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Neurology Today:
doi: 10.1097/01.NT.0000343213.56710.da
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NEW AAN PRACTICE PARAMETERS ON DSP

SAMSON, KURT

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For a more complete case example and comprehensive advice on coding for reimbursement, visit the AAN Web site: www.aan.com.

Laboratory and genetic tests can help to identify distal symmetric polyneuropathy (DSP), the most common type of polyneuropathy. However, more research and better diagnostic standards are needed, according to two new practice parameters developed by a task force led by the AAN.

The Polyneuropathy Task Force included 19 physicians, with representatives from the AAN, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation.

Because evaluation of the disorder is not standardized, the literature was reviewed to provide evidence-based guidelines about autonomic testing, nerve and skin biopsy, and for laboratory and genetic testing.

In a telephone interview with Neurology Today, task force member John D. England, MD, the Grace Benson Professor and Chairman of the department of neurology at Louisiana State University Health Sciences Center in New Orleans, helped explain the panel's findings, which were publishing online Dec. 3 ahead of the print Neurology.

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HOW USEFUL ARE LABORATORY TESTS IN SCREENING FOR DISTAL SYMMETRIC POLYNEUROPATHY?

Our findings indicate that they are probably useful in determining the cause of DSP and may be considered for all patients, but their usefulness and sensitivity varies depending upon the particular test.

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WHAT TESTS ARE MOST EFFECTIVE?

The tests with the highest diagnostic sensitivity and specificity are blood glucose, serum B12 with metabolites (methylmalonic acid with or without homocysteine), and serum protein immunofixation electrophoresis. Patients with distal symmetric sensory polyneuropathy have a relatively high prevalence of diabetes or prediabetes (impaired glucose tolerance), which can be documented by blood glucose or a glucose tolerance test (GTT).

When routine blood glucose testing is not clearly abnormal, other tests for prediabetes (impaired glucose tolerance) such as a GTT may be considered in patients with distal symmetric sensory polyneuropathy, especially if it is accompanied by pain.

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WHEN SHOULD AUTONOMIC TESTING BE USED?

Autonomic testing can with a high degree of accuracy document autonomic system dysfunction in polyneuropathy, especially suspected autonomic neuropathy and distal small fiber sensory polyneuropathy (SFSN).

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WHICH AUTONOMIC TESTS HAVE THE HIGHEST SENSITIVITY AND SPECIFICITY FOR DIAGNOSING DSP?

Currently available autonomic tests can provide measurements of cardiovagal, adrenergic, and postganglionic sudomotor function and, as such, they provide indices for both parasympathetic and sympathetic autonomic function. Heart rate variability testing is a simple and reliable test of cardiovagal function. It detects the presence of diabetic polyneuropathy with nearly the same sensitivity as nerve conduction studies (NCSs).

The composite autonomic scoring scale (CASS), which includes the orthostatic blood pressure, quantitative sudomotor axon reflex test (QSART), heart rate response to tilt, heart rate response to deep breathing, the Valsalva ratio, and beat-to-beat blood pressure measurements during phases II and IV of the Valsalva maneuver, tilt, and deep breathing, provides a useful 10 point scale of autonomic function. The CASS battery of validated tests is recommended to achieve the highest diagnostic accuracy. Such testing is particularly relevant to small fiber polyneuropathy and the autonomic neuropathies.

This combination of autonomic tests provides the highest sensitivity and specificity for documenting autonomic dysfunction in DSP. If the full CASS battery of tests is not available, a combination of tests of cardiovagal function — for example, heart rate response to deep breathing — and some test of adrenergic function may be considered as alternatives. Details about the tests are available in references in the AAN parameter.

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WHY IS AUTONOMIC TESTING IMPORTANT?

Figure. DR. JOHN ENG...
Figure. DR. JOHN ENG...
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More research is necessary to determine whether the documentation of autonomic abnormalities is important in modifying the evaluation and treatment of polyneuropathy. Specific tests such as QSART can document small fiber (i.e., sudomotor axon) loss with a high degree of sensitivity, making the test useful to confirm the diagnosis of small fiber polyneuropathy.

Since skin biopsy with determination of intra-epidermal nerve fibers (IENF) density can also document small fiber loss, more studies are needed to compare and correlate skin and nerve biopsies in these disorders.

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WHICH PATIENTS WITH POLYNEUROPATHY SHOULD BE SCREENED FOR HEREDITARY NEUROPATHIES?

Genetic testing may be considered in patients with a cryptogenic polyneuropathy and the classic hereditary neuropathy phenotype. To achieve the highest yield, the genetic testing profile should be guided by the clinical phenotype, inheritance pattern (if available), and EDX features (demyelinating versus axonal). There is insufficient evidence to support or refute the usefulness of routine genetic testing in cryptogenic polyneuropathy patients without a classic hereditary phenotype. More clearly defined guidelines for genetic testing are also needed to maximize yield and to curtail the cost of DNA analysis.

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HOW USEFUL IS GENETIC TESTING?

Hereditary neuropathies are an important subtype of polyneuropathy with a prevalence of approximately 1:2,500 people. DSP is the predominant phenotype, but phenotypic heterogeneity may be present even within the same family. When genetic testing is contemplated all neuropathy phenotypes need to be considered.

In evaluating polyneuropathy, a comprehensive family history should always be taken. Although molecular diagnostic techniques are also available, guidelines for their usefulness in the evaluation of polyneuropathy are needed.

Most genetic polyneuropathies are variants of Charcot-Marie-Tooth (CMT) disease, and genetic testing is available for an increasing number of these neuropathies. The CMT phenotype has been linked to 36 loci and mutations in 28 different genes, several of which can be identified by commercially available genetic testing.

Several prospective cohort studies indicate that the results of currently available genetic screening tests are unequivocal for diagnosing pathogenic mutations, providing a specificity of 100 percent, or no false positives.

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HOW USEFUL IS SKIN BIOPSY?

Skin biopsy is a validated technique for determining intra-epidermal nerve fiber (IENF) density and may be considered for the diagnosis of DSP, particularly SFSN, and it provides an opportunity for research in different varieties of neuropathy. However, additional studies are needed to characterize the diagnostic accuracy of skin biopsy in distinguishing patients with suspected polyneuropathy, particularly SFSN, from patients with sensory complaints or pain unrelated to peripheral neuropathy.

That said, prospective studies with appropriate control subjects are needed to assess the sensitivity, specificity, and predictive value of IENF density measurement to identify SFSN in patients with lower extremity pain or sensory complaints.

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CAN A NERVE BIOPSY BE USEFUL?

There are no controlled studies of nerve biopsy in the evaluation of DSP, therefore no evidence to support or refute any conclusion about nerve biopsy in evaluating routine DSP. But nerve biopsy is generally accepted as being useful in evaluating amyloid neuropathy, mononeuropathy multiplex due to vasculitis, or atypical forms of chronic inflammatory demyelinating polyneuropathy (CIDP).

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WHAT ADDITIONAL STUDIES ARE NEEDED AT THIS POINT?

We need more prospective studies in order to develop better guidelines for evaluating SFSN. As a prelude, a formal case definition for SFSN should be developed. Investigators also need to determine whether such a case definition should be based upon clinical criteria, pathologic criteria (for example, skin biopsy), or a combination of clinical, paraclinical, and pathologic criteria.

In addition, the diagnostic accuracy of morphologic changes (for example, axonal swellings) in the diagnosis of SFSN versus both healthy and other-disease control groups needs to be better defined. Studies exploring other uses for skin biopsy beyond identification and quantification of DSP and SFSN have been reported and should also be further explored.

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REFERENCES

• England J, et al. Practice Parameter: The evaluation of distal symmetric polyneuropathy: The role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 2008;E-pub 2008 Dec. 3.

• England J, et al. Practice Parameter: The evaluation of distal symmetric polyneuropathy: The role of laboratory and genetic testing (an evidence-based review). Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 2008;E-pub 2008 Dec. 3.

©2008 American Academy of Neurology

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