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Painful and painless neuropathies are distinct and largely undiagnosed entities in subjects participating in an educational initiative (PROTECT study)
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Contents available at ScienceDirect
Diabetes Research and Clinical Practice journal homepage: www.elsevier.com/locat e/dia bre s
Painful and painless neuropathies are distinct and largely undiagnosed entities in subjects participating in an educational initiative (PROTECT study) Dan Ziegler a,b,*, Ru¨diger Landgraf c, Ralf Lobmann d, Karlheinz Reiners e, Kristian Rett f, Oliver Schnell g, Alexander Strom a a
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Du¨sseldorf, Germany b Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Du¨sseldorf, Germany c German Diabetes Foundation, Munich, Germany d Clinic for Endocrinology, Diabetology and Geriatrics, Klinikum Stuttgart – Bad Cannstatt, Stuttgart, Germany e Department of Neurology, Hermann Josef Hospital, Erkelenz, Germany f Endokrinologikum, Munich, Germany g Forschergruppe Diabetes e.V. at the Helmholtz Center Munich, Neuherberg, Germany
A R T I C L E I N F O
A B S T R A C T
Article history:
Aims: We conducted a nationwide educational initiative to determine the prevalence and
Received 24 January 2018
risk factors of diagnosed and undiagnosed painful and painless distal sensory polyneu-
Received in revised form
ropathy (DSPN).
14 February 2018
Methods: Among 1850 participants, 781 had no history of diabetes (ND), 126 had type 1 dia-
Accepted 27 February 2018
betes (T1D), and 943 had type 2 diabetes (T2D). Painful DSPN was defined as polyneuropa-
Available online 6 March 2018
thy detected by bedside tests with pain and/or burning in the feet, while painless DSPN was defined as polyneuropathy with paresthesias, numbness, or absence of symptoms.
Keywords: Neuropathic pain Polyneuropathy Diagnosis Screening Foot care Risk factors Glycemic control Peripheral arterial disease
Results: DSPN was detected in 48.2% of ND, 44.3% of T1D, and 55.3% of T2D subjects. DSPN was painful, painless, or atypical in 62.1, 24.8, and 13.1% of the participants. Painful DSPN was more severe than painless DSPN. Painful and painless DSPN were previously undiagnosed in 61.5 and 81.1% of the participants, respectively. In T2D subjects, painful and painless DSPN were associated with a higher and lower BMI, respectively. Among ND participants 39.2% had HbA1c levels indicating prediabetes/diabetes. Conclusions: Around half of participants in an educational initiative had DSPN, 62% of whom had the painful entity that correlated with BMI in T2D. Since many cases of neuropathy and diabetes remain undiagnosed, effective strategies to timely detect both conditions should be implemented. Ó 2018 Elsevier B.V. All rights reserved.
* Corresponding author at: German Diabetes Center, Auf’m Hennekamp 65, 40225 Du¨sseldorf, Germany. E-mail address: [email protected] (D. Ziegler). https://doi.org/10.1016/j.diabres.2018.02.043 0168-8227/Ó 2018 Elsevier B.V. All rights reserved.
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1.
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Introduction
Most common among diabetic neuropathies is chronic distal sensory polyneuropathy (DSPN), accounting for about 75% of diabetic neuropathies [1] and affecting about one third of all diabetic patients [2]. DSPN manifests mainly as a painful entity with neuropathic pain as a hallmark and a painless variant which may culminate in foot ulceration [3]. A simple definition of DSPN for clinical practice is the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes [1]. Pain associated with DSPN exerts a substantial impact on the quality of life, particularly by causing considerable interference in sleep and enjoyment of life [2]. Chronic painful DSPN is encountered in 13–26% of diabetic patients [2]. In a general-population health survey conducted in the US, the prevalence estimate of probable neuropathic pain using the PainDetect questionnaire amounted to 10% [4]. Pain is a subjective symptom of major clinical importance as it is often this complaint that motivates patients to seek health care. Regrettably, in one UK survey only 65% of diabetic patients received treatment for their neuropathic pain [5]. On the other hand, up to 50% of diabetic peripheral neuropathies may be asymptomatic. If not recognized and if preventive foot care is not implemented, patients are at risk for injuries to their insensate feet [1]. The prevalence of DSPN, defined as 1 insensate area based on monofilament testing, in the US adult population >40 years of age was 15% [6]. Bed-side screening instruments to detect clinically manifest DSPN such as the tuning fork and 10 g monofilament have been shown to predict diabetic foot ulcers [7,8]. Consequently, the American Diabetes Association (ADA) recommends that all patients should be assessed for DSPN starting at diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes and at least annually thereafter [1]. However, neuropathy screening is underutilized in primary care practice [9,10]. In a recent survey from Spain, diabetic foot screening was performed only in 37% of patients with diabetes in primary care [11]. Moreover, the clinical impact of DSPN is still being underestimated by both physicians and patients. In a large US nation-wide survey, physicians reported a neuropathy prevalence of 18%, but subsequent monofilament testing detected a prevalence of 37% in type 2 diabetes patients. Moreover, physicians prospectively identified only 31% and 66% of patients with mild/moderate and severe neuropathy, respectively [12]. Moreover, people with diabetes are frequently unaware of having neuropathy [13–15]. We previously reported that more than half of the first 983 subjects from this nationwide educational initiative with and without diabetes had DSPN which was reported as previously undiagnosed by two thirds [16]. However, data on neuropathic symptoms including pain were not reported and in a substantial proportion of these patients demographic and clinically relevant data such as BMI and HbA1c were not available [16]. The present final analysis comprising 1850 participants with a considerably more robust database aimed to estimate the rates of (1) painful and pain-
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less DSPN and to identify the associated risk factors, (2) previously undiagnosed painful and painless DSPN in participants with and without history of diabetes, and (3) prediabetes and diabetes in persons without history of diabetes.
2.
Subjects, materials and methods
2.1.
Study population
This nationwide educational initiative (Nationale Aufkla¨rungsinitiative [NAI]) ‘‘Diabetes! Do you listen to your feet?‘‘ (PROTECT study) was conducted in accordance with the Declaration of Helsinki and was approved by the ethics committee of Heinrich Heine University, Du¨sseldorf, Germany. All participants provided a written informed consent. From May 2013 through November 2016, 70 action days with promotional stands have been performed nationwide in 47 cities in Germany, 13 of which were organized in shopping centers and 34 in diabetes and health care fairs including >25,000 visitors, 1850 of whom underwent a foot examination. Visitors attending the promotional stand were also invited to test their foot sensation by walking over a barefoot course with four different floorings. Furthermore, educational measures included lectures and consultations with experts about diabetes and diabetic neuropathy given by diabetologists at the promotional stand, consultations by the podologists during and after the foot examination, broad public relations activities by print, online, and broadcasting media, news services, editorial media reports, and distribution of information material at the promotional stand (newsletter, brochures, guides, etc.), regional letters of announcement to physicians and pharmacists, and nationwide information letters to (around 50,000) general practitioners and diabetologists. Each year since 2013, a press conference for the specialist and end-user media was held on the occasion of the annual congress of the German Diabetes Association. The NAI website (www.hoerensieaufihrefuesse.de) is the central online platform for all activities and information provided by NAI. As an added value, it features a video consultation by five diabetologists/neurologists on topics related to diabetes and neuropathy.
2.2.
Methods
Study participants with or without known diabetes underwent a foot examination and completed a questionnaire including age, sex, history of type 1 or type 2 diabetes and answered the following questions: (1) ”Have you ever been diagnosed with neuropathy?”, (2) ”Are you currently being treated by a physician because of neuropathy?” Foot examination was carried out by certified podologists in quiet ambience in a mobile cube (9 m2) with a sliding door closed and included bilateral assessment of pressure, temperature, and vibration sensation which were tested two times on each site and foot. The subject was asked to close his eyes during each test. Pressure perception was determined twice on the plantar aspect of each second metatarsal head using
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the 10 g monofilament (Rehaforum Medical, Elmshorn, Germany) avoiding callous skin. Subjects indicated when a touch occurred which was classified as normal and as abnormal if the monofilament was not felt [17]. Pressure perception was defined as abnormal if the subject did not feel the monofilament twice on both sides or twice on one side and once on the other. Temperature perception was carried out twice on each dorsum of the foot using the tip thermÒ device (tip therm, Bru¨ggen, Germany). The examiner placed each of the two flat surfaces of the device at irregular intervals avoiding callous skin and asked whether it feels cold or not so cold [18]. Thermal perception was defined as abnormal if the subject did not answer correctly twice on both sides or twice on one side and once on the other. Vibration perception threshold (VPT) was determined on the dorsum of the interphalangeal joint of the hallux and medial malleolus using the Rydel-Seiffer tuning fork (Arno Barthelmes Zella-Mehlis, Zella-Mehlis, Germany) as previously described [19]. The readings of two repeated tests were averaged and defined as VPT for each of the two sites of examination. The age- and sex-dependent limits of normal previously reported by Martina et al. [19] defined at the 5th percentile of healthy subjects were used. VPT was defined as abnormal if the mean of two sides on the dorsum of the interphalangeal joint of the hallux and/or medial malleolus was below the 5th percentile of healthy subjects. DSPN was defined as possible (mild), probable (moderate), and definite (severe) if 1 out of 3, 2 out of 3, and 3 out of 3 tests (pressure, temperature, vibration perception), respectively, were abnormal. Painful DSPN was defined as the presence of DSPN with pain and/or burning at rest in the feet, while painless DSPN was defined as the presence of DSPN with paraesthesias, numbness, or absence of symptoms. Atypical DSPN was defined as the presence of DSPN with symptoms only while walking. Pedal pulses of the dorsalis pedis and posterior tibial arteries were examined in a subset of 1437 participants. Foot pulses were classified as indicating peripheral arterial disease (PAD) if at least two out of the four pulses were not palpable.
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HbA1c was measured using a point of care DCA Vantage Analysis System (Siemens Healthcare Diagnostics GmbH, Eschborn, Germany) in a subset of 955 participants. According to the ADA criteria [20], diabetes was defined as HbA1c 6.5% and prediabetes as HbA1c 5.7% to <6.5%, while HbA1c <5.7% was considered normal.
2.3.
Statistical analysis
Continuous data were expressed as mean ± SD. Categorical data were given as absolute or relative frequencies and were analyzed by Fisher’s exact test. For normally distributed data, parametric tests (t-test or Pearson product-moment correlation), otherwise nonparametric tests (Mann-Whitney U test or Spearman rank correlation) were applied. To determine associations between two variables, univariate correlations and multiple logistic regression analyses were performed. The level of significance was set at a=0.05.
3.
Results
Among 1850 individuals participating in the initiative, 781 had no diabetes by history (ND), 126 had type 1 diabetes, and 943 had type 2 diabetes. The demographic and clinical data of the three groups studied are shown in Table 1. Men were represented more frequently in both diabetes groups compared to ND participants (P < 0.05). Type 1 diabetic subjects were younger than those with type 2 diabetes and ND participants, while the latter were younger than those with type 2 diabetes (P < 0.05). BMI and weight were higher in the type 2 diabetes group compared to ND subjects, while the latter were smaller than those with type 1 diabetes (P < 0.05). Waist circumference was higher in participants with type 2 diabetes than in the other two groups (P < 0.05). HbA1c was higher in the groups with diabetes than in ND subjects and also higher in participants with type 1 diabetes than in those with type 2 diabetes (P < 0.05). Notably, 35.5% of the ND subjects had HbA1c levels indicative of prediabetes and 3.7% presumably
Table 1 – Demographic and clinical data of the participants (n=1850).
n Sex (% male) Age (years) BMI (kg/m2) [n = 369/37/339] Weight (kg) [n = 369/37/339] Height (cm) [n = 369/37/339] Waist circumference (cm) [n = 258/31/227] HbA1c (%) [n = 459/53/443] HbA1c (mmol/mol) HbA1c <5.7 (%) [n = 279/2/23] HbA1c 5.7 to <6.5 (%) [n = 163/11/170] HbA1c 6.5 (%) [n = 17/40/250] Peripheral arterial disease (%) [n = 621/94/722] Values are mean ± SD or percentages. P < 0.05 no diabetes vs type 1 diabetes. P < 0.05 no diabetes vs type 2 diabetes. P < 0.05 type 1 diabetes vs type 2 diabetes.
# § †
No diabetes
Type 1 diabetes
Type 2 diabetes
781 36.9 67.7 ± 11.9 27.8 ± 4.6 77.3 ± 15.6 166 ± 9 98 ± 13 5.63 ± 0.51 38.1 ± 5.6 60.8 35.5 3.7 7.4
126 46.8# 59.5 ± 15.4# 27.5 ± 5.1 79.2 ± 16.2 170 ± 10# 96 ± 13 7.52 ± 1.34# 58.7 ± 14.7# 3.8# 20.7# 75.5# 10.6
943 50.6§ 70.0 ± 9.6§,† 29.4 ± 5.2§ 82.6 ± 16.7§ 167 ± 10 104 ± 11§,† 6.72 ± 0.94§,† 50.0 ± 10.3§,† 5.2§ 38.4† 56.4§,† 12.3§
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Table 2 – Percentages of abnormal sensory tests, distal sensory polyneuropathy (DSPN), and symptoms in the feet. No diabetes Reduced thermal perception (%) [n = 776/124/929] Reduced vibration perception (%) [n = 777/125/939] Reduced pressure perception (%) [n = 775/123/936] Possible (mild) DSPN (%) [n = 769/122/923] Probable (moderate) DSPN (%) [n = 769/122/923] Definite (severe) DSPN (%) [n = 769/122/923] Total DSPN (%) [n = 769/122/923] Pain (%) [n = 530/80/595] Burning (%) [n = 535/80/606] Paresthesias (%) [n = 537/80/605] Numbness (%) [n = 532/79/605] Symptoms continuous (%) [n = 531/80/598] Symptoms at night (%) [n = 531/80/596] Symptoms at rest (%) [n = 533/80/598] Pain during walking only (%) [n = 530/80/595]
Type 1 diabetes
Type 2 diabetes §
All
21.5
21.8
28.1
24.9
34.0
24.8
37.2†
35.0
16.8
13.0
20.2
18.3
29.5
33.6
31.7
30.9
13.3
6.6#
16.8§,†
14.6
5.5 48.2 59.6 52.1 68.5 52.8 13.9
4.1 44.3 45.0# 41.3 56.3# 44.3 11.3
6.7 55.3§,† 56.3 51.3 67.6 59.5§,† 15.2
6.0 51.5 57.0 51.0 67.3 55.6 14.4
24.5
13.8#
27.9†
25.4
30.8
27.5
27.6
29.0
15.7
16.3
14.5
15.1
Values are mean ± SD or percentages. P < 0.05 no diabetes vs type 1 diabetes. P < 0.05 no diabetes vs type 2 diabetes P < 0.05 type 1 diabetes vs type 2 diabetes.
# § †
had diabetes. PAD was more frequent in the group with type 2 diabetes than in ND subjects (P < 0.05). The percentages of abnormal sensory tests, DSPN, and symptoms in the feet are given in Table 2. Thermal perception was more frequently abnormal in type 2 diabetes subjects than in the ND group (P < 0.05). VPT was more frequently abnormal in participants with type 2 diabetes compared to those with type 1 diabetes (P < 0.05). Probable DSPN was more frequent in type 2 diabetes individuals than in the groups with type 1 diabetes and ND and was also more frequent in the latter than in type 1 diabetes subjects (P < 0.05). Pain and paresthesias were more frequent in ND subjects than in those with type 1 diabetes (P < 0.05). Numbness was more prevalent in the group with type 2 diabetes compared to the other two groups (P < 0.05). Symptoms at night were less common in
type 1 diabetes subjects than in the other two groups (P < 0.0 5). No other differences between the groups were noted. The percentages of painful, painless, asymptomatic, and atypical DSPN in subjects with DSPN are presented in Table 3. Painful DSPN comprised 62.1% of the participants with DSPN, while painless and atypical DSPN accounted for 24.8 and 13.1%, respectively. No significant differences between the groups were noted. With respect to the severity of the neuropathy, possible (mild) DSPN was less frequent in participants with painful DSPN compared to those with painless DSPN (59.4 vs 73.7%; P = 0.003), whereas definite (severe) DSPN was more frequent in the group with painful compared to painless DSPN (12.3 vs 3.6%; P < 0.003). No difference between the groups was noted for probable (moderate) DSPN (28.4 vs 22.6%; P = 0.211).
Table 3 – Percentages of painful, painless, asymptomatic, and atypical distal sensory polyneuropathy (DSPN) in subjects with DSPN.
Painful DSPN [n = 140/17/184] with pain or burning with pain and burning Painless DSPN [n = 52/9/75] with paresthesias or numbness with paresthesias and numbness asymptomatic DSPN Atypical DSPN [n = 28/5/39]
No diabetes [n = 220] (%)
Type 1 diabetes [n = 31] (%)
Type 2 diabetes [n = 298] (%)
All [n = 549] (%)
63.6 27.7 35.9 23.7 10.5 7.7 5.5 12.7
54.8 25.8 29.0 29.1 9.7 9.7 9.7 16.1
61.7 26.5 35.2 25.2 9.1 8.4 7.7 13.1
62.1 27.0 35.2 24.8 9.7 8.2 6.9 13.1
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The question ”Have you ever been diagnosed with neuropathy?” was answered by 218 subjects with DSPN in the ND group, 30 of those with type 1 diabetes, and 293 participants with type 2 diabetes. Table 4 shows the percentages of previously diagnosed and undiagnosed neuropathy in total as well as separately for the painful and painless entities, excluding subjects with atypical DSPN, in subjects with DSPN are given for this subset of 541 participants. The ND group showed the highest rate of undiagnosed DSPN (75.2%), followed by the groups with type 2 diabetes (69.9%) and type 1 diabetes (53.3%). Overall, more than two thirds of the participants had previously undiagnosed DSPN. The percentage of undiagnosed DSPN was lower in type 1 diabetes subjects compared to the other two groups (P < 0.05). The prevalence of undiagnosed painful DSPN was higher in ND subjects than in those with type 2 diabetes (P < 0.05). The prevalence of undiagnosed painless DSPN was higher in ND participants than in those with type 1 diabetes (P < 0.05). The highest percentages of undiagnosed DSPN were observed for the painless entity in type 2 diabetes and ND subjects (each >80%). The question ”Are you currently being treated by a physician because of neuropathy?” was answered by 387 subjects in the ND group, 5.9% of whom answered ‘‘yes”, 61 individuals with type 1 diabetes, 14.8% of whom answered ‘‘yes”, and 483 individuals with type 2 diabetes, 16.6% of whom answered ‘‘yes”. The correlation analyses of painful and painless DSPN with sex, age, BMI, and PAD are given in Table 5. Painless DSPN correlated with male sex in type 2 diabetes and ND subjects (P < 0.05). Both painful and painless DSPN correlated positively with age in the ND group (P < 0.05). Painful DSPN correlated positively with BMI, whereas painless DSPN correlated inversely with BMI in the group with type 2 diabetes (P < 0.05). Painful DSPN correlated with PAD in type 2 diabetes subjects, while painless DSPN correlated with PAD in type 1 diabetes and ND participants (P < 0.05). No other correlations were found. In a multiple logistic regression analyses, with painful/painless DSPN as a dependent variable and sex, age, BMI, and PAD as covariates, painful DSPN was associated with age (OR [95% CI]: 1.028 [1.003–1.053]; P = 0.029) and PAD with (12.49 [3.53–44.11]; P < 0.0001) in the ND group. In the type 2 diabetes group, painful DSPN was associated with higher BMI (1.056 [1.001–1.115]; P = 0.046) and PAD (4.54 [1.71–12.07]; P = 0.002), while painless DSPN was associated with lower BMI (0.854 [0.766–0.953]; P = 0.005) and PAD (4.14 [1.14–15.03]; P = 0.031). ND participants with DSPN who had HbA1c levels in the diabetes range 6.5% showed higher mean HbA1c levels than the corresponding group without DSPN (8.3 ± 0.4 vs 7.1 ± 0.1%; P = 0.003). Likewise, DSPN correlated with HbA1c in the ND group showing HbA1c levels 6.5% (r = 0.61, P = 0.009).
4.
Discussion
This nationwide educational initiative ‘‘Diabetes! Do you listen to your feet?‘‘ conducted in Germany unveiled that (1). The rates of previously undiagnosed painful DSPN were 57% in type 2 diabetes subjects, lower (47%) in those with type 1 diabetes, and highest (70%) in people without history of dia-
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betes, while the corresponding percentages for painless DSPN were higher by 25, 9 and 15%; (2). The risk factors for the painful and painless DSPN entities may differ, with the most intriguing finding of a dichotomy in the association of higher/lower BMI with painful/painless DSPN in type 2 diabetes subjects; (3) Among participants without history of diabetes, 36% and 4% showed HbA1c levels within the range of prediabetes and diabetes, respectively; (4.) Participants with DSPN without history of diabetes but with HbA1c levels in the diabetes range 6.5% showed a higher mean HbA1c than the corresponding group without DSPN. Thus, the surprisingly high rate of newly detected cases with painful DSPN may indicate undertreatment of neuropathic pain, and unrecognized diabetes could be an important cause of neuropathy. Since people with and without previously known diabetes are insufficiently informed about their neuropathy, even if the latter presents with pain, patient education about the implications of neuropathic symptoms and neuropathy should be improved. The differential associations of various risk factors and PAD, albeit assessed only by palpation of foot pulses, with painful and painless DSPN deserve comment. In participants with type 2 diabetes, painful DSPN was positively associated with a higher BMI, whereas painless DSPN was associated with a lower BMI, and both entities were associated with prevalent PAD. In contrast, in the group without history of diabetes, painful DSPN was associated with a higher age and PAD. However, these results should be interpreted with caution, since it was not feasible in the present setting to confirm the diagnosis of PAD by duplex ultrasonography. We confirm our previous studies reporting associations of painful DSPN with weight and waist circumference in elderly subjects with diabetes from the general population [21,22]. A novel finding is the correlation between painless DSPN and lower BMI, the reasons for which remain unclear, but it is conceivable that the relationship between DSPN and obesity is specific for the painful entity. Another novel finding is the correlation of painless DSPN with male sex in both type 2 diabetes and ND subjects. Notably, an association between painful DSPN and female sex was recently reported [23]. Moreover, we showed that painful DSPN was more severe than painless DSPN, since mild DSPN was more frequent in participants with painless DSPN, whereas severe DSPN was more frequent in those with painful DSPN. This finding is in line with a recent study suggesting that the severity of neuropathic pain due to DSPN is associated with the severity of neuropathy, i.e. sensory deficits (signs) [23]. Altogether, these findings suggest that distinct risk factors and neuropathy severity may be important determinants to differentiate between the painful and painless DSPN phenotype and could be helpful in addressing the conundrum of why some people develop the insensate entity of DSPN whilst others experience distressing neuropathic pain [3]. The vast majority of patients with diabetes are unlikely to have foot examinations in their primary medical care [10]. Our results with a rate of 70% of DSPN being previously undiagnosed in type 2 diabetic subjects are in line with these observations. In a German population based survey, 77% of diabetic subjects with polyneuropathy were unaware of
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Table 4 – Prevalence of previously diagnosed and undiagnosed neuropathy in subjects with distal sensory polyneuropathy (DSPN) in subjects who completed the questionnaire. No diabetes
Type 1 diabetes
Type 2 diabetes
All
DSPN total Diagnosed Undiagnosed
24.8 75.2
46.7 53.3#
33.1 69.9§
30.5 69.5
Painful DSPN* Diagnosed Undiagnosed
30.9 69.5
53.3 46.7
43.0 57.0§
38.5 61.5
Painless DSPN* Diagnosed Undiagnosed
15.7 84.3
44.4 55.6#
18.1 81.9
18.9 81.1
*
Excluding subjects with symptoms during walking only. P < 0.05 no diabetes vs type 1 diabetes. P < 0.05 no diabetes vs type 2 diabetes
# §
having the disorder, defined as answering ‘‘no” to the question ‘‘Has a physician ever told you that you are suffering from nerve damage, neuropathy, polyneuropathy, or diabetic foot?” Approximately one quarter of the subjects with known diabetes had never undergone a foot examination. Even among individuals with known diabetes who reported to have had their feet examined by a physician, 72% of those with polyneuropathy emerged unaware of having polyneuropathy [13]. Among diabetes patients from rural Arkansas who presented with neuropathic symptoms and attended a diabetes education program, 79% had not been diagnosed with DSPN [14]. Among participants from the Australian communitybased Fremantle Diabetes Study Phase II who had diabetes and considered their feet to be normal, 67.9% had DSPN, suggesting that self-assessment of diabetes-related foot problems by patients is unreliable [15]. Thus, underdiagnosis and unawareness of diabetic polyneuropathy could have an adverse impact on the development of diabetic foot ulcers and even amputations. Our study extends the current knowledge by demonstrating that although the percentages of participants with undiagnosed DSPN were highest across the
groups for the painless entity, the prevalence of undiagnosed painful DSPN was still considerable despite the fact that pain per se motivates patients to seek health care. In patients with diabetes, the reasons for this deficiency may include inadequate attention to diabetic foot prevention practice and insufficient adherence to clinical guidelines. It has been suggested that self-perceived foot health should be assessed in conjunction with foot examination findings and that intensive education and monitoring may be necessary in those who consider their feet to be normal but who have precursors of serious foot pathology [15]. Indeed, a simple, low-cost educational intervention over 6 months resulted in an increase in the performance of proper foot examination from 14 to 62% [10]. In patients without diabetes, similarly structured programs are totally missing. At the primary health care level, professional sensitivity towards neuromuscular disorders is generally low, and many patients with neuropathic foot problems commonly turn to orthopedic surgeons rather than to adequate neurological care. The present study also shows that among participants without history of diabetes, 35.5% and 3.7% had HbA1c levels
Table 5 – Correlation analyses of painful and painless DSPN with demographic variables and peripheral arterial disease. No diabetes r Sex Painful DSPN* Painless DSPN§
0.062 0.125
Type 2 diabetes
r
P
0.215 0.030
0.077 0.040
0.582 0.801
r
P 0.066 0.169
0.172 0.003
Age Painful DSPN* Painless DSPN§
0.191 0.178
0.0001 0.002
0.233 0.247
0.094 0.115
0.052 0.027
0.283 0.645
BMI Painful DSPN* Painless DSPN§
0.064 0.022
0.288 0.751
0.063 0.000
0.759 1.000
0.158 0.223
0.015 0.004
0.002 <0.0001
0.120 0.480
0.396 0.001
0.224 0.053
<0.0001 0.364
Peripheral arterial disease 0.157 Painful DSPN* Painless DSPN§ 0.340 *
§
Type 1 diabetes P
Excluding subjects with symptoms during walking only or with painless DSPN. Excluding subjects with symptoms during walking only or with painful DSPN.
diabetes research and clinical practice
within the range of prediabetes and diabetes, respectively. In high-income countries, about one in three diabetes cases is not diagnosed [24] In a recent population-based German survey, the prevalence of diagnosed diabetes and undiagnosed diabetes was 7.2 and 2.0%, respectively, while the prevalence of undiagnosed prediabetes was 21%. Thus, the proportion of persons unaware of their diabetes was 22% [25]. The higher percentages of persons with undiagnosed diabetes and prediabetes found in the present study could be due to a possible selection bias towards the more motivated individuals seeking to have their feet examined. Moreover, there is evidence to suggest that people with undiagnosed diabetes and those with prediabetes strongly underestimate their probability of having or developing diabetes [26]. More than 70% of persons with undiagnosed diabetes/prediabetes believed that their probability of having undetected diabetes was low/very low or believed that they were not at risk of developing diabetes, respectively. Thus, early detection of diabetes and prediabetes seems favorable for patients, but may be delayed by patients being overly optimistic about their own health [26]. Therefore, it has been suggested that against the background of the increasing risk of diabetes and the burden of the disease, a combination of strategies to avoid misperceptions of diabetes risk may be considered [26]. The present study has several limitations. First, since this survey was primarily an educational campaign performed in public settings, definitive diagnostic studies to confirm neuropathy and PAD could not be conducted and the causes of DSPN other than diabetes such as vitamin B12 deficiency, alcohol abuse, monoclonal gammopathy, hypothyroidism, inflammation, drugs as well as renal, hepatic, infectious, autoimmune, or neoplastic disorders could not be verified. Second, selection bias cannot be avoided due to the study setting, and recall bias is also possible. Third, several demographic and disease variables were assessed in subsets only. In conclusion, around a half of subjects with and without diabetes participating in an educational initiative presented with DSPN, 62% of whom had the painful entity which correlated with higher BMI in participants with type 2 diabetes. Since DSPN was previously undiagnosed in 70% of all participants and almost 40% of the participants without previous history of diabetes actually had an increased risk of diabetes, effective strategies to reveal both undetected diabetes and neuropathy should be implemented. Future educational programs for people with diabetes should address the gaps arising from underestimating DSPN in primary care practice and inadequate adherence to the clinical guidelines for diabetes care aimed at prevention of diabetic foot and amputations.
Acknowledgments The National Educational Initiative was financed by Wo¨rwag Pharma, Bo¨blingen, Germany. This study was supported in part by the Ministry of Science and Research of the State of North RhineWestphalia (MIWF NRW), the German Federal Ministry of Health (BMG), and the German Diabetes Foundation.
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The authors thank Michael Martell, Helen Fo¨rster, and Fanny v. Hesberg (newswerk, Stuttgart, Germany) for organizing and conducting this study. DZ wrote the manuscript. DZ, AS, RLa, RL, KhR, KR, and OS researched data, contributed to discussion and reviewed and edited the manuscript. DZ is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Conflict of interest DZ, RL, KhR, KR, and OS are advisory board members of the National Education Initiative and received honoraria for speaking activities from Wo¨rwag Pharma. RLa received a grant for prevention activities of the German Diabetes Foundation.
R E F E R E N C E S
[1] Pop-Busui R, Boulton AJM, Feldman EL, Bril V, Freeman R, Malik RA, et al. Diabetic neuropathy. A statement by the American Diabetes Association. Diabetes Care 2017;40:136–54. [2] Ziegler D, Papanas N, Vinik AI, Shaw JE. Epidemiology of polyneuropathy in diabetes and prediabetes. Handb Clin Neurol 2014;126:3–22. [3] Spallone V, Greco C. Painful and painless diabetic neuropathy: one disease or two? Curr Diab Rep 2013;13:533–49. [4] DiBonaventura MD, Sadosky A, Concialdi K, Hopps M, Kudel I, Parsons B, et al. The prevalence of probable neuropathic pain in the US: results from a multimodal general-population health survey. J Pain Res 2017;10:2525–38. [5] Daousi C, Benbow SJ, Woodward A, MacFarlane IA. The natural history of chronic painful peripheral neuropathy in a community diabetes population. Diabet Med 2006;23:1021–4. [6] Gregg EW, Sorlie P, Paulose-Ram R, Gu Q, Eberhardt MS, Wolz M, et al. Prevalence of lower-extremity disease in the US adult population 40 years of age with and without diabetes: 1999– 2000 national health and nutrition examination survey. Diabetes Care 2004;27:1591–7. [7] Abbott CA, Carrington AL, Ashe H, Bath S, Every LC, Griffiths J, et al. North-West diabetes foot care study. The North-West diabetes foot care study: incidence of, and risk factors for, new diabetic foot ulceration in a community-based patient cohort. Diabet Med 2002;19:377–84. [8] Crawford F, McCowan C, Dimitrov BD, Woodburn J, Wylie GH, Booth E, et al. The risk of foot ulceration in people with diabetes screened in community settings: findings from a cohort study. QJM 2011;104:403–10. [9] Kirkman MS, Williams SR, Caffrey HH, Marrero DG. Impact of a program to improve adherence to diabetes guidelines by primary care physicians. Diabetes Care 2002;25:1946–51. [10] O’Brien KE, Chandramohan V, Nelson DA, Fischer Jr JR, Stevens G, Poremba JA. Effect of a physician-directed educational campaign on performance of proper diabetic foot exams in an outpatient setting. J Gen Intern Med 2003;18:258–65. [11] Alonso-Ferna´ndez M, Mediavilla-Bravo JJ, Lo´pez-Simarro F, Comas-Samper JM, Carramin˜ana-Barrera F, Mancera-Romero J, et al., Grupo de Trabajo de Diabetes de SEMERGEN.
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Contents available at ScienceDirect
Diabetes Research and Clinical Practice journal homepage: www.elsevier.com/locat e/dia bre s
Painful and painless neuropathies are distinct and largely undiagnosed entities in subjects participating in an educational initiative (PROTECT study) Dan Ziegler a,b,*, Ru¨diger Landgraf c, Ralf Lobmann d, Karlheinz Reiners e, Kristian Rett f, Oliver Schnell g, Alexander Strom a a
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Du¨sseldorf, Germany b Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Du¨sseldorf, Germany c German Diabetes Foundation, Munich, Germany d Clinic for Endocrinology, Diabetology and Geriatrics, Klinikum Stuttgart – Bad Cannstatt, Stuttgart, Germany e Department of Neurology, Hermann Josef Hospital, Erkelenz, Germany f Endokrinologikum, Munich, Germany g Forschergruppe Diabetes e.V. at the Helmholtz Center Munich, Neuherberg, Germany
A R T I C L E I N F O
A B S T R A C T
Article history:
Aims: We conducted a nationwide educational initiative to determine the prevalence and
Received 24 January 2018
risk factors of diagnosed and undiagnosed painful and painless distal sensory polyneu-
Received in revised form
ropathy (DSPN).
14 February 2018
Methods: Among 1850 participants, 781 had no history of diabetes (ND), 126 had type 1 dia-
Accepted 27 February 2018
betes (T1D), and 943 had type 2 diabetes (T2D). Painful DSPN was defined as polyneuropa-
Available online 6 March 2018
thy detected by bedside tests with pain and/or burning in the feet, while painless DSPN was defined as polyneuropathy with paresthesias, numbness, or absence of symptoms.
Keywords: Neuropathic pain Polyneuropathy Diagnosis Screening Foot care Risk factors Glycemic control Peripheral arterial disease
Results: DSPN was detected in 48.2% of ND, 44.3% of T1D, and 55.3% of T2D subjects. DSPN was painful, painless, or atypical in 62.1, 24.8, and 13.1% of the participants. Painful DSPN was more severe than painless DSPN. Painful and painless DSPN were previously undiagnosed in 61.5 and 81.1% of the participants, respectively. In T2D subjects, painful and painless DSPN were associated with a higher and lower BMI, respectively. Among ND participants 39.2% had HbA1c levels indicating prediabetes/diabetes. Conclusions: Around half of participants in an educational initiative had DSPN, 62% of whom had the painful entity that correlated with BMI in T2D. Since many cases of neuropathy and diabetes remain undiagnosed, effective strategies to timely detect both conditions should be implemented. Ó 2018 Elsevier B.V. All rights reserved.
* Corresponding author at: German Diabetes Center, Auf’m Hennekamp 65, 40225 Du¨sseldorf, Germany. E-mail address: [email protected] (D. Ziegler). https://doi.org/10.1016/j.diabres.2018.02.043 0168-8227/Ó 2018 Elsevier B.V. All rights reserved.
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1.
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Introduction
Most common among diabetic neuropathies is chronic distal sensory polyneuropathy (DSPN), accounting for about 75% of diabetic neuropathies [1] and affecting about one third of all diabetic patients [2]. DSPN manifests mainly as a painful entity with neuropathic pain as a hallmark and a painless variant which may culminate in foot ulceration [3]. A simple definition of DSPN for clinical practice is the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes [1]. Pain associated with DSPN exerts a substantial impact on the quality of life, particularly by causing considerable interference in sleep and enjoyment of life [2]. Chronic painful DSPN is encountered in 13–26% of diabetic patients [2]. In a general-population health survey conducted in the US, the prevalence estimate of probable neuropathic pain using the PainDetect questionnaire amounted to 10% [4]. Pain is a subjective symptom of major clinical importance as it is often this complaint that motivates patients to seek health care. Regrettably, in one UK survey only 65% of diabetic patients received treatment for their neuropathic pain [5]. On the other hand, up to 50% of diabetic peripheral neuropathies may be asymptomatic. If not recognized and if preventive foot care is not implemented, patients are at risk for injuries to their insensate feet [1]. The prevalence of DSPN, defined as 1 insensate area based on monofilament testing, in the US adult population >40 years of age was 15% [6]. Bed-side screening instruments to detect clinically manifest DSPN such as the tuning fork and 10 g monofilament have been shown to predict diabetic foot ulcers [7,8]. Consequently, the American Diabetes Association (ADA) recommends that all patients should be assessed for DSPN starting at diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes and at least annually thereafter [1]. However, neuropathy screening is underutilized in primary care practice [9,10]. In a recent survey from Spain, diabetic foot screening was performed only in 37% of patients with diabetes in primary care [11]. Moreover, the clinical impact of DSPN is still being underestimated by both physicians and patients. In a large US nation-wide survey, physicians reported a neuropathy prevalence of 18%, but subsequent monofilament testing detected a prevalence of 37% in type 2 diabetes patients. Moreover, physicians prospectively identified only 31% and 66% of patients with mild/moderate and severe neuropathy, respectively [12]. Moreover, people with diabetes are frequently unaware of having neuropathy [13–15]. We previously reported that more than half of the first 983 subjects from this nationwide educational initiative with and without diabetes had DSPN which was reported as previously undiagnosed by two thirds [16]. However, data on neuropathic symptoms including pain were not reported and in a substantial proportion of these patients demographic and clinically relevant data such as BMI and HbA1c were not available [16]. The present final analysis comprising 1850 participants with a considerably more robust database aimed to estimate the rates of (1) painful and pain-
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less DSPN and to identify the associated risk factors, (2) previously undiagnosed painful and painless DSPN in participants with and without history of diabetes, and (3) prediabetes and diabetes in persons without history of diabetes.
2.
Subjects, materials and methods
2.1.
Study population
This nationwide educational initiative (Nationale Aufkla¨rungsinitiative [NAI]) ‘‘Diabetes! Do you listen to your feet?‘‘ (PROTECT study) was conducted in accordance with the Declaration of Helsinki and was approved by the ethics committee of Heinrich Heine University, Du¨sseldorf, Germany. All participants provided a written informed consent. From May 2013 through November 2016, 70 action days with promotional stands have been performed nationwide in 47 cities in Germany, 13 of which were organized in shopping centers and 34 in diabetes and health care fairs including >25,000 visitors, 1850 of whom underwent a foot examination. Visitors attending the promotional stand were also invited to test their foot sensation by walking over a barefoot course with four different floorings. Furthermore, educational measures included lectures and consultations with experts about diabetes and diabetic neuropathy given by diabetologists at the promotional stand, consultations by the podologists during and after the foot examination, broad public relations activities by print, online, and broadcasting media, news services, editorial media reports, and distribution of information material at the promotional stand (newsletter, brochures, guides, etc.), regional letters of announcement to physicians and pharmacists, and nationwide information letters to (around 50,000) general practitioners and diabetologists. Each year since 2013, a press conference for the specialist and end-user media was held on the occasion of the annual congress of the German Diabetes Association. The NAI website (www.hoerensieaufihrefuesse.de) is the central online platform for all activities and information provided by NAI. As an added value, it features a video consultation by five diabetologists/neurologists on topics related to diabetes and neuropathy.
2.2.
Methods
Study participants with or without known diabetes underwent a foot examination and completed a questionnaire including age, sex, history of type 1 or type 2 diabetes and answered the following questions: (1) ”Have you ever been diagnosed with neuropathy?”, (2) ”Are you currently being treated by a physician because of neuropathy?” Foot examination was carried out by certified podologists in quiet ambience in a mobile cube (9 m2) with a sliding door closed and included bilateral assessment of pressure, temperature, and vibration sensation which were tested two times on each site and foot. The subject was asked to close his eyes during each test. Pressure perception was determined twice on the plantar aspect of each second metatarsal head using
diabetes research and clinical practice
the 10 g monofilament (Rehaforum Medical, Elmshorn, Germany) avoiding callous skin. Subjects indicated when a touch occurred which was classified as normal and as abnormal if the monofilament was not felt [17]. Pressure perception was defined as abnormal if the subject did not feel the monofilament twice on both sides or twice on one side and once on the other. Temperature perception was carried out twice on each dorsum of the foot using the tip thermÒ device (tip therm, Bru¨ggen, Germany). The examiner placed each of the two flat surfaces of the device at irregular intervals avoiding callous skin and asked whether it feels cold or not so cold [18]. Thermal perception was defined as abnormal if the subject did not answer correctly twice on both sides or twice on one side and once on the other. Vibration perception threshold (VPT) was determined on the dorsum of the interphalangeal joint of the hallux and medial malleolus using the Rydel-Seiffer tuning fork (Arno Barthelmes Zella-Mehlis, Zella-Mehlis, Germany) as previously described [19]. The readings of two repeated tests were averaged and defined as VPT for each of the two sites of examination. The age- and sex-dependent limits of normal previously reported by Martina et al. [19] defined at the 5th percentile of healthy subjects were used. VPT was defined as abnormal if the mean of two sides on the dorsum of the interphalangeal joint of the hallux and/or medial malleolus was below the 5th percentile of healthy subjects. DSPN was defined as possible (mild), probable (moderate), and definite (severe) if 1 out of 3, 2 out of 3, and 3 out of 3 tests (pressure, temperature, vibration perception), respectively, were abnormal. Painful DSPN was defined as the presence of DSPN with pain and/or burning at rest in the feet, while painless DSPN was defined as the presence of DSPN with paraesthesias, numbness, or absence of symptoms. Atypical DSPN was defined as the presence of DSPN with symptoms only while walking. Pedal pulses of the dorsalis pedis and posterior tibial arteries were examined in a subset of 1437 participants. Foot pulses were classified as indicating peripheral arterial disease (PAD) if at least two out of the four pulses were not palpable.
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HbA1c was measured using a point of care DCA Vantage Analysis System (Siemens Healthcare Diagnostics GmbH, Eschborn, Germany) in a subset of 955 participants. According to the ADA criteria [20], diabetes was defined as HbA1c 6.5% and prediabetes as HbA1c 5.7% to <6.5%, while HbA1c <5.7% was considered normal.
2.3.
Statistical analysis
Continuous data were expressed as mean ± SD. Categorical data were given as absolute or relative frequencies and were analyzed by Fisher’s exact test. For normally distributed data, parametric tests (t-test or Pearson product-moment correlation), otherwise nonparametric tests (Mann-Whitney U test or Spearman rank correlation) were applied. To determine associations between two variables, univariate correlations and multiple logistic regression analyses were performed. The level of significance was set at a=0.05.
3.
Results
Among 1850 individuals participating in the initiative, 781 had no diabetes by history (ND), 126 had type 1 diabetes, and 943 had type 2 diabetes. The demographic and clinical data of the three groups studied are shown in Table 1. Men were represented more frequently in both diabetes groups compared to ND participants (P < 0.05). Type 1 diabetic subjects were younger than those with type 2 diabetes and ND participants, while the latter were younger than those with type 2 diabetes (P < 0.05). BMI and weight were higher in the type 2 diabetes group compared to ND subjects, while the latter were smaller than those with type 1 diabetes (P < 0.05). Waist circumference was higher in participants with type 2 diabetes than in the other two groups (P < 0.05). HbA1c was higher in the groups with diabetes than in ND subjects and also higher in participants with type 1 diabetes than in those with type 2 diabetes (P < 0.05). Notably, 35.5% of the ND subjects had HbA1c levels indicative of prediabetes and 3.7% presumably
Table 1 – Demographic and clinical data of the participants (n=1850).
n Sex (% male) Age (years) BMI (kg/m2) [n = 369/37/339] Weight (kg) [n = 369/37/339] Height (cm) [n = 369/37/339] Waist circumference (cm) [n = 258/31/227] HbA1c (%) [n = 459/53/443] HbA1c (mmol/mol) HbA1c <5.7 (%) [n = 279/2/23] HbA1c 5.7 to <6.5 (%) [n = 163/11/170] HbA1c 6.5 (%) [n = 17/40/250] Peripheral arterial disease (%) [n = 621/94/722] Values are mean ± SD or percentages. P < 0.05 no diabetes vs type 1 diabetes. P < 0.05 no diabetes vs type 2 diabetes. P < 0.05 type 1 diabetes vs type 2 diabetes.
# § †
No diabetes
Type 1 diabetes
Type 2 diabetes
781 36.9 67.7 ± 11.9 27.8 ± 4.6 77.3 ± 15.6 166 ± 9 98 ± 13 5.63 ± 0.51 38.1 ± 5.6 60.8 35.5 3.7 7.4
126 46.8# 59.5 ± 15.4# 27.5 ± 5.1 79.2 ± 16.2 170 ± 10# 96 ± 13 7.52 ± 1.34# 58.7 ± 14.7# 3.8# 20.7# 75.5# 10.6
943 50.6§ 70.0 ± 9.6§,† 29.4 ± 5.2§ 82.6 ± 16.7§ 167 ± 10 104 ± 11§,† 6.72 ± 0.94§,† 50.0 ± 10.3§,† 5.2§ 38.4† 56.4§,† 12.3§
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Table 2 – Percentages of abnormal sensory tests, distal sensory polyneuropathy (DSPN), and symptoms in the feet. No diabetes Reduced thermal perception (%) [n = 776/124/929] Reduced vibration perception (%) [n = 777/125/939] Reduced pressure perception (%) [n = 775/123/936] Possible (mild) DSPN (%) [n = 769/122/923] Probable (moderate) DSPN (%) [n = 769/122/923] Definite (severe) DSPN (%) [n = 769/122/923] Total DSPN (%) [n = 769/122/923] Pain (%) [n = 530/80/595] Burning (%) [n = 535/80/606] Paresthesias (%) [n = 537/80/605] Numbness (%) [n = 532/79/605] Symptoms continuous (%) [n = 531/80/598] Symptoms at night (%) [n = 531/80/596] Symptoms at rest (%) [n = 533/80/598] Pain during walking only (%) [n = 530/80/595]
Type 1 diabetes
Type 2 diabetes §
All
21.5
21.8
28.1
24.9
34.0
24.8
37.2†
35.0
16.8
13.0
20.2
18.3
29.5
33.6
31.7
30.9
13.3
6.6#
16.8§,†
14.6
5.5 48.2 59.6 52.1 68.5 52.8 13.9
4.1 44.3 45.0# 41.3 56.3# 44.3 11.3
6.7 55.3§,† 56.3 51.3 67.6 59.5§,† 15.2
6.0 51.5 57.0 51.0 67.3 55.6 14.4
24.5
13.8#
27.9†
25.4
30.8
27.5
27.6
29.0
15.7
16.3
14.5
15.1
Values are mean ± SD or percentages. P < 0.05 no diabetes vs type 1 diabetes. P < 0.05 no diabetes vs type 2 diabetes P < 0.05 type 1 diabetes vs type 2 diabetes.
# § †
had diabetes. PAD was more frequent in the group with type 2 diabetes than in ND subjects (P < 0.05). The percentages of abnormal sensory tests, DSPN, and symptoms in the feet are given in Table 2. Thermal perception was more frequently abnormal in type 2 diabetes subjects than in the ND group (P < 0.05). VPT was more frequently abnormal in participants with type 2 diabetes compared to those with type 1 diabetes (P < 0.05). Probable DSPN was more frequent in type 2 diabetes individuals than in the groups with type 1 diabetes and ND and was also more frequent in the latter than in type 1 diabetes subjects (P < 0.05). Pain and paresthesias were more frequent in ND subjects than in those with type 1 diabetes (P < 0.05). Numbness was more prevalent in the group with type 2 diabetes compared to the other two groups (P < 0.05). Symptoms at night were less common in
type 1 diabetes subjects than in the other two groups (P < 0.0 5). No other differences between the groups were noted. The percentages of painful, painless, asymptomatic, and atypical DSPN in subjects with DSPN are presented in Table 3. Painful DSPN comprised 62.1% of the participants with DSPN, while painless and atypical DSPN accounted for 24.8 and 13.1%, respectively. No significant differences between the groups were noted. With respect to the severity of the neuropathy, possible (mild) DSPN was less frequent in participants with painful DSPN compared to those with painless DSPN (59.4 vs 73.7%; P = 0.003), whereas definite (severe) DSPN was more frequent in the group with painful compared to painless DSPN (12.3 vs 3.6%; P < 0.003). No difference between the groups was noted for probable (moderate) DSPN (28.4 vs 22.6%; P = 0.211).
Table 3 – Percentages of painful, painless, asymptomatic, and atypical distal sensory polyneuropathy (DSPN) in subjects with DSPN.
Painful DSPN [n = 140/17/184] with pain or burning with pain and burning Painless DSPN [n = 52/9/75] with paresthesias or numbness with paresthesias and numbness asymptomatic DSPN Atypical DSPN [n = 28/5/39]
No diabetes [n = 220] (%)
Type 1 diabetes [n = 31] (%)
Type 2 diabetes [n = 298] (%)
All [n = 549] (%)
63.6 27.7 35.9 23.7 10.5 7.7 5.5 12.7
54.8 25.8 29.0 29.1 9.7 9.7 9.7 16.1
61.7 26.5 35.2 25.2 9.1 8.4 7.7 13.1
62.1 27.0 35.2 24.8 9.7 8.2 6.9 13.1
diabetes research and clinical practice
The question ”Have you ever been diagnosed with neuropathy?” was answered by 218 subjects with DSPN in the ND group, 30 of those with type 1 diabetes, and 293 participants with type 2 diabetes. Table 4 shows the percentages of previously diagnosed and undiagnosed neuropathy in total as well as separately for the painful and painless entities, excluding subjects with atypical DSPN, in subjects with DSPN are given for this subset of 541 participants. The ND group showed the highest rate of undiagnosed DSPN (75.2%), followed by the groups with type 2 diabetes (69.9%) and type 1 diabetes (53.3%). Overall, more than two thirds of the participants had previously undiagnosed DSPN. The percentage of undiagnosed DSPN was lower in type 1 diabetes subjects compared to the other two groups (P < 0.05). The prevalence of undiagnosed painful DSPN was higher in ND subjects than in those with type 2 diabetes (P < 0.05). The prevalence of undiagnosed painless DSPN was higher in ND participants than in those with type 1 diabetes (P < 0.05). The highest percentages of undiagnosed DSPN were observed for the painless entity in type 2 diabetes and ND subjects (each >80%). The question ”Are you currently being treated by a physician because of neuropathy?” was answered by 387 subjects in the ND group, 5.9% of whom answered ‘‘yes”, 61 individuals with type 1 diabetes, 14.8% of whom answered ‘‘yes”, and 483 individuals with type 2 diabetes, 16.6% of whom answered ‘‘yes”. The correlation analyses of painful and painless DSPN with sex, age, BMI, and PAD are given in Table 5. Painless DSPN correlated with male sex in type 2 diabetes and ND subjects (P < 0.05). Both painful and painless DSPN correlated positively with age in the ND group (P < 0.05). Painful DSPN correlated positively with BMI, whereas painless DSPN correlated inversely with BMI in the group with type 2 diabetes (P < 0.05). Painful DSPN correlated with PAD in type 2 diabetes subjects, while painless DSPN correlated with PAD in type 1 diabetes and ND participants (P < 0.05). No other correlations were found. In a multiple logistic regression analyses, with painful/painless DSPN as a dependent variable and sex, age, BMI, and PAD as covariates, painful DSPN was associated with age (OR [95% CI]: 1.028 [1.003–1.053]; P = 0.029) and PAD with (12.49 [3.53–44.11]; P < 0.0001) in the ND group. In the type 2 diabetes group, painful DSPN was associated with higher BMI (1.056 [1.001–1.115]; P = 0.046) and PAD (4.54 [1.71–12.07]; P = 0.002), while painless DSPN was associated with lower BMI (0.854 [0.766–0.953]; P = 0.005) and PAD (4.14 [1.14–15.03]; P = 0.031). ND participants with DSPN who had HbA1c levels in the diabetes range 6.5% showed higher mean HbA1c levels than the corresponding group without DSPN (8.3 ± 0.4 vs 7.1 ± 0.1%; P = 0.003). Likewise, DSPN correlated with HbA1c in the ND group showing HbA1c levels 6.5% (r = 0.61, P = 0.009).
4.
Discussion
This nationwide educational initiative ‘‘Diabetes! Do you listen to your feet?‘‘ conducted in Germany unveiled that (1). The rates of previously undiagnosed painful DSPN were 57% in type 2 diabetes subjects, lower (47%) in those with type 1 diabetes, and highest (70%) in people without history of dia-
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betes, while the corresponding percentages for painless DSPN were higher by 25, 9 and 15%; (2). The risk factors for the painful and painless DSPN entities may differ, with the most intriguing finding of a dichotomy in the association of higher/lower BMI with painful/painless DSPN in type 2 diabetes subjects; (3) Among participants without history of diabetes, 36% and 4% showed HbA1c levels within the range of prediabetes and diabetes, respectively; (4.) Participants with DSPN without history of diabetes but with HbA1c levels in the diabetes range 6.5% showed a higher mean HbA1c than the corresponding group without DSPN. Thus, the surprisingly high rate of newly detected cases with painful DSPN may indicate undertreatment of neuropathic pain, and unrecognized diabetes could be an important cause of neuropathy. Since people with and without previously known diabetes are insufficiently informed about their neuropathy, even if the latter presents with pain, patient education about the implications of neuropathic symptoms and neuropathy should be improved. The differential associations of various risk factors and PAD, albeit assessed only by palpation of foot pulses, with painful and painless DSPN deserve comment. In participants with type 2 diabetes, painful DSPN was positively associated with a higher BMI, whereas painless DSPN was associated with a lower BMI, and both entities were associated with prevalent PAD. In contrast, in the group without history of diabetes, painful DSPN was associated with a higher age and PAD. However, these results should be interpreted with caution, since it was not feasible in the present setting to confirm the diagnosis of PAD by duplex ultrasonography. We confirm our previous studies reporting associations of painful DSPN with weight and waist circumference in elderly subjects with diabetes from the general population [21,22]. A novel finding is the correlation between painless DSPN and lower BMI, the reasons for which remain unclear, but it is conceivable that the relationship between DSPN and obesity is specific for the painful entity. Another novel finding is the correlation of painless DSPN with male sex in both type 2 diabetes and ND subjects. Notably, an association between painful DSPN and female sex was recently reported [23]. Moreover, we showed that painful DSPN was more severe than painless DSPN, since mild DSPN was more frequent in participants with painless DSPN, whereas severe DSPN was more frequent in those with painful DSPN. This finding is in line with a recent study suggesting that the severity of neuropathic pain due to DSPN is associated with the severity of neuropathy, i.e. sensory deficits (signs) [23]. Altogether, these findings suggest that distinct risk factors and neuropathy severity may be important determinants to differentiate between the painful and painless DSPN phenotype and could be helpful in addressing the conundrum of why some people develop the insensate entity of DSPN whilst others experience distressing neuropathic pain [3]. The vast majority of patients with diabetes are unlikely to have foot examinations in their primary medical care [10]. Our results with a rate of 70% of DSPN being previously undiagnosed in type 2 diabetic subjects are in line with these observations. In a German population based survey, 77% of diabetic subjects with polyneuropathy were unaware of
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Table 4 – Prevalence of previously diagnosed and undiagnosed neuropathy in subjects with distal sensory polyneuropathy (DSPN) in subjects who completed the questionnaire. No diabetes
Type 1 diabetes
Type 2 diabetes
All
DSPN total Diagnosed Undiagnosed
24.8 75.2
46.7 53.3#
33.1 69.9§
30.5 69.5
Painful DSPN* Diagnosed Undiagnosed
30.9 69.5
53.3 46.7
43.0 57.0§
38.5 61.5
Painless DSPN* Diagnosed Undiagnosed
15.7 84.3
44.4 55.6#
18.1 81.9
18.9 81.1
*
Excluding subjects with symptoms during walking only. P < 0.05 no diabetes vs type 1 diabetes. P < 0.05 no diabetes vs type 2 diabetes
# §
having the disorder, defined as answering ‘‘no” to the question ‘‘Has a physician ever told you that you are suffering from nerve damage, neuropathy, polyneuropathy, or diabetic foot?” Approximately one quarter of the subjects with known diabetes had never undergone a foot examination. Even among individuals with known diabetes who reported to have had their feet examined by a physician, 72% of those with polyneuropathy emerged unaware of having polyneuropathy [13]. Among diabetes patients from rural Arkansas who presented with neuropathic symptoms and attended a diabetes education program, 79% had not been diagnosed with DSPN [14]. Among participants from the Australian communitybased Fremantle Diabetes Study Phase II who had diabetes and considered their feet to be normal, 67.9% had DSPN, suggesting that self-assessment of diabetes-related foot problems by patients is unreliable [15]. Thus, underdiagnosis and unawareness of diabetic polyneuropathy could have an adverse impact on the development of diabetic foot ulcers and even amputations. Our study extends the current knowledge by demonstrating that although the percentages of participants with undiagnosed DSPN were highest across the
groups for the painless entity, the prevalence of undiagnosed painful DSPN was still considerable despite the fact that pain per se motivates patients to seek health care. In patients with diabetes, the reasons for this deficiency may include inadequate attention to diabetic foot prevention practice and insufficient adherence to clinical guidelines. It has been suggested that self-perceived foot health should be assessed in conjunction with foot examination findings and that intensive education and monitoring may be necessary in those who consider their feet to be normal but who have precursors of serious foot pathology [15]. Indeed, a simple, low-cost educational intervention over 6 months resulted in an increase in the performance of proper foot examination from 14 to 62% [10]. In patients without diabetes, similarly structured programs are totally missing. At the primary health care level, professional sensitivity towards neuromuscular disorders is generally low, and many patients with neuropathic foot problems commonly turn to orthopedic surgeons rather than to adequate neurological care. The present study also shows that among participants without history of diabetes, 35.5% and 3.7% had HbA1c levels
Table 5 – Correlation analyses of painful and painless DSPN with demographic variables and peripheral arterial disease. No diabetes r Sex Painful DSPN* Painless DSPN§
0.062 0.125
Type 2 diabetes
r
P
0.215 0.030
0.077 0.040
0.582 0.801
r
P 0.066 0.169
0.172 0.003
Age Painful DSPN* Painless DSPN§
0.191 0.178
0.0001 0.002
0.233 0.247
0.094 0.115
0.052 0.027
0.283 0.645
BMI Painful DSPN* Painless DSPN§
0.064 0.022
0.288 0.751
0.063 0.000
0.759 1.000
0.158 0.223
0.015 0.004
0.002 <0.0001
0.120 0.480
0.396 0.001
0.224 0.053
<0.0001 0.364
Peripheral arterial disease 0.157 Painful DSPN* Painless DSPN§ 0.340 *
§
Type 1 diabetes P
Excluding subjects with symptoms during walking only or with painless DSPN. Excluding subjects with symptoms during walking only or with painful DSPN.
diabetes research and clinical practice
within the range of prediabetes and diabetes, respectively. In high-income countries, about one in three diabetes cases is not diagnosed [24] In a recent population-based German survey, the prevalence of diagnosed diabetes and undiagnosed diabetes was 7.2 and 2.0%, respectively, while the prevalence of undiagnosed prediabetes was 21%. Thus, the proportion of persons unaware of their diabetes was 22% [25]. The higher percentages of persons with undiagnosed diabetes and prediabetes found in the present study could be due to a possible selection bias towards the more motivated individuals seeking to have their feet examined. Moreover, there is evidence to suggest that people with undiagnosed diabetes and those with prediabetes strongly underestimate their probability of having or developing diabetes [26]. More than 70% of persons with undiagnosed diabetes/prediabetes believed that their probability of having undetected diabetes was low/very low or believed that they were not at risk of developing diabetes, respectively. Thus, early detection of diabetes and prediabetes seems favorable for patients, but may be delayed by patients being overly optimistic about their own health [26]. Therefore, it has been suggested that against the background of the increasing risk of diabetes and the burden of the disease, a combination of strategies to avoid misperceptions of diabetes risk may be considered [26]. The present study has several limitations. First, since this survey was primarily an educational campaign performed in public settings, definitive diagnostic studies to confirm neuropathy and PAD could not be conducted and the causes of DSPN other than diabetes such as vitamin B12 deficiency, alcohol abuse, monoclonal gammopathy, hypothyroidism, inflammation, drugs as well as renal, hepatic, infectious, autoimmune, or neoplastic disorders could not be verified. Second, selection bias cannot be avoided due to the study setting, and recall bias is also possible. Third, several demographic and disease variables were assessed in subsets only. In conclusion, around a half of subjects with and without diabetes participating in an educational initiative presented with DSPN, 62% of whom had the painful entity which correlated with higher BMI in participants with type 2 diabetes. Since DSPN was previously undiagnosed in 70% of all participants and almost 40% of the participants without previous history of diabetes actually had an increased risk of diabetes, effective strategies to reveal both undetected diabetes and neuropathy should be implemented. Future educational programs for people with diabetes should address the gaps arising from underestimating DSPN in primary care practice and inadequate adherence to the clinical guidelines for diabetes care aimed at prevention of diabetic foot and amputations.
Acknowledgments The National Educational Initiative was financed by Wo¨rwag Pharma, Bo¨blingen, Germany. This study was supported in part by the Ministry of Science and Research of the State of North RhineWestphalia (MIWF NRW), the German Federal Ministry of Health (BMG), and the German Diabetes Foundation.
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The authors thank Michael Martell, Helen Fo¨rster, and Fanny v. Hesberg (newswerk, Stuttgart, Germany) for organizing and conducting this study. DZ wrote the manuscript. DZ, AS, RLa, RL, KhR, KR, and OS researched data, contributed to discussion and reviewed and edited the manuscript. DZ is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Conflict of interest DZ, RL, KhR, KR, and OS are advisory board members of the National Education Initiative and received honoraria for speaking activities from Wo¨rwag Pharma. RLa received a grant for prevention activities of the German Diabetes Foundation.
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