Abstract and Introduction
Peripheral neuropathy is a common neurological disorder, with high prevalence especially in the aged population. The general evaluative approach is to first identify the type of peripheral neuropathy prior to investigating for a possible underlying etiology, which is an increasingly important endeavor, as many causes of peripheral neuropathy are now recognized as treatable. To this end, laboratory testing plays an important adjunctive role to a detailed history and examination. This review will discuss possible diagnostic laboratory testing pathways for different types of peripheral neuropathy, with the goal of minimizing costs and false-positive results while maximizing the likelihood of identifying a potentially reversible etiology.
Peripheral neuropathy is among the most common neurological disorders, with an overall prevalence estimated at 2.4% in the general population and as high as 50% for adults over the age of 85 years. It is a significant cause of morbidity, with symptoms ranging from pain and frequent falls to limb amputation secondary to inability to detect injury.[3,4] Many causes of peripheral neuropathy are treatable, and as such, conscientious effort must be made to identify the underlying etiology. The older estimation of approximately 25% of peripheral neuropathy being idiopathic after a thorough evaluation is likely reduced with modern testing. The first steps in establishing a diagnosis of peripheral neuropathy and delineating its cause are a detailed clinical history and physical examination. Neurophysiological testing should be pursued if any atypical features are identified, specifically asymmetry, relatively fast progression, profound sensory complaints including ataxia, or motor involvement that is early or predominant. Upon establishing a diagnosis of peripheral neuropathy and characterizing its type, the underlying etiology may be investigated by laboratory testing, which is the topic of this review.
For essentially all types of peripheral neuropathy, there are no clear evidence-based algorithms to guide laboratory testing, owing to (1) inherent clinical heterogeneity even among types of peripheral neuropathy; (2) limitations in studies on the "yield" of different laboratory tests (in some studies on genetic testing called "hit rate"), as this number is highly dependent on pretest suspicion and therefore would be falsely low if tests are obtained indiscriminately on patients without corresponding signs and symptoms; and (3) difficulty with establishing a condition as the direct cause of peripheral neuropathy; for example, a proportion of the healthy elderly population has monoclonal gammopathy or uncertain significance (MGUS), and those with concurrent peripheral neuropathy may have both purely by coincidence. As such, there is high variability of practice patterns in ordering investigations for peripheral neuropathy. In arguably the most useful practice parameter on the topic copublished by the American Academy of Neurology (AAN), the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM), and the American Academy of Physical Medicine and Rehabilitation (AAPM&R), the question was posed "What is the yield of screening laboratory tests in the evaluation of DSP [distal symmetric polyneuropathy], and which tests should be performed?" The answer remained somewhat limited, with the recommendation that a small number of tests be pursued as an initial screen, while a large number of possible other tests may be considered based on clinical judgment.
Conscientious testing is important to maximize the chance of identifying an underlying, potentially treatable etiology, while minimizing costs to the patient and the healthcare system as well as the inconvenience of excessive testing and possible false-positive results. One study found that in the "diagnostic period," defined as the time interval between 6 months prior to and 6 months after a diagnosis of peripheral neuropathy was made based on ICD-code, the average Medicare expenditure for patients was approximately $14,000 compared with $8100 (<0.001) in the "baseline period," defined as the time interval between 18 months prior to and 6 months prior to diagnosis.
Prior important work has detailed the nuances of individual laboratory tests,[10,11] and for each test discussed its role in different patterns of peripheral neuropathy. This article will take a different approach. For chronic polyneuropathies, only one pattern of peripheral neuropathy may arguably be diagnosed clinically without the need for neurophysiological testing: chronic, distal, slowly progressive, symmetric, predominantly sensory polyneuropathy (DSP). If any atypical feature is noted in the initial or subsequent evaluation—asymmetry, severe early sensory complaints such as ataxia and loss of proprioception, early or severe pain, predominance of or early motor involvement, proximal symptoms, and fast progression—neurophysiological testing should be pursued for characterization. Only after identifying the peripheral neuropathy type, should further targeted laboratory studies be performed (Figure 1). Similarly, for acute polyneuropathies, other than in classic presentations of Guillain-Barre syndrome, neurophysiological testing should be performed to help target further diagnostics (Figure 2).
Approach to identify type of chronic peripheral neuropathy. DSP, distal symmetric polyneuropathy.
Approach to identify type of acute or subacute peripheral neuropathy. GBS, Guillain-Barré syndrome.
This article will discuss the differential diagnoses and possible laboratory diagnostic pathway for each type of chronic and acute peripheral neuropathy. Due to the limitations detailed earlier, for each type of peripheral neuropathy, the recommendations will focus on the investigations that should be considered in every case, and list other possible tests and contexts in which they may be useful (Table 1). The goal of the article is to provide the general neurologist with a possible framework to pursue laboratory testing in a targeted and cost-effective manner.
Semin Neurol. 2019;39(5):531-541. © 2019 Thieme Medical Publishers