Yang Et Al-2014-The Cochrane Library

Cochrane Database of Systematic Reviews
Scoring systems to screen for diabetic peripheral neuropathy

(Protocol)
Yang Z, Chen R, Zhang Y, Huang Y, Hong T, Sun F, Ji L, Zhan S
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.
www.cochranelibrary.com
Scoring systems to screen for diabetic peripheral neuropathy (Protocol)

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Scoring systems to screen for diabetic peripheral neuropathy (Protocol) i

[Diagnostic Test Accuracy Protocol]
Scoring systems to screen for diabetic peripheral neuropathy
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.
Editorial group: Cochrane Metabolic and Endocrine Disorders Group.

Publication status and date: New, published in Issue 3, 2014.
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.
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
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).

Index test(s) Diabetic neuropathy examination (DNE)
Various clinical scoring systems are used for screening DPN (Table The DNE (Table 6) is an examination adapted from the NDS, in
3). Each system may involve symptom scoring, sign scoring or both which only eight items were retained. In this examination, only
(Cornblath 2004; Perkins 2003). They can enhance the diagnostic the right side of the limb is examined, and the maximum score
accuracy because individual examination findings from different is 16 points. A score of greater than three points is considered
simple screening tests are combined into a composite examination abnormal (Meijer 2000). It is recommended for the daily use in
score (England 2005). diagnosing DPN in clinical practice (Meijer 2000; Meijer 2003).
Neurological symptom score (NSS), neuropathy Clinical neurological examination (CNE)

symptom profile (NSP) and diabetic neuropathy The CNE is a composite scoring system for measurement of sen-
symptom score (DNS) sory signs and reflexes in the lower limb (Table 7). It involves clini-
The NSS initially consists of symptoms of muscle weakness, sen- cal testing of sensory dysfunction (pinprick, light touch, vibration,
sory disturbances, autonomic symptoms and can be further di- and position sense) of the feet, the anatomic level below which
vided into 17 items (Dyck 1980). An NSS score of 1 could be light touch sensation is impaired, muscle strength of the feet and
considered abnormal (Dyck 1988). Another scoring system also ankle reflexes (Valk 1992; Valk 1997).
for assessing neurological symptoms is named NSP, which con- Two versions of CNE are available. In the older one, the maximal
tains 34 test categories, where an abnormal score is defined as score of the CNE is 33 points. A total score of zero can be graded
97.5 percentile (Dyck 1986). However, both scores are developed as no polyneuropathy, one to nine as mild, 10 to 18 as moderate,
for general neuropathy rather than specifically for DPN. However, and 19 to 33 as severe polyneuropathy (Valk 1992). The other
the NSS was later shown not to reflect the progress of DPN (Dyck version, with a maximal score of 37 points is quantified on the
1997). A more simplified scoring system, the diabetic neuropathy basis of the older one, but the diagnostic criteria have not been
symptom score (DNS) (Table 4) assessing pain, numbness, tin- presented in detail (Valk 1997).
gling and ataxia, is now available. The maximum score of DNS is
four points, one point or more indicates neurological abnormali-
ties (Meijer 2002). Michigan neuropathy screening instrument (MNSI)
The MNSI is an instrument including two parts, a question-
naire with 15 questions and a foot examination (Feldman 1994).
Neuropathy disability score (NDS) and neuropathic The questionnaire inquires about positive (pain, temperature sen-
impairment score in the lower limbs (NIS-LL) sation, tingling) and negative (numbness) sensory symptoms,
The NDS can be used to assess the signs of neuropathy by 35 cramps and muscle weakness, foots ulcers or cracks and ampu-
items for both sides. The evaluation is derived from cranial nerve tation. Neuropathy can be defined as seven or more positive re-
damage, muscle strength, reflex loss, and loss of sensation (Dyck sponses on the MNSI questionnaire (Feldman 1994). Compared
1980). However, some items have been found not to be essentially with the questionnaire, the foot examination is more frequently
abnormal in DPN and therefore, the neuropathy impairment score used. It encompasses foot appearance and foot ulcers, ankle reflex
(NIS), revised on the basis of the NDS, has been proposed (Dyck and the 128-Hz tuning fork test (Table 8). The maximum score
1995). of the foot examination is eight points and bilateral limbs are in-
Considering that the typical DPN is a distal symmetric sensorimo- dependently scored. A MNSI examination score of equal to or
tor polyneuropathy, the neuropathy impairment score in the lower greater than two is positive for DPN (Feldman 1994). MNSI has
limbs (NIS-LL), as a subset of the NIS for the lower limbs, has been used in combination with the Semmes-Weinstein monofil-
been adopted in the evaluation of peripheral neuropathy (Dyck ament test (SWMT) to evaluate the prevalence and clinical char-
1997). The performance of the NIS-LL in the detection of DPN acteristics of diabetic peripheral neuropathy in hospital patients
is almost similar to that of the NDS but the main drawback is with type 2 diabetes in Korea (Won 2012).
too much emphasis on the motor nerve function. In addition,
no recognised diagnostic threshold for neuropathy has been set
(Singleton 2008). Toronto clinical scoring system (TCSS)
Currently, another clinical scoring system, the revised NDS (Table Also called the Toronto clinical neuropathy score (TCNS), the
5), is more commonly used. It includes the ankle reflex, vibration, system was first adopted by a research group in Toronto for the
pin-prick and temperature (cold tuning fork) sensation at both screening of DPN. The TCSS (Table 9) consists of three parts:
sides of the great toes with a maximum score of 10 points. People symptom scores, reflex scores and sensory test scores. The max-
with an NDS of six points or more are considered to show abnor- imum score is 19 points (Bril 2002; Perkins 2003). The criteria
mal reactions (Abbott 2002; Moreira 2005; Weintrob 2007). of classification for DPN have also been proposed according to

the TCSS score: zero to five points, without DPN; six to eight As recommended by the 1988 consensus statement from the
points, mild DPN; nine to 11 points, moderate DPN; and 12 to San Antonio conference on diabetic neuropathy, multiple assess-
19 points, severe DPN (Perkins 2003). The TCSS has been em- ments, including clinical symptoms, clinical signs, electrodiagnos-
ployed in people with type 2 diabetes to assess the prevalence of tic studies, quantitative sensory testing and autonomic function
painful DPN (Davies 2006). testing, should be applied for the diagnosis and classification of
DPN (American Diabetes Association 1988). The report from the
American Academy of Neurology in conjunction with the Amer-
Clinical pathway ican Association of Electrodiagnostic Medicine and the American
Academy of Physical Medicine and Rehabilitation define distal
It is recommended that all patients should be screened for DPN symmetric polyneuropathy (of which DPN of limbs is a member)
at the diagnosis of type 2 diabetes and five years after the diag- and suggests that patients with abnormal NCS have a relatively
nosis of type 1 diabetes and should receive one or more of the high likelihood of this condition (England 2005). Recently, it was
following tests annually: pinprick, temperature, ankle reflex, and proposed that an abnormality of NCS combined with symptom(s)
vibration perception (128-Hz tuning fork) or pressure sensation or sign(s) is essential to confirm the diagnosis of DPN since NCS
(10 g monofilament test) (American Diabetes Association 2013; appear to be the first objective and quantitative indication. Symp-
Boulton 1998; Boulton 2005a). Combinations of more than one toms and/or signs without abnormal NCS contribute to the di-
test may help to detect DPN more sensitively (Boulton 2005a). agnosis of possible clinical DPN or probable clinical DPN, while
In such screening, any history of neuropathic symptoms should abnormal nerve conduction alone without symptoms or signs may
be elicited and a careful clinical examination of the feet and lower support the diagnosis of subclinical DPN (Dyck 2011a; Tesfaye
limbs should be performed (Boulton 2005a); NCS and exclusion 2010). The procedure of screening and diagnosis of DPN in clin-
of other causes are rarely needed except when the diagnosis of DPN ical care has been summarised in a flow chart (Figure 1).
needs to be confirmed (American Diabetes Association 2013).

Figure 1. Flow chart of screening and diagnosis of DPN of limbs in clinical practiceScreening tests could be
tests to identify symptoms and/or signs
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).

Other types of composite scoring systems, for example, the neu- other review found that abnormal results on monofilament testing
ropathy symptom change score (NSC) (Dyck 1997), the total and vibratory perception (alone or in combination with the ap-
symptom score (TSS) (Ziegler 1995), the neuropathy total symp- pearance of the feet, ulceration, and ankle reflexes) were the most
tom score - 6 (NTSS - 6) (Bastyr 2005) and the modified Toronto helpful signs (Kanji 2010). However, this review limited the set-
clinical neuropathy score (mTCNS) (Bril 2009), which are pri- ting to the bedside, where the accuracy of tests may differ from
marily developed for the evaluation of therapeutical efficacy or that in community due to possibly different disease spectra. In
the longitudinal assessment of polyneuropathy, will be excluded the Kanji 2010 review, only two databases were searched and the
in our review as well (Table 3). language of studies was restricted to English. Further, the authors
only provided limited rather than integral detailed information on
Rationale the methodological quality for each included study.
With reference to the problems mentioned above, this review will
DPN places a large burden on healthcare budgets. Of all the
therefore further assess the accuracy of all potential scoring systems
complications of diabetes mellitus, lifetime expenditures on DPN
for screening DPN to supply more comprehensive evidence.
ranks third after macrovascular disease and diabetic nephropathy
(Caro 2002). If patients with DPN progress to diabetic foot, any
foot lesion occurring as a result of diabetes and its complications
(Boulton 2008), makes the costs of long-term treatment much
heavier. Curing one case of diabetic foot without requiring am- OBJECTIVES
putation would cost 17,500 US dollars (13,075 EUR, Septem- To determine the diagnostic accuracy of each scoring system as
ber 2012 conversion), while the cost of an amputation is 30,000 triage to screen for diabetic peripheral neuropathy (DPN) involv-
US dollars to 35,000 US dollars (23,075 EUR to 26,920 EUR, ing limbs within different settings, or as replacement of nerve con-
September 2012 conversion) (Ragnarson 2004). But if DPN could duction studies (NCS) for the clinical diagnosis of DPN involving
be detected in the early stage, enhanced glucose control might pre- limbs, with NCS as the reference standard.
vent the development of clinical neuropathy and reduce nerve con-
duction and vibration threshold abnormalities (Callaghan 2012).
From the perspective of clinical practice, screening for DPN in Secondary objectives
community and outpatient settings successfully predicts those at
risk of ulceration (Abbott 2002; Adler 1997). Hospitalised patients To estimate the relative accuracy of scoring systems for screening
with diabetes, who are likely to be older, bed bound and with more DPN involving limbs, with NCS as the reference standard.
co-morbidities, should also be screened so that foot protection To assess the impact of potential sources of heterogeneity on the
can be targeted, because 3.3% of people with diabetes in hospital performance of scoring systems for DPN involving limbs: (1) re-
acquired a foot lesion (Rayman 2010). Although some tests have lated to the study population (spectrum of the disease: with versus
been recommended in related clinical guidelines for the diagnosis without other vascular complications; symptoms of DPN: people
or screening of DPN (Boulton 2003; Boulton 2005a; Boulton with no neurological symptoms versus neurological symptoms (if
2005b; Vijan 1997), the development of these recommendations available, positive versus negative neurological symptoms); dura-
was based more on expert consensus than sound evidence. So far, tion of diabetes; level of glycosylated haemoglobin A1c (HbA1c)
there is no agreement which standardised screening tool should be in adults: < 7% versus 7%; body mass index (BMI) in adults:
applied in clinical practice. < 25 versus 25 kg/m; types of diabetes: type 1 versus type 2
As for epidemiological research, index tests used for the assessment diabetes mellitus; age: <18 years old versus 18 years old); (2)
of the prevalence of DPN varied in different studies and thus, the related to the scoring systems (different thresholds; examiners ex-
studies resulted in different estimates ranging from 17% to 60% pertise: specialists in diabetes or neurology versus other health-
(Adler 1997; Davies 2006; Gregg 2004; Liu 2010; Tesfaye 1996; care professionals); (3) related to the reference standard (numbers
Won 2012; Young 1993). Not only were the varied estimates at- of body sites tested with NCS; examiners expertise: specialists in
tributed to different populations but also to the different screening electrodiagnosis versus other healthcare professionals); (4) related
tools (Davies 2006). to the healthcare setting (community versus outpatient setting ver-
There are three related systematic reviews published: two focus sus inpatient setting); (5) related to the methodology based on the
on the SWMT while another involves SWMT, tuning fork, NSS, QUADAS-2 items (risk of bias for patient selection, index test,
NDS and MNSI (Dros 2009; Feng 2009; Kanji 2010). They all reference standard, and flow and timing; concerns regarding ap-
prefer to use NCS as the reference standard. In the two studies plicability of patient selection, index test, and reference standard).
that are only relevant to SWMT, variation in both of the diagnos-
tic values and the accuracy was found (Dros 2009; Feng 2009).
However, both reviews solely evaluated the accuracy of SWMT,
failing to provide the whole spectrum of tests in this field. An- METHODS

Criteria for considering studies for this review The metaRegister of Controlled Trials (
www.controlled-trials.com/mrct/)
The EU Clinical Trials register (
Types of studies www.clinicaltrialsregister.eu/)
Prospective and retrospective single-gate studies (that is cohort The US National Institutes of Health trials register
type accuracy studies) (Deeks 2009; Rutjes 2005) and studies with ClinicalTrials.gov (www.clinicaltrials.gov/)
fully paired or randomised comparison design (Bossuyt 2008) will The Australian New Zealand Clinical Trials Registry (
be eligible, regardless of language of publication. www.anzctr.org.au)
The WHO International Clinical Trials Registry
Platform Search Portal (apps.who.int/trialsearch/)
Participants
Grey literature:
People with type 1 or type 2 diabetes, who are being screened for The Grey Literature Report (www.greylit.org/)
neuropathy, regardless of age and gender. We will exclude those OpenGrey (www.opengrey.eu/)
who already have overt neuropathy with foot ulcers and other OAISTER (www.oaister.org/)
related manifestations.
For detailed search strategies please see Appendix 1. We will use
Web of Science for forward citation tracking of early key publi-
Index tests cations. We will continuously apply PubMeds My NCBI (Na-
Any of the following (but not limited to) scoring systems including tional Center for Biotechnology Information) email alert service
NSS, NSP, DNS, NDS, NIS, NIS-LL, DNE, CNE, MNSI, TCSS. for identification of newly published studies using a basic search
strategy (see Appendix 1). Four weeks before we submit the final
review draft to the Cochrane Metabolic and Endocrine Disorders
Target conditions Group (CMED) for editorial approval, we will perform a com-
We will focus on DPN that involves limbs. Any stage of DPN will plete update search on all specified databases. Should we detect
be dichotomised as no DPN versus DPN of any stage, which new studies for inclusion, we will evaluate these and incorporate
may include mild, moderate and severe DPN. Where different findings in our review before submission of the final review draft.
classifications were used in primary studies, we will require and If we detect additional relevant key words during any of the elec-
convert the data according to our stage dichotomous classification. tronic or other searches, we will modify the electronic search strate-
gies to incorporate these terms and document the changes. We will
place no restrictions on the language of publication when search-
Reference standards ing the electronic databases or reviewing reference lists in identi-
We will include studies in which nerve conduction studies (NCS) fied studies.
have been applied solely or combined with other tests in a parallel We will send results of electronic searches to Cochrane Metabolic
and/or serial way as reference standard. We will specify and criti- and Endocrine Disorders Group for databases that are not available
cally consider the differences of reference standards among all the at the editorial office.
eligible studies in our review.
Searching other resources

Search methods for identification of studies We will try to identify other potentially eligible studies or ancillary
publications by searching the reference lists of retrieved included
studies, (systematic) reviews, meta-analyses, and health-technol-
Electronic searches ogy assessment reports.
We will try to contact manufacturers of related index tests to iden-
We will use the following sources from inception to present time
tify studies.
for the identification of studies.
The Cochrane Library
MEDLINE (Ovid)
EMBASE (Ovid) Data collection and analysis
MEDION
ARIF
Web of Science: Science Citation Index Expanded Selection of studies
Trials registers: To determine the studies to be assessed further, two review au-
thors (ZY, YH) will independently scan the abstract, titles or both

sections of every record retrieved. All potentially relevant articles
will be investigated as full text. Differences will be resolved by
a third party (YZ). If resolving disagreement is not possible, the
article will be added to those awaiting assessment and authors
will be contacted for clarification. An adapted PRISMA (preferred
reporting items for systematic reviews and meta-analyses) flow-
chart of study selection (Figure 2) will be attached (Liberati 2009;
Moher 2009).

Figure 2. Flow chart of study inclusion

(Whiting 2011). We will complete the assessment in four phases
Data extraction and management
with QUADAS-2 as required (Whiting 2011).
Two review authors (ZY, YZ) will independently extract data con- We will assess the applicability of a study and risk of bias. Two
cerning details of study design, study population, reference test, review authors (ZY, RC) will independently rate each of the four
index test(s) and their performance using standard data extrac- key domains (patient selection, index test(s), reference standard,
tion templates (Table 10; Appendix 2; Appendix 3; Appendix 4; flow and timing) using signalling questions (Appendix 7). Possible
Appendix 5) with any disagreements to be resolved by discussion, disagreement will be resolved by consensus, or with consultation
or if required by a third party (TH). of a third review author (SZ) in case of disagreement.
The following items will be included. We have followed the process for tailoring QUADAS-2 to our
General information: published/unpublished, title, authors, coun- systematic review as described in the publication (Whiting 2011)
try, language of publication, year of publication, sponsoring, set- by omitting a signalling question in the domain of patient selection
ting, prevalence in study centre(s). and adding one signalling question in the domain of index test.
Participants: sampling (consecutive/convenience), inclusion crite- We have also developed preliminary review-specific guidance on
ria, exclusion criteria, total number and number in comparison how to assess each signalling question to judge risk of bias. We will
groups, sex, age, ethnicity, BMI, type of diabetes mellitus, dura- pilot the tool and apply criteria in a small number of studies by at
tion of diabetes mellitus, glycaemic control, antihyperglycaemic least two review authors (ZY, RC). If agreement is not good, we
treatment, clinical presentation, severity of target condition. will add further refinement to the tool. We will use our guidelines
Index test: type of scoring system, diagnostic criteria, additional to judge risk of bias as low, high or unclear.
sources of clinical material, qualification of assessor. We will primarily analyse studies at low risk of bias, low concern
Reference test: type of test, type of device, diagnostic criteria, sites regarding applicability or both for all or specified domains. We will
investigated, additional sources of clinical material, qualification explore the influence of individual criteria in a sensitivity analysis
of assessor. (Sensitivity analyses).
Results: number of true positives, false positives, true negatives, We will present a Risk of bias and applicability concerns figure
false negatives, adverse events. and a Risk of bias and applicability concerns summary figure.
We will send an email request to contact persons of included stud-
ies to enquire whether study authors are willing to answer ques-
tions regarding their studies. The results of this survey will be pub- Statistical analysis and data synthesis
lished in Appendix 6. Thereafter, we will seek relevant missing
The unit of analysis is a patient rather than a limb or a part of
information on the study from the study author(s) of the article,
limb. Data for the true positive, true negative, false positive and
if required. For example, when we find studies with a limb rather
false negative values for each study will be tabulated. Test results
than a patient as the unit of analysis, we will email the authors to
will be treated as positive or negative for the cut-off values of
ask whether they have summary data on the individual, as the unit
the index tests as described above. Forest plots showing pairs of
of analysis in our review is the whole person.
sensitivity and specificity, with 95% confidence intervals (CI) will
be constructed for each study. The sensitivity and specificity pairs
will be visualised in the receiver operator characteristic (ROC)
Dealing with duplicate publications and companion papers
space for each test.
In the case of duplicate publications and companion papers of a Our primary analyses will compare each scoring system with the
primary study, we will try to maximise the yield of information reference standard. For each scoring system, the same common
by simultaneous evaluation of all available data but we will not threshold (as described in the section of Index test(s) for each scor-
include the same group of patients more than once in any given ing system) will be used according to the description in the manu-
analysis. als or the original empirical studies. We will use bivariate random-
effects model to conduct meta-analyses of pairs of sensitivity and
specificity (Reitsma 2005). Where different thresholds have been
Assessment of methodological quality applied, we will report accuracy estimates for all the thresholds, use
In the QUADAS-2 (quality assessment of diagnostic accuracy the bivariate model to calculate the summary sensitivity and speci-
studies) instrument, quality is defined as both the risk of bias and ficity at each specific threshold respectively, and use the hierarchi-
applicability of a study, i.e. 1) the degree to which estimates of cal summary receiver operating characteristics (HSROC) model
diagnostic accuracy avoided risk of bias, and 2) the extent to which (Rutter 2001) to estimate a summary ROC curve. For HSROC
primary studies are applicable to the reviews research question model, we will give priority to the common threshold as described

in the section of Index test(s). Where the common threshold is separately of the subgroup of less than 18 years old versus the sub-
not available, we will select the one that is closest to the com- group 18 years and older), if available within a study. However, if
mon threshold. We will use SAS software to fit the bivariate and not available, we will convert the covariates age, effect of treatment
HSROC model. Results from these hierarchical models will be to percentages and the covariate duration of diabetes to mean and
input into Review Manager 5.2 to provide plots of the estimated then add the converted numerical covariates to the model.
curve(s), or summary point(s) and confidence region(s).
Secondly, we will focus on the comparative accuracy of the scoring
systems with the reference standard. We will compare the accu- Sensitivity analyses
racy within SAS software by adding covariate terms for test type We will perform sensitivity analyses to explore the impact of study
to the parameters of the models. We will use the bivariate model quality on the meta-analytic results.
(Reitsma 2005) at specific thresholds to conduct indirect and di- Restricting the analyses to the studies with either low risk of
rect comparisons separately. We will use likelihood ratio tests com- bias or low concerns regarding applicability in each domain of
paring models with and without the covariate terms in the bivari- the QUADAS-2 instrument.
ate model to assess the statistical significant difference in sensitiv- Restricting the analysis to the studies with prospective
ity or specificity between tests (Macaskill 2010). When the studies design.
report several different thresholds, the HSROC model will be used Restricting the analysis taking account of three individual
(Rutter 2001), in which case we will also choose the threshold as quality items: blinding of reference standard results, blinding of
is used in our primary analyses. We will assess the fit of model by index test results and interval of less than two months between
likelihood ratio tests comparing models with and without the co- index tests and reference test.
variates for shape and accuracy parameters successively (Macaskill Restricting the analysis on the data resources (published
2010). All studies will be included in each indirect comparison. versus unpublished).
Only those studies that make a direct fully paired or randomised
comparison will be included in the direct comparisons.
Assessment of reporting bias
We will not undertake any formal assessment of reporting bias in
our review due to current uncertainty about how to assess reporting
Investigations of heterogeneity
bias in diagnostic test accuracy reviews, especially in the presence
We will investigate heterogeneity by visual inspection of forest of heterogeneity (Macaskill 2010).
plots and ROC curves. Given adequate amount of data (10 or
more studies for one index test), we will investigate heterogeneity
within SAS environment by adding the covariates specified under
Secondary objectives as potential determinants or sources of het-
ACKNOWLEDGEMENTS
erogeneity to the bivariate model or HSROC model to identify
statistically significant covariates. We thank the editorial staff of the Cochrane Metabolic and En-
For individual patients characteristics such as age, metabolic con- docrine Disosorders Group for providing us with all useful sug-
trol, effect of treatment, and duration of diabetes, we will first gestions for the development of the protocol, and for helping us
extract and analyse stratified accuracy results (for example, results revise and establish the search strategy.
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ADDITIONAL TABLES
Table 1. Classification of diabetic peripheral neuropathy
Classificationa Subgroup
Generalised symmetric polyneuropathies Chronic sensorimotor (typical DPN)
Acute sensory
Autonomic
Focal and multifocal neuropathies Cranial
Truncal
Focal limb
Proximal motor (amyotrophy)
Co-existing CIDP
a
According to Boulton et al. (Boulton 2005a)
DPN: diabetic peripheral neuropathy; CIDP: chronic in ammatory demyelinating polyneuropathy

Table 2. Stages of diabetic peripheral neuropathy
Stage of diabetic peripheral neuropathy Characteristics
Stages 0/1: no clinical neuropathy
No symptoms or signs
Stage 2: clinical neuropathy
Chronic painful Positive symptomatology (increasing pain at night): burning, shooting, stabbing pains
pins and needles
Absent sensation to several modalities and reduced or absent reflexes
Acute painful Less common
Diabetes poorly controlled, weight loss
Diffuse (trunk)
Hyperaesthesia may occur
May be associated with initiation of glycaemic therapy
Minor sensory signs or even normal peripheral neurological examination
Painless with complete/partial sensory loss No symptoms or numbness/deadness of feet; reduced thermal sensitivity; painless injury
Signs of reduced or absent sensation with absent reflexes
Diabetic amyotrophy Muscle weakness and wasting
Sensory loss is slight, but pain at night common
Subacute onset
Stage 3: late complications of clinical neuropathy
Foot lesions, e.g. ulcers
Neuropathic deformity, e.g. Charcot joint
Non-traumatic amputation

Table 3. Summary of scoring systems with their abbreviations
Abbreviation Full names
Scoring systems that we will include
CNE Clinical Neurological Examination
DNE Diabetic Neuropathy Examination
DNS Diabetic Neuropathy Symptom Score
MNSI Michigan Neuropathy Screening Instrument
NDS Neuropathy Disability Score
NIS Neuropathy Impairment Score
NIS-LL Neuropathy Impairment Score in the Lower Limbs
NSP Neuropathy Symptom Profile
NSS Neuropathy Symptom Score
TCSS Toronto Clinical Scoring System
Scoring systems that we will exclude
MDNS Michigan Diabetic Neuropathy Score
mTCNS modified Toronto Clinical Neuropathy Score
NIS-LL+4 Neuropathy Impairment Score in the Lower Limbs +4
NTSS - 6 Neuropathy Total Symptom Score - 6
NSC Neuropathy Symptom Change Score
TNS Total Neuropathy Score
TSS Total Symptom Score

Table 4. Diabetic neuropathy symptom score (DNS)
DNS items Rate
Unsteadiness in walking 0 = absent, 1 = present
Numbness 0 = absent, 1 = present
Burning, aching pain or tenderness in legs or feet 0 = absent, 1 = present
Prickling sensations 0 = absent, 1 = present
Table 5. Revised neuropathy disability score (NDS)
NDS items Description
Vibration sensation (128 Hz tuning fork) 0 = present, 1 = reduced/absent
Temperature sensation (cold tuning fork) 0 = present, 1 = reduced/absent
Pin-prick 0 = present, 1 = reduced/absent
Ankle reflex 0 = normal, 1 = present with reinforcement, 2 = absent per side
Table 6. Diabetic neuropathy examination (DNE)
DNE items Description
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
Reflex Triceps surae 0 = normal

1 = mild/moderate deficit: decreased but present
2 = absent
Sensation: index finger Sensitivity to pinpricks Score for each item:

0 = normal
Sensation: big toe Sensitivity to pinpricks 1 = decreased but present
2 = absent
Sensitivity to touch
Vibration perception
Sensitivity to joint position

Table 7. Clinical neurological examination (CNE)
CNE items Description
Sensory dysfunction of the feet Pinprick Score for each item:

0 = normal
Light touch 2 = impaired in comparison with proximal sensation (for
position sense, comparison between the first toe and the first
Vibration finger)
4 = absent
Position sense
Anatomic level below which light touch 0 = normal

sensation is impaired 1 = toe
2 = mid-foot
3 = ankle
4 = mid-calf
5 = knee
Muscle strength Extensor hallucis longus Score for each item:

0 = normal
Gastrocnemius 2 = impaired
muscles 4 = absent
Ankle reflexes 0 = normal

2 = impaired in comparison with the other reflexes
4 = absent
Table 8. Michigan neuropathy screening instrument (MNSI)
MNSI items Description
Appearance of feet 0 = normal, 1 = abnormal
Ulceration 0 = normal, 1 = abnormal
Ankle reflexes 0 = present, 0.5 = present with reinforcement, 1 = absent
Vibration perception 0 = present, 0.5 = reduced, 1 = absent
Table 9. Toronto clinical scoring system (TCSS)
TCSS items Description
Symptoms score Pain 0 = absent, 1 = present
Numbness 0 = absent, 1 = present
Tingling 0 = absent, 1 = present

Table 9. Toronto clinical scoring system (TCSS) (Continued)
Weakness 0 = absent, 1 = present
Ataxia 0 = absent, 1 = present
Upper-limb symptoms 0 = absent, 1 = present
Reflex score Knee reflexes Score for each side: 0 = normal, 1 = reduced, 2 = absent
Ankle reflexes Score for each side: 0 = normal, 1 = reduced, 2 = absent
Sensory test score Pinprick 0 = normal, 1 = abnormal
Temperature 0 = normal, 1 = abnormal
Light touch 0 = normal, 1 = abnormal
Vibration sense 0 = normal, 1 = abnormal
Position sense 0 = normal, 1 = abnormal
Table 10. Overview of study populations
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
Total ... ... ... ...

- denotes not reported

APPENDICES
Appendix 1. Search strategies
Search terms and databases
Unless otherwise stated, search terms are free text terms.

$: stands for any character; ?: substitutes one or no character; adj: adjacent (i.e. number of words within range of search term); exp:
exploded MeSH; MeSH: medical subject heading (MEDLINE medical index term); pt: publication type; sh: MeSH; tw: text word;
ot: original title
The Cochrane Library
#1 MeSH descriptor Diabetes mellitus explode all trees

#2 diabet* in All Text
#3 (#1 or #2)
#4 MeSH descriptor peripheral nervous system diseases explode all trees
#5 MeSH descriptor Polyneuropathies explode all trees
#6 ((peripheral in All Text and (nervous in All Text near/6 diseas* in All Text)) or (peripheral in All Text and (nervous in All Text
near/6 disorder* in All
Text))
#7 polyneuropath* in All Text
#8 (#4 or #5 or #6 or #7)
#9 (#3 and #8)
#10 MeSH descriptor Diabetic neuropathies explode all trees
#11 ((diabet* in All Text near/6 neuropath* in All Text) or (diabet* in All Text near/6 polyneuropath* in All Text))
#12 (#10 or #11)
#13 (#9 or #12)
#14 ((neurological in All Text and (symptom* in All Text near/6 scor* in All Text)) or (diabetic in All Text and (neuropathy in All
Text and (symptom* in
All Text near/6 scor* in All Text)))
#15 (composite in All Text and scor* in All Text and system* in All Text)
#16 ((scor* in All Text near/3 test* in All Text) or (scor* in All Text near/3 examination* in All Text) or (scor* in All Text near/3
instrument* in All Text) or (scor* in All Text near/3 system* in All Text) or (scor* in All Text near/3 symptom* in All Text))
#17 (scor* in All Text near/3 sign* in All Text)
#18 ((diabetic in All Text and (neuropathy in All Text near/6 examination* in All Text)) or (clinical in All Text and (neurological in
All Text near/6 examination* in All Text)))
#19 ((neurologic* in All Text near/6 scor* in All Text) or (neuropath* in All Text near/6 scor* in All Text) or (diagnos* in All Text
near/6 scor* in All Text))
#20 ((disability in All Text near/6 scor* in All Text) or (impairment in All Text near/6 scor* in All Text))
#21 ((Toronto in All Text near/6 scor* in All Text) or (Michigan in All Text near/6 scor* in All Text) or (Utah in All Text near/6 scor*
in All Text) or (United in All Text and (Kingdom in All Text near/6 scor* in All Text)))
#22 ((Toronto in All Text near/6 test* in All Text) or (Michigan in All Text near/6 test* in All Text) or (Utah in All Text near/6 test*
in All Text) or (United in All Text and (Kingdom in All Text near/6 test* in All Text)))
#23 ((Toronto in All Text near/6 examination* in All Text) or (Michigan in All Text near/6 examination* in All Text) or (Utah in All
Text near/6 examination* in All Text) or (United in All Text and (Kingdom in All Text near/6 examination* in All Text)))
#24 ((Toronto in All Text near/6 instrument* in All Text) or (Michigan in All Text near/6 instrument* in All Text) or (Utah in All
Text near/6 instrument* in All Text) or (United in All Text and (Kingdom in All Text near/6 instrument* in All Text)))
#25 ((Toronto in All Text near/6 method* in All Text) or (Michigan in All Text near/6 method* in All Text) or (Utah in All Text

(Continued)
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
1 exp Diabetes Mellitus/

2 diabet*.tw,ot.
3 1 or 2
4 exp Peripheral Nervous System Diseases/
5 (peripheral nervous adj6 (diseas* or disorder*)).tw,ot.
6 exp Polyneuropathies/
7 polyneuropath*.tw,ot.
8 or/4-7
9 3 and 8
10 exp Diabetic Neuropathies/
11 (diabet* adj6 (neuropath* or polyneuropath*)).tw,ot.
12 10 or 11
13 9 or 12
14 ((neurological symptom* or diabetic neuropathy symptom*) adj6 scor*).tw,ot.
15 composite scor* system*.tw,ot.
16 (scor* adj3 (test* or examination* or instrument* or system* or symptom* or sign*)).tw,ot.
17 ((diabetic neuropathy or clinical neurological) adj6 examination*).tw,ot.
18 ((neuro* or diagnos* or clinical) adj6 scor*).tw,ot.
19 ((disability or impairment or utility) adj6 scor*).tw,ot.
20 ((Toronto or Michigan or Utah or United Kingdom) adj6 (scor* or test* or examination* or instrument* or method* or model*)
).tw,ot.
21 neuropathy symptom profile*.tw,ot.
22 ((scale* or questionnaire* or instrument* or tool* or checklist* or index or indices or inventor*) adj6 (diagnos* or screen*)).tw,ot.
23 (MNSI or TCSS).tw,ot.
24 or/14-23
25 13 and 24
26 limit 25 to humans
EMBASE
1 exp diabetes mellitus/

2 diabet*.tw,ot.
3 1 or 2
4 exp peripheral neuropathy/
5 exp polyneuropathy/
6 polyneuropath*.tw,ot.

(Continued)
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
Web of Science: Science Citation Index Expanded
# 1 Topic=(peripheral nervous diseas*) OR Topic=(peripheral nervous disorder*) OR Topic=(polyneuropath*) OR Topic=(neu-

ropath*)
# 2 Topic=(diabet*)
# 3 #2 AND #1
# 4 Topic=(neurological symptom* scor*) OR Topic=(diabet* neuropathy symptom scor*) OR Topic=(composite scor* system*)
# 5 Topic=(scor* test*) OR Topic=(scor* examination*) OR Topic=(scor* instrument*) OR Topic=(scor* system*) OR Topic=(scor*
sign*) OR
Topic=(scor* symptom*)
# 6 Topic=(diabetic neuropathy examination*) OR Topic=(clinical neurological examination*)
# 7 Topic=(neurologic scor*) OR Topic=(neuropath* scor*) OR Topic=(diagnos scor*)
# 8 Topic=(disability scor*) OR Topic=(impairment scor*)
# 9 Topic=(Toronto scor*) OR Topic=(Toronto test*) OR Topic=(Toronto examination*) OR Topic=(Toronto instrument*) OR
Topic=(Toronto
method*) OR Topic=(Toronto model*)
# 10 Topic=(Michigan scor*) OR Topic=(Michigan test*) OR Topic=(Michigan examination*) OR Topic=(Michigan instrument*)
OR Topic=(Michigan
method*) OR Topic=(Michigan model*)
# 11 Topic=(Utah scor*) OR Topic=(Utah test*) OR Topic=(Utah examination*) OR Topic=(Utah instrument*) OR Topic=(Utah
method*) OR
Topic=(Utah model*)
# 12 Topic=(United Kingdom scor*) OR Topic=(United Kingdom test*) OR Topic=(United Kingdom examination*) OR Topic=
(United Kingdom

(Continued)
instrument*) OR Topic=(United Kingdom method*) OR Topic=(United Kingdom model*)

# 13 Topic=(neuropathy symptom profile*)
# 14 Topic=(scale diagnos*) OR Topic=(scale screen*) OR Topic=(scale scor*)
# 15 Topic=(questionnaire* diagnos*) OR Topic=(questionnaire* screen*) OR Topic=(questionnaire* scor*)
# 16 Topic=(MNSI) OR Topic=(TCSS)
# 17 #16 OR #15 OR #14 OR #13 OR #12 OR #11 OR #10 OR #9 OR #8 OR #7 OR #6 OR #5 OR #4
# 18 #17 AND #3
# 19 Topic=(animal) OR Topic=(animals)
# 20 #18 NOT #19
MEDION
ICPCcode: Neurological or Endocrine metabolic and nutritional

Filter: Systematic Reviews of Diagnostic Studies
ARIF
neuropath*
Trial registers
The metaRegister of Controlled Trials: diabetes and neuropathy

The EU Clinical Trials register: neuropath*
The US National Institutes of Health trials register ClinicalTrials.gov: Diabetic Neuropathies(by topics)
The Australian New Zealand Clinical Trials Registry: neuropathy
The WHO International Clinical Trials Registry Platform Search Portal: diabetes and neuropathy
Grey literature
neuropath*
My NCBI alert service
(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]))
Appendix 2. Outline of index test

Characteristic Order of test ex- Type of scoring Diagnostic cri- Average time to Additional Qualification of
Study ID ecution system teria complete sources of clini- assessor
the scoring sys- cal material
tem per person
Study 1
Study 2
Study 3
Study 4
- denotes not reported.
Appendix 3. Outline of reference test
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

a For reference standards involving follow-up; NCS: nerve conduction studies
Appendix 4. Baseline characteristics (I)

Charac- Study de- Study pe- Tar- Country Setting Sex Age Ethnic BMI Type 2 di-
teristic sign/ riod get con- [female [mean groups [kg/m2 ] abetes
Study ID sampling [year to dition %] years [%] [%]
year] (SD)/
range]
Study 1
Study 2
Study 3
Study 4

BMI: body mass index; SD: standard deviation.
Appendix 5. Baseline characteristics (II)
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

DPN: diabetic peripheral neuropathy; SD: standard deviation.

Appendix 6. Survey of authors providing information on included trials
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]
Study 1 Yes, date: Yes, date: / No
N/A: not applicable.
Appendix 7. QUADAS-2 tool
Domain Yes No Unclear
Patient selection (describe methods of patient selection):
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
Risk of bias: Low High Unclear
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)

(Continued)
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 question
tion 1 and 3 are answered yes
Concerns regarding applicability
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

(Continued)
other trained professionals in diabetes or neuropathy or

other trained professionals
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
Concerns regarding applicability
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:

(Continued)
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.

DECLARATIONS OF INTEREST
ZY: none known.
RC: none known.
YZ: none known.
YH: none known.
TH: none known.
FS: none known.
LJ: none known.
SZ: none known.
SOURCES OF SUPPORT
Internal sources
Peking University, China.
External sources
Specialized Research Fund for the Doctoral Program of Higher Education (20120001110015), China.


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Cochrane Database of Systematic Reviews

Scoring systems to screen for diabetic peripheral neuropathy

Yang Z, Chen R, Zhang Y, Huang Y, Hong T, Sun F, Ji L, Zhan S

Yang Z, Chen R, Zhang Y, Huang Y, Hong T, Sun F, Ji L, Zhan S.

Scoring systems to screen for diabetic peripheral neuropathy (Protocol)

Scoring systems to screen for diabetic peripheral neuropathy (Protocol) i

Scoring systems to screen for diabetic peripheral neuropathy

Editorial group: Cochrane Metabolic and Endocrine Disorders Group.

Scoring systems to screen for diabetic peripheral neuropathy (Protocol) 2

Neurological symptom score (NSS), neuropathy Clinical neurological examination (CNE)

Scoring systems to screen for diabetic peripheral neuropathy (Protocol) 3

Scoring systems to screen for diabetic peripheral neuropathy (Protocol) 4

Scoring systems to screen for diabetic peripheral neuropathy (Protocol) 5

Scoring systems to screen for diabetic peripheral neuropathy (Protocol) 6

Searching other resources

Scoring systems to screen for diabetic peripheral neuropathy (Protocol) 7

Scoring systems to screen for diabetic peripheral neuropathy (Protocol) 8

Scoring systems to screen for diabetic peripheral neuropathy (Protocol) 9

Scoring systems to screen for diabetic peripheral neuropathy (Protocol) 10

Additional references Abbott 2002

Abbott 1998 Adler 1997

Bastyr 2005 Caro 2002

Scoring systems to screen for diabetic peripheral neuropathy (Protocol) 14

Generalised symmetric polyneuropathies Chronic sensorimotor (typical DPN)

Focal and multifocal neuropathies Cranial

Proximal motor (amyotrophy)

DPN: diabetic peripheral neuropathy; CIDP: chronic in ammatory demyelinating polyneuropathy

Scoring systems to screen for diabetic peripheral neuropathy (Protocol) 15

Stage of diabetic peripheral neuropathy Characteristics

Stages 0/1: no clinical neuropathy

Stage 2: clinical neuropathy

Absent sensation to several modalities and reduced or absent reflexes

Acute painful Less common

Diabetes poorly controlled, weight loss

Hyperaesthesia may occur

May be associated with initiation of glycaemic therapy

Minor sensory signs or even normal peripheral neurological examination

Signs of reduced or absent sensation with absent reflexes

Diabetic amyotrophy Muscle weakness and wasting

Sensory loss is slight, but pain at night common

Stage 3: late complications of clinical neuropathy

Foot lesions, e.g. ulcers

Neuropathic deformity, e.g. Charcot joint

Scoring systems to screen for diabetic peripheral neuropathy (Protocol) 16

Abbreviation Full names

Scoring systems that we will include

CNE Clinical Neurological Examination

DNE Diabetic Neuropathy Examination

DNS Diabetic Neuropathy Symptom Score

MNSI Michigan Neuropathy Screening Instrument

NDS Neuropathy Disability Score

NIS Neuropathy Impairment Score

NIS-LL Neuropathy Impairment Score in the Lower Limbs

NSP Neuropathy Symptom Profile

NSS Neuropathy Symptom Score

TCSS Toronto Clinical Scoring System

Scoring systems that we will exclude

MDNS Michigan Diabetic Neuropathy Score

mTCNS modified Toronto Clinical Neuropathy Score

NIS-LL+4 Neuropathy Impairment Score in the Lower Limbs +4

NIS-LL+5 Neuropathy Impairment Score in the Lower Limbs +5

NIS-LL+7 Neuropathy Impairment Score in the Lower Limbs +7

NTSS - 6 Neuropathy Total Symptom Score - 6

NSC Neuropathy Symptom Change Score

# 1 Topic=(peripheral nervous diseas) OR Topic=(peripheral nervous disorder) OR Topic=(polyneuropath*) OR Topic=(neu-

instrument) OR Topic=(United Kingdom method) OR Topic=(United Kingdom model*)