Distaal Sym
mmetrric Poolyneuuropatthy
J. D. England, MD
D, G. S. Grronseth, MD,
M G. Fran
nklin, MD,, R. G. Milller, MD, A
A. K.
y, MD, G. T.
T Carter, MD,
M J. A. Cohen,
C
MD
D, M. A. Fiisher, MD, J. F. Howaard,
Asbury
MD, L. J. Kinsellla, MD, N. Latov, MD
D, R. A. Lew
wis, MD, P
P. A. Low, MD, and A
A. J.
Sumn
ner, MD, K
K. S
No one in
nvolved in thee planning of this CME actiivity have anyy relevant finaancial relationships to discclose. Autthors/faculty have nothingg to disclose.
CM
ME is availablle 8/31/2009 - 8/31/2012
Copy
yright: 20005
America
an Associatio
on of Neurom
muscular and
d Electrodiaggnostic Mediicine
2621 Superior
S
Dr NW
N Rochestter, MN 55901
ons in this Praactice Guideliine are solelyy those of the author and doo not necessarily
The ideeas and opinio
represent th
hose of the AA
ANEM
Producct: PP08 ME Informatio
on CM
Prroduct: PP08 ‐ Distal Symme
etric Polyneuro
opathy ourse Descripttion Co
Distal symmetric polyneuropathy (DSP) is the most commo
on variety of n europathy. Sin
nce the evaluattion of this disorder is not he available litterature was reviewed r
to provide evidencce‐based guideelines regardin
ng the role off autonomic sttandardized, th
teesting, nerve biopsy, and skin
n biopsy for the
e assessment o
of polyneuropaathy. In
ntended Audience Th
his course is intended for Neurologists,, Physiatrists, and others w
who practice neuromuscular, musculoskkeletal, and electrodiagnostic medicine with w
the intent to improve the quality oof medical carre to patientss with muscle and nerve diisorders. Leearning Objecttives Upon conclusion
n of this prograam, participants should be ab
ble to: 1. acknow
wledge recomm
mendations for the evaluatio
on of distal sym
mmetric polyn
neuropathy(DSSP) based on aa prescribed review and analysis o
of the peer‐reviewed literature. be the role of laaboratory and genetic tests ffor the assessm
ment of polyneeuropathy. 2. describ
3. recognize evidence‐b
based guideline
es regarding th
he role of autoonomic testingg, nerve biopsyy, and skin bio
opsy for the ment of polyne
europathy. assessm
Reelease Date: 8/31/2009 Exxpiration Date
e: 8/31/2012. YYour request to
o receive AMA PRA Category 1 Credits™ mu
ust be submitteed on or beforre the credit exxpiration date. Duration/Comp
pletion Time: 3
3 hours nd Designation
n Statements Acccreditation an
Th
he American Association A
of Neuromuscular and Electro
odiagnostic M edicine (AANEEM) is accrediited by the Acccreditation Co
ouncil for Con
ntinuing Mediccal Education to t provide con
ntinuing mediccal education for physicianss. The AANEM designates M bo
oth sections off this enduringg material for aa combined maaximum of 3 A MA PRA Categgory 1 creditsTM
. Physicians should claim on
nly the credit ccommensurate
e with the extent of their partticipation in thhe activity. ow to Obtain C
CME Ho
Once you have reviewed the materials, you
u can obtain C
CME credit by clicking on the link in the ee‐mail received
d when you urchased this p
product. Answ
wer the questio
ons and click su
ubmit. Once yyour answers h
have been subm
mitted, you will be able to pu
view a transcrript of your CME by loggging into ww
ww.aanem.orgg and clickingg View Profile and then My CME.
AAEM PRACTICE TOPIC IN ELECTRODIAGNOSTIC MEDICINE
American Association of Electrodiagnostic Medicine
421 First Avenue S.W., Suite 300 East, Rochester, MN 55902 (507/288-0100)
ABSTRACT: The objective of this report was to develop a case definition
of “distal symmetrical polyneuropathy” to standardize and facilitate clinical
research and epidemiological studies. A formalized consensus process was
employed to reach agreement after a systematic review and classification of
evidence from the literature. The literature indicates that symptoms alone
have relatively poor diagnostic accuracy in predicting the presence of polyneuropathy; signs are better predictors of polyneuropathy than symptoms;
and single abnormalities on examination are less sensitive than multiple
abnormalities in predicting the presence of polyneuropathy. The combination of neuropathic symptoms, signs, and electrodiagnostic findings provides
the most accurate diagnosis of distal symmetrical polyneuropathy. A set of
case definitions was rank ordered by likelihood of disease. The highest
likelihood of polyneuropathy (useful for clinical trials) occurs with a combination of multiple symptoms, multiple signs, and abnormal electrodiagnostic
studies. A modest likelihood of polyneuropathy (useful for field or epidemiological studies) occurs with a combination of multiple symptoms and multiple signs when the results of electrodiagnostic studies are not available. A
lower likelihood of polyneuropathy occurs when electrodiagnostic studies
and signs are discordant. For research purposes, the best approach for
defining distal symmetrical polyneuropathy is a set of case definitions rank
ordered by estimated likelihood of disease. The inclusion of this formalized
case definition in clinical and epidemiological research studies will ensure
greater consistency of case selection.
Muscle Nerve 31: 113–123, 2005
DISTAL SYMMETRICAL POLYNEUROPATHY:
DEFINITION FOR CLINICAL RESEARCH
J. D. ENGLAND, MD, G. S. GRONSETH, MD, G. FRANKLIN, MD, R. G. MILLER, MD, A. K. ASBURY, MD,
G. T. CARTER, MD, J. A. COHEN, MD, M. A. FISHER, MD, J. F. HOWARD, MD, L. J. KINSELLA, MD,
N. LATOV, MD, R. A. LEWIS, MD, P. A. LOW, MD, and A. J. SUMNER, MD
American Association of Electrodiagnostic Medicine, 421 First Avenue SW,
Suite 300E, Rochester, MN 55902, USA
The
American Association of Electrodiagnostic
Medicine (AAEM) in conjunction with the American
Academy of Neurology (AAN) and the American
Academy of Physical Medicine and Rehabilitation
(AAPM&R) determined that there was a need for a
formal case definition of polyneuropathy. Because of
inconsistency in the literature, no consistent case
definition exists. The use of a formal case definition
across future research studies would ensure greater
consistency of patient selection. This review describes the development of such a case definition for
“distal symmetrical polyneuropathy.”
This article was prepared and reviewed by the AAEM and did not
undergo the separate review process of Muscle & Nerve.
Key words: case definition; clinical research; electrodiagnosis; epidemiology; polyneuropathy
Correspondence to: T. Schmidt; e-mail: [email protected]
This article is a joint report of the American Association of Electrodiagnostic
Medicine, the American Academy of Neurology, and the American Academy
of Physical Medicine and Rehabilitation
Abbreviations: EMG, electromyography; MDNS, Michigan diabetic neuropathy score; MNSI, Michigan neuropathy screening instrument; NCS, nerveconductions study/studies; NDS, neuropathy disability score; NIS-LL, neuropathy impairment score in the lower limbs; QST, quantitative sensory testing
Distal Symmetrical Polyneuropathy
© 2004 American Association of Electrodiagnostic Medicine. Published by
Wiley Periodicals, Inc.
Published online 9 November 2004 in Wiley InterScience (www.interscience.
wiley.com). DOI 10.1002/mus.20233
MUSCLE & NERVE
January 2005
113
Polyneuropathy is a common neurological disorder with a diverse etiology. Although experienced
clinicians can usually diagnose polyneuropathy in
patients presenting with the characteristic history
and classic neurological examination findings, the
exact criteria for diagnosis are not formalized. In
particular, accurate criteria for the diagnosis of “distal symmetrical polyneuropathy” are debated.
The principal purpose of this project was to develop a definition of distal symmetrical polyneuropathy with a reasonably high sensitivity and specificity
that would serve as a basis for future research studies.
Clinicians may find the criteria useful for routine
clinical diagnosis. To achieve greater focus, other
neuropathy phenotypes, including polyradiculopathy, mononeuropathy multiplex, Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and related conditions, were excluded
from the final case definition. Although “small-fiber”
polyneuropathy is an important subset of “distal symmetrical polyneuropathy,” the evidence-based medical literature is insufficient to provide an adequate
case definition for isolated or pure small-fiber polyneuropathy at this time.
The case definition of “distal symmetrical polyneuropathy” described herein is based on a systematic analysis of peer-reviewed literature supplemented by consensus from an expert panel.
PROCESS
The polyneuropathy task
force included 14 physicians with representatives
from the AAN, AAEM, and AAPM&R. All task force
members had extensive experience and expertise in
the area of polyneuropathy. In addition, three physicians with expertise in evidence-based methodology and practice parameter development participated in the project.
Formation of Expert Panel.
The literature search included OVID Medline (1970 to April 2004), OVID
Excerpta Medica (EMBASE; 1980 to April 2004),
and OVID Current Contents (2000 to April 2004).
The search included articles on humans only and in
all languages. The search terms selected were polyneuropathy, distal symmetrical polyneuropathy, distal axonopathy, fiber length– dependent polyneuropathy, and distal axonal loss polyneuropathy. The
search terms, mononeuropathy, mononeuropathy
multiplex, radiculopathy, polyradiculopathy, plexopathy, multifocal motor neuropathy, acute inflammatory demyelinating polyneuropathy, Guillain–
Barré syndrome, and chronic inflammatory deFinding the Best Evidence.
114
Distal Symmetrical Polyneuropathy
myelinating polyneuropathy, were included only
when they appeared in studies wherein the primary
focus was “distal symmetrical polyneuropathy.”
Panel experts were asked to identify additional
articles missed by the initial search strategy. Furthermore, the bibliographies of the selected articles were
reviewed for potentially relevant articles.
Three committee members reviewed the titles
and abstracts of citations identified from this original search for those that were potentially relevant for
defining “distal symmetrical polyneuropathy.” Articles considered potentially relevant by any panel
member were also obtained.
Potentially relevant articles were subsequently reviewed in their entirety by three reviewers and were
included in the initial analysis if they met the following criteria: (1) The study included patients with and
without distal symmetrical polyneuropathy. In order
to assess the likelihood of “spectrum bias,” the characteristics of the comparison group without distal
symmetrical polyneuropathy were noted. Those
studies in which the control group included subjects
with neuropathic features that may mimic or overlap
with “distal symmetrical polyneuropathy” were rated
as more relevant. (2) The patients had a potential
diagnostic predictor (i.e., symptom, sign, or test result) measured. (3) The patients were determined to
have a distal symmetrical polyneuropathy on the
basis of an explicitly defined independent reference
standard (an acceptable standard was not prespecified by panel members). (4) The presentation of the
data in the study allowed calculation of sensitivities
and specificities.
From each study the following methodological
characteristics were abstracted (see Appendix 1,
Glossary of Terms): the study design (case– control,
cross-sectional, cohort survey); the number of patients; the target disorder, including the spectrum of
severity of the target disorder; the diagnostic predictor(s); the reference standard employed; whether
the reference standard was measured without knowledge of the result of the diagnostic predictor; the
proportion of patients with the target disorder who
were positive for the diagnostic predictor (sensitivity); and the proportion of patients without the target disorder who were negative for the diagnostic
predictor (specificity).
Each reviewer graded the risk of bias in each
study by using the diagnostic test classification-ofevidence scheme in Appendix 2. In this scheme,
articles attaining a grade of Class IV are judged to
have the highest risk of bias, and articles attaining
Class I are judged to have the lowest risk of bias. Only
studies attaining a grade of Class I, II, or III were
MUSCLE & NERVE
January 2005
Table 1. Estimated likelihood of distal symmetrical polyneuropathy for case definitions that include symptoms, signs, and nerve conduction
studies (recommendations for clinical research studies).
Neuropathic
symptoms
Decreased or absent
ankle reflexes*
Decreased distal
sensation
Distal muscle weakness
or atrophy
NCS†
Present
Present
Present
Present
Absent
Present
Absent
Absent
Present
Present
Absent
Present§
Present
Present
Present
Absent
Present
Absent
Absent
Absent
Absent
Present
Present‡
Present§
Present
Present
Absent
Absent
Absent
Present
Absent
Absent
Absent
Absent
Absent
Present§
Abnormal
Abnormal
Abnormal
Abnormal
Abnormal
Abnormal
Abnormal
Abnormal
Abnormal
Normal
Normal‡
Normal§
Present
Absent
Present
Present
Present
Absent
Present
Absent
Absent
Present
Present‡
Present§
Ordinal
likelihood
⫹⫹⫹⫹
⫹⫹⫹⫹
⫹⫹⫹⫹
⫹⫹⫹⫹
⫹⫹⫹⫹
⫹⫹⫹
⫹⫹⫹
⫹⫹
⫹⫹
⫹⫹
⫹
⫺
Neuropathic symptoms: numbness, altered sensation, or pain in the feet. NCS, nerve conduction studies. For clinical research studies enrollment should be
limited to cases above the bold horizontal line (i.e., ⫹⫹⫹⫹).
*Ankle reflexes may be decreased in normal individuals ⬎65–70 years.
†
Abnormal NCS is defined in text.
‡
This phenotype is common in “small-fiber” sensory polyneuropathy. Determination of intraepithelial nerve fiber density in skin biopsy may be useful to confirm
the diagnosis (see text).
§
This phenotype in the presence of normal NCS is not a distal symmetrical polyneuropathy. This situation is given a negative (⫺) ordinal likelihood because the
condition cannot be classified as a distal symmetrical polyneuropathy. It is included here to emphasize the importance of including NCS as part of the case
definition for clinical research studies.
further considered in the analysis. In the grading of
studies, electrodiagnostic studies were considered an
“objective” outcome. Disagreements among the reviewers regarding an article’s grade were resolved
through discussion.
A formal consensus process
(nominal group process)12,22 was used to develop the
case definition. Because there is no single “gold
standard” that defines distal symmetrical polyneuropathy, the case definition must account for different levels of certainty for the presence or absence of
the disorder. In line with this goal, participants were
given several guidelines for developing a case definition. The case definition should: (1) be restricted
to “distal symmetrical polyneuropathy”; (2) serve as a
definition for the identification of cases in research
studies; (3) acknowledge varying levels of diagnostic
certainty by including a set of case definitions rank
ordered by estimated ordinal likelihood of disease;
(4) be simple, practical, and widely applicable by
practicing clinicians; and (5) be based, as much as
possible, on current best evidence.
Through several face-to-face meetings, electronic
mail, and telephone conferences, committee members reviewed the results of the literature review and
proposed case definitions of varying ordinal likelihood of distal symmetrical polyneuropathy. Points of
agreement and disagreement were identified, discussed, and resolved. The elements of the proposed
Consensus Process.
Distal Symmetrical Polyneuropathy
case definitions were repeatedly tested against the
conclusions from the literature review. What evolved
from this process was an ordered set of case definitions ranked by likelihood of disease. The essence of
the case definition procedure is shown in Tables 1
and 2.
The Quality Standards Subcommittee of the
AAN, the Practice Issues Review Panel of the AAEM,
and the Practice Guidelines Committee of the
AAPM&R (Appendix 3), reviewed and approved a
draft of this paper with the proposed case definition.
The draft was then sent to members of the AAN,
AAEM, and AAPM&R for further review and then to
the journal Neurology for peer review. Boards of the
AAN, AAEM, and AAPM&R reviewed and approved
the final version of the paper. At each step of the
review process, external reviewers’ suggestions were
explicitly considered. When appropriate, the expert
panel made changes to the document.
EVIDENCE
The search yielded 1450 references. After reviewing
titles and abstracts, 61 articles were retrieved and
reviewed in their entirety. After comprehensive review of these papers, 12 articles attained a grade of
Class I, II, or III.2,3,7–10,15,17,18,24 –26 These articles
serve as the major evidence basis for the case definition and are tabulated in Table 3.
MUSCLE & NERVE
January 2005
115
Table 2. Estimated likelihood of distal symmetrical polyneuropathy for case definitions that include only symptoms and signs
(recommendations for field or epidemiological studies).
Neuropathic
symptoms
Present
Present
Present‡
Present
Absent
Decreased or absent
ankle reflexes*
Decreased distal
sensation
Distal muscle weakness
or atrophy
NCS†
Ordinal
likelihood
Present
Present
Absent
Absent
Present
Present
Present
Present‡
Absent
Absent
Present
Absent
Absent
Absent
Absent
ND
ND
ND
ND
ND
⫹⫹
⫹⫹
⫹
⫹
⫹
Neuropathic symptoms: numbness, altered sensation, or pain in the feet NCS, nerve conduction studies. For field epidemiology studies enrollment should be
limited to cases above the bold horizontal line (i.e., ⫹⫹).
*Ankle reflexes may be decreased in normal individuals ⬎65–70 years.
†
Nerve conduction studies (NCS) are not included as part of the case definitions for epidemiology studies. ND, not done.
‡
This phenotype is common in “small-fiber” sensory polyneuropathy. Determination of intraepithelial nerve fiber density in skin biopsy may be useful to confirm
the diagnosis (see text).
Study Characteristics. Diabetic peripheral neuropathy, which is the most prevalent and rigorously
studied type of distal symmetrical polyneuropathy,
was the target disorder in most studies. There is a
relative lack of high-quality evidence for other varieties of distal symmetrical polyneuropathy. However,
three of the studies (25% of the total) focused on
cryptogenic sensory peripheral neuropathy. Although limited in quantity, the quality of the articles
was high and allowed the development of a case
definition for “distal symmetrical polyneuropathy.”
The diagnostic predictors studied varied. Several
articles described the diagnostic accuracy of single
symptoms including foot numbness, foot pain, and
complaints of “sensory alteration.” In addition, some
articles measured the accuracy of more complex
composite symptom checklists. The accuracy of single examination elements was also determined.
These included absent ankle reflexes, decreased distal lower extremity strength, and decreased vibration
or cold detection. Some articles also measured the
accuracy of composite examinations that included
two or more examination elements.
The studies used different reference standards to
determine the presence of a symmetric distal peripheral neuropathy. These included nerve conduction
studies (NCS), a clinician’s global impression, and
composite clinical examination scores.
All studies collected data prospectively. Most
were cohort surveys, but some used a case– control
design. Four studies described measuring the presence of a polyneuropathy using the reference standard in a fashion that was masked to measurement of
the diagnostic predictor. Two studies attained a
grade of Class I,8,9 five attained a grade of Class
II,2,10,15,18,25 and five attained a grade of Class
III.3,7,17,24,26
116
Distal Symmetrical Polyneuropathy
The diagnostic accuracy of
the predictors was determined by calculating their
sensitivities and specificities. One way of displaying
these data is to plot sensitivities against specificities
in a receiver operator characteristics (ROC) curve
(Fig. 1).
Predictors encompassing a single specific symptom such as foot numbness have low sensitivity but
high specificity for the presence of polyneuropathy.
Predictors incorporating the presence of any one of
a number of neuropathic symptoms, such as the
presence of foot numbness or pain, attain a greater
sensitivity but have lower specificity.
Particular single examination findings, such as
absent ankle tendon reflexes, have moderate sensitivity and high specificity for the presence of polyneuropathy. When individual examination findings
are combined into a composite examination score,
higher diagnostic accuracy results. The examination
scores with the highest sensitivity and specificity include the screening examination used in the San
Luis Valley Diabetes Study,8 the neuropathy disability score (NDS),2– 6 the neuropathy impairment
score in the lower limbs (NIS-LL),3 the Michigan
neuropathy screening instrument (MNSI) the Michigan diabetic neuropathy score (MDNS),7 and two
other well-described clinical examination scores.17,25
Notably, simple composite examination scores are as
accurate as more complex examinations.
The sensitivities and specificities of quantitative
sensory testing (QST) varied widely among studies.
These psychophysical tests have greater inherent
variability, making their results more difficult to standardize and reproduce. Reproducibility of QST varied from poor to excellent.21,23 For these reasons,
QST was not included as part of the final case definition.
Diagnostic Accuracy.
MUSCLE & NERVE
January 2005
Table 3. Studies meeting inclusion criteria.
Article
(reference
number)
9
Target disorder
Diabetic PN
8
Diabetic PN
10
Diabetic PN
18
2
Predictor
Symptom checklist
“pain,” “sensory
alteration,” “feet
numbness”
2 of 3⫹:
symptoms, abn
temp. sens,
2ankle DTRs
Symptom
questionnaire,
neurologic
exam, vibration
detection
Chronic
symmetric PN
in elderly
Neuropathy
symptoms
Diabetic
neuropathy
Symptom score,
disability score,
vibration
detection, cold
detection
Reference
standard
Clinical exam
score ⬎4
Cases
Controls
Design
Spectrum
Masked
Class
Sensitivity
(%)
Specificity
(%)
188
400
Ch
B
Y
1
18
91
91
93
91
Neurologist
clinical
evaluation
15
23
Ch
B
Y
1
26
28
87
NCS
47
157
Ch
N
ND
2
87
60
92
9718
82
Bilateral
impaired
sensation,
strength, or
DTR
Two or more
abn NCS
11
9
CC
B
Y
2
94
64
78
125
55
Ch
N
ND
2
70
84
91
86
87
43
Ch
N
Y
2
65
59
44
100
50
Ch
B
ND
3
43
96
76
51
11
11
CC
N
ND
3
100
18
48
47
CC
N
ND
3
100
60
91
85
3
40
75
69
15
11
87
60
91
96
58
91
83
15
Diabetic PN
Vibration detection
threshold,
thermal
threshold
Clinically overt
neuropathy
17
Diabetic PN
Neuropathy exam
23
26
CIAP vs. CIDP
Absent ankle
DTRs, ⫹ biceps
and ⫺ ankle
DTRs
Monofilaments
vibration
detection
Published
criteria
24
CIAN vs. HSMN
Onset sensory,
onset motor,
absent ankle
DTR
Family history
3
Diabetic
polyneuropathy
NIS-LL
NIS-LL ⫹ 7
tests
58
137
Ch
B
ND
Abn ankle DTR,
Abn vibration,
One or more
abn NCS, Two
or more abn
NCS
25
7
Diabetic
polyneuropathy
Diabetic
polyneuropathy
Exam scoring
system
Symptoms,
sensory exam,
strength exam,
reflexes,
composite
exam, screening
exam
NCS
Mayo criteria
49
29
Ch
N
ND
2
17
93
81
88
Ch
B
ND
3
74
55
74
59
80
80
80
100
100
100
100
95
Abn, abnormal; B, broad spectrum of patients included; CC, case control; Ch, cohort survey; CIAN, chronic idiopathic ataxic polyneuropathy; CIAP, chronic idiopathic axonal
neuropathy; CIDP, chronic inflammatory demyelinating polyneuropathy; DTRs, deep tendon reflexes; HSMN, hereditary sensory motor neuropathy; LL, lower limb; N, narrow
spectrum of patients included; NCS, nerve conduction studies; ND, not described; NIS, neuropathy impairment score; PN, peripheral neuropathy; Sens, sensitivity; Spec,
specificity; temp, temperature; Y, yes; ⫹, positive; ⫺, negative; 2, decreased.
Distal Symmetrical Polyneuropathy
MUSCLE & NERVE
January 2005
117
FIGURE 1. The diagnostic accuracy levels of symptoms, signs, or combinations of symptoms or signs (predictors) for the presence
of distal symmetric polyneuropathy are expressed. Predictors are plotted according to their sensitivity and specificity. Points plotted
near the top of the graph correspond to predictors with high sensitivity for distal symmetric polyneuropathy. Points plotted near the
left side of the graph correspond to predictors with high specificity. Thus, points nearest the upper left-hand corner correspond to
predictors with the highest diagnostic accuracy (both high sensitivity and specificity) for distal symmetric polyneuropathy. Points
falling near the diagonal line correspond to predictors with low diagnostic accuracy. Diamonds: diagnostic accuracy of symptoms;
triangles: signs; shaded ⫹ or X symbols: quantitative sensory tests. Points describing the diagnostic accuracy of a single symptom
(e.g., “numbness”) or a single examination finding (e.g., absent ankle reflexes) are enclosed by dashed ovals and circles. Points
describing the diagnostic accuracy of more than one symptom (e.g., “numbness” or “pain”) or more than one sign (e.g., “absent
ankle reflexes” or “decreased distal sensation”) are not enclosed in dashed ovals and circles. The number just to the upper right of
each plotted point indicates the study (reference no.) from which the sensitivity and specificity of that predictor was obtained.
The sensitivities and specificities of quantitative
autonomic testing are relatively high for documenting the presence or absence of autonomic dysfunction.3,4 However, these tests are not routinely performed at all medical centers. Because a usable case
definition must be based on tests that are simple,
practical, and easily available, quantitative autonomic testing is not included as part of the final case
definition.
Evidence-Based Conclusions for the Case Definition.
Using the definitions for strength of recommendation (Appendix 4) the following conclusions and
recommendations can be supported from formal
analysis and classification of the literature:
2.
3.
4.
5.
1. Symptoms alone have relatively poor diagnostic
accuracy in predicting the presence of polyneuropathy. Multiple neuropathic symptoms are
118
Distal Symmetrical Polyneuropathy
more accurate than single symptoms and should
be weighted more heavily (Level B).
Signs are better predictors of polyneuropathy
than symptoms and should be weighted more
heavily (Level B).
A single abnormality examination is less sensitive
than multiple abnormalities in predicting the
presence of polyneuropathy; therefore, an examination for polyneuropathy should look for a
combination of signs (Level B).
Relatively simple examinations are as accurate in
diagnosing polyneuropathy as complex scoring
systems; therefore, the case definition can use
simple examinations without compromising accuracy (Level B).
There is too much inconsistency among the studies describing the accuracy of QST for its incorporation into the case definition (Level U).
MUSCLE & NERVE
January 2005
CONSENSUS-BASED PRINCIPLES
The concept of distal symmetrical polyneuropathy
requires a clear definition of “distal” and “symmetrical” in the context of polyneuropathy. Distal refers to
those parts most distant from the center of the body.
The polyneuropathy must begin in the feet. “Symmetrical” indicates that the symptoms and signs are
the same on both sides of the body. Persistent or
striking asymmetry of symptoms or signs is inconsistent with the case definition. The case definition
must encompass a description of symptoms and signs
with an easily recognizable phenotype.
Symptoms may be primarily sensory,
primarily motor, or both.3,7–9,17,18,24 Symptoms begin
distally in the feet. Sensory symptoms are either
persistent or intermittent alterations of sensation
initially involving the toes or feet. Occasionally, an
isolated digital sensory neuropathy affecting one or
more toes may be difficult to distinguish from an
early polyneuropathy. The differentiation may be
discernible only with time. Frequently described sensory symptoms include numbness, burning, prickling paresthesias, dysesthesias, and allodynia. When
motor symptoms are the first manifestation of polyneuropathy, the patient may note weakness in the
distal legs. Distal symmetrical polyneuropathy may
be asymptomatic, especially in its early stage. An
asymptomatic presentation is more likely when positive sensory symptoms, such as dysesthesias or paresthesias, are lacking, or when motor deficits alone
are the presenting features. A number of symptom
questionnaires and methods for scoring symptoms
have been described.2,3,7–10,15,17,18,24 –26
Symptoms.
Signs of distal symmetrical polyneuropathy
evident on clinical examination may include abnormalities of primary sensory modalities (pain, touch,
hot, cold, vibration, and proprioception), the motor
system (weakness and atrophy), tendon reflexes (especially depressed or absent ankle jerks), or the
autonomic system.
Signs of sensory loss occur in an acral, nondermatomal, nonsingle-nerve distribution. Sensory
symptoms and their concomitant signs evolve in a
centripetal manner.
Motor signs may include atrophy and weakness of
intrinsic foot muscles and associated foot deformities such as hammer toes and pes cavus. Because pes
cavus does not always indicate a polyneuropathy, it
alone is not sufficient evidence of polyneuropathy.
With centripetal progression of motor involvement,
Signs.
Distal Symmetrical Polyneuropathy
weakness of toe dorsiflexion followed by weakness of
foot dorsiflexion can be expected.
Tendon reflexes are often depressed or unelicitable. Ankle jerks that are relatively depressed or
unelicitable are valuable signs of polyneuropathy;
however, the interpretation of such findings requires
considerable clinical experience and judgment. In
addition, other possible causes of depressed or absent ankle jerks, such as S-1 radiculopathy, focal
neuropathies, and age-related decreases, must be
excluded.
Signs of autonomic nervous system involvement
may also constitute findings consistent with a distal
symmetrical polyneuropathy if small fibers are affected. Autonomic dysfunction should begin distally
and may include abnormalities of sweating or circulatory instability in the feet.
Studies. No single “reference
standard” defines distal symmetrical polyneuropathy. The most accurate diagnosis of distal symmetrical polyneuropathy comprises a combination of
clinical symptoms, signs, and electrodiagnostic findings. Electrodiagnostic findings should be included
as part of the case definition because they provide a
higher level of specificity for the diagnosis.3,5,7,24
Electrodiagnostic studies are sensitive, specific,
validated measures of the presence of polyneuropathy.2,3,4,5,7,10,19,20,24 Electrodiagnostic evaluations
commonly include both NCS and needle electromyography (EMG). In the diagnosis of polyneuropathy, NCS are the most informative part of the
electrodiagnostic evaluation.4,5,7,10,19,20,24 NCS are
noninvasive, standardized, and provide a sensitive
measure of the functional status of sensory and motor nerve fibers. NCS are also widely performed and
suitable for population studies or longitudinal evaluations. The inclusion of NCS in the assessment of
polyneuropathy adds a higher level of specificity to
the diagnosis.3,5,7,24 For these reasons, NCS are included as an integral part of the case definition of
polyneuropathy.
The protocol for performing NCS was determined by the structured consensus process described previously. There are have been many recommendations regarding NCS criteria for the
diagnosis of polyneuropathy, but no formal consensus exists. The recommendations that follow are
based on electrophysiological principles that combine both the highest sensitivity and specificity as
well as the highest efficiency for the diagnosis of
distal symmetrical polyneuropathy.
Electrodiagnostic
MUSCLE & NERVE
January 2005
119
Recommended Protocol for Nerve Conduction Studies.
The following set of sensory and motor NCS should be
performed if patients are entering a clinical research
trial in which NCS will be tracked longitudinally. This
protocol includes unilateral studies of sural sensory,
ulnar sensory, and median sensory nerves, and peroneal, tibial, median, and ulnar motor nerves with F
waves. Other NCS may be necessary as determined by
clinical judgment. The minimum case definition criterion for electrodiagnostic confirmation of distal symmetrical polyneuropathy is an abnormality (ⱖ99th or
ⱕ1st percentile) of any attribute of nerve conduction
in two separate nerves, one of which must be the sural
nerve. Electrodiagnostic studies should follow rigorous
guidelines such as those set by the AAEM.1 Variables
such as skin temperature, age, height, gender, and
weight should be measured and accounted for when
reporting a NCS as normal or abnormal.1
A simplified NCS protocol may be used for the
purpose of defining the presence of distal symmetrical polyneuropathy. However, the abbreviated protocol is not sufficient to determine the subtype or
severity of the polyneuropathy. For these purposes,
as well as for clinical trials in which electrodiagnostic
measures will be tracked serially, the more comprehensive set of NCS is recommended.
The simplified NCS protocol is as follows:
1. Sural sensory and peroneal motor NCS are performed in one lower extremity. Taken together,
these NCS are the most sensitive for detecting a
distal symmetrical polyneuropathy. If both studies
are normal, there is no evidence of typical distal
symmetrical polyneuropathy. In such a situation,
no further NCS are necessary.
2. If sural sensory or peroneal motor NCS are abnormal, then additional NCS are recommended. This
should include NCS of at least the ulnar sensory,
median sensory, and ulnar motor nerves in one
upper extremity. A contralateral sural sensory and
one tibial motor NCS may also be performed according to the discretion of the examiner. Caution
is warranted when interpreting median and ulnar
studies because there is a possibility of abnormality
due to compression of these nerves at the wrist or
ulnar neuropathy at the elbow.
3. If a response is absent for any of the nerves studied (sensory or motor), NCS of the contralateral
nerve should be performed.
4. If a peroneal motor response is absent, an ipsilateral tibial motor NCS should be performed.
Minimal criteria for the electrodiagnostic confirmation of distal symmetrical polyneuropathy are the
same as those listed previously.
120
Distal Symmetrical Polyneuropathy
COMBINING EVIDENCE AND CONSENSUS: CASE
DEFINITION OF DISTAL SYMMETRICAL
POLYNEUROPATHY
The best approach for defining distal symmetrical
polyneuropathy is an ordered set of definitions
ranked by likelihood of disease. The likelihood of
distal symmetrical polyneuropathy was rated on an
ordinal scale from highest likelihood (⫹⫹⫹⫹) to
lowest likelihood (⫹). Because diagnostic certainty
for polyneuropathy follows a continuum of probability, this manner of definition is the most sensible. In
each set of case definitions a hierarchy of parameter
combinations was established to provide the most
relevant combinations for the diagnosis of distal symmetrical polyneuropathy. Combinations of parameters that were considered clinically unusual and not
appropriate for research studies were not included.
For these reasons not every possible combination of
parameters is presented.
The essential characteristics of the case definition are given in Tables 1 and 2. Important aspects of
the case definition that warrant emphasis include:
1. The combination of neuropathic symptoms,
signs, and abnormal electrodiagnostic studies
provides the most accurate diagnosis of distal symmetrical polyneuropathy (Table 1).
2. Electrodiagnostic studies are recommended as
part of the clinical research case definition (Table
1) because they are objective and validated tests
of peripheral nerve function. Abnormal electrodiagnostic studies increase the likelihood of the
presence of distal symmetrical polyneuropathy
and provide a higher level of specificity to the
case definition. Electrodiagnostic studies should
not be used alone to make the diagnosis because
their sensitivity and specificity are not perfect.
3. Electrodiagnostic studies are not required for
field or epidemiological studies (Table 2), but the
likelihood of diagnosis must be downgraded accordingly.
4. For research studies, enrollment should be limited to cases that are most likely to have distal
symmetrical polyneuropathy (i.e., those that
achieve the highest specificity for the diagnosis).
For clinical research studies, this consists of cases
with an ordinal likelihood of ⫹⫹⫹⫹ (Table 1).
For epidemiological studies, this consists of cases
with an ordinal likelihood of ⫹⫹ (Table 2).
LIMITATIONS AND FUTURE RESEARCH
This case definition is heavily weighted toward distal
symmetrical polyneuropathy with predominant in-
MUSCLE & NERVE
January 2005
volvement of “large fibers,” and it is not intended to
emphasize the subset of distal symmetrical polyneuropathy termed small-fiber polyneuropathy. Because
this type of polyneuropathy may present with only
pain and numbness in the feet accompanied by few
signs and normal NCS, a formal case definition restricted to small-fiber polyneuropathy is difficult to
develop at this time. This is especially true because
there is no widely available method to confirm the
diagnosis. Determination of intraepithelial nerve fiber density in punch biopsies of skin is a promising
technique.11,13,14,16 Inclusion of small-fiber polyneuropathy in a formal case definition must await further studies.
Another limitation of the case definition is that
most of the available best evidence is restricted to
diabetic peripheral neuropathy. The reason that diabetic neuropathy figures so prominently in the
analysis is that it is the most common and rigorously
studied variety of distal symmetrical polyneuropathy.
The other studies included in the analysis focused
on cryptogenic sensory peripheral neuropathy.
Thus, some uncertainty exists with respect to the
generalization of the case definition for distal symmetical polyneuropathy associated with other etiologies.
The process just described is an attempt to
develop formal criteria for a case definition of
distal symmetrical polyneuropathy. The principal
purpose of the case definition is the identification
of cases for clinical research and epidemiological
studies. The criteria were formulated using a nominal group process in addition to the best available
scientific evidence. Validation and refinement of
these criteria in future studies is encouraged. Specifically, additional studies are needed before conclusions can be made regarding the role of QST
and skin biopsy in the diagnosis of distal symmetrical polyneuropathy. As quantitative autonomic
testing becomes more routinely available, these
tests could easily be incorporated into the case
definition. Future studies should also compare the
criteria delineated in this study with evolving, new
criteria. A major aim of the AAN, AAEM, and
AAPM&R is that the case definition be modified
and refined as new evidence accumulates.
was a specific type of distal symmetrical polyneuropathy (e.g., diabetic peripheral neuropathy).
Reference standard (“gold standard”): The test
or procedure (or series of tests or procedures) performed to determine the actual presence or absence
of a distal symmetrical polyneuropathy.
Nominal group process: A formalized, iterative
method for achieving consensus from a group of
experts that attempts to maximize group reasoning
while preserving individual input.
ROC (receiver operator characteristic) curve: A
standardized graph of sensitivity (true positive rate)
by specificity (true negative rate) designed to depict
diagnostic accuracy and the trade-off between increasing sensitivity and decreasing specificity.
APPENDIX 2: DEFINITIONS FOR STRENGTH OF
EVIDENCE
Class I: Evidence provided by a
prospective study of a broad spectrum of persons
with the suspected condition. The study measures
the diagnostic accuracy of the test using an acceptable independent reference standard for case definition. The test, if not objective, is applied in an
evaluation that is masked to the person’s clinical
presentations and the reference standard is applied
in an evaluation that is masked to the test result.
Class II: Evidence provided by a prospective study
of a narrow spectrum of persons with the suspected
condition, or by a retrospective study of a broad
spectrum of persons with the condition compared
with a broad spectrum of control subjects. The study
measures the diagnostic accuracy of the test using an
acceptable independent reference standard for case
definition. The test is applied in an evaluation that is
masked to the reference standard.
Class III: Evidence provided by a retrospective
study when either the persons with the condition or
the control subjects are of a narrow spectrum. The
study measures the diagnostic accuracy of the test
using an acceptable independent reference standard
for case definition.
Class IV: Evidence provided by expert opinion or
case series without control subjects. Any study not
measuring the diagnostic accuracy of the test using
an acceptable independent reference standard for
case definition.
Diagnostic Evidence.
APPENDIX 1: GLOSSARY OF TERMS
Predictor (diagnostic predictor): A symptom, examination finding, or test result potentially predicting
the presence of a distal symmetrical polyneuropathy.
Target disorder: The condition or disease being
sought. In the current context, the target disorder
Distal Symmetrical Polyneuropathy
APPENDIX 3: REVIEWERS
AAN
Quality
Standards
Subcommittee
Members.
Gary Franklin, MD, MPH—Co-Chair; Catherine
Zahn, MD—Co-Chair; Milton Alter, MD, PhD; Ste-
MUSCLE & NERVE
January 2005
121
phen Ashwal, MD; Richard M. Dubinsky, MD; Jacqueline French, MD; Gary Friday, MD; Michael
Glantz, MD; Gary Gronseth, MD; Deborah Hirtz,
MD; Robert G. Miller, MD; David Thurman, MD;
and William Weiner, MD.
Richard M. Dubinsky, MD, Chair, Michael T. Andary,
MD, MS, Carmel Armon, MD, MHS, MS, William W.
Campbell, MD, Joseph V. Campellone Jr., MD, Earl J.
Craig, MD, Kenneth James Gaines, MD, James
Howard Jr., MD, Robert G. Miller, MD, Atul Patel,
MD, Yuen T. So, MD, PhD, and Robert A. Werner,
MD, MS.
AANEM Practice Issue Review Panel Members.
AAPM&R Guidelines Committee Members.
Hilary
Siebens, MD, Chair, Greg Carter, MD, David Chen,
MD, John Cianca, MD, Gerard Francisco, MD,
Deanna Janora, MD, Bharat Patel, MD, Gerard
Malanga, MD, Jay Meythaler, MD, JD, Frank Salvi,
MD, Richard Zorowitz, MD, and Maury Ellenberg,
MD.
APPENDIX 4. DEFINITIONS FOR STRENGTH OF
RECOMMENDATIONS
Level A: Established as effective, ineffective, or harmful for the given condition in the specified population. Usually, a Level A recommendation requires
that the pooled result from two or more distinct
Class I studies demonstrates a consistent, significant,
and important effect.
Level B: Probably effective, ineffective, or harmful for the given condition in the specified population. Usually, a Level B recommendation requires
that a single Class I study demonstrates a significant
and important effect, or the pooled result from two
or more distinct Class II studies demonstrates a consistent, significant, and important effect.
Level C: Possibly effective, ineffective, or harmful
for the given condition in the specified population.
Usually, a Level C recommendation requires that a
single Class II study demonstrates a significant and
important effect, or the pooled result of two or more
distinct Class III studies demonstrates a consistent,
significant, and important effect.
Level U: Data that are inadequate or conflicting.
Given the current knowledge the intervention is unproven and an evidence-based recommendation cannot be made.
DISCLAIMER
The diagnosis of polyneuropathy is complex. The
case definition is not intended to replace the clinical
122
Distal Symmetrical Polyneuropathy
judgment of experienced physicians in the diagnosis
of polyneuropathy, because none of the criteria have
perfect diagnostic accuracy. This statement is provided as an educational service of the AAN, the
AAEM, and the AAPM&R. It is based on an assessment of current scientific and clinical information. It
is not intended to include all possible proper methods of care for a particular neurological problem or
all legitimate criteria for choosing to use a specific
procedure. Neither is it intended to exclude any
reasonable alternative methodologies. The AAN,
AAEM, and AAPM&R recognize that specific care
decisions are the prerogative of the patient and physician caring for the patient, based on all of the
circumstances involved.
REFERENCES
Strength of evidence is indicated for references used
to formulate case definition.
1. American Association of Electrodiagnostic Medicine. Guidelines in electrodiagnostic medicine. Muscle Nerve 1999;
22(Suppl 8):S3–S300.
2. Dyck PJ, Bushek W, Spring EM, Karnes JL, Litchy WJ, O’Brien
PC, et al. Vibratory and cooling detection thresholds compared with other tests in diagnosing and staging diabetic
neuropathy. Diabetes Care 1987;10:432– 440. (Class II)
3. Dyck PJ, Davies JL, Litchy WJ, O’Brien PC. Longitudinal
assessment of diabetic polyneuropathy using a composite
score in the Rochester Diabetic Neuropathy Study cohort.
Neurology 1997;49:229 –239. (Class III)
4. Dyck PJ, Karnes JL, Daube J, O’Brien P, Service FJ. Clinical
and neuropathological criteria for the diagnosis and staging
of diabetic polyneuropathy. Brain 1985;108:861– 880.
5. 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.
6. Dyck PJ, Sherman WR, Hallcher LM, Service FJ, O’Brien PC,
Grina LA, et al. Human diabetic endoneurial sorbital, fructose and myo-inositol related to sural nerve morphometry.
Ann Neurol 1980;8:590 –596.
7. Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal N,
Greene DA. A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of
diabetic neuropathy. Diabetes Care 1994;17:1281–1289.
(Class III)
8. Franklin GM, Kahn LB, Baxter J, Marshall JA, Hamman RF.
Sensory neuropathy in non-insulin-dependent diabetes mellitus. The San Luis Valley Diabetes Study. Am J Epidemiol
1990;131:633– 643. (Class I)
9. Franse LV, Valk GD, Dekker JH, Heine RJ, van Eijk JTM.
“Numbess of the feet” is a poor indicator for polyneuropathy
in type 2 diabetic patients. Diabet Med 2000;17:105–110.
(Class I)
10. Gentile S, Turco S, Corigliano, Marmo R, The SIMSDN
Group. Simplified diagnostic criteria for diabetic distal polyneuropathy. Preliminary data of a multicentre study in the
Campania region. Acta Diabetol 1995;32:7–12. (Class II)
11. Holland NR, Stocks A, Hauer P, Cornblath DR, Griffin JW,
McArthur JC. Intraepidermal nerve fiber density in patients
with painful sensory neuropathy. Ann Neurol 1997;48:708 –
711.
12. Jones J, Hunter D. Consensus methods for medical and health
services research. BMJ 1995;311:376 –380.
MUSCLE & NERVE
January 2005
13. Kennedy WR, Wendelschafer-Crabb G. The innervation of
human epidermis. J Neurol Sci 1993;115:184 –190.
14. Lauria G, Sghirlanzoni A, Lombardi R, Pareyson D. Epidermal nerve fiber density in sensory ganglionopathies: clinical
and neurophysiologic correlations. Muscle Nerve 2001;24:
1034 –1039.
15. Maser RE, Becker DJ, Drash AL, Ellis D, Kuller LH, Greene
DA, et al. Pittsburgh epidemiology of diabetes complications
study. Measuring diabetic neuropathy follow-up results. Diabetes Care 1992;15:525–527. (Class II)
16. McArthur JC, Stocks AE, Hauer P, Cornblath DR, Griffin JW.
Epidermal nerve fiber density. Normative reference range
and diagnostic efficiency. Arch Neurol 1998;55:1513–1520.
17. Meijer JWG, van Sonderen E, Blaauwwiekel EE, Smit AJ,
Groothoff JW, Eisma WH, et al. Diabetic neuropathy examination. A hierarchial scoring system to diagnose distal polyneuropathy in diabetes. Diabetes Care 2000;23:750 –753.
(Class III)
18. Monticelli ML, Beghi E, the Italian General Practitioner Study
Group (IGPSG). Chronic symmetric polyneuropathy in the
elderly. A field screening investigation in two regions of Italy:
background and methods of assessment. Neuroepidemiology
1993;12:96 –105. (Class II)
19. Peripheral Nerve Society. Diabetic polyneuropathy in controlled clinical trials: consensus report of the Peripheral
Nerve Society. Ann Neurol 1995;38:478 – 482.
20. Proceedings of a consensus development conference on standardized measures in diabetic neuropathy. Neurology 1992;
42:1823–1839.
Distal Symmetrical Polyneuropathy
21. Quantitative sensory testing: A consensus report from the
Peripheral Neuropathy Association. Neurology 1993;43:1050 –
1052.
22. Rempel D, Evanoff B, Amadio PC, de Krom M, Franklin G,
Franzblau A, et al. Consensus criteria for the classification of
carpal tunnel syndrome in epidemiologic studies. Am J Public
Health 1998;88:1447–1451.
23. Shy ME, Frohman EM, So YT, Arezzo JC, Cornblath DR,
Giuliani MJ, et al. Therapeutics and technology assessment subcommittee of the American Academy of Neurology. Quantitative sensory testing. Report of the Therapeutics and Technology Assessment Subcommittee of the
American Academy of Neurology. Neurology 2003;60:898 –
904.
24. Teunissen LL, Notermans NC, Franssen H, van der Graaf Y,
Oey PL, Linssen WH, et al. Differences between hereditary
motor and sensory neuropathy type 2 and chronic idiopathic
axonal neuropathy. A clinical and electrophysiological study.
Brain 1997;120:955–962. (Class III)
25. Valk GD, Nauta JJP, Strijers RLM, Bertelsmann FW. Clinical
examination versus neurophysiological examination in the
diagnosis of diabetic polyneuropathy. Diabetic Med 1992;9:
716 –721. (Class II)
26. Van Dijk GW, Wokke JHJ, Notermans NC, van Gijn J, Franssen H.
Diagnostic value of myotatic reflexes in axonal and demyelinating
polyneuropathy. Neurology 1999;53:1573–1576. (Class III)
MUSCLE & NERVE
January 2005
123
AANEM PRACTICE PARAMETER
ABSTRACT: Distal symmetric polyneuropathy (DSP) is the most common
variety of neuropathy. Since the evaluation of this disorder is not standardized,
the available literature was reviewed to provide evidence-based guidelines
regarding the role of autonomic testing, nerve biopsy, and skin biopsy for the
assessment of polyneuropathy. A literature review using MEDLINE, EMBASE,
Science Citation Index, and Current Contents was performed to identify the best
evidence regarding the evaluation of polyneuropathy published between 1980
and March 2007. Articles were classified according to a four-tiered level of
evidence scheme and recommendations were based on the level of evidence.
(1) Autonomic testing may be considered in the evaluation of patients with
polyneuropathy to document autonomic nervous system dysfunction (Level B).
Such testing should be considered especially for the evaluation of suspected
autonomic neuropathy (Level B) and distal small fiber sensory polyneuropathy
(SFSN) (Level C). A battery of validated tests is recommended to achieve the
highest diagnostic accuracy (Level B). (2) Nerve biopsy is generally accepted as
useful in the evaluation of certain neuropathies as in patients with suspected
amyloid neuropathy, mononeuropathy multiplex due to vasculitis, or with atypical forms of chronic inflammatory demyelinating polyneuropathy (CIDP). However, the literature is insufficient to provide a recommendation regarding when
a nerve biopsy may be useful in the evaluation of DSP (Level U). (3) Skin biopsy
is a validated technique for determining intraepidermal nerve fiber (IENF) density and may be considered for the diagnosis of DSP, particularly SFSN (Level
C). There is a need for additional prospective studies to define more exact
guidelines for the evaluation of polyneuropathy.
Muscle Nerve 39: 106 –115, 2009
EVALUATION OF DISTAL SYMMETRIC POLYNEUROPATHY: THE
ROLE OF AUTONOMIC TESTING, NERVE BIOPSY, AND SKIN
BIOPSY (AN EVIDENCE-BASED REVIEW)
J .D . E N G L A N D , M D ,1 G .S . G R O N S E T H , M D ,2 G . F R A N K L IN , M D ,3 G .T . C A R T E R , M D ,4 L .J . K IN S E L L A , M D ,5 J .A . C O H E N , M D ,6
A .K . A S B U R Y , M D ,7 K . S Z IG E T I, M D , P H D ,8 J .R . L U P S K I, M D , P H D ,9 N . L A T O V , M D ,10 R .A . L E W IS , M D ,11 P .A . L O W , M D ,12
M .A . F IS H E R , M D ,13 D . H E R R M A N N , M D ,14 J .F . H O W A R D , M D ,15 G . L A U R IA , M D ,16 R .G . M IL L E R , M D ,17
M . P O L Y D E F K IS , M D ,18 a n d A .J . S U M N E R , M D 19 R e p o r t o f th e A m e r ic a n A c a d e m y o f N e u r o lo g y , th e A m e r ic a n A s s o c ia tio n
o f N e u r o m u s c u la r a n d E le c tr o d ia g n o s tic M e d ic in e , a n d th e A m e r ic a n A c a d e m y o f P h y s ic a l M e d ic in e a n d R e h a b ilita tio n
1
Louisiana State University Health Sciences Center, Baton Rouge, Louisiana, USA
University of Kansas, Lawrence, Kansas, USA
3
University of Washington, Seattle, Washington, USA
4
Providence Health System, Southwest Washington, Seattle, Washington, USA
5
Tenet-Forest Park Hospital, St. Louis, Missouri, USA
6
Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
7
University of Pennsylvania Hospital, Philadelphia, Pennsylvania, USA
8
Baylor College of Medicine, Houston, Texas, USA
9
Baylor College of Medicine, Houston, Texas, USA
10
Weill Medical College of Cornell, Ithaca, New York, USA
11
Wayne State University School of Medicine, Detroit, Michigan, USA
12
Mayo Clinic, Rochester, Minnesota
2
A b b re v ia tio n s : AAN, American Academy of Neurology; AANEM, American Academy of Neuromuscular and Electrodiagnostic Medicine; AAPM&R, American Academy
of Physical Medicine and Rehabilitation; CASS, composite autonomic scoring scale; CIDP, chronic inflammatory demyelinating polyneuropathy; CMT, Charcot–Marie–
Tooth; DSP, distal symmetric polyneuropathy; EDX, electrodiagnostic; EFNS, European Federation of Neurological Societies; IENF, intraepidermal nerve fiber; NCS, nerve
conduction study; QSART, quantitative sudomotor axon reflex test; SFSN, small fiber sensory polyneuropathy; TST, thermoregulatory sweat testing
K e y w o r d s : prospective studies; evaluation; distal symmetric polyneuropathy
C o r r e s p o n d e n c e to : American Association of Neuromuscular & Electrodiagnostic Medicine, 2621 Superior Drive NW, Rochester, MN 55901; e-mail:
[email protected]
© 2008 Wiley Periodicals, Inc.
Published online 15 December 2008 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mus.21227
10 6
AANEM Practice Parameter
MUSCLE & NERV E
J anuary 2009
13
Loyola University Chicago Stritch School of Medicine, Chicago, Illinois, USA
University of Rochester Medical Center, Rochester, New York, USA
15
University of North Carolina, Chapel Hill, North Carolina, USA
16
National Neurological Institute “ Carlo Besta,” Milan, Italy
17
California Pacifi c Medical Center, San Francisco, California, USA
18
Johns Hopkins Medical Institute, Baltimore, Maryland, USA
19
Louisiana State University Health Sciences Center, Baton Rouge, Louisiana, USA
14
Accepted 9 October 2008
INTRODUCTION
J u s tifi c a tio n . Polyneuropathy is a relatively common neurological disorder.10 The overall prevalence
is !2,400 ( 2.4% ) per 100,000 population, but in
individuals older than 55 years the prevalence rises
to !8,000 ( 8% ) per 100,000.9,32 Since there are
many etiologies of polyneuropathy, a logical clinical
approach is needed for evaluation and management.
This practice parameter provides recommendations for the evaluation of distal symmetric polyneuropathy ( DSP) based on a prescribed review and
analysis of the peer-reviewed literature. The parameter was developed to provide physicians with evidence-based guidelines regarding the role of autonomic testing, nerve biopsy, and skin biopsy for the
assessment of polyneuropathy. The diagnosis of DSP
should be based on a combination of clinical symptoms, signs, and electrodiagnostic criteria as outlined in the previous case defi nition.10 ( See Mission
Statement, below, for details.)
o f Ex p e r t Pa n e l. The Polyneuropathy
Task Force included 19 physicians with representatives from the American Academy of Neurology
( AAN) , the American Academy of Neuromuscular
and E lectrodiagnostic Medicine ( AANE M) , and the
American Academy of Physical Medicine and Rehabilitation ( AAPM& R) . All of the task force members
had extensive experience and expertise in the area
of polyneuropathy. Additionally, four members had
expertise in evidence-based methodology and practice parameter development. Three are current
members ( J.D.E ., G .S.G ., G .F.) , and one is a former
member ( R.G .M.) of the Q uality Standards Subcommittee ( Q SS) of the AAN. The task force developed
a set of clinical q uestions relevant to the evaluation
of DSP, and subcommittees were formed to address
each of these q uestions.
Fo r m a tio n
cluded articles on humans only and in all languages.
The search terms selected were peripheral neuropathy, polyneuropathy, and distal symmetric polyneuropathy. These terms were cross-referenced with the
terms diagnosis, electrophysiology, autonomic testing, nerve biopsy, and skin biopsy.
Panel experts were asked to identify additional
articles missed by the initial search strategy. Further,
the bibliographies of the selected articles were reviewed for potentially relevant articles.
Subgroups of committee members reviewed the
titles and abstracts of citations identifi ed from the
original searches and selected those that were potentially relevant to the evaluation of polyneuropathy.
Articles deemed potentially relevant by any panel
member were also obtained.
E ach potentially relevant article was subseq uently
reviewed in entirety by at least three panel members.
E ach reviewer graded the risk of bias in each article
by using the diagnostic test classifi cation-of-evidence
scheme ( Appendix 2) . In this scheme, articles attaining a grade of Class I are judged to have the lowest
risk of bias, and articles attaining a grade of Class IV
are judged to have the highest risk of bias. Disagreements among reviewers regarding an article’s grade
were resolved through discussion. Final approval was
determined by the entire panel.
The Q uality Standards Subcommittee ( AAN) , the
Practice Issues Review Panel ( AANE M) , and the
Practice G uidelines Committee ( AAPM& R) ( Appendix 1A– C) reviewed and approved a draft of the
article. The draft was next sent to members of the
AAN, AANE M, and AAPM& R for further review and
then to Neurology for peer review. Boards of the AAN,
AANE M, and AAPM& R reviewed and approved the
fi nal version of the article. At each step of the review
process, external reviewers’ suggestions were explicitly considered. When appropriate, the expert panel
made changes to the document.
DESCRIPTION OF THE ANALYTIC PROCESS
The
literature search included O V ID ME DLINE
( 1966 to March 2007) , O V ID E xcerpta Medica ( E MBASE ; 1980 to March 2007) , and O V ID Current
Contents ( 2000 to March 2007) . The search in-
AANEM Practice Parameter
ANALYSIS OF THE EVIDENCE
The search yielded 1,045 references with abstracts.
After reviewing titles and abstracts, 106 articles were
reviewed and classifi ed.
MUSCLE & NERV E
J anuary 2009
10 7
Ro le o f Clin ic a l Au to n o m ic Te s tin g in th e Ev a lu a tio n o f
Autonomic nervous system dysfunction occurs in several phenotypes. It may occur
as one component of a generaliz ed polyneuropathy
such as DSP of diabetes. Such polyneuropathies are
usually diagnosed by a combination of neuropathic
symptoms, decreased or absent ankle refl exes, decreased distal sensation, distal muscle weakness or
atrophy, and abnormal nerve conduction studies
( NCSs) .10 The majority of these features constitute
evidence of “ large fi ber” sensory and motor involvement. However, signs of autonomic nervous system
involvement may also constitute fi ndings indicative
of DSP. In DSP with autonomic involvement, the
most common clinical fi ndings are abnormalities of
sweating and circulatory instability in the feet.9,10
A second phenotype is that of an autonomic
neuropathy such as in amyloidosis and autoimmune
autonomic neuropathy, where autonomic nerves are
affected disproportionately relative to somatic
nerves.29 In these neuropathies, autonomic fi bers
can be affected in isolation and their involvement
may precede somatic fi ber involvement.47
A third relatively common phenotype is distal
small fi ber sensory polyneuropathy ( SFSN) , which
can manifest as burning pain affecting the feet, often
with allodynia and sometimes with erythromelalgia
( red hot and painful skin) . Involvement of autonomic and somatic C fi bers usually occurs concurrently in small fi ber polyneuropathy.47
Po ly n e u r o p a th y .
Wh a t Is th e Us e fu ln e s s o f Clin ic a l Au to n o m ic Te s tin g in
th e Ev a lu a tio n o f Po ly n e u r o p a th y , a n d Wh ic h Te s ts
Ha v e th e Hig h e s t Se n s itiv ity a n d Sp e c ifi c ity ? Currently available autonomic tests can provide indices
of cardiovagal, adrenergic, and postganglionic sudomotor function. 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 NCSs ( Class II) .7 Specifi city is high
( 97.5% ) for identifying parasympathetic defi cits if
the recommended age-controlled values are used
( Class II) .26 Intrinsic cardiac disease can affect the
results of this test, and this possibility must be considered in the interpretation.
Cardiovagal function can be evaluated using different indices in the time and freq uency domains.56
There is no compelling evidence that one method is
better than another or that the use of multiple indices confers any advantage. Heart rate variability to
deep breathing is the most widely used test of car-
10 8
AANEM Practice Parameter
diovagal function and has a specifi city of !80%
( Class II) .24
The vagal component of the barorefl ex can be
evaluated by q uantitating the heart period response
to induced changes in blood pressure ( BP) . A wellstudied test is the modifi ed O xford method.8 The
test consists of an evaluation of heart period responses to induced increases and decreases in arterial BP. The increase is evoked by intravenous phenylephrine and decrease by nitroprusside in
incremental doses. Barorefl ex sensitivity is defi ned
by the slope of the heart period to BP relationship.
Linearity is req uired ( R " 0.85) . The advantage of
this test is that it evaluates vagal barorefl ex sensitivity; however, the disadvantage is that the test is invasive and not widely performed. Approximation of
this method is possible by relating heart period alterations to changes in BP induced by the V alsalva
maneuver.52 The sensitivity and specifi city of invasive
and noninvasive tests of barorefl ex function are
high, but these tests are not generally used in the
study of neuropathy since their value is considered
only additive to current tests of cardiovagal function
( Class II) .24,29,44,54
Thermoregulatory sweat testing ( TST) is a sensitive
test of sudomotor function that utiliz es an indicator
substance whose color changes upon exposure to
sweat.12,30 The test results can be semiq uantitated by
estimating the percentage of skin surface that is anhidrotic. Since the test is tedious, messy, and timeconsuming, it is not routinely done. Additionally, TST
is not able to distinguish between postganglionic,
preganglionic, and central lesions.12,30 The most q uantitative test of sudomotor function is the q uantitative
sudomotor axon refl ex test ( Q SART) .25 Q SART is mediated by impulses traveling antidromically then orthodromically along the postganglionic sympathetic sudomotor axon. Q SART can detect distal sudomotor loss
with a sensitivity of 75% – 90% ( Class III) .26,35,50,51 Several studies have demonstrated that Q SART can determine sudomotor abnormalities with relatively high
sensitivity and specifi city in many types of polyneuropathies ( Class II and III) .7,25,26,28,29,31,35,47,50 In three
Class III studies, Q SART was shown capable of detecting distal small fi ber polyneuropathy with a sensitivity
of "75% .35,50,51
Skin vasomotor refl exes assessed by monitoring
skin blood fl ow using laser Doppler fl owmeter has
not been well studied. Limited data from one Class
III study using this techniq ue demonstrated an unacceptably large coeffi cient of variation.27
Analysis of the available Class II and III studies on
autonomic testing indicate that a combination of
autonomic refl ex screening tests provides distinct
MUSCLE & NERV E
J anuary 2009
advantages over single modality methods. The composite autonomic scoring scale ( CASS) , which includes Q SART, orthostatic blood pressure, heart rate
response to tilt, heart rate response to deep breathing, the V alsalva ratio, and beat-to-beat BP measurements during Phases II and IV of the V alsalva maneuver, tilt, and deep breathing provides a useful
10-point scale of autonomic function ( Class II) .24,29
In a study of 78 patients with graded autonomic
failure obtained by selecting approximately eq ual
numbers of patients with multiple system atrophy,
Parkinson’s disease, autonomic neuropathies, and
idiopathic peripheral neuropathies, this combination of tests provided a noninvasive, sensitive, specifi c, and reproducible methodology for grading the
degree of autonomic dysfunction ( Class II) .24
Conclusions. Autonomic testing is probably useful in documenting autonomic nervous system involvement in polyneuropathy ( Class II and III) . The
sensitivity and specifi city vary with the particular test.
The utiliz ation of the combination of autonomic
refl ex screening tests in the CASS provides the highest sensitivity and specifi city for documenting autonomic dysfunction ( Class II) .
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) . If the full battery of tests in the CASS
is not available, a combination of tests of cardiovagal
function ( e.g., heart rate response to deep breathing) and some test of adrenergic function may be
considered as an alternative ( Level C) .24
Ro le o f Ne r v e Bio p s y in th e Ev a lu a tio n o f Po ly n e u r o p a th y . Nerve biopsy is generally accepted as useful in
the diagnosis of infl ammatory diseases of nerves
such as vasculitis, sarcoidosis, CIDP, infectious diseases such as leprosy, or infi ltrative disorders such as
tumor or amyloidosis.9 Nerve biopsy is most valuable
in mononeuropathy multiplex or suspected vasculitic neuropathy. There are no studies regarding the
role of nerve biopsy in the evaluation of DSP, although on occasion the above-noted diseases may
present in that fashion.
Wh a t Is th e Us e fu ln e s s o f Ne r v e Bio p s y in De te r m in in g
th e Etio lo g y o f Dis ta l Sy m m e tr ic Po ly n e u r o p a th y ?
AANEM Practice Parameter
O ut of 50 articles judged to be relevant, no article
attained a grade greater than Class IV . Most of the
articles discussed the nerve biopsy fi ndings in specifi c diseases, the clinical suspicion of which had
prompted the biopsy.1– 3,5,6,13,14,34,39,40 – 42 No article
provided guidance regarding when to perform a
nerve biopsy in the evaluation of DSP.
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) .
Ro le o f Sk in Bio p s y in th e Ev a lu a tio n o f Po ly n e u r o p a th y .
Skin biopsy is being increasingly used to evaluate
patients with polyneuropathy. The most common
techniq ue involves a 3-mm punch biopsy of skin
from the leg. After sectioning by microtome, the
tissue is immunostained with anti-protein-gene-product 9.5 ( PG P 9.5) antibodies and examined with
immunohistochemical or immunofl uorescent methods. This staining allows for the identifi cation and
counting of intraepidermal nerve fi bers ( IE NF) .
PG P 9.5 immunohistochemistry has been validated
as a reliable method for IE NF density determination
with good intra- and interobserver reliability in normal controls and patients with DSP.15,20,33,48
In March 2005 the E uropean Federation of Neurological Societies ( E FNS) published a guideline on
the use of skin biopsy in peripheral neuropathy.20
This comprehensive review focused on the technical
aspects of skin biopsy as well as normative data and
correlations with other clinical, physiologic, and
pathologic tools. The E FNS concluded that skin biopsy is a safe, validated, and reliable techniq ue for
the determination of IE NF density. The major conclusion was that skin biopsy ( IE NF density) was diagnostically effi cient at distinguishing polyneuropathy patients ( including small fi ber neuropathy)
from normal controls. The E FNS guideline also reviewed the literature on IE NF morphologic changes
such as axonal swellings as a measure of distal symmetric polyneuropathy.16,20,21 The E FNS concluded
that axonal swellings may be predictive of progression of polyneuropathy but further studies were
needed to determine their diagnostic accuracy.20
Wh a t Is th e Us e fu ln e s s a n d Dia g n o s tic Ac c u r a c y o f Sk in
Bio p s y in th e Ev a lu a tio n o f Po ly n e u r o p a th y ? Beyond
distinguishing asymptomatic normals from polyneuropathy patients, one clinical q uestion not addressed
by the E FNS guideline was the diagnostic accuracy of
skin biopsy in distinguishing symptomatic patients
MUSCLE & NERV E
J anuary 2009
10 9
110
AANEM Practice Parameter
T a b le 1. Evidence table for autonomic testing.
MUSCLE & NERV E
Reference
Y ear
Target disorder
50
1992
Distal small fiber
neuropathy
7
1992
Diabetic PN
26
1997
51
1999
PN, Park inson’s,
multisystem
atrophy
Peripheral (small
fiber) neuropathy
35
2001
Painful neuropathy
24
1993
Diabetic PN
44
2007
54
2005
47
2004
Adrenergic
autonomic failure
Multi system
atrophy,
peripheral
neuropathy
DSFN, PN, DN, IAN
Predictor
Reference
standard
QSART,
QST,
H RV
QAE
Neurologic
exam and
EDx
EDx
QSART
Older scale
Cases
Controls
40
129
3 80
3 57*
18
557
QSART,
EDx
QST,
Clinical
Symptoms
QSART,
Clinical
ART,
evaluation
CASS
CASS
EDx and
standard
clinical
exam
B RSI
MSNA
13 8
PRT,
CASS
CASS
Design
Spectrum
Mask ed
Class
Retrospective
Review
N
N
Concurrent
comparative
Concurrent
comparison
B
3 57* (per Dr.
L ow)
Concurrent
comparative
B
126
3 57* (per Dr.
L ow)
Non-comparative
N
78
3 50
Concurrent
comparative
N
U nmask ed/
Independent
II
84
29
B
86%
"90%
162
32
U nmask ed/
Independent
U nmask ed/
Independent
II
Clinical exam
Concurrent
comparative
Concurrent
comparative
II
"90%
"90%
Neurological
exam
11
38
III
95%
90%
Concurrent
comparative
B
B
N
Sens
Spec
III
80%
72%
U nmask ed/
Independent
U nmask ed/
Independent
II
QAE:97%
"90%
II
"90%
"90%
U nmask ed/
Independent
III
QSART:80% ;
QST:67%
93 %
III
ART:93 % ;
QSART:
73 %
"90%
94 %
N
U nmask ed/
Independent
"90%
Ac ro n y m s D is ta l s m a ll fi b e r n e u ro p a th y : D S F N; D ia b e tic p e rip h e ra l n e u ro p a th y : D PN; Pe rip h e ra l n e u ro p a th y : PN; Q u a n tita tiv e s u d o m o to r a x o n re fl e x te s tin g : Q S ART; Co m p o s ite a u to n o m ic s e v e rity s c o re : CAS S ;
Q u a n tita tiv e a u to n o m ic e x a m in a tio n : Q AE; Id io p a th ic a u to n o m ic n e u ro p a th y : IAN; Q u a n tita tiv e s e n s o ry te s tin g : Q S T; Au to n o m ic re fl e x te s tin g : ART; Ele c tro d ia g n o s is : Ed x ; H e a rt ra te v a ria b ility : H RV ; Q u a n tita tiv e
s w e a t te s tin g ; B a ro re fl e x s e n s itiv ity in d e x : B RS I; Mu s c le s y m p a th e tic n e rv e a c tiv ity : MS NA; B lo o d p re s s u re re c o v e ry tim e : PRT.
J anuary 2009
with polyneuropathy from symptomatic patients
without polyneuropathy. For example, in patients
with painful feet, would skin biopsy accurately distinguish patients with polyneuropathy from patients
with other conditions causing painful feet?
To address this separate q uestion, a subgroup of
the Polyneuropathy Task Force ( J.D.E ., R.A.L., D.H.,
G .L., M.P., and G .S.G .) independently reviewed the
literature regarding the diagnostic accuracy of skin
biopsy in DSP and in the SFSN form of DSP. To be
considered for review, studies needed to determine
IE NF density in patients with and without polyneuropathy. Furthermore, the data from studies had to
be presented in such a way as to allow calculation of
the sensitivity and specifi city of skin biopsy for polyneuropathy.
Nine studies met inclusion criteria.4,16 – 18,21–
22,33,36 – 37 O ne was a prospective cohort survey of
patients presenting with bilateral painful feet and
normal strength, but skin biopsy was done only in
those with normal NCS.36 Patients with reduced
IE NF density and normal NCS were assumed to have
painful small fi ber neuropathies. However, the study
did not compare the results of the IE NF density to an
independent reference standard to confi rm the presence of small fi ber neuropathy. Thus, for the purposes of determining the diagnostic accuracy of skin
biopsy for polyneuropathy, this study was graded
Class IV .
The remaining studies employed a case-control
design.16,18,21,22,33 In these studies the investigators
performed skin biopsies on patients with established
polyneuropathy and normal controls. No study included patients with conditions causing lower extremity pain or sensory complaints that might be
confused with polyneuropathy. Thus, all studies had
potential spectrum bias. Following the evidence classifi cation scheme for studies of diagnostic accuracy,
all of these studies were graded Class III.
All of the case-control studies showed a signifi cant reduction in IE NF density in polyneuropathy
patients as compared to controls.16,18,21,22,33 The sensitivity of decreased IE NF density for the diagnosis of
polyneuropathy was moderate to good ( range 45% –
90% ) . The specifi city of normal IE NF density for the
absence of polyneuropathy was very good ( range
95% – 97% ) . Thus, the absence of reduced IE NF density ( using the clinical impression as the diagnostic
reference standard) would not “ rule out” polyneuropathy, but the presence of reduced IE FN density
would importantly raise the likelihood of polyneuropathy.
The form of DSP for which IE NF assessment is
particularly diagnostically attractive is SFSN for the fol-
AANEM Practice Parameter
lowing reasons: ( 1) IE NF are the nerve terminals of
somatic unmyelinated C fi bers, which are hypothesiz ed
to be predominantly affected in SFSN; ( 2) There has
been a lack of a direct objective measure of small fi ber
sensory nerves since objective measures of large fi ber
function ( e.g., NCS) are by most defi nitions normal in
SFSN19; 3) Patients in whom SFSN is clinically suspected manifest with symptoms of small fi ber sensory
dysfunction ( e.g., tingling, numbness, and neuropathic
pain) but few objective signs, making it diffi cult to
diagnose and to distinguish SFSN from nonneurological causes of sensory complaints.19
Since no validated objective gold standard exists
for the diagnosis of SFSN, the authors considered
whether demonstration of a pathologic lesion ( small
sensory fi ber pathology on skin biopsy) should be
the de facto diagnostic standard or whether a clinical
impression of SFSN should be the independent reference standard. For the purposes of this parameter,
a clinical impression of SFSN was adopted as the
independent reference standard for calculation of
sensitivity and specifi city of IE NF density in the detection of SFSN.
In order to assess the diagnostic accuracy of IE NF
density assessment for SFSN, the literature was surveyed for studies assessing IE NF density in subjects
with clinically suspected SFSN ( symptoms or symptoms and signs of DSP but with normal NCS) and
controls where the diagnostic accuracy of IE NF density for clinically defi ned SFSN could be determined.
Four Class III studies met these criteria.18,23,46,55 The
sensitivity of IE NF density assessment at the ankle for
DSP with normal NCS was 58% ( 20% for subjects
with symptoms but no signs of SFSN; 100% for subjects with symptoms and signs of SFSN) ,46 90% ,18
and 24% .23 In these studies, the specifi city of the test
ranged from 95% – 97.5% .18,23,46 The other case-control study found that among patients with symptoms
of SFSN and an abnormal pinprick examination in
the feet, but normal ankle refl exes, normal vibration
sensibility, and normal NCS that an IE NF density of
#8 fi bers/ mm at the dorsal foot provided a sensitivity of 88% , a specifi city of 91% , a positive predictive
value of 0.9, and a negative predictive value of 0.83
for the diagnosis of SFSN.55
Conclusions. IE NF density assessment using PG P
9.5 immunohistochemistry is a validated, reproducible marker of small fi ber sensory pathology. Skin
biopsy with IE NF density assessment is possibly useful to identify DSP that includes SFSN in symptomatic patients with suspected polyneuropathy. ( Class
III) .
Recommendations. For symptomatic patients
with suspected polyneuropathy, skin biopsy may be
MUSCLE & NERV E
J anuary 2009
111
considered to diagnose the presence of a polyneuropathy, particularly SFSN ( Level C) .
RECOMMENDATIONS FOR FUTURE RESEARCH
This comprehensive review reveals several weaknesses in the current approach to the evaluation of
polyneuropathy and highlights opportunities for research.
● Auton om ic testin g. Autonomic testing can, with a
high degree of accuracy, document autonomic
system dysfunction in polyneuropathy. This is
particularly relevant to small fi ber 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. Specifi c tests such as Q SART
can document small fi ber ( i.e., sudomotor
axon) loss with a high degree of sensitivity, making the test useful to confi rm the diagnosis of
small fi ber polyneuropathy. Since skin biopsy
with determination of IE NF density can also
document small fi ber loss, there is a need for
studies that compare and correlate the two techniq ues.
● Nerv e biopsy. There are no studies of nerve biopsy in the evaluation of DSP. Although it
would be useful to know the outcome of welldesigned prospective studies in this area, it is
unlikely that such studies will be done.
● S k in biopsy. Skin biopsy with determination of
IE NF density is a techniq ue that has come of
age for the objective documentation of small
fi ber loss. This techniq ue provides a uniq ue
opportunity for research in different varieties of
neuropathy. Further studies are needed to characteriz e 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. Prospective studies with
appropriate “ other disease” controls should be
done to assess the sensitivity, specifi city, and
predictive values of IE NF 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 specifi cally stated in such
studies.
● A case defi nition of SFSN should be developed.
Investigators need to determine whether this
case defi nition should be based on clinical cri-
112
AANEM Practice Parameter
teria, pathological criteria ( e.g., skin biopsy) , or
a combination of clinical, paraclinical, and
pathologic criteria.
● The diagnostic accuracy of morphologic
changes ( e.g., axonal swellings) in the diagnosis
of SFSN versus healthy controls and disease controls needs to be better defi ned.
● Studies exploring other uses for skin biopsy
beyond identifi cation and q uantifi cation of DSP
and SFSN have been reported and should be
further explored. Biopsies of glabrous skin and
dermal skin include myelinated nerve fi bers,
and have been shown to have potential utility in
the diagnosis of immune-mediated neuropathies, Charcot– Marie– Tooth ( CMT) , and related diseases.22 O ther studies have employed
skin biopsy for detection or monitoring of leprosy, hereditary amyloidosis, vasculitic neuropathy, and Fabry’s disease.49,53 Additional studies
are req uired to determine the usefulness of skin
biopsy in the diagnosis and monitoring of these
and other varieties of neuropathy.
● Serial IE NF density measurements and IE NF
regenerative capacity are being studied and
used as outcome measures in therapeutic trials.38,43 Further studies are needed to validate
and determine the value of skin biopsy for this
purpose.
Mis s io n Sta te m e n t. The AAN, the AANE M, and the
AAPM& R determined that there was a need for an
evidence-based and clinically relevant practice parameter for the evaluation of polyneuropathy. As a
prelude to this project, the three organiz ations developed a formal case defi nition of distal symmetric
polyneuropathy DSP.10 As outlined in this previous
publication, the most accurate diagnosis of distal
symmetric polyneuropathy is provided by a combination of neuropathic symptoms, signs, and electrodiagnostic ( E DX ) studies. Since E DX studies are
sensitive, specifi c, and validated measures of the
presence of polyneuropathy and can distinguish between demyelinating and axonal types of neuropathy, they should be included as an integral part of
the diagnosis.10 This practice parameter assumes
that a clinical diagnosis of polyneuropathy has been
determined based on such criteria.
D isclaimer . The diagnosis and evaluation of
polyneuropathy is complex. The practice parameter
is not intended to replace the clinical judgment of
experienced physicians in the evaluation of polyneuropathy. The particular kinds of tests utiliz ed by a
physician in the evaluation of polyneuropathy de-
MUSCLE & NERV E
J anuary 2009
pend on the specifi c clinical situation and the informed medical judgment of the treating physician.
This statement is provided as an educational service of the AAN, AANE M, and the AAPM& R. It is
based on an assessment of current scientifi c and
clinical information. It is not intended to include all
possible proper methods of care for a particular
neurologic problem or all legitimate criteria for
choosing to use a specifi c test or procedure. Neither
is it intended to exclude any reasonable alternative
methodologies. The AAN, AANE M, and AAPM& R
recogniz e that specifi c care decisions are the prerogative of the patient and physician caring for the
patient, based on all of the circumstances involved.
o f In te r e s t. The AAN, AANE M, and
AAPM& R are committed to producing independent,
critical, and truthful clinical practice guidelines
( CPG s) . Signifi cant efforts are made to minimiz e the
potential for confl icts of interest to infl uence the
recommendations of this CPG . To the extent possible, the AAN, AANE M, and AAPM& R keep separate
those who have a fi nancial stake in the success or
failure of the products appraised in the CPG s and
the developers of the guidelines. Confl ict of interest
forms were obtained from all authors and reviewed
by an oversight committee prior to project initiation.
AAN, AANE M, and AAPM& R limit the participation
of authors with substantial confl icts of interest. The
AAN, AANE M, AAPM& R forbid commercial participation in, or funding of, guideline projects. Drafts of
the guideline have been reviewed by at least three
AAN committees, AANE M and AAPM& R committees, a network of neurologists, Neurology peer reviewers, and representatives from related fi elds. The
AAN G uideline Author Confl ict of Interest Policy
can be viewed at www.aan.com.
APPENDIX 1 B
Yuen T. So,
MD, PhD ( chair) ; Michael T. Andary, MD; Atul Patel, MD; Carmel Armon, MD; David del Toro, MD;
E arl J. Craig, MD; James F. Howard, MD; Joseph V .
Campellone Jr., MD; Kenneth James G aines, MD;
Robert Werner, MD; Richard Dubinsky, MD.
Pr a c tic e Is s u e s Re v ie w Pa n e l (AANEM).
APPENDIX 1 C
Dexanne
B. Clohan, MD ( chair) ; William L. Bockenek, MD;
Lynn G erber, MD; E dwin Hanada, MD; Ariz R.
Mehta, MD; Frank J. Salvi, MD, MS; and Richard D.
Z orowitz , MD.
Pr a c tic e Gu id e lin e s Co m m itte e (AAPM& R).
Co n fl ic t
APPENDIX 1 A
Q u a lity Sta n d a r d s Su b c o m m itte e (AAN). Jacq ueline
French, MD, FAAN ( co-chair) ; G ary S. G ronseth, MD
( co-chair) ; Charles E . Argoff, MD; E ric Ashman, MD;
Stephen Ashwal, MD, FAAN ( ex-offi cio) ; Christopher Bever Jr., MD, MBA, FAAN; John D. E ngland,
MD, FAAN ( Q SS facilitator) ; G ary M. Franklin, MD,
MPH, FAAN ( ex-offi cio) ; Deborah Hirtz , MD ( exoffi cio) ; Robert G . Holloway, MD, MPH, FAAN;
Donald J. Iverson, MD, FAAN; Steven R. Messé, MD;
Leslie A. Morrison, MD; Pushpa Narayanaswami,
MD, MBBS; James C. Stevens, MD, FAAN ( E x-O ffi cio) David J. Thurman, MD, MPH ( ex-offi cio) ; Samuel Wiebe, MD; Dean M. Wingerchuk, MD, MSc,
FRCP( C) ; and Theresa A. Z esiewicz , MD, FAAN.
AANEM Practice Parameter
APPENDIX 2
Cla s s ifi c a tio n o f Ev id e n c e fo r Stu d ie s o f Dia g n o s tic Ac -
Class I. E vidence provided by a prospecc u ra c y .
tive study in a broad spectrum of persons with the
suspected condition, using a “ gold standard” for case
defi nition, where a test is applied in a blinded evaluation, and enabling the assessment of appropriate
tests of diagnostic accuracy.
Class II. E vidence provided by a prospective
study of a narrow spectrum of persons with the suspected condition, or a well-designed retrospective
study of a broad spectrum of persons with an established condition ( by “ gold standard” ) compared to a
broad spectrum of controls, where a test is applied in
a blinded evaluation, and enabling the assessment of
appropriate tests of diagnostic accuracy.
Class III. E vidence provided by a retrospective
study when either persons with the established condition or controls are of a narrow spectrum, and
where a test is applied in a blinded evaluation.
Class IV . Any design where a test is not applied
in blinded evaluation or evidence provided by expert
opinion alone or in descriptive case series ( without
controls) .
APPENDIX 3
A $ E stablished
as effective, ineffective, or harmful for the given
condition in the specifi ed population. ( Level A rating req uires as least two consistent Class I studies.)
B $ Probably effective, ineffective, or harmful for
the given condition in the specifi ed population.
( Level B rating req uires at least one Class I study or
at least two consistent Class II studies.)
C $ Possibly effective, ineffective, or harmful for
the given condition in the specifi ed population.
Cla s s ifi c a tio n o f Re c o m m e n d a tio n s .
MUSCLE & NERV E
J anuary 2009
113
( Level C rating req uires at least one Class II study or
two consistent Class III studies.)
U $ Data inadeq uate or confl icting; given current knowledge, treatment is unproven.
Approved by the AANE M Board of Directors on May 1, 2008. With
regard to confl icts of interest, the authors disclose the following:
( 1) Holds fi nancial interests in Pfi z er. ( 2) Holds fi nancial interests
in Pfi z er and G laxoSmithKline and Boeheringer Ingelheim for
speaker honoraria and O rtho-McNeil for serving on the IDMC
Committee. ( 3) Nothing to disclose. ( 4) Nothing to disclose. ( 5)
Received royalties from the American Medical Resources, E nduring Medical Materials ( CD/ DV D) , has received honorarium from
Medical E ducation Resources, CME LLC, E xpert Witness testimony and record review, Peters Marketing Research, Delve Marketing Research, Cross Country E ducation and American Medical
Seminars. Dr. Kinsella holds corporate appointments with Cross
Country E ducation and Forest Park Hospital. ( 6) Nothing to
disclose. ( 7) Receives residual royalties from E lsevier for editorial
work done prior to 2005. He receives honoraria from the Dana
Foundation, NY, and the International Society for Neuroimmunology. His wife is a consultant for the Dana Foundation. ( 8)
Nothing to disclose. ( 9) Financial interests in Athena Diagnostics
and has received research funding from NIH/ NE I, NIH/ NIDCR,
Charcot-Marie-Tooth Association, and the March of Dimes. ( 10)
Serves as a Scientifi c Advisor for Q uest Diagnostics and is a
member of a Steering Committee, Talecris Biotherapeutics. Dr.
Latov receives royalties from Demos publications and has received
research support from the NIH and Talecris Biotherapeutics. He
holds stock options in Therapath LLC and is the benefi ciary of
license fee payments from Athena Diagnostics to Columbia University. He has given expert testimony in legal proceedings related
to neuropathy and has prepared an affi davit with regarding to the
legal proceeding related to neuropathy. ( 11) Financial interests in
Talecris and has received research funding from MDA and
CMTA. He estimates that approximately 33% of his clinical effort
is spent on electromyography. He has received payment for expert testimony regarding the use of IV Ig in CIDP; neuropathic
pain after breast reduction. ( 12) Served as a consultant for WR
Medical, V iatris, E li Lilly and Company, Chelsea Therapeutics,
and Q uigley Corporation. ( 13) Financial interests in Astraz eneca,
Photothera, Wyeth, Jalmarjone Sahron, Inarx, Boehringer-Ingelheim, Dullehi-Arubio, Axaron, U-Servicer, and PAIO N. ( 14)
E stimates that approximately 15% – 20% of his clinical effort is
spent on skin biopsies. ( 15) Serves on a myasthenia gravis medical
scientifi c board, has served as an Associate E ditor, Journ a l of
Clin ica l Neurom uscula r D isea se ( 1998 – 2006) , receives honoraria
from Duke University Medical Center, and Medical E ducational
Resources. He is the director of ME G laboratories and estimates
that 75% of his time is spent there. He also holds stock options in
G E , Pfi z er, and Johnson & Johnson. In addition, he has provided
an affi davit on two cases regarding myasthenia gravis. ( 16) Financial interests in G laxoSmithKline and Formenti-G runenthal. In
addition he has received research funding from Pfi tz er, FormentiG runenthal, Foramenti-G runenthal, Italian Ministry of Health,
and Regione Lombardia. ( 17) Financial interests in Celgene and
Pathologica. ( 18) Financial interests in DSMB, Pfi z er, Johnson &
Johnson, Mitsubishi Pharma, Merck, X enoport, and G SK. He has
received research funding from JDRF, NIH, Astellas Pharma,
Mitsubishi Pharma, and Sanofi -Aventis. He estimates that 10% of
his clinical effort is devoted to E MG , 5% to skin biopsy, and #1%
on lumbar puncture. ( 19) Received payment for expert testimony
in the possible neurotoxic injury of the peripheral nerve.
114
AANEM Practice Parameter
REFERENCES
[ Note. Strength of evidence is indicated for references used to formulate conclusions and recommendations.]
1. Argov Z , Nagle D, G iger U, Leigh JS Jr. The yield of sural
nerve biopsy in the evaluation of peripheral neuropathies.
Acta Neurol Scand 1989;79:243– 245.
2. Bosboom WM, V an den Berg LH, Franssen H, G iesbergen PC,
Flach HZ , van Putten AM, et al. Diagnostic value of sural
nerve demyelination in chronic demyelinating polyneuropathy. Brain 2001;124:2427– 2438.
3. Chia L, Fernandez A, Lacroix C, Adams D, Planté V , Said G .
Contribution of the nerve biopsy fi ndings to the diagnosis of
disabling neuropathy in the elderly: a retrospective review of
100 consecutive patients. Brain 1996;119:1091– 1098.
4. Chien HF, Tseng TJ, Lin WM, Yang CC, Chang YC, Chen RC,
et al. Q uantitative pathology of cutaneous nerve terminal
degeneration in the human skin. Acta Neuropathol 2001;102:
455– 461. ( Class III)
5. Deprez M, Ceuterick-DeG roote C. Clinical and neuropathological parameters affecting the diagnostic yield of nerve biopsy. Neuromusc Disorders 2000;10:92– 98.
6. Deprez M, Ceuterick-de G roote C, Schoenen J, Rez nik M,
Martin JJ. Nerve biopsy: indications and contribution of the
diagnosis of peripheral neuropathy. Acta Neurol Belg 2000;
100:162– 166.
7. 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)
8. E bert TJ, Morgan BJ, Barney JA, Denahan T, Smith JJ. E ffects
of aging on barorefl ex regulation of sympathetic activity in
humans. Am J Physiol 1992; 263:798 – 803.
9. E ngland JD, Asbury AK. Peripheral neuropathy. Lancet 2004;
363:2151– 2161.
10. E ngland JD, G ronseth G S, Franklin G , Miller RG , Asbury AK,
Carter G T, et al. Distal symmetric polyneuropathy: a defi nition for clinical research. Report of the American Academy of
Neurology, the American Association of E lectrodiagnostic
Medicine, and the American Academy of Physical Medicine
and Rehabilitation. Neurology 2005;64:199 – 207.
11. Facer P, Mann D, Mathur R, Pandya S, Ladiwala U, Singhal B,
et al. Do nerve growth factor-related mechanisms contribute
to loss of cutaneous nociception in leprosy? Pain 2000;85:
231– 238.
12. Fealey RD, Low PA, Thomas JE . Thermoregulatory sweating
abnormalities in diabetes mellitus. Mayo Clin Proc 1989;64:
617– 628.
13. Flachenecker P, Janka M, G oldbrunner R, Toyka KV . Clinical
outcome of sural nerve biopsy: a retrospective study. J Neurol
1999;246:93– 96.
14. G abriel CM, Howard R, et al. Prospective study of the usefulness of sural nerve biopsy. J Neurol Neurosurg Psychiatry
2000;69:442– 446.
15. G oranson LG , Mellgren SI, Lindal S, O mdal R. The effect of
age and gender on epidermal nerve fi ber density. Neurology
2004;62:774 – 777.
16. Herrmann DN, McDermott MP, Henderson D, Chen L,
Akowuah K, Schifi tto G , and The North E ast Aids Dementia
( Nead) Consortium. E pidermal nerve fi ber density, axonal
swellings and Q ST as predictors of HIV distal sensory neuropathy. Muscle Nerve 2004;29:420 – 427. ( Class III)
17. Kennedy WR, Wendelschafer-Crabb G , Johnson T. Q uantitation of epidermal nerves in diabetic neuropathy. Neurology
1996;47:1042– 1048. ( Class III)
18. Koskinen M, Hietaharju A, Kylaniemi M, Peltola J, Rantala I,
Udd B, et al. A q uantitative method for the assessment of
intraepidermal nerve fi bers in small-fi ber neuropathy. J Neurol 2005;252:789 – 794. ( Class III)
MUSCLE & NERV E
J anuary 2009
19. Lacomis D. Small-fi ber neuropathy. Muscle Nerve 2002;26:
173– 188.
20. Lauria G , Cornblath DR, Johansson O , McArthur JC, Mellgren SI, Nolano M, et al. E FNS G uidelines on the use of skin
biopsy in the diagnosis of peripheral neuropathy. E ur J Neurol 2005;12:1– 12.
21. Lauria G , Morbin M, Lombardi R, et al. Axonal swellings
predict the degeneration of epidermal nerve fi bers in painful
neuropathies. Neurology 2003;61:631– 636. ( Class III)
22. Li J, Bai Y, G handour K, et al. Skin biopsies in myelin-related
neuropathies: bringing molecular pathology to the bedside.
Brain 2005;128:1168 – 1177. ( Class III)
23. Loseth S, Lindal S, Stalberg E , Mellgren SI. Intraepidermal
nerve fi bre density, q uantitative sensory testing and nerve
conduction studies in a patient material with symptoms and
signs of sensory polyneuropathy. E ur J Neurol 2006;13:105–
111. ( Class III)
24. Low PA. Composite Autonomic Scoring Scale for laboratory
q uantifi cation of generaliz ed autonomic failure. Mayo Clin
Proc 1993;68:748 – 752. ( Class II)
25. Low PA, Caskey PE , Tuck RR, Fealey RD, Dyck PJ. Q uantitative sudomotor axon refl ex test in normal and neuropathic
subjects. Ann Neurol 1983;14:573– 580.
26. Low PA, Denq JC, O pfer-G ehrking TL, Dyck PJ, O ’Brien PC,
Slez ak JM. E ffect of age and gender on sudomotor and cardiovagal function and blood pressure response to tilt in normal subjects. Muscle Nerve 1997;20:1561– 1568. ( Class II)
27. Low PA, Neumann C, Dyck PJ, Fealey RD, Tuck RR. E valuation of skin vasomotor refl exes by using laser Doppler velocimetry. Mayo Clin Proc 1983;58:583– 592. ( Class III)
28. Low PA, O pfer-G ehrking TL, Proper CJ, Z immerman I. The
effect of aging on cardiac autonomic and postganglionic
sudomotor function. Muscle Nerve 1990;13:152– 157.
29. Low PA, V ernino S, Suarez G . Autonomic dysfunction in
peripheral nerve disease. Muscle Nerve 2003;27:646 – 661.
30. Low PA, Walsh JC, Huang C, McLeod JG . The sympathetic
nervous system in diabetic neuropathy: a clinical and pathological study. Brain 1975;98:341– 356.
31. Low PA, Z immerman BR, Dyck PJ. Comparison of distal sympathetic with vagal function in diabetic neuropathy. Muscle
Nerve 1986;9:592– 596.
32. Martyn CN, Hughes RAC. E pidemiology of peripheral neuropathy. J Neurol Neurosurg Psychiatry 1997;62:310 – 318.
33. McArthur JC, Stocks E A, Hauer P, Cornblath DR, G riffi n JW.
E pidermal nerve fi ber density: normative reference range and
diagnostic effi ciency. Arch Neurol 1998;55:1513– 1520. ( Class
III)
34. Molenacv DSM, V ermeulen M, et al. Diagnostic value of sural
nerve biopsy in chronic infl ammatory demyelinating polyneuropathy. J Neurol Neurosurg Psychiatry 1998;64:84 – 89.
35. Novak V , Freimer ML, Kissel JT, et al. Autonomic impairment
in painful neuropathy. Neurology 2001;56:861– 868. ( Class
III)
36. Periq uet MI, Novak V , Collins MP, et al. Painful sensory
neuropathy: prospective evaluation using skin biopsy. Neurology 1999;53:1641– 1647. ( Class IV )
37. Pittenger G L, Ray M, Burcus NI, et al. Intraepidermal nerve
fi bers are indicators of small-fi ber neuropathy in both diabetic and nondiabetic patients. Diabetes Care 2004;27:1974 –
1979. ( Class III)
AANEM Practice Parameter
38. Polydefkis M, Sirdofsky M, Hauer P, Petty BG , Murinson B,
McArthur JC. Factors infl uencing nerve regeneration in a trial
of timcodar dimesylate. Neurology 2006;66:259 – 261.
39. Rappaport WD, V alente J, et al. Clinical utiliz ation and complications of sural nerve biopsy. Am J Surg 1993;166:252– 256.
40. Said G . Indications and usefulness of nerve biopsy. Arch
Neurol 2002;59:1532– 1535.
41. Said G . Indications and value of nerve biopsy. Muscle Nerve
1999;22:1617– 1619.
42. Said G . V alue of nerve biopsy. Lancet 2001;357:1220 – 1221.
43. Schiffmann R, Hauer P, Freeman B, et al. E nz yme replacement therapy and intraepidermal innervation density in Fabry
disease. Muscle Nerve 2006;34:53– 56.
44. Schrez enmaier C, Singer W, Muenter-Swift N, Sletten D,
Tanabe J, Low PA. Adrenergic and vagal barorefl ex sensitivity
in autonomic failure. Arch Neurol 2007;64:381– 386. ( Class II)
45. Scott LJ, G riffi n JW, Luciano C, et al. Q uantitative analysis of
epidermal innervation in Fabry disease. Neurology 1999;52:
1249 – 1254.
46. Shun CT, Chang YC, Wu HP, et al. Skin denervation in type
2 diabetes: correlations with diabetic duration and functional
impairments. Brain 2004;127:1593– 1605. ( Class III)
47. Singer W, Spies JM, McArthur, et al. Prospective evaluation of
somatic and autonomic small fi bers in selected neuropathies.
Neurology 2004;62:612– 618. ( Class III)
48. Smith AG , Howard JR, Kroll R, Ramchandran P, Hauer P,
Singleton JR, et al. The reliability of skin biopsy with measurement of intraepidermal nerve fi ber density. J Neurol Sci 2005;
228:65– 69.
49. 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.
50. Stewart AG , Low PA, Fealey RD. Distal small fi ber neuropathy:
results of tests of sweating and autonomic cardiovascular refl exes. Muscle Nerve 1992;15:661– 665. ( Class III)
51. Tobin K, G uliani MJ, LaComis D. Comparison of different
modalities for detection of small fi ber neuropathy. Clin Neurophysiol 1999;110:1909 – 1912. ( Class III)
52. Trimarco B, V olpe M, Ricciardelli B, V igorito C, de Luca N,
Sacca L, et al. V alsalva maneuver in the assessment of barorefl ex responsiveness in borderline hypertensives. Cardiology
1983;70:6 – 14.
53. Tseng MT, Hsieh SC, Shun CT, et al. Skin denervation and
cutaneous vasculitis in systemic lupus erythematosus. Brain
2006;129:977– 985.
54. V ogel E R, Sandroni P, Low PA. Blood pressure recovery from
V alsalva maneuver in patients with autonomic failure. Neurology 2005;65:1533– 1537. ( Class II)
55. Walk D, Wendelschafer-Crabb G , Davey C, Kennedy WR.
Concordance between epidermal nerve fi ber density and sensory examination in patients with symptoms of idiopathic
small fi ber neuropathy. J Neurol Sci 2007;255:23– 26. ( Class
III)
56. Z iegler D, Dannehl K, Muhlen, Spuler M, G ries FA. Presence
of cardiovascular autonomic dysfunction assessed by spectral
analysis, and standard tests of heart rate variation and blood
pressure response at various stages of diabetic neuropathy.
Diabet Med 1992;9:806 – 814.
MUSCLE & NERV E
J anuary 2009
115
AANEM PRACTICE PARAMETER
ABSTRACT: Distal symmetric polyneuropathy (DSP) is the most common
variety of neuropathy. Since the evaluation of this disorder is not standardized, the available literature was reviewed to provide evidence-based guidelines regarding the role of laboratory and genetic tests for the assessment of
DSP. A literature review using MEDLINE, EMBASE, Science Citation Index,
and Current Contents was performed to identify the best evidence regarding
the evaluation of polyneuropathy published between 1980 and March 2007.
Articles were classified according to a four-tiered level of evidence scheme
and recommendations were based on the level of evidence. (1) Screening
laboratory tests may be considered for all patients with polyneuropathy
(Level C). Those tests that provide 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). If there is no definite evidence of diabetes mellitus by routine testing of
blood glucose, testing for impaired glucose tolerance may be considered in
distal symmetric sensory polyneuropathy (Level C). (2) Genetic testing is
established as useful for the accurate diagnosis and classification of hereditary neuropathies (Level A). Genetic testing may be considered in patients
with cryptogenic polyneuropathy who exhibit a hereditary neuropathy phenotype (Level C). Initial genetic testing should be guided by the clinical
phenotype, inheritance pattern, and electrodiagnostic (EDX) features and
should focus on the most common abnormalities, which are CMT1A duplication/HNPP deletion, Cx32 (GJB1), and MFN2 mutation screening. There
is insufficient evidence to determine the usefulness of routine genetic testing
in patients with cryptogenic polyneuropathy who do not exhibit a hereditary
neuropathy phenotype (Level U).
Muscle Nerve 39: 116 –125, 2009
EVALUATION OF DISTAL SYMMETRIC POLYNEUROPATHY:
THE ROLE OF LABORATORY AND GENETIC TESTING
(AN EVIDENCE-BASED REVIEW)
J.D. ENGLAND, MD,1 G.S. GRONSETH, MD,2 G. FRANKLIN, MD,3 G.T. CARTER, MD,4 L.J. KINSELLA, MD,5 J.A. COHEN, MD,6
A.K. ASBURY, MD,7 K. SZIGETI, MD, PHD,8 J.R. LUPSKI, MD, PHD,9 N. LATOV, MD,10 R.A. LEWIS, MD,11 P.A. LOW, MD,12
M.A. FISHER, MD,13 D. HERRMANN, MD,14 J.F. HOWARD, MD,15 G. LAURIA, MD,16 R.G. MILLER, MD,17
M. POLYDEFKIS, MD,18 A.J. SUMNER, MD19 Report of the American Academy of Neurology, the American Association of
Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation
1
Louisiana State University Health Sciences Center, Baton Rouge, Louisiana, USA
University of Kansas, Lawrence, Kansas, USA
3
University of Washington, Seattle, Washington, USA
4
Providence Health System, Southwest Washington, Seattle, Washington, USA
5
Tenet-Forest Park Hospital, St. Louis, Missouri, USA
6
Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
7
University of Pennsylvania Hospital, Philadelphia, Pennsylvania, USA
8
Baylor College of Medicine, Houston, Texas, USA
9
Baylor College of Medicine, Houston, Texas, USA
2
Abbreviations: AAN, American Academy of Neurology; AANEM, American Academy of Neuromuscular and Electrodiagnostic Medicine; AAPM&R, American
Academy of Physical Medicine and Rehabilitation; CMT, Charcot–Marie–Tooth; CPG, clinical practice guideline; CSF, cerebrospinal fluid; DSP, distal symmetric
polyneuropathy; EDX, electrodiagnostic; GTT, glucose tolerance testing; immunofixation electrophoresis; QSS, Quality Standards Subcommittee; SPEP, serum
protein electrophoresis
Key words: prospective studies; evaluation; distal symmetric polyneuropathy
Correspondence to: American Association of Neuromuscular & Electrodiagnostic Medicine, 2621 Superior Drive NW, Rochester, MN 55901; e-mail:
[email protected]
© 2008 Wiley Periodicals, Inc.
Published online 15 December 2008 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mus.21226
116
AANEM Practice Parameter
MUSCLE & NERVE
January 2009
10
Weill Medical College of Cornell, Ithaca, New York, USA
Wayne State University School of Medicine, Detroit, Michigan, USA
12
Mayo Clinic, Rochester, Minnesota
13
Loyola University Chicago Stritch School of Medicine, Chicago, Illinois, USA
14
University of Rochester Medical Center, Rochester, New York, USA
15
University of North Carolina, Chapel Hill, North Carolina, USA
16
National Neurological Institute “Carlo Besta,” Milan, Italy
17
California Pacific Medical Center, San Francisco, California, USA
18
Johns Hopkins Medical Institute, Baltimore, Maryland, USA
19
Louisiana State University Health Sciences Center, Baton Rouge, Louisiana, USA
11
Accepted 9 October 2008
INTRODUCTION
Justification. Polyneuropathy is a relatively common neurological disorder.8 The overall prevalence
is ⬇2,400 (2.4%) per 100,000 population, but in
individuals older than 55 years the prevalence rises
to ⬇8,000 (8%) per 100,000.7,22 Since there are
many etiologies of polyneuropathy; a logical clinical
approach is needed for evaluation and management.
This practice parameter provides recommendations for the role of laboratory and genetic tests in
the evaluation of distal symmetric polyneuropathy
(DSP) based on a prescribed review and analysis of
the peer-reviewed literature. The parameter was developed to provide physicians with evidence-based
guidelines regarding the role of laboratory and genetic tests for the assessment of polyneuropathy.
The diagnosis of DSP should be based on a combination of clinical symptoms, signs, and electrodiagnostic criteria as outlined in the previous case definition.8
[See Mission Statement, below, for details.]
The Polyneuropathy
Task Force included 19 physicians with representatives from the American Academy of Neurology
(AAN), the American Academy of Neuromuscular
and Electrodiagnostic Medicine (AANEM), and the
American Academy of Physical Medicine and Rehabilitation (AAPM&R). All of the task force members
had extensive experience and expertise in the area
of polyneuropathy. Additionally, four members had
expertise in evidence-based methodology and practice parameter development. Three are current
members (J.D.E., G.S.G., G.F.), and one is a former
member (R.G.M.) of the Quality Standards Subcommittee (QSS) of the AAN. The task force developed
a set of clinical questions relevant to the evaluation
of DSP, and subcommittees were formed to address
each of these questions.
Formation of Expert Panel.
DESCRIPTION OF THE ANALYTIC PROCESS
The
literature search included OVID MEDLINE
(1966 to March 2007), OVID Excerpta Medica (EM-
AANEM Practice Parameter
BASE; 1980 to March 2007), and OVID Current
Contents (2000 to March 2007). The search included articles on humans only and in all languages.
The search terms selected were peripheral neuropathy, polyneuropathy, and distal symmetric polyneuropathy. These terms were cross-referenced with the
terms laboratory test, diagnosis, electrophysiology,
and genetic testing.
Panel experts were asked to identify additional
articles missed by the initial search strategy. Further,
the bibliographies of the selected articles were reviewed for potentially relevant articles.
Subgroups of committee members reviewed the
titles and abstracts of citations identified from the
original searches and selected those that were potentially relevant to the evaluation of polyneuropathy.
Articles deemed potentially relevant by any panel
member were also obtained.
Each potentially relevant article was subsequently
reviewed in entirety by at least three panel members.
Each reviewer graded the risk of bias in each article
by using the diagnostic test classification-of-evidence
scheme (Appendix 2). In this scheme, articles attaining a grade of Class I are judged to have the lowest
risk of bias, and articles attaining a grade of Class IV
are judged to have the highest risk of bias. Disagreements among reviewers regarding an article’s grade
were resolved through discussion. Final approval was
determined by the entire panel.
The Quality Standards Subcommittee (AAN),
the Practice Issues Review Panel (AANEM), and
the Practice Guidelines Committee (AAPM&R)
(Appendix 1A–C) reviewed and approved a draft
of the article. The draft was next sent to members
of the AAN, AANEM, and AAPM&R for further
review and then to Neurology for peer review.
Boards of the AAN, AANEM, and AAPM&R reviewed and approved the final version of the article. At each step of the review process, external
reviewers’ suggestions were explicitly considered.
When appropriate, the expert panel made
changes to the document.
MUSCLE & NERVE
January 2009
117
ANALYSIS OF THE EVIDENCE
The search yielded 4,500 references with abstracts.
After reviewing titles and abstracts, 450 articles were
reviewed and classified.
Role of Laboratory Testing in the Evaluation of Polyneuropathy. With the exception of electrodiagnostic
(EDX) studies, laboratory tests are not utilized to
diagnose polyneuropathy; however, laboratory tests
are routinely utilized in patients with a diagnosis of
polyneuropathy as a screening test for specific etiologies. Several questions regarding the use of laboratory testing as a screening tool in the evaluation of
polyneuropathy were assessed.
What Is the Yield of Screening Laboratory Tests in the
Evaluation of DSP, and Which Tests Should Be Performed? The cause of most polyneuropathies is ev-
ident when the information obtained from the medical history, neurological examination, and EDX
studies are combined with simple screening laboratory tests. Such a comprehensive investigation yields
an etiological diagnosis in 74%– 82% of patients with
polyneuropathy.1,6,9,12,14,21,23,28,29,40 Laboratory test
results must be interpreted in the context of other
clinical information since the etiologic yield of laboratory testing alone is limited by the low specificity
of many of the tests. For example, one study of
idiopathic polyneuropathy found that laboratory
tests alone had only a 37% diagnostic yield (Class
III).21 In another study, laboratory abnormalities
were documented in 58% of 91 patients with chronic
cryptogenic polyneuropathy, but only 9% were etiologically diagnostic (Class III).9 The majority of studies indicated that screening laboratory tests comprised of a complete blood count, erythrocyte
sedimentation rate, comprehensive metabolic
panel (blood glucose, renal function, liver function), thyroid function tests, serum B12, and serum
protein immunofixation electrophoresis are indicated for most patients with polyneuropathy.1,6,9,12,14,21,23,28,29,40 Five Class III studies indicated that the highest yield of abnormality was
seen with screening for blood glucose, serum B12,
and serum protein immunofixation electrophoresis (Class III).1,9,14,21,32 The test with the highest
yield was the blood glucose, consistent with the
well-known fact that diabetes mellitus is the commonest cause of DSP. In patients with DSP blood
glucose was elevated in ⬇11%, serum protein electrophoresis or immunofixation was abnormal in
9%, and serum B12 was low in ⬇3.6%. Two Class III
studies showed that routine cerebrospinal fluid
118
AANEM Practice Parameter
(CSF) analysis had a low diagnostic yield except in
demyelinating polyneuropathies, which usually
showed an increased CSF protein level.12,28
Vitamin B12 deficiency was relatively frequent in
patients with polyneuropathy, and the yield was
greater when the metabolites of cobalamin (methylmalonic acid and homocysteine) were tested (Class
II and III).1,19,20,32,33 Serum methylmalonic acid and
homocysteine were elevated in 5%–10% of patients
whose serum B12 levels were in the low normal range
of 200 –500 pg/dL.20,33 In large series of patients
with polyneuropathy, between 2.2%– 8% of patients
had evidence of B12 deficiency as indicated by elevations of these metabolites.1,32 In one Class III study
involving 27 patients with polyneuropathy and B12
deficiency, 12 (44%) had B12 deficiency based on
the finding of abnormal metabolites alone.32 Thus,
serum B12 assays with metabolites (methylmalonic
acid and homocysteine) are useful in documenting
B12 deficiency.
Although both methylmalonic acid and homocysteine are sensitive for B12 deficiency, methylmalonic
acid is more specific. In a large Class III study involving 434 patients with vitamin B12 deficiency, serum
methylmalonic acid was elevated in 98.4% and serum homocysteine was elevated in 95.9%.33 In the
same study serum methylmalonic acid was elevated
in 12.2%, but serum homocysteine was elevated in
91% of 123 patients with isolated folate deficiency.33
Homocysteine may also be elevated in pyridoxine
deficiency and heterozygous homocysteinemia. Both
homocysteine and methylmalonic acid may be elevated in hypothyroidism, renal insufficiency, and hypovolemia.
Several studies highlight the relatively high prevalence of pre-diabetes (impaired glucose tolerance)
in patients with DSP who do not fulfill the criteria for
definite diabetes mellitus (Class III).30,35,37 In these
studies glucose tolerance testing (GTT) was performed in patients with idiopathic DSP. Impaired
glucose tolerance was documented in 25%–36% of
patients compared to ⬇15% of controls. Additionally, patients with painful sensory polyneuropathies
were more likely to have impaired glucose tolerance
than those with painless sensory polyneuropathies.
Only one major study has not found an increased
prevalence of impaired glucose tolerance in chronic
idiopathic axonal polyneuropathy (Class III).11
Monoclonal gammopathies are more common in
patients with polyneuropathy than in the normal
population. IgM monoclonal gammopathies may be
associated with autoantibody activity, type I or II
cryoglobulinemia, macroglobulinemia, or chronic
lymphocytic leukemia. IgG or IgA monoclonal gam-
MUSCLE & NERVE
January 2009
Table 1. Basic laboratory investigation of polyneuropathy.
Hematology: complete blood count, erythrocyte sedimentation
rate or C-reactive protein, vitamin B12,* folate. Methylmalonic
acid with or without homocysteine for low normal vitamin B12
levels.*
Biochemical and endocrine: comprehensive metabolic panel
(fasting blood glucose,* renal function, liver function), thyroid
function tests. Serum protein immunofixation electrophoresis.*
Glucose tolerance test if indicated to look for impaired glucose
tolerance.*
Urine: urinalysis, urine protein electrophoresis with
immunofixation.
Drugs and toxins: inquire about drugs and toxins.
*Tests with the highest yield (Class III).
This list is not intended to include all possible tests or methods that may be
useful in the evaluation of polyneuropathy. Neither is it intended to exclude
any reasonable alternative tests or methodologies.
mopathies may be associated with myeloma, POEMS
syndrome, primary amyloidosis, or chronic inflammatory conditions. In one Class III study of 279
consecutive patients with polyneuropathy of otherwise unknown etiology seen at a referral center, 10%
had monoclonal gammopathy, a significant increase
over that reported in community studies.16 Serum
protein immunofixation electrophoresis (IFE) is
more sensitive than serum protein electrophoresis
(SPEP), especially for detecting small or nonmalignant monoclonal gammopathies. Ten of 58 (17%)
monoclonal gammopathies, including 10 of 36
(30%) with IgM ⬍5 g/L, were identified by IFE but
not by SPEP.15
Conclusions. Screening laboratory tests are probably useful in determining the cause of DSP, but the
yield varies depending on the particular test (Class
III). 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). 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. Screening laboratory tests
may be considered for all patients with DSP (Level
C). Although routine screening with a panel of basic
tests is often performed (Table 1), those tests with
the highest yield of abnormality are blood glucose,
serum B12 with metabolites (methymalonic acid with
or without homocysteine), and serum protein immunofixation electrophoresis (Level C). 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).
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 2) are necessary.
Role of Genetic Testing in the Evaluation of Polyneuropathy. Hereditary neuropathies are an important
subtype of polyneuropathy, with a prevalence of ⬇1:
Table 2. Specialized laboratory investigation of acute and chronic polyneuropathy.*
Connective tissue diseases and vasculitis (Sjogren’s disease, systemic lupus erythematosus, rheumatoid arthritis, mixed connective tissue
disease, polyarteritis nodosa, Churg–Strauss disease, Wegener’s granulomatosis, ANCA syndrome): antinuclear antigen profile,
rheumatoid factor, anti-Ro/SSA, anti-La/SSB, antineutrophil cytoplasmic antigen antibody (ANCA) profile, cryoglobulins.
Infectious agents: Campylobacter jejuni, cytomegalovirus (CMV), hepatitis panel (B and C), HIV tests, Lyme disease tests, herpes viruses
tests, West Nile virus tests, cerebrospinal fluid analysis.
Diseases of gut: antibodies for celiac disease (gliadin, transglutaminase, endomysial), vitamin E level, B vitamin levels; most require
endoscopic confirmation with biopsy.
Sarcoidosis: serum angiotensin converting enzyme (ACE), cerebrospinal fluid analysis including ACE.
Heavy metal toxicity: blood, urine, hair and nail analysis for heavy metals (arsenic, lead, mercury, thallium).
Porphyria: blood, urine, and stool for porphyrins.
Dysimmune: antiganglioside antibody profile (GM1, GD1a, GD1b, GD3, GQ1b, GT1b) , anti-myelin associated glycoprotein (MAG)
antibodies, paraneoplastic antibody profile (anti -Hu, anti-CV2), cerebrospinal fluid analysis including immunoglobulin oligoclonal bands.
Hereditary:† molecular genetic tests tailored to the clinical profile and available for an increasing number of hereditary neuropathies such as
Charcot–Marie–Tooth disease, hereditary neuropathy with liability to pressure palsies, and hereditary amyloidosis.
Malignancies (carcinoma, myeloma, lymphoma): skeletal radiographic survey; mammography; computed tomography or magnetic
resonance imaging of chest, abdomen, and pelvis; ultrasound of abdomen and pelvis; positron emission tomography, cerebrospinal fluid
analysis including cytology, serum paraneoplastic antibody profile (anti-Hu, anti-CV2).
*No controlled trials exist for most of these specialized laboratory tests (Level U) except for molecular genetic tests in hereditary neuropathies† (Level A and B).
Clinical judgment will determine which tests are necessary (Level U).
This list is not intended to include all possible tests or methods that may be useful in the evaluation of polyneuropathy. Neither is it intended to exclude any
reasonable alternative tests or methodologies.
AANEM Practice Parameter
MUSCLE & NERVE
January 2009
119
2,500 people. DSP is the predominant phenotype,
but phenotypic heterogeneity may be present even
within the same family; therefore, when genetic testing is contemplated all neuropathy phenotypes need
to be considered. In the evaluation of polyneuropathy a comprehensive family history should always be
elicited. A high index of suspicion for a hereditary
neuropathy phenotype is essential. Since molecular
diagnostic techniques are available, guidelines for
their usefulness in the evaluation of polyneuropathy
are needed.
The majority of genetically determined polyneuropathies are variants of Charcot–Marie–Tooth
(CMT) disease, and genetic testing is available for an
increasing number of these neuropathies. The clinical phenotype of CMT is extremely variable, ranging
from a severe polyneuropathy with respiratory failure through the classic picture with pes cavus and
“stork legs” to minimal neurological findings.2,3
Since a substantial proportion of CMT patients have
de novo mutations, a family history of neuropathy
may be lacking.2,3,10 Additionally, different genetic
mutations can cause a similar phenotype (genetic
heterogeneity) and different phenotypes can result
from the same genotype (phenotypic heterogeneity).
How Accurate Is Genetic Testing for Identifying Patients with Genetically Determined Neuropathies?
The CMT phenotype has been linked to 36 loci and
mutations have been identified in 28 different genes,
several of which can be identified by commercially
available genetic testing. Previous segregation studies followed by several prospective cohort studies
have documented that the results of currently available genetic testing are unequivocal for diagnosis of
established pathogenic mutations, providing a specificity of 100% (i.e., no false-positives) and high sensitivity (Class I and II).4,5,13,17,24 –27,34,39 The interpretation of novel mutations may require further
characterization available in specialized centers.
Data from six Class I, six Class II, and one Class III
study indicate that genetic testing is useful for the
accurate classification of hereditary polyneuropathies.2,4,5,10,13,17,24 –27,34,38,39
Which Patients with Polyneuropathy Should Be
Screened for Hereditary Neuropathies? Genetic stud-
ies of hereditary neuropathies have tested the prevalence of various mutations in selected patients with
the classic CMT phenotype with and without a family
history of polyneuropathy.5,17,24 –27,39 (Class III evidence for screening.) For these patients the yield of
genetic tests has been relatively high.
120
AANEM Practice Parameter
Data from seven studies indicate that the demyelinating form of Charcot–Marie–Tooth (CMT1) is
the most prevalent, and about 70% of these patients
have a duplication of PMP22 gene (CMT1A).5,17,24 –
27,39 CMT1A is also the most common variety of
sporadic CMT1, accounting for 76%–90% of cases.10,26 Six studies showed that when the test for
CMT1A duplication is restricted to patients with clinically probable CMT1 (i.e., autosomal dominant, primary demyelinating polyneuropathy), the yield is
54%– 80% as compared to testing a cohort of patients suspected of having any variety of hereditary
peripheral neuropathy where the yield is only 25%–
59% (average of 43%).5,13,24,26,34,39
Axonal forms of Charcot–Marie–Tooth (CMT2)
are most commonly caused by MFN2 mutations,
which account for ⬇33% of the cases.38 MFN2 mutations have not occurred in the CMT1 group.
Data from eight studies indicate that Cx32(GJB1)
mutations cause an X-linked neuropathy (CMTX),
which may present with either a predominantly demyelinating or axonal phenotype and account for
⬇12% of all cases of CMT.4,5,13,24,25,27,34,39 If the pedigree is uninformative as to whether the inheritance
is autosomal dominant or X-linked (lack of father to
son transmission), Cx32(GJB1) mutation is in the
differential diagnosis for both predominantly demyelinating and axonal neuropathies.
Data from seven studies has established average
mutation frequencies of 2.5% for PMP22 point mutations, and 5% for MPZ mutations in the CMT
population.4,5,13,24,25,39 CMT caused by other genes is
much less frequent (see Fig. 1).
Given the relationships between pattern of inheritance, EDX results, and specific mutations, the efficiency of genetic testing can be improved by following a stepwise evaluation of patients with possible
hereditary neuropathy. First, a clinical classification
that includes EDX studies should be performed to
determine whether the neuropathy is primarily demyelinating or primarily axonal in type. Since EDX
studies are sometimes problematic in children, some
physicians may opt to proceed directly to genetic
testing of symptomatic children suspected of having
CMT. Second, the inheritance pattern (autosomal
dominant, autosomal recessive, or X-linked) should
be ascertained. Based on this information, the most
appropriate genetic profile testing can then be performed.
Figure 1 indicates an evidence-based, tiered approach for the evaluation of suspected hereditary neuropathies, and Table 3 shows the relative frequency of
the most common genetic abnormalities accounting
for the CMT phenotype from population studies.
MUSCLE & NERVE
January 2009
Evaluation of Suspected Hereditary Neuropathies
Positive Family History
Negative Family History
EMG/NCS
EMG/NCS
Index of suspicion
for CMT high
Axonal
Demyelinating
30% of mutations are de
novo, molecular testing
AD
First tier
Second tier
Third tier
PMP22 dup 70%
AR
X
GJB1 12%
MPZ mut 5%
PMP22 mut 2.5%
EGR2 mut
LITAF mut
AD
AR
GJB1 12%
MFN2 mut 33%
RAB7 mut
GARS mut
NEFL mut
HSPB1 mut
Demyelinating
PMP22 dup
GJB1 mut
MPZ mut 5%
PMP22 mut 2.5%
MPZ mut 5%
PRX mut
GDAP1 mut
X
GDAP1 mut
EGR2 mut
LITAF mut
PRX mut
GDAP1 mut
Axonal
MFN2 mut
GJB1 mut
MPZ mut 5%
RAB7 mut
GARS mut
NEFL mut
HSPB1 mut
GDAP1 mut
FIGURE 1. Evaluation of suspected hereditary neuropathies.
Decision algorithm for use in the diagnosis of suspected hereditary polyneuropathies using family history and NCSs. *PMP22
denotes peripheral myelin protein 22; MPZ myelin protein zero;
PRX periaxin; GDAP1 ganglioside-induced differentiation-associated protein 1; GJB1 gap-junction beta-1 protein (connexin 32);
MFN2 mitofusin 2; EGR2 early growth response 2; LITAF lipopolysaccharide-induced tumor necrosis factor ␣; RAB7 small
guanosine triphosphatase late endosomal protein; GARS glycyltransfer RNA synthetase; NEFL neurofilament light chain;
HSPB1 heat shock protein beta-1.
The previous discussion applies to patients with
polyneuropathy and a classical hereditary neuropathy phenotype with or without a family history. The
authors were not able to find studies of the yield of
genetic screening in polyneuropathy patients without a classical hereditary neuropathy phenotype.
Some patients with CMT genetic mutations have
minimal neurological findings and do not have the
classical CMT phenotype.2,3 Thus, some patients
with cryptogenic polyneuropathies without the clas-
sical CMT phenotype may also have hereditary neuropathies. The prevalence of mutations in this population is unknown.
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.
There is insufficient evidence to determine the usefulness of routine genetic screening in cryptogenic
polyneuropathy patients without a classical hereditary neuropathy phenotype.
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 Fig. 1
for guidance.)
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).
RECOMMENDATIONS FOR FUTURE RESEARCH
This comprehensive review reveals several weaknesses in the current approach to the evaluation of
Table 3. Mutation frequencies for Charcot-Marie-Tooth (CMT) and related neuropathies in various populations. The mutation frequencies
are given in the total CMT cohort and in the clinical phenotypes (CMT1 and HNPP) when available.
Population
American39
Spanish4
Belgian13
Finnish34
Slovene17
European26
Australian27
Russian24
Italian25
Korean5
Average
Cohort (# of pt)
Total/CMT1/
HNPP
75/63
52
443
157
71
975/819/156
224
174/108/3
172
57
CMT1A Duplication
Total/CMT1
HNPP Deletion
Total/HNPP
PMP22 mutation
Total/CMT1
Cx32 mutation
Total/CMT1
MPZ mutation
Total/CMT1
56/68
Excluded
24.6
40.7
81
59.4/70.7
61
33.9/53.7
57.6
26/54
43%/70%
ND
Excluded
10.6
26.1
ND
13.4/84
ND
100
ND
ND
11%/92%
3.9
3.8 0.8*
2.7
ND
ND
ND
1.3
1.1/1.9
1.2
1.7
2.5%
7.2
19.2 7.7*
5.4
7.6
ND
ND
12
6.8/7.4
6.9
5.3
12%
3.3
9.6 3.8*
0.7
ND
ND
ND
3.1
3.4 5.6
2.3
5.3
5%
Bold: CMT1 subpopulation.
Italicized: HNPP subpopulation.
*Extrapolated total number and mutation frequencies recalculated for the total number. For the estimation of the total number the authors calculated with the
average frequencies for CMT1A duplication and HNPP deletion derived from the other studies.
AANEM Practice Parameter
MUSCLE & NERVE
January 2009
121
Table 4. Evidence table for genetic testing
Reference
Data collection
10
Prospective
Prospective
Prospective
Prospective
Prospective
Prospective
Prospective
Prospective
Prospective
Prospective
Prospective
Prospective
Prospective
39
4
13
34
17
26
27
24
25
2
5
38
Setting*
Sampling
Completeness Gene dependent
Masking
Class
Referral center
Referral center
Referral center
Referral center
Referral center
NA
Referral center
Referral center
Referral center
Referral center
Referral center
Referral center
Referral center
NA
Consecutive
Consecutive
Consecutive
Consecutive
NA
Consecutive
Consecutive
Consecutive
Consecutive
Consecutive
Consecutive
Selected
PMP22 dup
PMP22 dup
PMP22 mut, Cx32, MPZ
PMP22 dup, del, mut, Cx32, MPZ
PMP22 dup, del, Cx32
PMP22 dup
PMP22 dup, del
PMP22 dup, mut, Cx32, MPZ
PMP22 dup, del, mut, Cx32, MPZ
PMP22 dup, mut, Cx32, MPZ
PMP22 dup, mut, Cx32, MPZ
PMP22 dup, mut, Cx32, MPZ
MFN2
Waived
Waived
Waived
Waived
Waived
Waived
Waived
Waived
Waived
Waived
Waived
Waived
Waived
II
II
I
I
II
III
I
II
II
I
I
I
II
*Referral center for test, not for patient; patients come from general neurology clinics
polyneuropathy and highlights opportunities for research.
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 is a need to
determine whether aggressive treatment or reversal
of specific laboratory abnormalities improves or alters the course of polyneuropathy.
Laboratory Testing.
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 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.
Mission Statement. The AAN, the AANEM, and the
AAPM&R determined that there was a need for an
evidence-based and clinically relevant practice pa-
122
AANEM Practice Parameter
rameter for the evaluation of polyneuropathy. As a
prelude to this project, the three organizations developed a formal case definition of DSP.8 As outlined
in this previous publication, the most accurate diagnosis of distal symmetric polyneuropathy is provided
by a combination of neuropathic symptoms, signs,
and EDX studies. Since EDX studies are sensitive,
specific, and validated measures of the presence of
polyneuropathy and can distinguish between demyelinating and axonal types of neuropathy, they
should be included as an integral part of the diagnosis.8 This practice parameter assumes that a clinical diagnosis of polyneuropathy has been determined based on such criteria.
The diagnosis and evaluation of polyneuropathy is complex. The practice parameter is
not intended to replace the clinical judgment of
experienced physicians in the evaluation of polyneuropathy. The particular kinds of tests utilized by a
physician in the evaluation of polyneuropathy depend on the specific clinical situation and the informed medical judgment of the treating physician.
This statement is provided as an educational
service of the AAN, AANEM, and the AAPM&R. It
is based on an assessment of current scientific and
clinical information. It is not intended to include
all possible proper methods of care for a particular
neurologic problem or all legitimate criteria for
choosing to use a specific test or procedure. Neither is it intended to exclude any reasonable alternative methodologies. The AAN, AANEM, and
AAPM&R recognize that specific care decisions are
the prerogative of the patient and physician caring
for the patient, based on all of the circumstances
involved.
Disclaimer.
MUSCLE & NERVE
January 2009
of Interest. The AAN, AANEM, and
AAPM&R are committed to producing independent,
critical, and truthful clinical practice guidelines
(CPGs). Significant efforts are made to minimize the
potential for conflicts of interest to influence the
recommendations of this CPG. To the extent possible, the AAN, AANEM, and AAPM&R keep separate
those who have a financial stake in the success or
failure of the products appraised in the CPGs and
the developers of the guidelines. Conflict of interest
forms were obtained from all authors and reviewed
by an oversight committee prior to project initiation.
AAN, AANEM, and AAPM&R limit the participation
of authors with substantial conflicts of interest. The
AAN, AANEM, and AAPM&R forbid commercial
participation in, or funding of, guideline projects.
Drafts of the guideline have been reviewed by at least
three AAN committees, AANEM and AAPM&R committees, a network of neurologists, Neurology peer
reviewers, and representatives from related fields.
The AAN Guideline Author Conflict of Interest Policy can be viewed at www.aan.com.
Conflict
APPENDIX 1A
Jacqueline French, MD, FAAN (co-chair); Gary S. Gronseth, MD (co-chair); Charles E. Argoff, MD; Eric Ashman, MD; Stephen Ashwal, MD, FAAN (ex-officio);
Christopher Bever Jr., MD, MBA, FAAN; John D.
England, MD, FAAN (QSS facilitator); Gary M.
Franklin, MD, MPH, FAAN (ex-officio); Deborah
Hirtz, MD (ex-officio); Robert G. Holloway, MD,
MPH, FAAN; Donald J. Iverson, MD, FAAN; Steven
R. Messé, MD; Leslie A. Morrison, MD; Pushpa
Narayanaswami, MD, MBBS; James C. Stevens, MD,
FAAN (ex-officio) David J. Thurman, MD, MPH (exofficio); Samuel Wiebe, MD; Dean M. Wingerchuk,
MD, MSc, FRCP(C); and Theresa A. Zesiewicz, MD,
FAAN.
Quality Standards Subcommittee Members.
APPENDIX 1B
Practice Issues Review Panel (AANEM). Yuen T. So,
MD, PhD (chair); Michael T. Andary, MD; Atul Patel, MD; Carmel Armon, MD; David del Toro, MD;
Earl J. Craig, MD; James F. Howard, MD; Joseph V.
Campellone Jr., MD; Kenneth James Gaines, MD;
Robert Werner, MD; Richard Dubinsky, MD.
APPENDIX 1C
Clinical Quality Improvement Committee (AAPM&R).
Dexanne B. Clohan, MD (chair); William L. Bockenek, MD; Lynn Gerber, MD; Edwin Hanada, MD;
AANEM Practice Parameter
Ariz R. Mehta, MD; Frank J. Salvi, MD, MS; and
Richard D. Zorowitz, MD.
APPENDIX 2
Classification of Evidence for Studies of Diagnostic Ac-
Class I. Evidence provided by a prospective study in a broad spectrum of persons with the
suspected condition, using a “gold standard” for case
definition, where a test is applied in a blinded evaluation, and enabling the assessment of appropriate
tests of diagnostic accuracy.
Class II. Evidence provided by a prospective
study of a narrow spectrum of persons with the suspected condition, or a well-designed retrospective
study of a broad spectrum of persons with an established condition (by “gold standard”) compared to a
broad spectrum of controls, where a test is applied in
a blinded evaluation, and enabling the assessment of
appropriate tests of diagnostic accuracy.
Class III. Evidence provided by a retrospective
study when either persons with the established condition or controls are of a narrow spectrum, and
where a test is applied in a blinded evaluation.
Class IV. Any design where a test is not applied
in blinded evaluation or evidence provided by expert
opinion alone or in descriptive case series (without
controls).
curacy.
APPENDIX 3.
A ⫽ Established
as effective, ineffective, or harmful for the given
condition in the specified population. (Level A rating requires as least two consistent Class I studies.)
B ⫽ Probably effective, ineffective, or harmful for
the givencondition in the specified population.
(Level B rating requires at least one Class I study or
at least two consistent Class II studies.)
C ⫽ Possibly effective, ineffective, or harmful for
the given condition in the specified population.
(Level C rating requires at least one Class II study or
two consistent Class III studies.)
U ⫽ Data inadequate or conflicting; given current knowledge, treatment is unproven.
Classification of Recommendations.
Approved by the AANEM Board of Directors on May 1, 2008. With
regard to conflicts of interest, the authors disclose the following:
(1) Holds financial interests in Pfizer. (2) Holds financial interests
in Pfizer and GlaxoSmithKline and Boeheringer Ingelheim for
speaker honoraria and Ortho-McNeil for serving on the IDMC
Committee. (3) Nothing to disclose. (4) Nothing to disclose. (5)
Received royalties from the American Medical Resources, Enduring Medical Materials (CD/DVD), has received honorarium from
Medical Education Resources, CME LLC, Expert Witness testimony and record review, Peters Marketing Research, Delve Marketing Research, Cross Country Education and American Medical
MUSCLE & NERVE
January 2009
123
Seminars. Dr. Kinsella holds corporate appointments with Cross
Country Education and Forest Park Hospital. (6) Nothing to
disclose. (7) Receives residual royalties from Elsevier for editorial
work done prior to 2005. He receives honoraria from the Dana
Foundation, NY, and the International Society for Neuroimmunology. His wife is a consultant for the Dana Foundation. (8)
Nothing to disclose. (9) Financial interests in Athena Diagnostics
and has received research funding from NIH/NEI, NIH/NIDCR,
Charcot-Marie-Tooth Association, and the March of Dimes. (10)
Serves as a Scientific Advisor for Quest Diagnostics and is a
member of a Steering Committee, Talecris Biotherapeutics. Dr.
Latov receives royalties from Demos publications and has received
research support from the NIH and Talecris Biotherapeutics. He
holds stock options in Therapath LLC and is the beneficiary of
license fee payments from Athena Diagnostics to Columbia University. He has given expert testimony in legal proceedings related
to neuropathy and has prepared an affidavit with regarding to the
legal proceeding related to neuropathy. (11) Financial interests in
Talecris and has received research funding from MDA and
CMTA. He estimates that approximately 33% of his clinical effort
is spent on electromyography. He has received payment for expert testimony regarding the use of IVIg in CIDP; neuropathic
pain after breast reduction. (12) Served as a consultant for WR
Medical, Viatris, Eli Lilly and Company, Chelsea Therapeutics,
and Quigley Corporation. (13) Financial interests in Astrazeneca,
Photothera, Wyeth, Jalmarjone Sahron, Inarx, Boehringer-Ingelheim, Dullehi-Arubio, Axaron, U-Servicer, and PAION. (14)
Estimates that approximately 15%–20% of his clinical effort is
spent on skin biopsies. (15) Serves on a myasthenia gravis medical
scientific board, has served as an Associate Editor, Journal of
Clinical Neuromuscular Disease (1998 –2006), receives honoraria
from Duke University Medical Center, and Medical Educational
Resources. He is the director of MEG laboratories and estimates
that 75% of his time is spent there. He also holds stock options in
GE, Pfizer, and Johnson & Johnson. In addition, he has provided
an affidavit on two cases regarding myasthenia gravis. (16) Financial interests in GlaxoSmithKline and Formenti-Grunenthal. In
addition he has received research funding from Pfitzer, FormentiGrunenthal, Foramenti-Grunenthal, Italian Ministry of Health,
and Regione Lombardia. (17) Financial interests in Celgene and
Pathologica. (18) Financial interests in DSMB, Pfizer, Johnson &
Johnson, Mitsubishi Pharma, Merck, Xenoport, and GSK. He has
received research funding from JDRF, NIH, Astellas Pharma,
Mitsubishi Pharma, and Sanofi-Aventis. He estimates that 10% of
his clinical effort is devoted to EMG, 5% to skin biopsy, and ⬍1%
on lumbar puncture. (19) Received payment for expert testimony
in the possible neurotoxic injury of the peripheral nerve.
REFERENCES
[Note. Strength of evidence is indicated for references used to formulate conclusions and recommendations.]
1. Barohn RJ. Approach to peripheral neuropathy and myopathy. Semin Neurol 1998;18:7–18. (Class III)
2. Boerkoel CF, Takashima H, Garcia CA, et al. Charcot-MarieTooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation. Ann Neurol 2002;
51:190 –201. (Class I)
3. Boerkoel CF, Takashima H, Lupski JR. The genetic convergence of Charcot-Marie-Tooth disease types 1 and 2 and the
role of genetics in sporadic neuropathy. Curr Neurol Neurosci Rep 2002;2:70 –77.
124
AANEM Practice Parameter
4. Bort S, Nelis E, Timmerman V, et al. Mutational analysis of
the MPZ, PMP22 and Cx32 genes in patients of Spanish
ancestry with Charcot-Marie-Tooth disease and hereditary
neuropathy with liability to pressure palsies. Hum Genet
1997;99:746 –754. (Class I)
5. Choi BO, Lee MS, Shin SH, et al. Mutational analysis of
PMP22, MPZ, GJB1, EGR2 and NEFL in Korean CharcotMarie-Tooth neuropathy patients. Hum Mutat 2004;24:185–
186. (Class I)
6. Dyck PJ, Oviatt KF, Lambert EH. Intensive evaluation of referred unclassified neuropathies yields improved diagnosis.
Ann Neurol 1981;10:222–226. (Class IV)
7. England JD, Asbury AK. Peripheral neuropathy. Lancet 2004;
363:2151–2161.
8. 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.
9. Fagius J. Chronic cryptogenic polyneuropathy. Acta Neurol
Scand 1983;67:173–180. (Class III)
10. Hoogendijk JE, Hensels GW, Gabreels-Festen AA, et al. Denovo mutation in hereditary motor and sensory neuropathy
type I. Lancet 1992;339:1081–1082. (Class II)
11. Hughes RA, Umapathi T, Gray IA, et al. A controlled investigation of the cause of chronic idiopathic axonal polyneuropathy. Brain 2004;127:1723–1730. (Class III)
12. 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)
13. Janssen EA, Kemp S, Hensels GW, et al. Connexin32 gene
mutations in X-linked dominant Charcot-Marie-Tooth disease
(CMTX1). Hum Genet 1997;99:501–505. (Class I)
14. 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)
15. Kahn SN, Bina M. Sensitivity of immunofixation electrophoresis for detecting IgM paraproteins in serum. Clin Chem
1988;34:1633–1635.
16. Kelly JJ, Kyle RA, O’Brien PC, Dyck PJ. Prevalence of monoclonal proteins in peripheral neuropathy. Neurology 1981;31:
1480 –1483. (Class III)
17. Leonardis L, Zidar J, Ekici A, Peterlin B, Rautenstrauss B.
Autosomal dominant Charcot-Marie-Tooth disease type 1A
and hereditary neuropathy with liability to pressure palsies:
detection of the recombination in Slovene patients and exclusion of the potentially recessive Thr118MetPMP22 point
mutation. Int J Mol Med 1998;1:495–501. (Class III)
18. Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of
anemia or macrocytosis. N Engl J Med 1988;318:1720 –1728.
19. Lindenbaum J, Rosenberg IH, Wilson PWF, Stabler SP, Allen
RH. Prevalence of cobalamin deficiency in the Framingham
elderly population. Am J Clin Nutr 1994;60:2–11. (Class II)
20. Lindenbaum J, Savage DG, Stabler SP, et al. Diagnosis of
cobalamin deficiency. II. Relative sensitivities of serum cobalamin, methylmalonic acid and total homocysteine concentrations. Am J Hematol 1990;34:99 –107. (Class II)
21. 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)
22. Martyn CN, Hughes RAC. Epidemiology of peripheral neuropathy. J Neurol Neurosurg Psychiatry 1997;62:310 –318.
23. 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)
24. Mersiyanova IV, Ismailov SM, Polyakov AV, et al. Screening
for mutations in the peripheral myelin genes PMP22, MPZ
and Cx32 (GJB1) in Russian Charcot-Marie-Tooth neuropathy patients. Hum Mutat 2000;15:340 –347. (Class II)
MUSCLE & NERVE
January 2009
25. Mostacciuolo ML, Righetti E, Zortea M, et al. Charcot-MarieTooth disease type 1 and related demyelinating neuropathies:
mutation analysis in a large cohort of Italian families. Hum
Mutat 2001;18:32– 41. (Class I)
26. Nelis E, Van Broeckhoven C, De Jonghe P, et al. Estimation of
the mutation frequencies in Charcot-Marie-Tooth disease
type 1 and hereditary neuropathy with liability to pressure
palsies: a European collaborative study. Eur J Hum Genet
1996;4:25–33. (Class I)
27. Nicholson GA. Mutation testing in Charcot-Marie-Tooth neuropathy. Ann N Y Acad Sci 1999;883:383–388. (Class II)
28. 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)
29. 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)
30. Novella SP, Inzucchi SE, Goldstein JM. The frequency of
undiagnosed diabetes and impaired glucose tolerance in patients with idiopathic sensory neuropathy. Muscle Nerve 2001;
24:1229 –1231. (Class III)
31. Periquet MI, Novak V, Collins MP, et al. Painful sensory
neuropathy: prospective evaluation using skin biopsy. Neurology 1999;53:1641–1647.
32. Saperstein DS, Wolfe GI, Gronseth GS, et al. Challenges in
the identification of cobalamin-deficient polyneuropathy.
Arch Neurol 2003;60:1296 –1301. (Class III)
AANEM Practice Parameter
33. Savage DG, Lindenbaum J, Stabler SP, Allen RH. Sensitivity of
serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies.
Am J Med 1994;96:239 –246. (Class III)
34. Silander K, Meretoja P, Juvonen V, et al. Spectrum of mutations in Finnish patients with Charcot-Marie-Tooth disease
and related neuropathies. Hum Mutat 1998;12:59 – 68. (Class
II)
35. Singleton JR, Smith AG, Bromberg MB. Painful sensory polyneuropathy associated with impaired glucose tolerance. Muscle Nerve 2001;24:1225–1228. (Class IV)
36. Smith AG, Singleton JR. The diagnostic yield of a standardized approach to idiopathic sensory-predominant neuropathy. Arch Intern Med 2004;164:1021–1025.
37. Sumner CJ, Sheth S, Griffin JW, Cornblath DR, Polyfefkis M.
The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology 2003;60:108 –111. (Class III)
38. Verhoeven K, Claeys KG, Zuchner S, et al. MFN2 mutation
distribution and genotype/phenotype correlation in CharcotMarie-Tooth type 2. Brain 2006;129:2093–2102. (Class II)
39. Wise CA, Garcia CA, Davis SN, et al. Molecular analyses of
unrelated Charcot-Marie-Tooth (CMT) disease patients suggest a high frequency of the CMTIA duplication. Am J Hum
Genet 1993;53:853– 863. (Class II)
40. Wolfe GI, Baker NS, Amato AA, et al. Chronic cryptogenic
sensory polyneuropathy: clinical and laboratory characteristics. Arch Neurol 1999;56:540 –547. (Class III)
MUSCLE & NERVE
January 2009
125