Deep phenotyping neuropathy: An underestimated complication in patients with pre-diabetes and type 2 diabetes associated with albuminuria
Introduction
Diabetic polyneuropathy (DPNP) is the most common neurological complication, with a prevalence ranging from 8 to 30% in patients with diabetes mellitus [1], [2]. Recent trials described a similar prevalence of neuropathic deficits in patients with pre-diabetes [3], [4], thus emphasizing the preclinical early onset of the neuropathic pathology. DPNP leads to an increased risk for peripheral artery occlusive disease, foot ulcers, and amputations [5], [6]. The pathomechanisms underlying DPNP are only partly understood, with a gap between symptoms, large, medium, and small fibers and between loss and gain of function in diagnosis [7].
Nerve conduction studies (NCS) and questionnaires like the neuropathy symptom score (NSS) and the neuropathy deficit score (NDS) belong to the routine clinical diagnostics for diabetic neuropathy [8]. Obviously, questionnaires do not supply with quantifiable data on sensory abnormalities and are not able to differentiate between symptoms of increased sensitivity (‘gain’) or reduced somatosensory perception (‘loss’) [8]. NCS, though being able to detect deficits of large myelinated sensory-motor nerves, do not provide with information about small fiber function [9], [10], [11], [12]. A recent cross-sectional study, contrasting neurophysiological, psychophysical and blood flow measures to characterize nerve fiber function of patients with diabetes revealed sensitivity values between 59 and 73% for NCS, 61–89% for the assessment of thermal thresholds, and 76% for evaluation of vibration and monofilament thresholds [11]. These results emphasize our current diagnostic gap to identify sensory abnormalities in diabetic patients with high accuracy and sensitivity. Therefore, the German Research Network on Neuropathic Pain (DFNS), has developed a highly standardized quantitative sensory battery in order to assess both small and large fiber function [13], [14], [15]. A large data pool of somatosensory profiles was collected from more than 180 healthy controls of both sexes in order to obtain normative values from well-defined territories [13]. Based on this data set, ‘gain’ or ‘loss’ of somatosensory function can be evaluated for each individual patient by comparing the individual data with the normative data set.
The aims of this study were to assess whether questionnaires and comprehensive QST-battery could be used in order to characterize and compare somatosensory profiles of patients with pre-diabetes and type 2 diabetes. The hypothesis was that neuropathic deficits occur much more frequently than previously shown, because the clinical routine tests do not capture the variety of neuropathic dysfunction in patients with metabolic disorders. Furthermore, due to the small effects of glucose lowering therapy on neuropathy [16], a lack of association between the results of complete neurological testing and HbA1c was hypothesized.
Section snippets
Methods
All patients gave written informed consent. The study was approved by the local ethics committee of the Heidelberg University (No. S146-2015) and was performed in accordance with the Declaration of Helsinki 2013. Main inclusion criteria were patients diagnosed with impaired glucose tolerance (pre-diabetes) and patients diagnosed with type 2 diabetes mellitus with an age-range between 18 and 75 years. Patients were screened according to the following diagnostic criteria: An oral glucose
Results
One hundred and sixty participants were screened (120 patients with type 2 diabetes and 40 participants without known diabetes mellitus). Twelve patients with type 2 diabetes were excluded due to history of neuropathy caused by medication or other diseases. Twelve patients without diabetes were excluded due to a normal glucose tolerance test. Two patients (7%) with pre-diabetes and 72 (67%) patients with type 2 diabetes reported previous history for neuropathic symptoms. Detailed information on
Discussion
This study shows that DPNP prevalence is much higher when based on complete QST than described previously; the method is more sensitive than short-QST or NDS or a combination of both for detection of neuropathic deficits in patients with pre-diabetes and type 2 diabetes. Complete QST (or long-QST) alone detected 60% (n = 17) more patients with pre-diabetes and 32% (n = 35) more patients with type 2 diabetes and neuropathic deficits than commonly used NDS. Daily clinical routine tests (NDS and
Acknowledgement
This study was initiated and carried out by the support of the Deutsche Forschungsgemeinschaft (DFG) within Collaborative Research Center 1158 (CRC 1158; subprojects A03 and S01). Patient recruitment was supported by cooperation with the NeuroCentrum Odenwald, Darmstadt, Germany.
Authors contributions
S. Kopf takes full responsibility for the work, including study design, access data, and the decision to submit and publish the manuscript.
S. Kopf organized the study group, contributed to design the study, managed and analysed data and wrote the manuscript, J. B. Groener has investigated patients, collected data and was involved in completion of the manuscript, Z. Kender has investigated patients and collected data, T. Fleming was involved in data analyses and discussion, S. Bischoff was
Conflicts of interests
No conflicts of interests were reported by any author.
References (43)
- et al.
Epidemiology of polyneuropathy in diabetes and prediabetes
Handb Clin Neurol
(2014) - et al.
Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values
Pain
(2006) - et al.
Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from randomised controlled trials
Lancet Diabetes Endocrinol
(2017) - et al.
Quantitative sensory testing: a comprehensive protocol for clinical trials
Eur J Pain
(2006) - et al.
Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes
Pain
(2010) - et al.
Associations of serum anti-ganglioside antibodies and inflammatory markers in diabetic peripheral neuropathy
Diabetes Res Clin Pract
(2016) - et al.
Reference data for quantitative sensory testing (QST): refined stratification for age and a novel method for statistical comparison of group data
Pain
(2010) - et al.
Pain in chemotherapy-induced neuropathy–more than neuropathic?
Pain
(2013) - et al.
Recommendations for the clinical use of somatosensory-evoked potentials
Clin Neurophysiol
(2008) - et al.
Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments
Diabetes Care
(2010)
Metabolic syndrome components are associated with symptomatic polyneuropathy independent of glycemic status
Diabetes Care
Prevalence of neuropathy in patients with impaired glucose tolerance using various electrophysiological tests
Neurol India
Diabetic peripheral neuropathy and depressive symptoms: the association revisited
Diabetes Care
The diabetic foot in 2015: an overview
Diabetes Metab Res Rev.
The quest for more research on painful diabetic neuropathy
Neuroscience
A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population
Diabetologia
Invited review: limitations in predicting pathologic abnormality of nerves from the EMG examination
Muscle Nerve
Neuropathic pain: is quantitative sensory testing helpful?
Curr Diab Rep
Diabetic neuropathy: a cross-sectional study of the relationships among tests of neurophysiology
Diabetes Care
Significance of quantitative sensory testing in the diagnosis of diabetic peripheral neuropathy
J Clin Neurophysiol
Quantitative sensory testing of neuropathic pain patients: potential mechanistic and therapeutic implications
Curr Pain Headache Rep
Cited by (33)
Neuro-immune-metabolism: The tripod system of homeostasis
2021, Immunology LettersCitation Excerpt :A major complication of diabetes is also peripheral neuropathy, affecting nearly 50% of the diabetic patients [209]. In diabetic peripheral neuropathy (DPN), patients suffer from somatosensory dysfunction, resulting in heightened pain sensitivity in early stages followed by loss of pain sensation later due to degeneration of nerves in the extremities [210]. A chronic neurogenic inflammation is detected in the peripheral nerves during diabetes, shown by activated NF-kB signaling pathways [99].
Phenotypic similarity for rare disease: Ciliopathy diagnoses and subtyping
2019, Journal of Biomedical InformaticsCitation Excerpt :The challenges such as incompleteness, inaccuracy and complexity have been much discussed [11]. Many studies of deep phenotyping focused on a set of phenotypic features defined based on expert knowledge of specific diseases or medical issues [13,17,19], therefore, data were collected for a specific scientific and clinical research purpose to ensure the precision and comprehensiveness of phenotyping. Recently, Zhang et al. presented their method for mapping LOINC-encoded laboratory test results transmitted in Fast Healthcare Interoperability Resource (FHIR) standards to Human Phenotype Ontology (HPO) terms [32], which shared the same idea as we have for ciliopathy, i.e. using thresholds on quantitative lab test to transform them into phenotypes.