the neurologic exam, and confirmatory findings on nerve conduction studies and electromyography. It is debatable whether all patients with suspected neuropathy require electrodiagnostic evaluation (EDX). This does not occur in current clinical practice; a study utilizing a database of Medicare patients demonstrated that only 20% underwent EDX within 6 months of their initial diagnosis of neuropathy. If multiple symptoms and exam findings suggest DSP, EDX may indeed be low yield. In a sample of patients over age 65 with a high prevalence of diabetes, for example, EDX led to a change in diagnosis or management in <1% of patients. By contrast, in samples of patients referred to academic medical centers for evaluation of neuropathy, EDX led to a change in diagnosis in 24%–43% of patients.
Guidelines put forward by the American Association of Neuromuscular and Electrodiagnostic Medicine state that EDX is likely to be low yield in those patients in whom symptoms and physical exam findings are mild, the findings are symmetric and both distal- and sensory predominant, there is little suspicion of a coexisting nerve disorder (e.g., carpal tunnel syndrome), and there is a known cause of the neuropathy. There are certain features in the history or physical exam, however, that should always prompt further neurologic consultation and possible EDX ( Box 19.1 ). These features either raise the possibility that the neuropathy is demyelinating in nature or, when confirmed, change the differential diagnosis for the causative process in a significant way. EDX is the primary method by which a neuropathy is determined to be axonal or demyelinating in nature. Some findings in the history and physical examination can clue the clinician into a demyelinating neuropathy—diffuse areflexia, for example—but there is no definitive way to distinguish based on the history and exam alone. Recognition of demyelination is of critical importance because the differential diagnosis shrinks considerably, with CIDP or its variants and hereditary neuropathy being the primary considerations. It is especially important to recognize CIDP because it is amenable to treatment with immunosuppressive therapies; this can not only stabilize but also improve patient’s deficits. The most common presentation of CIDP is subacute, progressive, non–length-dependent weakness and sensory loss.
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
