Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
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
Overview
Background
Gaps in care
AAN guideline process
Analysis of evidence, conclusions,
recommendations
Recommendations for future research
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.312
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.
Background
DSP can involve the autonomic nervous system.
- Expressed as abnormalities of sweating and
circulatory instability in the feet2,13
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
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.
Literature Search/Review
Rigorous, Comprehensive, Transparent
Complete
Search
Review abstracts
Review full text
Relevant
2008 American Academy of Neurology
Select articles
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
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).
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?
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?
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
Methods
Strength of practice recommendations
were linked directly to levels of evidence
(Levels A, B, C, and U).
Conflicts of interest were disclosed.
Literature Review
Laboratory and
genetic testing
4,500 abstracts
450 articles
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
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
Analysis of Evidence
Question 1: What is the yield of
screening laboratory tests in the
evaluation of DSP, and which tests
should be performed?
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).
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).
Conclusion/Recommendation
Conclusion: Patients with distal symmetric sensory
Recommendation
Recommendation: Although there are no control
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?
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.
Recommendation
Recommendation: Genetic testing may be
considered in patients with a cryptogenic polyneuropathy
and classical hereditary neuropathy phenotype (Level
C).
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.
Figure 1
Conclusion/Recommendation
Conclusion: There is insufficient evidence to
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?
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).
Recommendations
Recommendations: Autonomic testing should be
Analysis of Evidence
Question 5: What is the usefulness of
nerve biopsy in determining the
etiology of distal symmetric
polyneuropathy?
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).
Analysis of Evidence
Question 6: What is the usefulness and
diagnostic accuracy of skin biopsy in
the evaluation of polyneuropathy?
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).
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
Future Research
is a need to determine whether aggressive treatment or reversal
of specific laboratory abnormalities improves or alters the
course of polyneuropathy.
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.
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.
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.
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 Fabrys disease. 1518
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
Future Research
Further studies are needed to validate and determine
the value of skin biopsy for this purpose.21
References
1.
2.
3.
4.
5.
6.
References
7.
8.
9.
10.
11.
References
12.
13.
14.
15.
References
16.
17.
18.
19.
20.
References
21.
Dyck PJ, Karnes JL, OBrien PC, Litchy WJ, Low PA, Melton LJ.
The Rochester Diabetic Neuropathy Study: Reassessment of
tests and criteria for diagnosis and staged severity. Neurology
1992;42:11641170. (Class II)
Questions/Comments