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Zhirong Yang1 ,2 , Ru Chen1 , Yuan Zhang3 , Yuansheng Huang1 , Tianpei Hong4 , Feng Sun1 , Linong Ji5 , Siyan Zhan1
1
Centre for Evidence Based Medicine and Clinical Research, Department of Epidemiology and Biostatistics, School of Public Health,
Peking University, Beijing, China. 2 Shantou-Oxford Clinical Research Unit, Shantou University Medical College, Shantou, Guang-
dong, China. 3 Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada. 4 Department of
Endocrinology, Peking University Third Hospital, Beijing, China. 5 Department of Endocrinology, Peking University Peoples Hospital,
Beijing, China
Contact address: Siyan Zhan, Centre for Evidence Based Medicine and Clinical Research, Department of Epidemiology and Biostatistics,
School of Public Health, Peking University, 38 Xueyuan Road, Haidian District, Beijing, 100191, China. siyan-zhan@bjmu.edu.cn.
Citation: Yang Z, Chen R, Zhang Y, Huang Y, Hong T, Sun F, Ji L, Zhan S. Scoring systems to screen for diabetic peripheral
neuropathy. Cochrane Database of Systematic Reviews 2014, Issue 3. Art. No.: CD010974. DOI: 10.1002/14651858.CD010974.
Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT
This is the protocol for a review and there is no abstract. The objectives are as follows:
To determine the diagnostic accuracy of each scoring system as triage to screen for diabetic peripheral neuropathy (DPN) involving
limbs within different settings, or as replacement of nerve conduction studies (NCS) for the clinical diagnosis of DPN involving limbs,
with NCS as the reference standard.
To estimate the relative accuracy of scoring systems for screening DPN involving limbs, with NCS as the reference standard.
To assess the impact of potential sources of heterogeneity on the performance of scoring systems for DPN involving limbs: (1) related
to the study population (spectrum of the disease: with versus without other vascular complications; symptoms of DPN: people with
no neurological symptoms versus neurological symptoms (if available, positive versus negative neurological symptoms); duration of
diabetes; level of glycosylated haemoglobin A1c (HbA1c) in adults: < 7% versus 7%; body mass index (BMI) in adults: < 25 versus
25 kg/m; types of diabetes: type 1 versus type 2 diabetes mellitus; age: <18 years old versus 18 years old); (2) related to the
scoring systems (different thresholds; examiners expertise: specialists in diabetes or neurology versus other healthcare professionals);
(3) related to the reference standard (numbers of body sites tested with NCS; examiners expertise: specialists in electrodiagnosis versus
other healthcare professionals); (4) related to the healthcare setting (community versus outpatient setting versus inpatient setting); (5)
related to the methodology based on the QUADAS-2 items (risk of bias for patient selection, index test, reference standard, and flow
and timing; concerns regarding applicability of patient selection, index test, and reference standard).
BACKGROUND 2006), of which 5% to 10% had type 1 diabetes and 90% to 95%
Diabetes mellitus is a metabolic disorder resulting from a defect had type 2 diabetes (Creager 2003). It is estimated that the num-
ber of people with diabetes will reach around 360 million in 2030
in insulin secretion, insulin action, or both. In 2000, more than
(Wild 2004; Yach 2006). Diabetes can induce long-term com-
175 million people all over the world suffered from diabetes (Yach
Scoring systems to screen for diabetic peripheral neuropathy (Protocol) 1
Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
plications, including retinopathy, nephropathy and neuropathy Reference standards
and other vascular complications (American Diabetes Association
2013).
Electrodiagnostic findings provide a higher level of specificity for
the diagnosis of polyneuropathy and should be included as part of
the work-up. Nerve conduction studies (NCS) are the most infor-
Target condition being diagnosed mative part of the electrodiagnostic evaluation which commonly
include both NCS and needle electromyogram (EMG) (England
2005). For NCS, small pads are taped to the skin, deliver mild
electric shocks and detect electric signals. Compared to the whole
Diabetic peripheral neuropathy (DPN) EMG, for which it may be necessary to insert thin needles into the
DPN is one of the most common microvascular complications in muscles, NCS alone are relatively simple, noninvasive and time-
both type1 and type 2 diabetes. DPN has been defined as the saving. Further, due to the objectivity, reliability and sensitivity
presence of symptoms and/or signs of peripheral nerve dysfunc- in the measurement of peripheral nerve function, NCS have long
tion in people with diabetes after the exclusion of other causes been a minimal criterion or a gold standard test for confirming
(Boulton 1998; Soliman 2002). It is the most common component the diagnosis of peripheral neuropathies (Buchthal 1957; Daube
in the causal sequence to foot ulceration (Reiber 1999). DPN can 1999; Donofrio 1990; Dyck 1988; Nasseri 1998).
be broadly separated into generalised symmetrical polyneuropa- Routine NCS include evaluation of motor function of the median,
thy, and asymmetrical (focal and multifocal) neuropathy (Boulton ulnar, peroneal, and tibial nerves, and sensory function of median,
2004; Boulton 2005a; Dyck 2011a; Thomas 1997) (Table 1). ulnar, radial, and sural nerves (Albers 1995). Recommended at-
Autonomic neuropathy can be either present or absent in DPN tributes encompass amplitude, distal latency, distance, conduction
(American Diabetes Association 1996). A staging system, which velocity, F-wave latency and other measurements. It is important
encompasses four stages, has also been developed to provide a to decide how many and which nerves and parameters to assess
framework for diagnosis and management for DPN (Boulton when performing NCS (American Diabetes Association 1992). As
1998) (Table 2). different nerves and multiple attributes can be chosen in NCS, di-
Some evidence has shown that the prevalence of DPN among peo- agnostic criteria might vary in different studies (Dyck 2011a; Dyck
ple with diabetes in the UK is estimated to be 50% (Sugimoto 2011b). Despite many previous recommendations regarding NCS
2000), while the World Health Organization (WHO) estimate for criteria of the diagnosis of polyneuropathy, no formal consensus
the UK is 29% (Wild 2001). A prospective study with 7.5% par- exists (England 2005). In our review, we will accept the minimal
ticipants diagnosed with DPN at baseline showed that the preva- diagnostic criteria as abnormality of one or more attributes (ex-
lence increased to 45% after 25 years of follow-up (Pfeifer 1995). ceeding the normal limits between the 1st and 99th percentiles, or
In a large cohort of people with DPN in the UK, 7% developed a exceeding mean 2.3 standard deviation; variables, such as age,
diabetic foot after one year (Abbott 1998). height, and temperature, should be considered when developing
DPN is largely concerned with the feet and lower limbs, although the reference range and interpreting the results) in two or more
in some severe cases the hands may also be affected (Boulton separate nerves to correctly define DPN (Dyck 1988; Dyck 2011a;
2005a; Boulton 2005b). Typically, it is a chronic, symmetrical Feldman 1994).
and length-dependent condition, compromising multiple nerves Results of NCS are vulnerable to many factors including filter set-
(Dyck 2011a; Tesfaye 2010). DPN of the limbs may involve large- ting, type of electrodes, the location of recording, limb tempera-
fibre nerves (more related to touch, vibration, position perception ture, qualification of examiner and other aspects. All these factors
and muscle control), small-fibre nerves (more related to thermal require meticulous attention to detail for reliable NCS (American
perception, pain and autonomic function) (Vinik 2004) or both. Diabetes Association 1992). Applicable variables such as skin tem-
Most patients, however, have both large- and small-nerve fibre perature, age, height, sex, and weight should be measured and ac-
damages in DPN of the limbs (Vinik 2004). counted for when reporting a NCS as normal or abnormal (AAEM
DPN of the limbs increases with both age and duration of di- 1999).
abetes, and seems more common in those with suboptimal gly- In addition, two potential disadvantages must be acknowledged
caemic control and obesity (Boulton 2005b; Smith 2013). It often when NCS are considered in clinical and research settings. First,
starts at the distal ends of the longest nerves with a stocking-glove NCS have limits on the availability for routine diagnostic evalua-
presentation and moves proximally (Boulton 2005b). Up to 50% tion of DPN. Second, NCS are insensitive for the identification of
of patients, however, may be asymptomatic (Boulton 2005a). Fre- small-fibre neuropathy (Perkins 2003), although the clinical im-
quently reported symptoms in DPN could be positive (painful) portance of small-fibre neuropathy is likely to be insignificant in
symptoms or negative (non painful) symptoms (Boulton 2005b; the context of DPN in which progressive loss of all nerve fibres is
Davies 2006; Melton 1999). observed (Giannini 1999; Perkins 2003).
Prior test(s)
of DPN (American Diabetes Association 1992; Boulton 2005a).
Type 1 or type 2 diabetes should be confirmed by diagnostic tests In the replacement of nerve conduction studies, they can be also
for diabetes. Information on the duration of diabetes, history of used as diagnostic tests in epidemiological studies to determine
foot ulcer, glycaemic control and complaints related to peripheral DPN independently.
neuropathy should be obtained.
Alternative test(s)
Role of index test(s) Some scoring systems are also available to diagnose DPN, such
Scoring systems combining some simple screening tests can be as the Michigan diabetic neuropathy score (MDNS) (paired with
used to assess symptoms, signs or both of DPN. Scoring systems NCS) (Feldman 1994), the NIS-LL+4/+5/+7 (Dyck 1997) and the
may serve as triage tests for screening in clinical practice. Their re- total neuropathy score (TNS) (Cornblath 1999). As they combine
sults require confirmation by more objective measures such as elec- the results of NCS scoring, it is relatively difficult to use them to
trodiagnostic, quantitative sensory and autonomic function tests, screen DPN in the community or clinic. Therefore, we will not
which can help establish the confirmed diagnosis and classification evaluate their accuracy in our review (Table 3).
REFERENCES
ADDITIONAL TABLES
Table 1. Classification of diabetic peripheral neuropathy
Classificationa Subgroup
Acute sensory
Autonomic
Truncal
Focal limb
Co-existing CIDP
a
According to Boulton et al. (Boulton 2005a)
No symptoms or signs
Chronic painful Positive symptomatology (increasing pain at night): burning, shooting, stabbing pains
pins and needles
Diffuse (trunk)
Painless with complete/partial sensory loss No symptoms or numbness/deadness of feet; reduced thermal sensitivity; painless injury
Subacute onset
Non-traumatic amputation
Muscle strength Quadriceps femoris: extension of the knee Score for each item:
0 = normal
1 = Medical Research Council scale 3-4
Tibialis anterior: dorsiflexion of the foot 2 = Medical Research Council scale 0-2
Vibration perception
Reflex score Knee reflexes Score for each side: 0 = normal, 1 = reduced, 2 = absent
Characteristic Eligible Recruited into Received index Received refer- Included in the Lost to follow-
Study ID [N] the study test ence standard analysis up
[N] [N] [N] [N] [N]
Study 1
Study 2
Study 3
Study 4
near/6 method* in All Text) or (United in All Text and (Kingdom in All Text near/6 method* in All Text)))
#26 ((Toronto in All Text near/6 model* in All Text) or (Michigan in All Text near/6 model* in All Text) or (Utah in All Text near/6
model* in All Text) or (United in All Text and (Kingdom in All Text near/6 model* in All Text)))
#27 (neuropathy in All Text and symptom in All Text and profile* in All Text)
#28 ((scal* in All Text near/6 diagnos* in All Text) or (scal* in All Text near/6 screen* in All Text) or (scal* in All Text near/6 scor*
in All Text))
#29 ((questionnaire* in All Text near/6 diagnos* in All Text) or (questionnaire* in All Text near/6 screen* in All Text) or (questionnaire*
in All Text near/6 scor* in All Text))
#30 (MNSI in All Text or TCSS in All Text)
#31 (#14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30)
#32 (#13 and #31)
MEDLINE
EMBASE
7 peripheral neuropath*.tw,ot.
8 (peripheral nervous adj6 (diseas* or disorder*)).tw,ot.
9 or/4-8
10 3 and 9
11 exp diabetic neuropathy/
12 (diabet* adj6 (neuropath* or polyneuropath*)).tw,ot.
13 11 or 12
14 10 or 13
15 exp scoring system/
16 ((neurological symptom* or diabetic neuropathy symptom*) adj6 scor*).tw,ot.
17 composite scor* system*.tw,ot.
18 (scor* adj3 (test* or examination* or instrument* or system* or symptom* or sign*)).tw,ot.
19 ((disability or impairment or utility) adj6 scor*).tw,ot.
20 ((diabetic neuropathy or clinical neurological) adj6 examination*).tw,ot.
21 ((neuro* or diagnos* or clinical) adj6 scor*).tw,ot.
22 ((Toronto or Michigan or Utah or United Kingdom) adj6 (scor* or test* or examination* or instrument* or method* or model*)
).tw,ot.
23 neuropathy symptom profil*.tw,ot.
24 ((scale* or questionnaire* or scor* or instrument* or tool* or checklist* or index or indexes or indices or inventor*) adj6 (diagnos*
or screen*)).tw,ot.
25 (MNSI or TCSS).tw,ot.
26 or/15-25
27 14 and 26
28 limit 27 to human
MEDION
ARIF
neuropath*
Trial registers
Grey literature
neuropath*
(diabetic neuropathies[MeSH Terms] OR (diabetic[All Fields] AND neuropathies[All Fields]) OR diabetic neuropathies[All
Fields] OR (diabetic[All Fields] AND neuropathy[All Fields]) OR diabetic neuropathy[All Fields]) AND (diagno-
sis[Subheading] OR diagnosis[All Fields] OR screening[All Fields] OR mass screening[MeSH Terms] OR (mass[All Fields]
AND screening[All Fields]) OR (early[All Fields] AND detection[All Fields]))
Study 1
Study 2
Study 3
Study 4
Characteris- Time interval Minimum Type of de- Diagnostic Sites investi- Additional Qualification
tic between scor- follow-up to vice criteria gated sources of of assessor
Study ID ing system assess if tar- clinical mate-
and NCS get condition rial
is presenta
Study 1
Study 2
Study 3
Study 4
Study 1
Study 2
Study 3
Study 4
Charac- Dura- Severity of Symp- Preva- Follow-up Glycaemic Antihy- Co-mor- Co-medi-
teristic tion of di- target toms lence in control pergly- bidities cations /
Study ID abetes condition (spectrum study cen- caemic Co-inter-
[mean of DPN) tre treatment ventions
years (SD)
/range]
Study 1
Study 2
Study 3
Study 4
Characteristic Study author contacted Study author replied Study author asked for Study author provided
[DD/MM/YY] [DD/MM/YY] additional information data
[short summary] [short summary]
1. Was a consecutive or random The enrolment was consecutive The enrolment was not consec- Insufficient information is
sample enrolled? or random. utive or random. available to answer yes or no
2. Was a case control design This question is irrelevant because studies with case-control design are excluded from the review
avoided?
3. Did the study avoid inappro- All diabetic patients (type 1 and Diabetic patients with some Insufficient information is
priate exclusions? 2) with suspicious DPN were characteristics which may mod- available to answer yes or no
recruited regardless of any other ify the performance of index
characteristic. But exclusion of tests were excluded, for exam-
those with no diabetes and es- ple, those who were asymp-
tablished diagnosis of DPN is tomatic
common and will be accepted
Could the selection of pa- Both signalling question 1 and Either signalling question 1 or Both signalling question 1 and
tients have introduced bias? 3 are answered yes. 3 is answered no. 3 can not be answered yes or
no because of insufficient in-
formation
Concerns regarding applicability (describe included patients (prior testing, presentation, intended use of index test and setting)
Is there concern that the included The study population repre- The study population is se- Insufficient informa-
patients do not match the review sents an unselected sample of lected by gender, presentation tion is available to answer low
questions? diabetics with suspected DPN or severity. Or the study in- or high
in community or outpatient cludes those with the estab-
setting or inpatient setting, re- lished diagnosis of DPN or with
gardless of gender, presentation treatment of DPN
and severity
Index test (describe the index test and how it was conducted and interpreted):
1. Were the index test results The outcome assessors for the The outcome assessors for the Insufficient information is
interpreted without knowledge scoring system(s) were not scoring system(s) were aware of available to answer yes or no
of the results of reference stan- aware of the results of the NCS the results of NCS
dard?
2. Where multiple index tests Scoring system results were in- Scoring system results were in- Insufficient information is
were compared in the study or terpreted without any knowl- terpreted with knowledge of available to answer yes or no
had been repeatedly used before edge of other index test results other index test results or the
the study, were the results of the or the previous test results previous test results.
index test interpreted without .
knowledge of other index
test results or the previous test
results?
3. If a threshold was used, was The threshold used to define The threshold used to define Insufficient information is
it pre-specified? DPN is pre-specified. DPN is derived from the re- available to answer yes or no
sults of the study, for example,
the optimal threshold in ROC
curve
Could the conduct or inter- When signalling 2 is applicable, Any one of the signalling ques- All the signalling questions can
pretation of the index test all the signalling question are tions is answered no. not be answered yes or no be-
have introduced bias? answered yes. When signalling cause of insufficient informa-
2 is not applicable, both ques- tion
tion 1 and 3 are answered yes
Are there concerns that the index The study met both of the fol- The study did not meet either Insufficient informa-
test, its conduct, or interpretation lowing items: of the following items: tion is available to answer low
differ from the review question? 1. Sufficient details are correctly 1. Sufficient details are correctly or high
described about the examina- described about the examina-
tion procedures of scoring sys- tion procedures of scoring sys-
tem(s) to permit its replication tem(s) to permit its replication
2. Scoring systems were per- 2. Scoring systems were per-
formed by qualified physicians formed by qualified physicians
in diabetes or neuropathy or
Reference standard (describe the reference standard and how it was conducted and interpreted):
1. Was the reference standard The study met all of the follow- The study did not meet any one Insufficient information is
likely to correctly classify the ing items: of the following items: available to answer yes or no
target condition? 1. Diagnostic criteria were up to 1. Diagnostic criteria were up to
the minimal diagnostic criteria the minimal diagnostic criteria
of NCS we have pre-defined of NCS we have pre-defined
2. Applicable variables, like age, 2. Applicable variables, like age,
height and temperature, for height and temperature, for
NCS were considered NCS were considered
3. NCS were performed by 3. NCS were performed by
qualified physicians in diabetes qualified physicians in diabetes
or neuropathy or other trained or neuropathy or other trained
professionals professionals
2. Were the reference stan- The outcome assessors for NCS The outcome assessors for NCS Insufficient information is
dard results interpreted without were not aware of the results of were aware of the results of the available to answer yes or no
knowledge of the results of the the simple test(s) simple test(s)
index test?
Could the reference standard, All the signalling question are Any one of the signalling ques- All the signalling questions can
its conduct, or its interpreta- answered yes. tions is answered no. not be answered yes or no be-
tion have introduced bias? cause of insufficient informa-
tion
Are there concerns that the target The study met both of the fol- The study did not meet either Insufficient informa-
condition as defined by the refer- lowing items: of the following items: tion is available to answer low
ence standard does not match the 1. Sufficient details are correctly 1. Sufficient details are cor- or high
review question? described about the examina- rectly described about the ex-
tion procedures of the NCS amination procedures of NCS
(thresholds, investigated sites, (thresholds, investigated sites,
etc.) to permit its replication etc.) to permit its replication
2. NCS were performed by 2. NCS were performed by
qualified physicians in diabetes qualified physicians in diabetes
or neuropathy or other trained or neuropathy or other trained
professionals professionals
Flow and timing (describe any patients who did not receive the index test(s) and/or reference standard or who were excluded
from the 2 x 2 table (refer to flow diagram); describe the time interval and any interventions between index test(s) and reference
standard:
1. Was there an appropriate in- The time period was two The time period was more than Insufficient information is
terval between index test(s) and months or less. two months. available to answer yes or no
reference standard?
2. Did all patients receive a ref- All patients receiving scoring Not all patients receiving scor- Insufficient information is
erence standard? system(s) underwent the refer- ing system(s) underwent NCS, available to answer yes or no
ence standard including the case in which a
random sample of those who
were tested negative by scoring
system(s) underwent NCS and
then analyses for sensitivity and
specificity were adjusted or not
3. Did patients receive the same The same NCS procedure was Different reference standards or Insufficient information is
reference standard? performed for the patients. different NCS procedures were available to answer yes or no
performed for the patients
4. Were all patients included in All patients recruited into the Not all the patients recruited Insufficient information is
the analysis? study were included in the anal- into the study were included in available to answer yes or no
ysis the analysis
Could the patient flow have All signalling questions are an- Any one of signalling question All the signalling questions can
introduced bias? swered yes. is answered no. not be answered yes or no be-
cause of insufficient informa-
tion
DPN: diabetic peripheral neuropathy; NCS: nerve conduction studies; ROC: receiver operator characteristic
CONTRIBUTIONS OF AUTHORS
Zhirong Yang (ZY): conception of study, protocol draft, search strategy development, study selection, data extraction, quality assessment,
data analysis, data interpretation, review draft and update draft.
Ru Chen (RC): protocol draft, quality assessment, data interpretation, review draft and update draft.
Yuan Zhang (YZ): protocol draft, acquirement of study copies, study selection, data extraction, review draft and update draft.
Yuansheng Huang (YH): study selection, data interpretation, review draft and update draft.
Tianpei Hong (TH): protocol draft, data extraction, data interpretation, review draft and update draft.
Feng Sun (FS): data analysis, data interpretation, review draft and update draft.
Linong Ji (LJ): protocol draft, data interpretation, review draft and update draft.
Siyan Zhan (SZ): conception of study, protocol draft, data extraction, quality assessment, data interpretation, review draft and update
draft.
SOURCES OF SUPPORT
Internal sources
Peking University, China.
External sources
Specialized Research Fund for the Doctoral Program of Higher Education (20120001110015), China.