Transcript Practice Parameter or Technology Assessment: TITLE (an

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
© 2008 American Academy of Neurology
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© 2008 American Academy of Neurology
Presentation Objectives
• To review the evidence for the role of the
following in assessing DSP:
- Laboratory, genetic, and autonomic testing
- Nerve biopsy
- Skin biopsy
• To present evidence-based
recommendations
© 2008 American Academy of Neurology
Overview
•
•
•
•
Background
Gaps in care
AAN guideline process
Analysis of evidence, conclusions,
recommendations
• Recommendations for future research
© 2008 American Academy of Neurology
Background
• DSP is the most common type of neuropathy.
• Prevalence is approximately 2,400 (2.4%) per
100,000 population but rises to approximately
8,000 (8%) per 100,000 in individuals older than
55 years.1,2
• Simple screening laboratory tests, along with
medical history, neurological examination, and
EDX studies, reveal the cause of DSP in 74 to
82% of patients with polyneuropathy.3–12
© 2008 American Academy of Neurology
Background
• Common causes include diabetes, alcohol
abuse, poor nutrition, and genetics.
- Expressed as decreased or absent ankle reflexes,
decreased distal sensation, distal muscle
weakness/atrophy, and abnormal nerve conduction
studies (NCSs)13
- Usually constitute evidence of “large fiber” sensory
and motor involvement.
© 2008 American Academy of Neurology
Background
• DSP can involve the autonomic nervous system.
- Expressed as abnormalities of sweating and
circulatory instability in the feet2,13
• Other autonomic neuropathies are not
uncommon.
- Include amyloidosis and autoimmune neuropathy
- Can affect autonomic fibers in isolation or can
precede somatic fiber involvement
- Also include distal small fiber sensory polyneuropathy
(SFSN), causing burning pain in the feet
© 2008 American Academy of Neurology
Gaps in Care
• Since there are many etiologies of
polyneuropathy, a logical clinical approach is
needed for evaluation and management.
• DSP diagnosis should be based on a
combination of clinical symptoms, signs, and
electrodiagnostic criteria.
• Laboratory test results must be interpreted within
the larger clinical context since the tests’ low
specificity limits their etiologic yield.13
© 2008 American Academy of Neurology
AAN Guideline Process
Clinical Question
Evidence
Conclusions
Recommendations
© 2008 American Academy of Neurology
Clinical Questions
• The first step of developing guidelines is to
clearly formulate questions to be answered.
• Questions address areas of controversy,
confusion, or variation in practice.
• Questions must be answerable with data
from the literature.
• Answering the question must have the
potential to improve care/patient outcomes.
© 2008 American Academy of Neurology
Literature Search/Review
Rigorous, Comprehensive, Transparent
Complete
Search
Review abstracts
Review full text
Select articles
Relevant
© 2008 American Academy of Neurology
AAN Classification of
Evidence
• All studies rated Class I, II, III, or IV
• Five different classification systems:
– Therapeutic
• Randomization, control, blinding
– Diagnostic
• Comparison to gold standard
– Prognostic
– Screening
– Causation
© 2008 American Academy of Neurology
AAN Level of
Recommendations
• A = Established as effective, ineffective or harmful (or
established as useful/predictive or not useful/predictive)
for the given condition in the specified population.
• B = Probably effective, ineffective or harmful (or
probably useful/predictive or not useful/predictive) for the
given condition in the specified population.
• C = Possibly effective, ineffective, or harmful (or
possibly useful/predictive or not useful/predictive) for the
given condition in the specified population.
• U = Data inadequate or conflicting; given current
knowledge, treatment (test, predictor) is unproven.
Note that recommendations can be positive or negative.
© 2008 American Academy of Neurology
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.
© 2008 American Academy of Neurology
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).
© 2008 American Academy of Neurology
Applying This Process
to the Issue
We will now turn our attention to the
guidelines.
© 2008 American Academy of Neurology
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?
© 2008 American Academy of Neurology
Clinical Questions
4. What is the usefulness of clinical autonomic
testing in the evaluation of polyneuropathy,
and which tests have the highest sensitivity
and specificity?
5. What is the usefulness of nerve biopsy in
determining the etiology of distal symmetric
polyneuropathy?
6. What is the usefulness and diagnostic
accuracy of skin biopsy in the evaluation of
polyneuropathy?
© 2008 American Academy of Neurology
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
© 2008 American Academy of Neurology
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).
© 2008 American Academy of Neurology
Methods
• Strength of practice recommendations
were linked directly to levels of evidence
(Levels A, B, C, and U).
• Conflicts of interest were disclosed.
© 2008 American Academy of Neurology
Literature Review
Laboratory and
genetic testing
4,500 abstracts
450 articles
© 2008 American Academy of Neurology
Inclusion criteria:
- Relevant to the clinical
questions
- Limited to human
subjects
- Bibliographies, articles
identified by panel
members
Exclusion criteria:
- Articles not relevant to
evaluation of
polyneuropathy
Literature Review
1,045 abstracts
106 articles
© 2008 American Academy of Neurology
Autonomic testing,
nerve biopsy, and
skin biopsy
Inclusion criteria:
- Relevant to the clinical
questions
- Limited to human
subjects
- Bibliographies, articles
identified by panel
members
Exclusion criteria:
- Articles not relevant to
evaluation of
polyneuropathy
AAN Classification of Evidence
for Diagnosis
• 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.
© 2008 American Academy of Neurology
AAN Classification of Evidence
for 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.
© 2008 American Academy of Neurology
AAN Classification of Evidence
for 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.
© 2008 American Academy of Neurology
Analysis of Evidence
Question 1: What is the yield of
screening laboratory tests in the
evaluation of DSP, and which tests
should be performed?
© 2008 American Academy of Neurology
Conclusion/Recommendation
Conclusion: Screening laboratory tests are probably
useful in determining the cause of DSP, but the yield
varies depending upon the particular test (Class III).
Recommendation: Screening laboratory tests may
be considered for all patients with DSP (Level C).
© 2008 American Academy of Neurology
Conclusion/Recommendation
Conclusion: 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).
Recommendation: 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).
© 2008 American Academy of Neurology
Conclusion/Recommendation
Conclusion: 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).
Recommendation: 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 (Level C).
© 2008 American Academy of Neurology
Recommendation
Recommendation: 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.
© 2008 American Academy of Neurology
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?
© 2008 American Academy of Neurology
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.
© 2008 American Academy of Neurology
Recommendation
Recommendation: Genetic testing may be
considered in patients with a cryptogenic polyneuropathy
and classical hereditary neuropathy phenotype (Level
C).
© 2008 American Academy of Neurology
Clinical Context
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.
© 2008 American Academy of Neurology
Figure 1
© 2008 American Academy of Neurology
Conclusion/Recommendation
Conclusion: There is insufficient evidence to
determine the usefulness of routine genetic screening in
cryptogenic polyneuropathy patients without a classical
hereditary neuropathy phenotype.
Recommendation: 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).
© 2008 American Academy of Neurology
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?
© 2008 American Academy of Neurology
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).
© 2008 American Academy of Neurology
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).
© 2008 American Academy of Neurology
Analysis of Evidence
Question 5: What is the usefulness of
nerve biopsy in determining the
etiology of distal symmetric
polyneuropathy?
© 2008 American Academy of Neurology
Conclusion/Recommendation
Conclusion: There is no evidence to support or refute
a conclusion regarding the role of nerve biopsy in the
evaluation of DSP (Class IV).
Recommendation: No recommendations can be
made regarding the role of nerve biopsy in determining
the etiology of DSP (Level U).
© 2008 American Academy of Neurology
Analysis of Evidence
Question 6: What is the usefulness and
diagnostic accuracy of skin biopsy in
the evaluation of polyneuropathy?
© 2008 American Academy of Neurology
Conclusion/Recommendation
Conclusion: 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).
Recommendation: For symptomatic patients with
suspected polyneuropathy, skin biopsy may be
considered to diagnose the presence of a
polyneuropathy, particularly SFSN (Level C).
© 2008 American Academy of Neurology
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
© 2008 American Academy of Neurology
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
© 2008 American Academy of Neurology
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
© 2008 American Academy of Neurology
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
© 2008 American Academy of Neurology
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),
© 2008 American Academy of Neurology
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© 2008 American Academy of Neurology
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
© 2008 American Academy of Neurology
Future Research
– Further studies are needed to validate and determine
the value of skin biopsy for this purpose.21
© 2008 American Academy of Neurology
References
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Martyn CN, Hughes RAC. Epidemiology of peripheral neuropathy.
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England JD, Asbury AK. Peripheral neuropathy. Lancet
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Barohn RJ. Approach to peripheral neuropathy and myopathy.
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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 workup in peripheral neuropathy: An analysis of 171 cases. Postgrad
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Wolfe GI, Baker NS, Amato AA, et al. Chronic cryptogenic
sensory polyneuropathy: clinical and laboratory characteristics.
Arch Neurol 1999;56:540–547. (Class III)
© 2008 American Academy of Neurology
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GW, Jennekens FG. Chronic idiopathic axonal polyneuropathy: a
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Dyck PJ, Oviatt KF, Lambert EH. Intensive evaluation of referred
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© 2008 American Academy of Neurology
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Johannsen L, Smith T, Havsager A-M, et al. Evaluation of patients
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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
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Li J, Bai Y, Ghandour K, et al. Skin biopsies in myelin-related
neuropathies: bringing molecular pathology to the bedside. Brain
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Sousa MM, Ferrao J, Fernandes R, et al. Deposition and
passage of transthyretin through the blood-nerve barrie in
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© 2008 American Academy of Neurology
References
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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
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Tseng MT, Hsieh SC, Shun Ct, et al. Skin denervation and
cutaneous vasculitis in systemic lupus erythematosus. Brain
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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
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Muscle Nerve 2006;34:53–56.
© 2008 American Academy of Neurology
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Dyck PJ, Karnes JL, O’Brien PC, Litchy WJ, Low PA, Melton LJ.
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For a complete list of references, please access the full
guideline at www.aan.com/guidelines
© 2008 American Academy of Neurology
Questions/Comments
© 2008 American Academy of Neurology
Thank you for your
participation!
© 2008 American Academy of Neurology