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How to Diagnose Peripheral Neuropathy? No Simple Answers

Experts Offer Some Guiding Principles

Moran, Mark

doi: 10.1097/01.NT.0000413291.48764.9a
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Investigators reported that almost one-quarter of patients receiving neuropathy diagnoses undergo MRI whereas few receive low-cost glucose tolerance tests. Experts in neuromuscular disorders noted that diagnosis of peripheral neuropathy is complex because it is a heterogeneous disorder with many causes; they offer some approaches for diagnosis.

The heterogeneous nature of peripheral neuropathy means that there is no simple approach to evaluate and diagnose neuropathic pain. Which is why one of the first studies to evaluate use of diagnostic steps inspired discussion — and some debate — among experts in neuromuscular disorders.

The study, published in the January Archives of Internal Medicine, used Medicare claims data from the 1996-2007 Health and Retirement Study to examine the number and patterns of tests and specific test utilization six months before and after the incident neuropathy diagnosis. The authors reported, among other findings, that almost one-quarter of patients receiving neuropathy diagnoses undergo MRI — which the authors defined as “high-cost, low-yield” — whereas few receive low-cost glucose tolerance tests.

They concluded that more research is needed to define effective and efficient strategies for the diagnostic evaluation of peripheral neuropathy. [For more on the protocols and findings, see “Tests and Expenditures in Diagnosis of Peripheral Neuropathy.”]

Experts who were not involved with the study were reluctant to comment on the specific data on diagnostic tests. There are limitations in the retrospective analysis, they said — not enough is known about the type of neuropathy considered or the accuracy of the claim codes. But they welcomed the analysis by lead author Brian Callaghan, MD, and senior author Eva Feldman, MD, as a first step to looking more closely at the selection of diagnostic tests for neuropathy.

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“Peripheral neuropathy is not a single disease entity,” said Peter J. Dyck, MD, professor of neurology and director of the Peripheral Nerve Research Laboratory at the Mayo Clinic in Rochester, MN, who was not involved with the study. “It is made up of at least 20 broad patterns of pathophysiologic disorders and hundreds of underlying causes. Therefore one should not expect physicians to order the same battery of tests to characterize and diagnose their causes. There are differences in which populations of neurons or fibers are affected, pathologic alterations, time course, symptoms and impairments, and underlying pathophysiologic mechanisms and causes, which may be diagnostically informative.”



Referring to the report's data on use of neuroimaging tests, he noted that even MRI may be appropriate in some circumstances and should not be excluded from the array of tests that may be vital in assessing symptoms that appear to be neuropathic.

John D. England, MD, the Grace Benson Professor and chair of the neurology department at Louisiana State University Health Sciences Center, noted, as well, that there are well over a 100 individual causes of neuropathic pain. He emphasized that evaluation by a neurologist of any form of peripheral neuropathy is a crucial first step toward ensuring that the most cost-effective test is matched to the individual patient's presenting neuropathy.

“It is not uncommon for primary care physicians or others with less specialized expertise in neuropathy to just start ordering a shot-gun of tests,” he said. The evaluation of neuropathy by non-neurologists may account for the high rate of MRI found in the study, he added.

Dr. Dyck pointed out that the choice of a diagnostic test may involve a balance of cost and benefit. “The benefits of MRI may include the early recognition of a serious perhaps untreatable condition, but especially of treatable conditions,” he told Neurology Today. “We have shown that high cost MRI of proximal nerves — roots, plexuses and proximal nerves — in highly selected cases has a high yield of diagnoses of treatable conditions.”



As cited in the 2010 book Companion to Peripheral Neuropathy Illustrated Cases and New Development — edited by Dr. Dyck and others — these treatable conditions include nerve lymphoma, focal inflammatory demyelination, granuloma, tumors and infection. ”So the issue is whether an MRI is ordered for the correct or for the wrong reasons,” Dr. Dyck told Neurology Today.

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David Simpson, MD, who co-authored the February issue of the AAN Continuum: Lifelong Learning publication on peripheral neuropathy, emphasized that a thorough history and initial neurological exam is critical. “Based on these steps, a clinician should be able to go a long way to narrowing the differential diagnosis,” he told Neurology Today. “One can ascertain the time course, symmetry, and clinical pattern as a first step.

“Then based on clinical impression, history and neurological exam one can proceed to further refine the diagnosis by blood testing, employing not a shot-gun approach but targeted blood screens, including a test of fasting blood sugar and of hemoglobin A1C.”

From there the clinician can proceed to electrophysiologic testing. “Not every single patient is going to require nerve conduction,” said Dr. Simpson, professor of neurology and director of the clinical neurophysiology laboratories at Mount Sinai Medical Center in New York. “If someone has a fairly classical symmetrical neuropathy it may not be necessary to use nerve conduction for confirming what is clinically obvious, but for more complex, asymmetric or potentially demyelinating neuropathies nerve conduction is extremely important,” he said.

And in a minority of cases a biopsy may be called for. “A skin biopsy with analysis of nerve density can be useful in small fiber neuropathies,” he added.

Finally, Dr. Simpson emphasized that while many forms of peripheral neuropathy do not have a treatable underlying cause — in which case the clinical goal is treatment of symptoms of pain — patients presenting with neuropathies may have treatable immunologic or autoimmune disease. Conditions such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy may be treated with intravenous immunoglobulin, he said.

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In 2008, John D. England, MD, of Louisiana State University Health Sciences Center, chaired an AAN panel that produced guidelines for diagnosis and evaluation of one common form of peripheral neuropathy — distal symmetric polyneuropathy. Those guidelines encompass the following basic principles:

  • Screening blood tests may be useful, and blood glucose, serum B12 with metabolites (methylmalonic acid with or without homocysteine), and serum protein immunofixation electrophoresis provide the highest yield.
  • Tailored genetic testing is recommended for the accurate diagnosis of hereditary neuropathies. Initial genetic testing should be guided by the clinical phenotype, inheritance pattern, and electrodiagnostic features, and should focus on the most common abnormalities, which are CMT1A duplication/HNPP deletion, Cx32 (GJB1) and MFN2 mutation screening.
  • Autonomic testing should be considered in the evaluation of patients suspected of having autonomic neuropathies and may be considered in patients with suspected distal small fiber sensory polyneuropathy (SFSN). For the highest diagnostic accuracy, the combination of autonomic screening tests in the composite autonomic scoring scale (CASS) should be considered.
  • Skin biopsy is a validated technique for determining intraepidermal nerve fiber density and may be considered for diagnosing symptomatic patients with suspected polyneuropathy, especially SFSN.
  • Nerve biopsy is generally accepted as useful in the evaluation of certain inflammatory nerve diseases, and is especially useful in diagnosing mononeuropathy multiplex and vasculitic neuropathy — conditions which can often present as DSP.

Excerpted from Neurology 2009;72(2):177-84. E-pub 2008 Dec 3.

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  • The 1996-2007 Health and Retirement Study Medicare claims-linked database was used to identify individuals with an incident diagnosis of peripheral neuropathy using International Classification of Diseases, Ninth Revision, codes and required no previous neuropathy diagnosis during the preceding 30 months.
  • Focusing on 15 relevant tests, investigators examined the number and patterns of tests and specific test utilization six months before and after the incident neuropathy diagnosis. Medicare expenditures were assessed during the baseline, diagnostic, and follow-up periods.
  • Of the 12,673 patients, 1031 (8.1 percent) received a new ICD-9 diagnosis of neuropathy and met the study inclusion criteria. Of the 15 tests considered, a median of 4 (interquartile range, 2-5) tests were performed, with more than 400 patterns of testing.
  • MRI of the brain or spine was ordered in 23.2 percent of patients, whereas a glucose tolerance test was rarely obtained (1.0 percent). Mean Medicare expenditures were significantly higher in the diagnostic period than in the baseline period ($14 362 vs $8067, p< .001).
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In “How to Diagnose Peripheral Neurology? No Simple Answers,” we highlight a “first of its kind” study that addresses the practice patterns and costs of evaluating patients with peripheral neuropathy using Medicare claims data. The study is relatively straightforward and the results are not that surprising: MRI scans are likely overused and oral glucose tolerance tests underused. The study also has considerable limitations as the authors point out, which limit definitive conclusions about test appropriateness or the most cost-effective approach. Yet, it is a game-changer.

The study signals a willingness to tackle the fundamental question: “What is the most cost-effective approach to evaluate peripheral neuropathy?” This question makes my head swim given that neuropathies have numerous pathophysiological patterns, hundreds of etiologies, and an evolving array of diagnostics and treatments. Indeed, the authors found over 400 patterns of test ordering, yet no pattern accounted for more than 4.8 percent of the total. The extraordinary amount of variation however, suggests enormous waste.

So what will it take to begin to focus on the most cost-effective or high-value clinical care — a question that will be increasingly asked across most neurological diseases and in the absence of an agreed upon and systematic approach to gauge value?

First, neurologists must be willing to contribute to this form of “team science.” To do that, we need to define meaningful cohorts of patients and outcomes in sufficient detail so that our questions about cost-effectiveness make sense. Indeed, the question — is MRI cost-effective? — is overly broad, even nonsensical.

Second, it will require not only the courage to define high-value, cost-conscious care, but also the guts to eliminate services that offer no or limited value to the patient. And if we are truly going to confront the possibility of medical reversals of established practices, neurologists will have to assume more economic risk than we have ever had to in the past.

Finally, neurologists will have to temporarily suspend judgment about how we and others contribute to the current inefficiencies. We will be much more effective if we avoid starting out by defending our value as neurologists or the procedures we provide. After all, the patients are at the center of this debate and pointing fingers at others will further undermine trust in the medical system. There is plenty of blame to go around.

In the Jan.17 issue of Annals of Internal Medicine, Amir Qaseem, MD, PhD, and co-authors describe 37 tests that do not reflect high-value care. Six of these tests involve patients with neurological complaints. (See “Clinical Situations in Neurology in Which a Test Does Not Reflect High-Value Care.”)

The American College of Physicians convened a workgroup of physicians to attend to this task — and, using a consensus-based process, they defined common clinical situations in which screening and diagnostic tests are used in ways that do not reflect high value care. The workgroup suggested these and other principles for providing high-value, cost-conscious care: 1) tests should usually not be performed if the results will not change management, 2) when the pretest probability of disease is low, the likelihood of a false positive test is higher than the likelihood of a true positive result, and 3) the true cost of a test includes the downstream costs (and savings) incurred because the test was performed.

Perhaps the American Academy of Neurology, like the American College of Physicians, can take a lead on convening neurology-specific workgroups, including one for peripheral neuropathy, to encourage thoughtful discussion about such lists to promote high-value, cost-conscious care. This may be a way to start a dialogue and begin to define high-value clinical care from the perspective of each patient.

Neurology Today Associate Editor Dr. Holloway is professor of neurology and community and preventive medicine at the University of Rochester Medical Center in New York.

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Clinical Situations in Neurology in Which a Test Does Not Reflect High-Value Care*

  1. Performing imaging studies in patients with nonspecific low back pain.
  2. Performing serologic testing for Lyme disease in patients with chronic nonspecific symptoms and no clinical evidence of disseminated Lyme disease.
  3. Performing imaging studies in patients with recurrent, classic migraine headache and normal findings on neurologic examination.
  4. Performing brain imaging studies (CT or MRI) to evaluate simple syncope in patients with normal findings on neurologic examination.
  5. Routinely performing echocardiography in the evaluation of syncope, unless the history, physical examination, and electrocardiogram do not provide a diagnosis or underlying heart disease is suspected.
  6. Performing an antinuclear antibody test in patients with nonspecific symptoms, such as fatigue and myalgia, or in patients with fibromyalgia.

*No particular order

Adapted from Qaseem A, et al. Appropriate use of screening and diagnostic tests to foster high-value, cost-conscious care. Ann Intern Med 2012;156:147-149.

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• Callaghan B, McCammon R, Feldman E, et al. Tests and expenditures in the initial evaluation of peripheral neuropathy. Arch Intern Med 2012;172(2):127-32.
    • England JD, Gronseth GS, Sumner AJ, et al. Practice parameter: Evaluation of distal symmetric polyneuropathy: role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology 2009;72(2):177-84. E-pub 2008 Dec 3.
      • England JD, Gronseth GS, Sumner AJ, et al. Practice parameter: Evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology 2009;72(2):185-192. Epub 2008 Dec 3.
        ©2012 American Academy of Neurology