Practice Parameter: Evaluation of distal symmetric polyneuropathy: Role of laboratory, genetic, and autonomic testing; n

1. Practice Parameter: Evaluation of distal symmetric polyneuropathy: Role of laboratory, genetic, and autonomic testing; nerve biopsy; and skin biopsy (an evidence-based review) Report of the Quality Standards Subcommittee of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation J.D. England, MD; G.S. Gronseth, MD, FAAN; G. Franklin, MD; G.T. Carter, MD; L.J. Kinsella, MD; J.A. Cohen, MD; A.K. Asbury, MD; K. Szigeti, MD, PhD; J.R. Lupski, MD, PhD; N. Latov, MD; R.A. Lewis, MD; P.A. Low, MD; M.A. Fisher, MD; D.N. Herrmann, MD; J.F. Howard Jr, MD; G. Lauria, MD; R.G. Miller, MD; M. Polydefkis, MD, MHS; and A.J. Sumner, MD

2. If you have questions, comments, or feedback regarding this slide presentation, or would like to modify the contents to present this in a lecture, please contact guidelines@aan.com

3. Presentation Objectives

4. Overview

5. Background

6. Background

7. Background

8. Gaps in Care

9. AAN Guideline Process

10. Clinical Questions

11.

12. AAN Classification of Evidence

13. AAN Level of Recommendations

14. Translating Class to Recommendations A = Requires at least two consistent Class I studies.* B = Requires at least one Class I study or two consistent Class II studies. C = Requires at least one Class II study or two consistent Class III studies. U = Studies not meeting criteria for Class I through Class III.

15. Translating Class to Recommendations * In exceptional cases, one convincing Class I study may suffice for an �A� recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome > 5 and the lower limit of the confidence interval is > 2).

16. Applying This Processto the Issue We will now turn our attention to the guidelines.

17. Clinical Questions 1. What is the yield of screening laboratory tests in the evaluation of DSP, and which tests should be performed? 2. How accurate is genetic testing for identifying patients with genetically determined neuropathies? 3. Which patients with polyneuropathy should be screened for hereditary neuropathies?

18. Clinical Questions What is the usefulness of clinical autonomic testing in the evaluation of polyneuropathy, and which tests have the highest sensitivity and specificity? What is the usefulness of nerve biopsy in determining the etiology of distal symmetric polyneuropathy? What is the usefulness and diagnostic accuracy of skin biopsy in the evaluation of polyneuropathy?

19. Methods OVID MEDLINE, OVID Excerpta Medica (EMBASE), OVID Current Contents Database creation to March 2007 Relevant, fully published, peer-reviewed articles Supplemented through manual searches by panel members Search terms Peripheral neuropathy, polyneuropathy, and distal symmetric polyneuropathy

20. Methods Cross-referenced with diagnosis, electrophysiology, autonomic testing, nerve biopsy, and skin biopsy At least two panelists reviewed each article for inclusion. A third panelist was added for arbitrating disagreements. Risk of bias was determined using the classification of evidence for each study (Classes I�IV).

21. Methods Strength of practice recommendations were linked directly to levels of evidence (Levels A, B, C, and U). Conflicts of interest were disclosed.

22. Literature Review

23. Literature Review

24. Class I: A cohort study with prospective data collection of a broad spectrum of persons with the suspected condition, using an acceptable reference standard for case definition. The diagnostic test is objective or performed and interpreted without knowledge of the patient�s clinical status. Study results allow calculation of measures of diagnostic accuracy. AAN Classification of Evidencefor Diagnosis

25. AAN Classification of Evidencefor Diagnosis Class II: A case control study of a broad spectrum of persons with the condition established by an acceptable reference standard compared to a broad spectrum of controls or a cohort study where a broad spectrum of persons with the suspected condition where the data was collected retrospectively. The diagnostic test is objective or performed and interpreted without knowledge of disease status. Study results allow calculation of measures of diagnostic accuracy.

26. AAN Classification of Evidencefor Diagnosis Class III: A case control study or cohort study where either persons with the condition or controls are of a narrow spectrum. The condition is established by an acceptable reference standard. The reference standard and diagnostic test are objective or performed and interpreted by different observers. Study results allow calculation of measures of diagnostic accuracy. Class IV: Studies not meeting Class I, II or III criteria including consensus, expert opinion or a case report.

27. Analysis of Evidence Question 1: What is the yield of screening laboratory tests in the evaluation of DSP, and which tests should be performed?

28. Conclusions/Recommendations Conclusions: Screening laboratory tests are probably useful in determining the cause of DSP, but the yield varies depending upon the particular test (Class III). Recommendations: Screening laboratory tests may be considered for all patients with DSP (Level C).

29. Conclusions/Recommendations Conclusions: The tests with the highest yield of abnormality are blood glucose, serum B12 with metabolites (methylmalonic acid with or without homocysteine), and serum protein immunofixation electrophoresis (Class III). Recommendations: Although routine screening with a panel of basic tests is often performed (Table E-1, available at www.neurology.org), those tests with the highest yield of abnormality are blood glucose, serum B12 with metabolites (methylmalonic acid with or without homocysteine), and serum protein immunofixation electrophoresis (Level C).

30. Conclusions/Recommendations Conclusions: Patients with distal symmetric sensory polyneuropathy have a relatively high prevalence of diabetes or pre-diabetes (impaired glucose tolerance), which can be documented by blood glucose, or GTT (Class III). Recommendations: When routine blood glucose testing is not clearly abnormal, other tests for pre-diabetes (impaired glucose tolerance) such as a GTT may be considered in patients with distal symmetric sensory polyneuropathy, especially if it is accompanied by pain (Level C).

31. Recommendations Recommendations: Although there are no control studies (Level U) regarding when to recommend the use of other specific laboratory tests, clinical judgment correlated with the clinical picture will determine which additional laboratory investigations (Table E-2, available at www.neurology.org) are necessary.

32. Analysis of Evidence Question 2: How accurate is genetic testing for identifying patients with genetically determined neuropathies? Question 3: Which patients with polyneuropathy should be screened for hereditary neuropathies?

33. Conclusions Conclusions: Genetic testing is established as useful for the accurate diagnosis and classification of hereditary polyneuropathies (Class I). For patients with a cryptogenic polyneuropathy who exhibit a classical hereditary neuropathy phenotype, routine genetic screening may be useful for CMT1A duplication/deletion and Cx32 mutations in the appropriate phenotype (Class III). Further genetic testing may be considered guided by the clinical question.

34. Recommendations Recommendations: Genetic testing may be considered in patients with a cryptogenic polyneuropathy and classical hereditary neuropathy phenotype (Level C). 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). See Figure 1 (next slide; also viewable in the full guideline) for guidance.

35. Figure 1

36. Conclusions/Recommendations Conclusions: There is insufficient evidence to determine the usefulness of routine genetic screening in cryptogenic polyneuropathy patients without a classical hereditary neuropathy phenotype. Recommendations: There is insufficient evidence to support or refute the usefulness of routine genetic testing in cryptogenic polyneuropathy patients without a classical hereditary phenotype (Level U).

37. Analysis of Evidence Question 4: What is the usefulness of clinical autonomic testing in the evaluation of polyneuropathy, and which tests have the highest sensitivity and specificity?

38. Conclusions Conclusions: Autonomic testing is probably useful in documenting autonomic nervous system involvement in polyneuropathy (Class II and III). The sensitivity and specificity vary with the particular test. The utilization of the combination of autonomic reflex screening tests in the CASS provides the highest sensitivity and specificity for documenting autonomic dysfunction (Class II).

39. Recommendations Recommendations: Autonomic testing should be considered in the evaluation of patients with polyneuropathy to document autonomic nervous system involvement (Level B). Autonomic testing should be considered in the evaluation of patients with suspected autonomic neuropathies (Level B) and may be considered in the evaluation of patients with suspected distal SFSN (Level C). The combination of autonomic screening tests in the CASS should be considered to achieve the highest diagnostic accuracy (Level B).

40. Analysis of Evidence Question 5: What is the usefulness of nerve biopsy in determining the etiology of distal symmetric polyneuropathy?

41. Conclusions/Recommendations Conclusions: There is no evidence to support or refute a conclusion regarding the role of nerve biopsy in the evaluation of DSP (Class IV). Recommendations: No recommendations can be made regarding the role of nerve biopsy in determining the etiology of DSP (Level U).

42. Analysis of Evidence Question 6: What is the usefulness and diagnostic accuracy of skin biopsy in the evaluation of polyneuropathy?

43. Conclusions/Recommendations Conclusions: IENF density assessment using PGP 9.5 immunohistochemistry is a validated, reproducible marker of small fiber sensory pathology. Skin biopsy with IENF density assessment is possibly useful to identify DSP which includes SFSN in symptomatic patients with suspected polyneuropathy (Class III). Recommendations: For symptomatic patients with suspected polyneuropathy, skin biopsy may be considered to diagnose the presence of a polyneuropathy, particularly SFSN (Level C).

44. Future Research This comprehensive review reveals several weaknesses in the current approach to the evaluation of polyneuropathy and highlights opportunities for research. Laboratory testing. The finding of a laboratory abnormality does not necessarily mean that the abnormality is etiologically significant. For instance, there is a relatively high prevalence of impaired glucose tolerance in patients with distal symmetric polyneuropathy; however, whether this is etiologically diagnostic is not known. This and other such examples point to the need for more research into the basic pathobiology of the peripheral nervous system. As an extension of this area of research, there

45. Future Research is a need to determine whether aggressive treatment or reversal of specific laboratory abnormalities improves or alters the course of polyneuropathy. Genetic testing. The genetic revolution has provided great insights into the mechanisms of hereditary neuropathies. Genetically determined neuropathies are more common and clinically diverse than previously appreciated. Further research to identify genotype-phenotype correlation is needed to improve the evaluation process for patients with suspected hereditary neuropathies. The issue of cost/benefit ratio of genetic testing is important since an ever-increasing number of genetic tests are commercially available. More clearly defined guidelines for genetic testing are needed to maximize yield and to curtail the

46. Future Research costs of such evaluations. Continued exploration into the genetic basis of neuropathies has tremendous potential for the understanding of basic pathophysiology and treatment of neuropathies. Autonomic testing. Autonomic testing can with a high degree of accuracy document autonomic system dysfunction in polyneuropathy. This is particularly relevant to small fiber polyneuropathy and the autonomic neuropathies. 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

47. Future Research diagnosis of small fiber polyneuropathy. Since skin biopsy with determination of IENF density can also document small fiber loss, there is a need for studies that compare and correlate the two techniques. Nerve biopsy. There are no studies of nerve biopsy in the evaluation of DSP. Although it would be useful to know the outcome of well-designed prospective studies in this area, it is unlikely that such studies will be done. Skin biopsy. Skin biopsy with determination of IENF density is a technique that has come of age for the objective documentation of small fiber loss. This technique provides a unique opportunity for research in different varieties of neuropathy. Further studies are needed to characterize the

48. Future Research diagnostic accuracy of skin biopsy in distinguishing patients with suspected polyneuropathy, particularly SFSN, from patients with sensory complaints or pain unrelated to peripheral neuropathy. Prospective studies with appropriate �other disease� controls should be done to assess the sensitivity, specificity and predictive values of IENF density measurement to identify SFSN in patients with lower extremity pain or sensory complaints. A predetermined independent reference standard for the diagnosis of SFSN should be specifically stated in such studies. A case definition of SFSN should be developed. Investigators need to determine whether this case definition should be based upon clinical criteria, pathological criteria (e.g., skin biopsy), a

49. Future Research or a combination of clinical, paraclinical, and pathologic criteria. The diagnostic accuracy of morphologic changes (e.g., axonal swellings) in the diagnosis of SFSN vs. healthy controls and disease controls 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 be further explored. Biopsies of glabrous skin and dermal skin include myelinated nerve fibers, and have been shown to have potential utility in the diagnosis of immune-

50. Future Research mediated neuropathies, Charcot-Marie-Tooth (CMT), and related diseases.14 Other studies have employed skin biopsy for detection or monitoring of leprosy, hereditary amyloidosis, vasculitic neuropathy, and Fabry�s disease.15�18 Additional studies are required to determine the usefulness of skin biopsy in the diagnosis and monitoring of these and other varieties of neuropathy. Serial IENF density measurements and IENF regenerative capacity are being studied and used as outcome measures in therapeutic trials.19, 20

51. Future Research Further studies are needed to validate and determine the value of skin biopsy for this purpose.21

52. References Martyn CN, Hughes RAC. Epidemiology of peripheral neuropathy. J Neurol Neurosurg Psychiatry 1997;62:310�318. England JD, Asbury AK. Peripheral neuropathy. Lancet 2004;363:2151�2161. Barohn RJ. Approach to peripheral neuropathy and myopathy. Seminars Neurology 1998;18:7�18. (Class III) Jann S, Beretta S, Bramerio M, Defanti CA. Prospective follow-up study of chronic polyneuropathy of undetermined cause. Muscle Nerve 2001;24:1197�1201. (Class III) Lubec D, Muellbacher W, Finsterer J, Mamoli B. Diagnostic work-up in peripheral neuropathy: An analysis of 171 cases. Postgrad Med J 1999;75:723�727. (Class III) Wolfe GI, Baker NS, Amato AA, et al. Chronic cryptogenic sensory polyneuropathy: clinical and laboratory characteristics. Arch Neurol 1999;56:540�547. (Class III)

53. References Notermans NC, Wokke JH, Franssen H, et al. Chronic idiopathic polyneuropathy presenting in middle or old age: a clinical and electrophysiological study of 75 patients. J Neurol Neurosurg Psychiatry 1993;10:1066�1071. (Class III) Notermans NC, Wokke JH, van der Graaf Y, Franssen H, van Dijk GW, Jennekens FG. Chronic idiopathic axonal polyneuropathy: a five year follow up. J Neurol Neurosurg Psychiatry 1994;57:1525�1527. (Class III) Fagius J. Chronic cryptogenic polyneuropathy. Acta Neurol Scand 1983;67:173�180. (Class III) Dyck PJ, Oviatt KF, Lambert EH. Intensive evaluation of referred unclassified neuropathies yields improved diagnosis. Ann Neurol 1981;10:222�26. (Class IV) McLeod JG, Tuck RR, Pollard JD, Cameron J, Walsh JC. Chronic polyneuropathy of undetermined cause. J Neurol Neurosurg Psychiatry 1984;47:530�535. (Class III)

54. References Johannsen L, Smith T, Havsager A-M, et al. Evaluation of patients with symptoms suggestive of chronic polyneuropathy. J Clin Neuromusc Dis 2001;3:47�52. (Class III) England JD, Gronseth GS, Franklin G, et al. Distal symmetric polyneuropathy: A definition for clinical research. Report of the American Academy of Neurology, the American Association of Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 2005;64:199�207. Li J, Bai Y, Ghandour K, et al. Skin biopsies in myelin-related neuropathies: bringing molecular pathology to the bedside. Brain 2005;128:1168�1177. (Class III). Sousa MM, Ferrao J, Fernandes R, et al. Deposition and passage of transthyretin through the blood-nerve barrie in recipients of familial amyloid polyneuropathy livers. Lab Invest 2004;84:865�873.

55. References Facer P, Mann D, Mathur, et al. Do nerve growth factor-related mechanisms contribute to loss of cutaneous nociception in leprosy? Pain 2000;85:231�238. Scott LJ, Griffin JW, Luciano C, et al. Quantitative analysis of epidermal innervation in Fabry disease. Neurology 1999;52:1249�1254. Tseng MT, Hsieh SC, Shun Ct, et al. Skin denervation and cutaneous vasculitis in systemic lupus erythematosus. Brain 2006;129:977�985. Polydefkis M, Sirdofsky M, Hauer P, Petty BG, Murinson B, McArthur JC. Factors influencing nerve regeneration in a trial of timcodar dimesylate. Neurology 2006;66:259�261. Schiffmann R, Hauer P, Freeman B, et al. Enzyme replacement therapy and intraepidermal innervation density in Fabry disease. Muscle Nerve 2006;34:53�56.

56. References 21. Dyck PJ, Karnes JL, O�Brien PC, Litchy WJ, Low PA, Melton LJ. The Rochester Diabetic Neuropathy Study: Reassessment of tests and criteria for diagnosis and staged severity. Neurology 1992;42:1164�1170. (Class II) For a complete list of references, please access the full guideline at www.aan.com/guidelines

57. Questions/Comments

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