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Insights into the Pathogenesis of Painful and Painless Diabetic Neuropathy
MD Thesis
July 2013
Rajiv A. Gandhi
Diabetes Research Unit
Royal Hallamshire Hospital
&
Academic Unit of Radiology
Faculty of Medicine, Dentistry & Health
University of Sheffield
There is a crack in everything That's how the light gets in.
Leonard Cohen
Synopsis
A complete understanding of the pathogenesis of diabetic neuropathy continues to be elusive and as a result, progress in developing effective therapies has been disappointing.
In particular, there is only limited understanding of why some patients suffer severe chronic pain, whilst others have painless symptoms. Assessment of the peripheral nerves frequently shows no differences between painful and painless diabetic peripheral neuropathy (DPN). There is growing evidence that the nerve damage in DPN is more generalized, involving the entire nervous system including the central nervous system (CNS). The advent of new radiological techniques, such as magnetic resonance spectroscopy (MRS) provides us with non-invasive modalities to study pathophysiological processes in greater detail.
In addition, although a clear link between DPN and cardiac autonomic neuropathy (CAN) is recognised, the relationship of autonomic neuropathy with sub-types of DPN is less clear. The development of novel and sensitive measures of CAN, such as spectral analysis of heart rate variability (HRV), may allow the detection of subclinical abnormalities not detected by conventional autonomic function tests (AFT).
The principal aim of this thesis was to better understand the nature of the relationship between painful and painless DPN with other parts of the nervous system, namely the CNS and the autonomic nervous system. In the first study the central processing of sensation in people with diabetes was assessed to determine whether central mechanisms have an important role in the perception of pain. In the second study, short-term HRV analysis was used to help define the nature of the relationship between CAN and painful and painless DPN more clearly. A secondary aim was to develop and validate a model incorporating HRV parameters as a sensitive measure of autonomic dysfunction.
In the first study, 110 subjects with type 1 diabetes (20 no DPN, 30 subclinical DPN, 30 painful DPN and 30 painless DPN) and 20 healthy volunteers (HV) underwent detailed clinical and neurophysiological assessments (Dyck's NIS(LL)+7 staging criteria). They all underwent proton magnetic resonance spectroscopy of the left thalamic nucleus and somatosensory cortex to measure established markers of neuronal function using long echo time (LET) and neuronal integrity using short echo time (SET) spectroscopic sequences.
The results demonstrated significant differences between painful and painless DPN. In the thalamus, at LET, subjects with painless DPN had significantly lower N-acetylaspartate (NAA) compared to other groups (ANOVA p<0.001). No differences were seen at SET. In contrast, in the somatosensory cortex, no inter-group differences were seen at LET, but at SET, the painless DPN group had lower NAA, compared to HV and subjects with diabetes but no DPN, whilst subjects with painful DPN had intermediate levels (ANOVA p<0.001). Various other differences were also seen between painful and painless DPN in other cerebral neurochemicals (particularly myo-inositol and glutamate), despite no differences between the groups in detailed peripheral nerve assessments. These results suggest that astrocyte dysfunction within a hyperglutaminergic state within the thalamus may be a key factor in the development of painful DPN.
In a second study, a subset of these patients (20 HV, 20 no DPN, 20 painful DPN and 20 painless DPN) underwent short-term HRV analysis, to assess sympathovagal modulation of the heart rate. Various frequency domain and time domain parameters were assessed. The results showed that despite no differences in conventional AFT, subjects with painful DPN had greater autonomic abnormalities when assessed using HRV analysis, suggesting that it is a more sensitive tool to detect autonomic dysfunction. The greater autonomic dysfunction seen in painful DPN may reflect more predominant small fibre involvement and adds to the growing evidence of its role in the pathophysiology of painful DPN.
In the third study, we demonstrated that this method of HRV analysis can be used to develop a sensitive tool to detect early autonomic dysfunction. Using discriminant function analysis, a model was developed which incorporated 8 HRV parameters as well as basic demographic data. It demonstrated a high degree of sensitivity and specificity.
From the above studies it can be inferred that changes in neuronal physiology and function may be important in the perception of pain in DPN. They have demonstrated that DPN is a disease that affects the entire nervous system, including the CNS which should trigger a critical rethinking of the disorder.
Acknowledgements
I would like to thank my two supervisors Professor Solomon Tesfaye and Professor Iain Wilkinson for their mentorship, patience and valuable advice over the years. Without their wisdom and guidance, this body of research would not have been possible.
Many of the original ideas and pilot work were the work of Dr. Dinesh Selvarajah. He was also instrumental in training me in many of the experimental techniques.
I would also like to acknowledge the contribution of Dr. Celia Emery, who as research coordinator ensured smooth running of the project.
I would also like to thank the major contribution of Dr. J.L. Marques, who came up with the original idea of using HRV analysis to assess autonomic neuropathy and developed both the hardware and software for the system. His advice on statistical analysis was also invaluable.
Much of this work would not have been possible without the hard work and skill of the magnetic resonance radiographers at the Academic Unit of Radiology, Royal Hallamshire Hospital, University of Sheffield.
I would like to thank Diabetes UK, who funded the magnetic resonance study.
None of these studies would have been possible without the help of the participants, who selflessly gave up their time to take part in the studies.
Finally, I would like to thank Ruth, not just for her patience and support, but also for proof reading my work and her uncompromising demand for linguistic clarity and grammatical correctness.
Authors Declaration
The studies that form the basis of this thesis are partly the result of collaborative work. My contributions were the following:
The primary role in the design of all the studies and ethics applications.
Recruitment and all clinical and neurophysiological assessment of all subjects.
Organisation of the MR imaging and supervision of MR radiographers, including placement of the voxels in the regions of interest. The MR imaging protocol was designed by Prof. I. D. Wilkinson.
Post-image processing and quantification of spectroscopic data was carried out by a blinded assessor (Prof. I. D. Wilkinson).
All autonomic function tests in the autonomic studies. The HRV analysis was carried out using an automated method developed by Dr. J.L. Marques.
Collation of all data and subsequent statistical analysis. The discriminant function analysis used in the development of the diagnostic model was carried out by Dr. J.L. Marques.
TABLE OF CONTENTS
TOC \o "1-3" \h \z \u HYPERLINK \l "_Toc370132680" Synopsis PAGEREF _Toc370132680 \h II
HYPERLINK \l "_Toc370132681" Acknowledgements PAGEREF _Toc370132681 \h V
HYPERLINK \l "_Toc370132682" Authors Declaration PAGEREF _Toc370132682 \h VI
HYPERLINK \l "_Toc370132683" TABLE OF CONTENTS PAGEREF _Toc370132683 \h VII
HYPERLINK \l "_Toc370132684" List of Tables PAGEREF _Toc370132684 \h X
HYPERLINK \l "_Toc370132685" List of Figures PAGEREF _Toc370132685 \h XI
HYPERLINK \l "_Toc370132686" List of Figures PAGEREF _Toc370132686 \h XI
HYPERLINK \l "_Toc370132687" Abbreviations PAGEREF _Toc370132687 \h XII
HYPERLINK \l "_Toc370132688" 1 Introduction PAGEREF _Toc370132688 \h 1
HYPERLINK \l "_Toc370132689" 1.1 Diabetes Mellitus PAGEREF _Toc370132689 \h 1
HYPERLINK \l "_Toc370132690" 1.1.1 Diagnosis and Classification PAGEREF _Toc370132690 \h 1
HYPERLINK \l "_Toc370132691" 1.1.2 Long Term Complications of Diabetes PAGEREF _Toc370132691 \h 2
HYPERLINK \l "_Toc370132692" 1.2 Diabetic Neuropathy PAGEREF _Toc370132692 \h 8
HYPERLINK \l "_Toc370132693" 1.2.1 Classification PAGEREF _Toc370132693 \h 8
HYPERLINK \l "_Toc370132694" 1.2.2 Clinical Features PAGEREF _Toc370132694 \h 15
HYPERLINK \l "_Toc370132695" 1.2.3 Epidemiology PAGEREF _Toc370132695 \h 16
HYPERLINK \l "_Toc370132696" 1.2.4 Pathogenesis PAGEREF _Toc370132696 \h 18
HYPERLINK \l "_Toc370132697" 1.2.5 Management PAGEREF _Toc370132697 \h 19
HYPERLINK \l "_Toc370132698" 2 Assessment of Neuropathy PAGEREF _Toc370132698 \h 25
HYPERLINK \l "_Toc370132699" 2.1 Clinical Assessment of Neuropathy PAGEREF _Toc370132699 \h 25
HYPERLINK \l "_Toc370132700" 2.2 Quantifying diabetic neuropathy in clinical trials PAGEREF _Toc370132700 \h 26
HYPERLINK \l "_Toc370132701" 2.3 Assessing neuropathic pain severity PAGEREF _Toc370132701 \h 31
HYPERLINK \l "_Toc370132702" 3 Magnetic Resonance Spectroscopy in diabetic neuropathy PAGEREF _Toc370132702 \h 32
HYPERLINK \l "_Toc370132703" 3.1 Introduction PAGEREF _Toc370132703 \h 32
HYPERLINK \l "_Toc370132704" 3.1.1 Central Nervous System Involvement in Diabetic Neuropathy PAGEREF _Toc370132704 \h 32
HYPERLINK \l "_Toc370132705" 3.1.2 Magnetic Resonance Spectroscopy PAGEREF _Toc370132705 \h 34
HYPERLINK \l "_Toc370132706" 3.2 Hypotheses PAGEREF _Toc370132706 \h 39
HYPERLINK \l "_Toc370132707" 3.3 Aims PAGEREF _Toc370132707 \h 40
HYPERLINK \l "_Toc370132708" 3.4 Subjects and Methods PAGEREF _Toc370132708 \h 40
HYPERLINK \l "_Toc370132709" 3.4.1 Subjects PAGEREF _Toc370132709 \h 40
HYPERLINK \l "_Toc370132710" 3.4.2 MR Protocol PAGEREF _Toc370132710 \h 43
HYPERLINK \l "_Toc370132711" 3.4.3 Data analysis PAGEREF _Toc370132711 \h 45
HYPERLINK \l "_Toc370132712" 3.5 Results PAGEREF _Toc370132712 \h 46
HYPERLINK \l "_Toc370132713" 3.5.1 Baseline Characteristics PAGEREF _Toc370132713 \h 46
HYPERLINK \l "_Toc370132714" 3.5.2 Reproducibility PAGEREF _Toc370132714 \h 47
HYPERLINK \l "_Toc370132715" 3.5.3 Spectroscopic findings in the Thalamus PAGEREF _Toc370132715 \h 47
HYPERLINK \l "_Toc370132716" 3.5.4 Spectroscopic findings in the Somatosensory Cortex PAGEREF _Toc370132716 \h 49
HYPERLINK \l "_Toc370132717" 3.6 Discussion PAGEREF _Toc370132717 \h 52
HYPERLINK \l "_Toc370132718" 4 Autonomic Dysfunction in Painful and Painless Diabetic Neuropathy PAGEREF _Toc370132718 \h 56
HYPERLINK \l "_Toc370132719" 4.1 Introduction PAGEREF _Toc370132719 \h 56
HYPERLINK \l "_Toc370132720" 4.2 Hypotheses PAGEREF _Toc370132720 \h 57
HYPERLINK \l "_Toc370132721" 4.3 Aims PAGEREF _Toc370132721 \h 57
HYPERLINK \l "_Toc370132722" 4.4 Subjects and Methods PAGEREF _Toc370132722 \h 57
HYPERLINK \l "_Toc370132723" 4.4.1 Subjects PAGEREF _Toc370132723 \h 57
HYPERLINK \l "_Toc370132724" 4.4.2 Neuropathy Assessment PAGEREF _Toc370132724 \h 58
HYPERLINK \l "_Toc370132725" 4.4.3 Spectral Analysis of Heart Rate Variability PAGEREF _Toc370132725 \h 59
HYPERLINK \l "_Toc370132726" 4.4.4 Statistical Analysis PAGEREF _Toc370132726 \h 62
HYPERLINK \l "_Toc370132727" 4.5 Results PAGEREF _Toc370132727 \h 62
HYPERLINK \l "_Toc370132728" 4.5.1 Baseline Characteristics PAGEREF _Toc370132728 \h 62
HYPERLINK \l "_Toc370132729" 4.5.2 Autonomic Function Test Results PAGEREF _Toc370132729 \h 64
HYPERLINK \l "_Toc370132730" 4.6 Discussion PAGEREF _Toc370132730 \h 70
HYPERLINK \l "_Toc370132731" 5 A Model to Detect Autonomic Dysfunction using Heart Rate Variability Analysis PAGEREF _Toc370132731 \h 75
HYPERLINK \l "_Toc370132732" 5.1 Introduction PAGEREF _Toc370132732 \h 75
HYPERLINK \l "_Toc370132733" 5.2 Aims PAGEREF _Toc370132733 \h 78
HYPERLINK \l "_Toc370132734" 5.3 Subjects and Methods PAGEREF _Toc370132734 \h 79
HYPERLINK \l "_Toc370132735" 5.3.1 Subjects PAGEREF _Toc370132735 \h 79
HYPERLINK \l "_Toc370132736" 5.3.2 Baroreceptor Sensitivity Testing PAGEREF _Toc370132736 \h 79
HYPERLINK \l "_Toc370132737" 5.3.3 Statistical Analysis PAGEREF _Toc370132737 \h 80
HYPERLINK \l "_Toc370132738" 5.3.4 Discriminant Function Analysis PAGEREF _Toc370132738 \h 82
HYPERLINK \l "_Toc370132739" 5.4 Results PAGEREF _Toc370132739 \h 83
HYPERLINK \l "_Toc370132740" 5.4.1 Baseline Characteristics and Group Distribution PAGEREF _Toc370132740 \h 83
HYPERLINK \l "_Toc370132741" 5.4.2 Discriminant Function Model PAGEREF _Toc370132741 \h 84
HYPERLINK \l "_Toc370132742" 5.4.3 Correlation with BRS PAGEREF _Toc370132742 \h 87
HYPERLINK \l "_Toc370132743" 5.5 Discussion PAGEREF _Toc370132743 \h 87
HYPERLINK \l "_Toc370132744" 6 Final Discussion and Future Work PAGEREF _Toc370132744 \h 90
HYPERLINK \l "_Toc370132745" 7 Publications, Abstracts and Prizes PAGEREF _Toc370132745 \h 93
HYPERLINK \l "_Toc370132746" 8 References PAGEREF _Toc370132746 \h 95
List of Tables
TOC \h \z \c "Table" \* MERGEFORMAT HYPERLINK \l "_Toc370133641" Table 1 WHO Criteria for diagnosis of diabetes based on a 75g OGTT PAGEREF _Toc370133641 \h 2
HYPERLINK \l "_Toc370133642" Table 2 Proposed mechanisms for the development of complications in diabetes PAGEREF _Toc370133642 \h 4
HYPERLINK \l "_Toc370133643" Table 3 Classification of Diabetic Neuropathy PAGEREF _Toc370133643 \h 9
HYPERLINK \l "_Toc370133644" Table 4 Features of Autonomic Neuropathy PAGEREF _Toc370133644 \h 14
HYPERLINK \l "_Toc370133645" Table 5 Mechanisms of Neuropathic Pain PAGEREF _Toc370133645 \h 19
HYPERLINK \l "_Toc370133646" Table 6 Dycks Staging of Diabetic Neuropathy PAGEREF _Toc370133646 \h 28
HYPERLINK \l "_Toc370133647" Table 7 Calculating the NIS(LL) + 7 Score PAGEREF _Toc370133647 \h 29
HYPERLINK \l "_Toc370133648" Table 8 Neuropathy Impairment Scale (NIS) PAGEREF _Toc370133648 \h 30
HYPERLINK \l "_Toc370133649" Table 9 Alternative analgesia protocol PAGEREF _Toc370133649 \h 41
HYPERLINK \l "_Toc370133650" Table 10 Baseline Characteristics of all 130 subjects who underwent MRS PAGEREF _Toc370133650 \h 46
HYPERLINK \l "_Toc370133651" Table 11 Spectroscopic measurements in the thalamus PAGEREF _Toc370133651 \h 47
HYPERLINK \l "_Toc370133652" Table 12 Spectroscopic measurements in the sensory cortex PAGEREF _Toc370133652 \h 49
HYPERLINK \l "_Toc370133653" Table 13 Baseline characteristics of 80 subjects who underwent AFT testing. PAGEREF _Toc370133653 \h 63
HYPERLINK \l "_Toc370133654" Table 14 Autonomic function test results using conventional methods and HRV analysis PAGEREF _Toc370133654 \h 65
HYPERLINK \l "_Toc370133655" Table 15 Classification of CAN Type PAGEREF _Toc370133655 \h 79
HYPERLINK \l "_Toc370133656" Table 16 HRV parameters used in discriminant function analysis model PAGEREF _Toc370133656 \h 81
HYPERLINK \l "_Toc370133657" Table 17 Baseline characteristics of the AFT groups PAGEREF _Toc370133657 \h 83
HYPERLINK \l "_Toc370133658" Table 18 Individual HRV measurements in AFT groups PAGEREF _Toc370133658 \h 84
HYPERLINK \l "_Toc370133659" Table 19 Three Group Analysis - No CAN vs. subclinical CAN vs. CAN PAGEREF _Toc370133659 \h 85
HYPERLINK \l "_Toc370133660" Table 20 Two Group Analysis No CAN vs. any CAN PAGEREF _Toc370133660 \h 86
List of Figures
TOC \h \z \c "Figure" HYPERLINK \l "_Toc361652624" Figure 1 Common complications of diabetes PAGEREF _Toc361652624 \h 3
HYPERLINK \l "_Toc361652625" Figure 2 Photomicrograph from a capillary from a nerve biopsy in diabetic neuropathy PAGEREF _Toc361652625 \h 5
HYPERLINK \l "_Toc361652626" Figure 3 Retinal photograph of proliferative diabetic retinopathy PAGEREF _Toc361652626 \h 6
HYPERLINK \l "_Toc361652627" Figure 4 Examples of MRS spectra obtained at a)SET and b)LET PAGEREF _Toc361652627 \h 37
HYPERLINK \l "_Toc361652628" Figure 5 Axial section of the brain with voxel positioned to encompass a) the ventroposterior thalamic subnucleus and b) precentral gyrus PAGEREF _Toc361652628 \h 44
HYPERLINK \l "_Toc361652629" Figure 6 Thalamus spectroscopy results for NAA PAGEREF _Toc361652629 \h 48
HYPERLINK \l "_Toc361652630" Figure 7 Thalamic neurochemical results at SET (NAA, mI, Glx) PAGEREF _Toc361652630 \h 49
HYPERLINK \l "_Toc361652631" Figure 8 Sensory cortex spectroscopy results for NAA PAGEREF _Toc361652631 \h 50
HYPERLINK \l "_Toc361652632" Figure 9 Sensory cortex neurochemical results at SET (NAA, mI, Glx) PAGEREF _Toc361652632 \h 51
HYPERLINK \l "_Toc361652633" Figure 10 Spectral Analysis of HRV PAGEREF _Toc361652633 \h 60
HYPERLINK \l "_Toc361652634" Figure 11 Examples of spectral analysis of HRV analysis PAGEREF _Toc361652634 \h 61
HYPERLINK \l "_Toc361652635" Figure 12 Correlations between NCS and HRV variables PAGEREF _Toc361652635 \h 67
HYPERLINK \l "_Toc361652636" Figure 13 Correlation of Spectral Analysis with traditional CVS risk factors. PAGEREF _Toc361652636 \h 68
HYPERLINK \l "_Toc361652637" Figure 14 Correlation of Spectral Analysis with motor (common peroneal nerve & tibial) and sensory (sural nerve) peripheral nerve function. PAGEREF _Toc361652637 \h 69
HYPERLINK \l "_Toc361652638" Figure 15 Distribution of CAN Groups PAGEREF _Toc361652638 \h 83
HYPERLINK \l "_Toc361652639" Figure 16 ROC Curve for no CAN vs. any CAN PAGEREF _Toc361652639 \h 86
HYPERLINK \l "_Toc361652640" Figure 17 Correlation between discriminant score and BRS PAGEREF _Toc361652640 \h 87
HYPERLINK \l "_Toc361652641" Figure 18 Individual TP measurements for no CAN and any CAN PAGEREF _Toc361652641 \h 88
Abbreviations
ADAAmerican Diabetes AssociationAFTAutonomic Function TestsANCOVAAnalysis of CovarianceANNArtificial Neural NetworkANOVAAnalysis of VarianceBMIBody Mass IndexBRSBaroreceptor SensitivityCANCardiac Autonomic NeuropathyCHESSChemical-shift Selective PulsesChoCholineCMAPCompound Muscle Action PotentialCNSCentral Nervous SystemCrCreatineCSFCerebrospinal FluidDANDiabetic Autonomic NeuropathyDCCTDiabetes Control and Complications TrialDMDiabetes MellitusDPNDiabetic Peripheral NeuropathyECGElectrocardiographic recordingEPIEcho-planar imagingfMRIFunctional Magnetic Resonance ImagingGlxGlutamate/ GlutamineHbA1cGlycosylated Haemoglobin CHFHigh FrequencyHIVHuman Immunodeficiency VirusHRVHeart Rate VariabilityHVHealthy VolunteersIFGImpaired Fasting GlucoseIGTImpaired Glucose ToleranceLETLong Echo TimeLFLow FrequencymIMyo-InositolMNCVMotor Nerve Conduction VelocityMNDLMotor Nerve Distant LatencyMRMagnetic ResonanceMRIMagnetic Resonance ImagingMRSMagnetic Resonance SpectroscopyNAAN-acetyl aspartateNCSNeuropathy Composite ScoreNISNeuropathy Impairment ScoreNIS(LL)Neuropathy Impairment Score of the Lower LimbsOGTTOral Glucose Tolerance TestPRESSPoint Resolved SpectroscopyRMSSDSquare Root of the Mean Squared Differences of Successive NN IntervalsROCReciever Operating CharacteristicROIRegion of InterestSBPSystolic Blood PressureSDPNNStandard Deviation of the NN IntervalSETShort Echo TimeSNAPSensory Nerve Action PotentialSNRISelective Serotonin Noradrenalin Reuptake InhibitorSTEAMStimulated Echo Acquisition ModeSVSSingle-voxel SpectroscopyT1DMType 1 Diabetes MellitusT2DMType 2 Diabetes MellitusTPTotal PowerUAERUrinary albumin excretion ratioUKPDSUnited Kingdom Prospective Diabetes StudyVASVisual Analogue ScaleVLFVery Low FrequencyVPTVibration Perception ThresholdWHOWorld Health Organisation
1 Introduction
1.1 Diabetes Mellitus
Diabetes Mellitus is a complex metabolic disorder that is manifested by chronic hyperglycaemia. It results in disturbances of carbohydrate, fat and protein metabolism that are a consequence of defects in insulin secretion, insulin action, or both.
1.1.1 Diagnosis and Classification
There are two main forms of diabetes: type 1 and type 2, which have different causes and patient populations. Whilst, ultimately, all types of diabetes are due to the failure of beta cells to produce enough insulin to prevent hyperglycaemia, the pathophysiology is quite different. Type 1 diabetes (T1DM) is thought to be predominantly due to autoimmune destruction of beta cells resulting in an absolute insulin deficiency. Type 2 diabetes (T2DM) is characterised by reduced insulin sensitivity (frequently termed insulin resistance) in target tissues. Although in the early stages beta cells are able to produce enough insulin (hyperinsulinaemia) to overcome this resistance and prevent hyperglycaemia, ultimately they cannot meet this demand. This is probably due to a combination of worsening insulin resistance (e.g. due to weight gain) and beta cell failure. In contrast to T1DM therefore, there is a relative insulin deficiency.
There is a large list of other specific types of diabetes such as diabetes caused by gene defects; diabetes secondary to pancreatic disease; diabetes secondary to other endocrine disorders or drugs. Gestational diabetes refers to glucose intolerance or diabetes diagnosed during pregnancy.
The World Health Organisation (WHO) criteria for the diagnosis of diabetes are based on either the fasting plasma glucose or 2 hour plasma glucose after a 75g oral glucose tolerance test (OGTT). Table 1 shows the current diagnostic criteria for diagnosing diabetes as well as impaired fasting glucose (IFG) and impaired glucose tolerance (IGT).
SHAPE \* MERGEFORMAT
Table SEQ Table \* ARABIC 1 WHO Criteria for diagnosis of diabetes based on a 75g OGTT
1.1.2 Long Term Complications of Diabetes
As discussed, diabetes mellitus is a metabolic disorder that is characterised by chronic hyperglycaemia and results in long term damage and failure of variety of different organs in the body. The complications associated with diabetes have traditionally been classified by being divided into microvascular and macrovascular complications and are summarised in Figure 1.
Figure SEQ Figure \* ARABIC 1 Common complications of diabetes
There is now a substantial body of evidence that implicates hyperglycaemia in the development of all of these long-term complications. In addition, the benefit of improved glycaemic control in preventing the development of microvascular, and to a degree macrovascular, complications has been demonstrated in both T1DM, in the Diabetes Control and Complications Trial ADDIN EN.CITE DCCT1993828217DCCTThe effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research GroupN Engl J MedN Engl J Med977-8632914AdolescentAdultBlood Glucose/analysisConfidence IntervalsDiabetes Mellitus, Type 1/blood/complications/ drug therapyDiabetic Nephropathies/prevention & controlDiabetic Neuropathies/prevention & controlDiabetic Retinopathy/ prevention & controlFemaleFollow-Up StudiesHumansInsulin/administration & dosage/adverse effects/ therapeutic useInsulin Infusion SystemsMaleTreatment Outcome1993Sep 308366922(DCCT, 1993) and in T2DM, in the UK Prospective Diabetes Study ADDIN EN.CITE UKPDS1998292917UKPDSIntensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) GroupLancetLancet837-533529131Blood Glucose/ analysisChlorpropamide/therapeutic useDiabetes Mellitus, Type 2/blood/complications/diet therapy/ drug therapyDiabetic Angiopathies/prevention & controlFemaleGlipizide/therapeutic useGlyburide/therapeutic useHemoglobin A, Glycosylated/analysisHumansHypoglycemic Agents/ therapeutic useInsulin/blood/ therapeutic useMaleMiddle AgedProspective StudiesRisk FactorsSulfonylurea Compounds/ therapeutic use1998Sep 129742976(UKPDS, 1998).
Just how chronic hyperglycaemia leads to complications is not yet fully understood, but it is likely that the underlying pathology is that of endothelial dysfunction. A number of different and complex mechanisms have been implicated in the pathogenesis of endothelial dysfunction, but the exact importance of each of these individual mechanisms in the development of different complications is not yet clear. It is likely, however, that they all have a role to play in the development of endothelial dysfunction and may explain why many trials looking at interventions targeting individual mechanisms have been generally disappointing. Table 2 lists a summary of the various proposed mechanisms.
Proposed mechanisms for the development of complications in diabetesPolyol pathway hyperactivity
Advanced glycation end product formation
Oxidative stress
Increased protein kinase C activity
Direct glucotoxicity
Familial and genetic aspectsTable SEQ Table \* ARABIC 2 Proposed mechanisms for the development of complications in diabetes
1.1.2.1 Microvascular Complications
Chronic hyperglycaemia results in a variety of metabolic and haemodynamic insults that eventually lead to the development of microangiopathy. Although initially functionally reversible, there is eventual structural change, with increased small vessel permeability, thickening of the basement membrane and luminal narrowing ADDIN EN.CITE Zatz1986797917Zatz, R.Brenner, B. M.Pathogenesis of diabetic microangiopathy. The hemodynamic viewAm J MedAm J Med443-53803Angiotensin II/physiologyAnimalsAnoxia/physiopathologyBasement Membrane/pathologyBlood PressureCapillaries/pathology/physiopathologyCapillary PermeabilityCatecholamines/physiologyDiabetes Mellitus, Experimental/physiopathologyDiabetic Angiopathies/ physiopathologyHemodynamicsHumansHypertension/physiopathologyKidney Glomerulus/blood supplyMicrocirculation/physiopathologyProstaglandins/secretionRatsReceptors, Angiotensin/physiologyRenin-Angiotensin SystemRetinal Vessels/physiopathologyVasodilation1986Mar3513561(Zatz and Brenner, 1986). Figure 2 shows an electron photomicrograph of a capillary taken from a nerve biopsy in a patient with diabetic neuropathy. It shows marked thickening of the basement membrane with proliferation of the endothelial cells leading to virtual occlusion of the lumen.
SHAPE \* MERGEFORMAT
Figure SEQ Figure \* ARABIC 2 Photomicrograph from a capillary from a nerve biopsy in diabetic neuropathy
(Image courtesy of S. Tesfaye)
This ultimately leads to complete obstruction, resulting in tissue hypoxia and eventual damage and failure. Depending on the site of the microvascular damage, reparative mechanisms can be induced. These mechanisms, however, are often abnormal and can be responsible for further tissue damage and dysfunction. For example, in diabetic retinopathy, tissue ischaemia leads to the development of new vessels (neovascularisation) in the retina (Figure 3). These new vessels, however, are structurally abnormal and more fragile, making them prone to leakage and haemorrhage. ADDIN EN.CITE Goh200280805Goh, KLTooke, JGale, EAmiel, SAAbnormalities of the microvasculatureOxford Textbook of Endocrinology and DiabetesFirst2002Oxford University Press(Goh and Tooke, 2002)
SHAPE \* MERGEFORMAT
Figure SEQ Figure \* ARABIC 3 Retinal photograph of proliferative diabetic retinopathy
with neovascularisation and haemorrhages
Although patients with T1DM and T2DM are both prone to developing microvascular complications, there are distinct differences in their manifestation. As T2DM has often been present for up to 10 years before being diagnosed, many patients will present with evidence of microvascular complications at the time of diagnosis. In T1DM, complications usually develop between 10-20 years after diagnosis. Visual loss in T1DM is usually due to proliferative retinopathy, whereas in T2DM, maculopathy is the predominant cause. In T1DM, nephropathy is usually due to the classical microvascular damage leading to albuminuria. In contrast, in T2DM, there are often multiple factors involved, including hypertensive nephropathy and renovascular disease. ADDIN EN.CITE Fioretto1998787817Fioretto, P.Stehouwer, C. D.Mauer, M.Chiesura-Corona, M.Brocco, E.Carraro, A.Bortoloso, E.van Hinsbergh, V. W.Crepaldi, G.Nosadini, R.Department of Internal Medicine and Center for the Study of Aging, National Research Council, University of Padova, Italy.Heterogeneous nature of microalbuminuria in NIDDM: studies of endothelial function and renal structureDiabetologiaDiabetologia233-6412AdultAgedAlbuminuria/blood/etiology/pathology/ physiopathologyDiabetes Mellitus, Type 2/blood/complications/pathology/ physiopathologyDiabetic Nephropathies/blood/pathology/physiopathologyDiabetic Retinopathy/blood/etiology/pathology/physiopathologyEndothelium, Vascular/ physiologyHumansKidney/ pathology/physiopathologyMiddle Agedvon Willebrand Factor/analysis1998Feb9498659(Fioretto et al., 1998)
Diabetic neuropathy can present in a variety of guises and is one of the most prevalent, if under-diagnosed, complications of diabetes. It is discussed in detail below.
1.2 Diabetic Neuropathy
Diabetic neuropathy is one of the most frequent complications of diabetes. It is a source of great distress, disability and premature death. It is the main initiating factor for foot ulceration and the commonest cause of non-traumatic lower limb amputation in the western world. The projected increase in the prevalence of diabetes will have important associated health implications both in terms of morbidity and mortality as well as being a major burden on scarce medical resources.
Diabetic neuropathy is not a single entity, but comprises several neuropathic syndromes, of which the commonest is chronic distal symmetrical peripheral neuropathy.
1.2.1 Classification
Diabetic neuropathy is defined as the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes ADDIN EN.CITE Boulton1998212117Boulton, A. J.Gries, F. A.Jervell, J. A.Department of Medicine, Manchester Royal Infirmary, UK.Guidelines for the diagnosis and outpatient management of diabetic peripheral neuropathyDiabet MedDiabet Med508-14156Ambulatory Care/ methodsDiabetic Foot/therapyDiabetic Neuropathies/ diagnosis/therapyEmergenciesHumansMedical History TakingPatient Education as TopicPractice Guidelines as TopicRisk Factors1998Jun9632127(Boulton et al., 1998). Careful clinical examination is essential as many subjects are asymptomatic or have other non-diabetic neuropathies (e.g. chronic inflammatory demyelinating polyneuropathy).
Peripheral nerve damage in diabetes mellitus can be broadly separated into generalised symmetrical polyneuropathies and focal neuropathies. Clinical classification of the various syndromes of diabetic neuropathy has proved very difficult. The variation and overlap in aetiology, clinical features, natural history and prognosis have meant that most classifications are necessarily oversimplified and none has proved capable of accounting for all of these factors. In 2005, the American Diabetes Association (ADA), in a consensus statement, proposed a classification shown in Table 3 ADDIN EN.CITE Boulton20051117Boulton, Andrew J. M.Vinik, Arthur I.Arezzo, Joseph C.Bril, VeraFeldman, Eva L.Freeman, RoyMalik, Rayaz A.Maser, Raelene E.Sosenko, Jay M.Ziegler, DanDiabetic Neuropathies: A statement by the American Diabetes AssociationDiabetes CareDiabetes Care956-9622842005April 1, 2005http://care.diabetesjournals.org 10.2337/diacare.28.4.956(Boulton et al., 2005). It is based on the premise that diabetic neuropathy is not a unitary condition, but is the result of a number of disturbances in the peripheral nervous system as a consequence of hyperglycaemia ADDIN EN.CITE Boulton20044417Boulton, Andrew J. M.Malik, Rayaz A.Arezzo, Joseph C.Sosenko, Jay M.Diabetic Somatic NeuropathiesDiabetes CareDiabetes Care1458-14862762004June 1, 2004http://care.diabetesjournals.org 10.2337/diacare.27.6.1458(Boulton et al., 2004b).
Focal and Multifocal NeuropathiesCranial
Truncal
Focal Limb
Proximal motor (amyotrophy)Generalised Symmetric Polyneuropathies Acute sensory
Chronic sensorimotor
AutonomicTable SEQ Table \* ARABIC 3 Classification of Diabetic Neuropathy
1.2.1.1 Focal and Multifocal Neuropathies
Focal Limb Neuropathies
Focal limb neuropathies are frequently due to entrapment and reflect the increased susceptibility of the nerves affected to compression in diabetes. The most common entrapment neuropathy is carpal tunnel syndrome (due to entrapment of the median nerve), causing pain and paraesthesia in the hands. It can be demonstrated electrophysiologically in up to 20-30% of people with diabetes, although is only symptomatic in around 6% ADDIN EN.CITE Wilbourn199964645Wilbourn, AJDyck, P. J.Thomas, P. K.Diabetic entrapment and compression neuropathiesDiabetic Neuropathy481-5081999PhiladelphiaWB Saunders(Wilbourn, 1999). It is three times more common in diabetes compared to the non-diabetic population ADDIN EN.CITE Karpitskaya2002666617Karpitskaya, Y.Novak, C. B.Mackinnon, S. E.Division of Plastic & Reconstructive Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.Prevalence of smoking, obesity, diabetes mellitus, and thyroid disease in patients with carpal tunnel syndromeAnn Plast SurgAnn Plast Surg269-73483Body Mass IndexCarpal Tunnel Syndrome/epidemiology/ etiologyDiabetes ComplicationsFemaleHumansHypothyroidism/ complicationsMaleMiddle AgedObesity/ complicationsOdds RatioPrevalenceRisk FactorsSmoking/ adverse effectsUnited States/epidemiology2002Mar11862031(Karpitskaya et al., 2002). Other nerves affected include the ulnar nerve, radial nerve, common peroneal nerve, and lateral femoral cutaneous nerve ADDIN EN.CITE Boulton20044417Boulton, Andrew J. M.Malik, Rayaz A.Arezzo, Joseph C.Sosenko, Jay M.Diabetic Somatic NeuropathiesDiabetes CareDiabetes Care1458-14862762004June 1, 2004http://care.diabetesjournals.org 10.2337/diacare.27.6.1458(Boulton et al., 2004b).
Cranial Neuropathies
Cranial neuropathies in people with diabetes are very rare. Ocular neuropathies affecting the III, IV, and VI nerves are the most common. The classical presentation in most textbooks is of an acute III nerve palsy causing diplopia and ptosis, but with pupillary sparing (due to preservation of sympathetic nerve fibres that run on the outside of the nerve). Although pupillary sparing is often quoted as being pathognomic of diabetic neuropathy, pupillary dysfunction is a common finding in diabetes due to the co-presence of autonomic neuropathy ADDIN EN.CITE Moster1999676717Moster, M. L.Department of Neurosensory Sciences, Albert Einstein Medical Center, Philadelphia, PA 19141, USA. mmoster@aol.comNeuro-ophthalmology of diabetesCurr Opin OphthalmolCurr Opin Ophthalmol376-81106Blindness/diagnosis/ etiology/prevention & controlDelivery of Health Care/methodsDiabetes ComplicationsDiabetes Mellitus/therapyEye Abnormalities/diagnosis/ etiology/prevention & controlHumansMacular Edema/diagnosis/ etiology/prevention & controlOcular Motility Disorders/diagnosis/ etiology/prevention & controlOptic Neuropathy, Ischemic/diagnosis/ etiology/prevention & controlVisual Acuity1999Dec10662241(Moster, 1999). Although other cranial neuropathies are even rarer, the presence of diabetes is a common finding in most case series of idiopathic VII nerve neuropathy (Bells palsy) ADDIN EN.CITE Abraham-Inpijn1982656517Abraham-Inpijn, L.Devriese, P. P.Hart, A. A.Predisposing factors in Bell's palsy: a clinical study with reference to diabetes mellitus, hypertension, clotting mechanism and lipid disturbanceClin Otolaryngol Allied SciClin Otolaryngol Allied Sci99-10572AdolescentAdultAgedChildDiabetic Neuropathies/ complicationsFacial Paralysis/blood/ etiologyFemaleHemostasisHumansHypertension/ complicationsLipids/ bloodMaleMiddle AgedRisk1982Apr7094388(Abraham-Inpijn et al., 1982).
Diabetic Amyotrophy
Diabetic amyotrophy (or proximal motor neuropathy) is most commonly seen in people with type 2 diabetes aged between 50-60 years. It frequently occurs in the context of initiation of treatment or rapidly improving control and is associated with significant weight loss. Severe deep pain in the thigh is often the initial symptom, but this is usually later superseded by marked proximal weakness as the main limiting factor. The patient usually complains of difficulty in getting out of a chair or climbing stairs and in severe cases can lead to them being confined to a wheelchair. On examination there is marked wasting of the quadriceps muscles. Sensory involvement is relatively unusual and usually reflects a co-existing distal sensory neuropathy. ADDIN EN.CITE Sander1996707017Sander, H. W.Chokroverty, S.Department of Neurology, Saint Vincents Hospital and Medical Center of New York, New York Medical College, NY 10011, USA.Diabetic amyotrophy: current conceptsSemin NeurolSemin Neurol173-8162Brachial Plexus Neuritis/etiology/pathology/ physiopathology/therapyDiabetic Neuropathies/pathology/ physiopathology/therapyElectromyographyHumansNeural Conduction/physiologyPredictive Value of Tests1996Jun8987131(Sander and Chokroverty, 1996)
The pathophysiology is not clear but is thought to be due to ischaemic damage to immune-mediated microvasculitis ADDIN EN.CITE Dyck2002696917Dyck, P. J.Windebank, A. J.Peripheral Neuropathy Research Laboratory, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA. dyck.pjames@mayo.eduDiabetic and nondiabetic lumbosacral radiculoplexus neuropathies: new insights into pathophysiology and treatmentMuscle NerveMuscle Nerve477-91254Diabetes Mellitus, Type 2/ complications/physiopathologyDiabetic Neuropathies/pathology/ physiopathology/ therapyHumansLumbosacral Plexus/pathology/ physiopathologyMethylprednisolone/therapeutic useMicrocirculation/pathology/physiopathologyMuscle Weakness/etiology/physiopathologyNeuralgia/etiology/physiopathologyPeripheral Nerves/pathology/physiopathologyRadiculopathy/pathology/ physiopathology/ therapy2002Apr11932965(Dyck and Windebank, 2002).
In the majority of cases, the pain usually starts to subside after 3 months and usually settles completely after 1 year ADDIN EN.CITE Coppack1991686817Coppack, S. W.Watkins, P. J.Diabetic Department, King's College Hospital, London.The natural history of diabetic femoral neuropathyQ J MedQ J Med307-1379288AdultAgedDiabetic Neuropathies/ diagnosis/drug therapy/physiopathologyFemaleFemoral NerveHumansInsulin/ therapeutic useMaleMiddle AgedPrognosisRecurrence1991Apr1852856(Coppack and Watkins, 1991). Management is largely supportive, predominantly to control the pain.
Truncal Radiculopathies
Diabetic truncal radiculopathies are characterised by a painful (often burning or stabbing in nature) neuropathy, in a dermatomal distribution in the lower thorax or abdomen ADDIN EN.CITE Stewart1989777717Stewart, J. D.Division of Neurology, Montreal General Hospital, Quebec, Canada.Diabetic truncal neuropathy: topography of the sensory deficitAnn NeurolAnn Neurol233-8253AgedDiabetic Neuropathies/ physiopathologyHumansMaleMiddle AgedNeurons, Afferent/ physiologySkin/innervation1989Mar2729914(Stewart, 1989). These are usually unilateral and are often accompanied by hyperaesthesia and marked weight loss. Rarely motor weakness can cause bulging of the anterior abdominal wall ADDIN EN.CITE Boulton1984717117Boulton, A. J.Angus, E.Ayyar, D. R.Weiss, D. R.Diabetic thoracic polyradiculopathy presenting as abdominal swellingBr Med J (Clin Res Ed)Br Med J (Clin Res Ed)798-92896448AbdomenAgedDiabetic Neuropathies/ diagnosisHumansMaleThoracic Nerves1984Sep 296434085(Boulton et al., 1984). In those presenting with abdominal pain and weight loss, it is often poorly diagnosed, resulting in patients undergoing unnecessary gastro-intestinal investigations for neoplasia. It bears many similarities to diabetic amyotrophy and also usually resolves within 12 months ADDIN EN.CITE Kikta1982767617Kikta, D. G.Breuer, A. C.Wilbourn, A. J.Thoracic root pain in diabetes: the spectrum of clinical and electromyographic findingsAnn NeurolAnn Neurol80-5111AdultAgedDiabetic Neuropathies/ diagnosisDiagnosis, DifferentialElectromyography/ methodsFemaleHumansMaleMiddle AgedNervous System Diseases/diagnosisRadiculopathy/ diagnosisSensation1982Jan7059131(Kikta et al., 1982).
1.2.1.2 Generalised Symmetrical Polyneuropathies
Acute Sensory Neuropathy
Acute sensory neuropathy is an uncommon syndrome associated with periods of poorly controlled diabetes, as well as sudden improvements in glycaemic control (so called insulin neuritis). It is characterised by acute or sub-acute onset of severe painful symptoms, in glove and stocking distribution, usually with nocturnal exacerbation. Despite the intensity of symptoms, there is often little objective abnormality found on examination or neurophysiological assessments. Clinical tests of sensory function are often normal and nerve conduction velocities are usually only mildly reduced. The most consistent abnormality is loss of small fibre function on quantitative sensory testing, often in association with allodynia ADDIN EN.CITE Boulton20044417Boulton, Andrew J. M.Malik, Rayaz A.Arezzo, Joseph C.Sosenko, Jay M.Diabetic Somatic NeuropathiesDiabetes CareDiabetes Care1458-14862762004June 1, 2004http://care.diabetesjournals.org 10.2337/diacare.27.6.1458(Boulton et al., 2004b).
In the context of poor glycaemic control there is usually accompanying precipitous weight loss, initially described by Ellenberg as neuropathic cachexia ADDIN EN.CITE Ellenberg1974232317Ellenberg, M.Diabetic neuropathic cachexiaDiabetesDiabetes418-23235AdultBody WeightCachexia/diagnosis/ physiopathologyDiabetes Mellitus/drug therapyDiabetic DietDiabetic Neuropathies/diagnosis/ physiopathologyDiagnosis, DifferentialEating Disorders/diagnosisErectile DysfunctionHumansInsulin, Long-Acting/therapeutic useMaleMiddle AgedNeoplasm MetastasisNeoplasms, Nerve Tissue/diagnosisNeuromuscular Diseases/diagnosisPainPeripheral Nervous System Diseases/diagnosisPrognosisTolbutamide/therapeutic use1974May4364389(Ellenberg, 1974).
Paradoxically, acute painful neuropathy has also been described following rapid improvements in glycaemic control ADDIN EN.CITE Ellenberg1958222217Ellenberg, M.Diabetic neuropathy precipitating after institution of diabetic controlAm J Med SciAm J Med Sci466-712364Diabetes ComplicationsDIABETES MELLITUS/complicationsNERVOUS SYSTEM/diseases1958Oct13582940Archer1983202017Archer, A. G.Watkins, P. J.Thomas, P. K.Sharma, A. K.Payan, J.The natural history of acute painful neuropathy in diabetes mellitusJ Neurol Neurosurg PsychiatryJ Neurol Neurosurg Psychiatry491-9466Acute DiseaseAdolescentAdultBiopsyBlood Glucose/metabolismBody WeightDiabetic Neuropathies/ diagnosisDiabetic Retinopathy/diagnosisHumansHyperalgesia/ diagnosisHyperesthesia/ diagnosisMaleMiddle AgedNerve Fibers, Myelinated/ultrastructureNeural ConductionParesthesia/diagnosisSural Nerve/pathology1983Jun6875582(Ellenberg, 1958, Archer et al., 1983).This is usually in the context of insulin use (as well as in insulinomas) and has therefore been termed insulin neuritis. There have been virtually no reports of a similar syndrome following rapid improvements in control after initiation of oral hypoglycaemic therapy, or pancreatic or islet cell transplantation ADDIN EN.CITE Leow2005242417Leow, M. K.Wyckoff, J.Department of Endocrinology, Division of Medicine, Tan Tock Seng Hospital, Singapore. mleowsj@massmed.orgUnder-recognised paradox of neuropathy from rapid glycaemic controlPostgrad Med JPostgrad Med J103-781952Blood Glucose/metabolismDiabetic Neuropathies/blood/ chemically inducedHemoglobin A, Glycosylated/ drug effectsHumansHyperglycemia/blood/ drug therapyHypoglycemia/blood/ chemically inducedHypoglycemic Agents/ adverse effectsInsulin/ adverse effectsRisk Factors2005Feb15701742(Leow and Wyckoff, 2005). The pathophysiology is unclear. Metabolic effects such as hypoglycaemia and hyperinsulinaemia have been shown to induce nerve injury in animal models ADDIN EN.CITE Sima1989272717Sima, A. A.Zhang, W. X.Greene, D. A.Neuropathology Research Laboratory, Department of Pathology, University of Manitoba, Winnipeg, Canada.Diabetic and hypoglycemic neuropathy--a comparison in the BB ratDiabetes Res Clin PractDiabetes Res Clin Pract279-9664AnimalsAxons/ultrastructureDiabetes Mellitus, Experimental/pathology/ physiopathologyDiabetic Neuropathies/pathology/ physiopathologyEvoked PotentialsHypoglycemia/physiopathologyMaleMyelin Sheath/ultrastructureNervous System Diseases/pathology/ physiopathologyPeripheral Nerves/pathology/ physiopathology/ultrastructurePrediabetic State/pathology/ physiopathologyRatsRats, Inbred BBReference Values1989May 152752883(Sima et al., 1989). Using fluorescein angiography and in vivo epineurial vessel photography, Tesfaye et al have also demonstrated epineurial arterio-venous shunting and new vessel formation (similar to diabetic retinopathy). They hypothesised that sudden change in glycaemic control leads to a steal effect and endoneurial ischaemia, suggesting the importance of vascular factors in the pathogenesis of neuropathic pain ADDIN EN.CITE Tesfaye1996282817Tesfaye, S.Malik, R.Harris, N.Jakubowski, J. J.Mody, C.Rennie, I. G.Ward, J. D.Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield, UK.Arterio-venous shunting and proliferating new vessels in acute painful neuropathy of rapid glycaemic control (insulin neuritis)DiabetologiaDiabetologia329-35393Acute DiseaseAdultArteries/pathologyBlood Glucose/ physiologyDiabetes Mellitus, Type 1/ drug therapy/ physiopathologyDiabetes Mellitus, Type 2/ drug therapy/ physiopathologyDiabetic Neuropathies/ etiology/physiopathologyElectrophysiologyFemaleFluorescein AngiographyHumansInsulin/ adverse effectsMaleMiddle AgedOptic Nerve/blood supply/pathology/ physiopathologyPainSural Nerve/blood supply/pathology/ physiopathologyVeins/pathology1996Mar8721779(Tesfaye et al., 1996a).
In both cases, establishment of stable glycaemic control usually results in gradual improvement of symptoms, usually over 8-12 months ADDIN EN.CITE Archer1983202017Archer, A. G.Watkins, P. J.Thomas, P. K.Sharma, A. K.Payan, J.The natural history of acute painful neuropathy in diabetes mellitusJ Neurol Neurosurg PsychiatryJ Neurol Neurosurg Psychiatry491-9466Acute DiseaseAdolescentAdultBiopsyBlood Glucose/metabolismBody WeightDiabetic Neuropathies/ diagnosisDiabetic Retinopathy/diagnosisHumansHyperalgesia/ diagnosisHyperesthesia/ diagnosisMaleMiddle AgedNerve Fibers, Myelinated/ultrastructureNeural ConductionParesthesia/diagnosisSural Nerve/pathology1983Jun6875582(Archer et al., 1983).
Autonomic Neuropathy
Diabetic autonomic neuropathy (DAN) is a serious complication of diabetes and carries up to a five-fold increased risk of mortality ADDIN EN.CITE O'Brien1991393917O'Brien, I. A.McFadden, J. P.Corrall, R. J.Department of Medicine, Royal Infirmary, Bristol.The influence of autonomic neuropathy on mortality in insulin-dependent diabetesQ J MedQ J Med495-50279290AdolescentAdultAgedAged, 80 and overAutonomic Nervous System Diseases/ mortalityChildDiabetes Mellitus, Type 1/ mortalityDiabetic Neuropathies/ mortalityDiscriminant AnalysisEnglandFemaleHumansMaleMiddle AgedRisk Factors1991Jun1946930(O'Brien et al., 1991). This high mortality rate is related in large part to silent myocardial ischaemia, cardiac arrhythmias, and cardio-respiratory instability. Despite its relationship to an increased risk of cardiovascular mortality and its association with significant morbidity, the importance of DAN is not fully appreciated and it frequently goes undiagnosed. A major reason for this is that whilst severe symptomatic DAN is relatively uncommon, many people have sub-clinical or asymptomatic DAN.
The major manifestations are cardiovascular, gastrointestinal and genitourinary dysfunction and are displayed in Table 4. Frequent complaints include symptomatic postural hypotension, gustatory sweating, gastroparesis, erectile dysfunction and poor hypoglycaemic awareness. Cardiovascular involvement is probably the most serious and is discussed further in Chapters 4 and 5.
Features of Autonomic NeuropathyCardiovascularGenitourinaryResting tachycardia
Exercise intolerance
Orthostatic hypotension
Silent myocardial ischaemiaNeurogenic bladder
Erectile dysfunction
Retrograde ejaculation
Female sexual dysfunctionGISudomotorOesophageal dysmotility
Gastroparesis
Constipation
Diarrhoea
Faecal incontinenceAnhidrosis
Heat intolerance
Gustatory sweating
Dry skin
Metabolic PupillaryHypoglycaemia unawareness
Pupillomotor function impairment
Argyll Robertson pupilTable SEQ Table \* ARABIC 4 Features of Autonomic Neuropathy
Methods of testing the autonomic nervous system range from simple blood pressure estimation with postural change to monitoring R-R variation (using electrocardiographic monitoring software) with deep breathing, Valsalva manoeuvre and postural changes. There is however a wide variability with repeat testing, which can be minimised by standardizing the methodology and using a central testing facility ADDIN EN.CITE Low199332325Low, P.Pfeifer, M.A.Low, P.Standardisation of clinical tests for practice and clinical trialsClinical Autonomic Disorders287-29619931993Boston, MA(Low and Pfeifer, 1993).
Chronic Sensorimotor Neuropathy
This is the most common and widely recognised form of diabetic neuropathy. This diabetic peripheral neuropathy (DPN) is usually insidious in onset and can present in a variety of different forms. It also has a major impact on the ability to function normally (both mental and physical functioning e.g. ability to maintain work), mood and quality of life. As DPN was the focus of this thesis, the remainder of this review will focus on its key features.
1.2.2 Clinical Features
Up to half of patients will complain of a variety of different symptoms. These range from burning pain, lancinating or electric shock-like sensations, paraesthesia, hyperaesthesia or contact allodynia, and deep aching pain. Other patients may describe negative symptoms such as numbness or their feet feeling dead. It is important to be aware that up to half of patients will be entirely asymptomatic and the diagnosis only apparent on clinical examination. Often, the first time the neuropathy is diagnosed is when the patient presents with a painless foot ulcer. Sensory loss dominates the early stages, starting at the toes and gradually progressing into the feet and legs.
When the disease is well established in the lower limbs in more severe cases, there is upper limb involvement, with a similar progression proximally starting in the fingers. As the disease advances further, motor manifestations, such as wasting of the small muscles of the hands and limb weakness, become apparent. Motor nerve involvement is usually sub-clinical, although it is easily detectable on neurophysiological testing ADDIN EN.CITE Andersen1997303017Andersen, H.Gadeberg, P. C.Brock, B.Jakobsen, J.Department of Neurology, Aarhus University Hospital, Denmark.Muscular atrophy in diabetic neuropathy: a stereological magnetic resonance imaging studyDiabetologiaDiabetologia1062-9409AdultAnkle Joint/pathologyDiabetes Mellitus, Type 1/pathology/radionuclide imagingDiabetic Neuropathies/complications/ diagnosis/radionuclide imagingFemaleHumansKnee/pathologyLeg/innervationMagnetic Resonance Imaging/methodsMaleMiddle AgedMuscles/pathologyMuscular Atrophy/complications/ diagnosis/radionuclide imagingPain/etiology1997Sep9300243(Andersen et al., 1997). Non-invasive imaging techniques have revealed atrophy of the musculature of the foot and this may be visible clinically in severe cases ADDIN EN.CITE Andersen1999313117Andersen, H.Department of Neurology, Aarhus University Hospital, Denmark.Motor function in diabetic neuropathyActa Neurol ScandActa Neurol Scand211-201004Diabetic Neuropathies/ physiopathologyHumansMuscles/physiopathology1999Oct10510679(Andersen, 1999). However, early and predominant motor involvement or asymmetry should raise the possibility of alternative diagnoses, such as CIDP ADDIN EN.CITE Boulton1998212117Boulton, A. J.Gries, F. A.Jervell, J. A.Department of Medicine, Manchester Royal Infirmary, UK.Guidelines for the diagnosis and outpatient management of diabetic peripheral neuropathyDiabet MedDiabet Med508-14156Ambulatory Care/ methodsDiabetic Foot/therapyDiabetic Neuropathies/ diagnosis/therapyEmergenciesHumansMedical History TakingPatient Education as TopicPractice Guidelines as TopicRisk Factors1998Jun9632127(Boulton et al., 1998).
Painful DPN can cause severe distress. It is characteristically more severe at night resulting in a high prevalence of sleep disorders. The unremitting nature of the pain can be highly distressing resulting mood disorders including depression and anxiety. ADDIN EN.CITE Gore200516516517Gore, M.Brandenburg, N. A.Dukes, E.Hoffman, D. L.Tai, K. S.Stacey, B.Avalon Health Solutions, Inc., Philadelphia, Pennsylvania 19102, USA.Pain severity in diabetic peripheral neuropathy is associated with patient functioning, symptom levels of anxiety and depression, and sleepJ Pain Symptom ManageJ Pain Symptom Manage374-85304AdolescentAdultAgedAnxiety/complications/ psychologyDepression/complications/ psychologyDiabetic Neuropathies/complications/ psychologyFemaleHumansMaleMiddle AgedPain/complications/ psychologySeverity of Illness IndexSleep Disorders/complications/ psychology2005Oct16256902(Gore et al., 2005) This has a high social and economic burden.
On clinical examination, there is usually a symmetrical ascending sensory loss in a stocking distribution. The hands can also be affected in more severe cases. Reflexes (especially ankle) are often reduced or absent. Wasting of the small muscles of the feet is frequently seen, leading to deformities such as clawing of the toes and subluxation of the metatarsal heads. This leads to abnormal pressure loading and the development of callus, a precursor to ulcer development. Local autonomic neuropathy also leads to a shiny, dry appearance to the feet (decreased sweating) and prominent veins (arterio-venous shunting). Fissures can form in areas of dry, calloused skin and be sources of introducing infection. There is also often accompanying peripheral vascular disease, which increases the vulnerability of the foot to developing complications. Loss of proprioception can also lead to unsteadiness and a positive Rombergs sign ADDIN EN.CITE Boulton1998212117Boulton, A. J.Gries, F. A.Jervell, J. A.Department of Medicine, Manchester Royal Infirmary, UK.Guidelines for the diagnosis and outpatient management of diabetic peripheral neuropathyDiabet MedDiabet Med508-14156Ambulatory Care/ methodsDiabetic Foot/therapyDiabetic Neuropathies/ diagnosis/therapyEmergenciesHumansMedical History TakingPatient Education as TopicPractice Guidelines as TopicRisk Factors1998Jun9632127(Boulton et al., 1998).
1.2.3 Epidemiology
Measuring the prevalence of neuropathy has been confounded by a lack of a consensus over diagnostic criteria, the wide variety of measurement techniques used and the subject selection for study. As a result the prevalence of diabetic neuropathy has been shown in clinical and population based studies to vary from 8% to 66% depending on the criteria used to diagnose neuropathy, as well as the nature of the population being assessed ADDIN EN.CITE Dyck19939917Dyck, P. J.Kratz, K. M.Karnes, J. L.Litchy, W. J.Klein, R.Pach, J. M.Wilson, D. M.O'Brien, P. C.Melton, L. J., 3rdService, F. J.Department of Neurology, Mayo Clinic, Rochester, MN 55905.The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy StudyNeurologyNeurology817-24434AdultAgedCohort StudiesCreatinine/bloodCross-Sectional StudiesDiabetes Mellitus, Type 1/complicationsDiabetes Mellitus, Type 2/complicationsDiabetic Nephropathies/diagnosis/ epidemiology/etiologyDiabetic Neuropathies/diagnosis/ epidemiology/etiologyDiabetic Retinopathy/diagnosis/ epidemiology/etiologyElectrophysiologyFemaleHumansLongitudinal StudiesMaleMiddle AgedMinnesota/epidemiologyPrevalenceProspective Studies1993Apr8469345(Dyck et al., 1993a). It can be present in up to 10% of newly diagnosed patients with type 2 diabetes ADDIN EN.CITE 1998292917UKPDSIntensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) GroupLancetLancet837-533529131Blood Glucose/ analysisChlorpropamide/therapeutic useDiabetes Mellitus, Type 2/blood/complications/diet therapy/ drug therapyDiabetic Angiopathies/prevention & controlFemaleGlipizide/therapeutic useGlyburide/therapeutic useHemoglobin A, Glycosylated/analysisHumansHypoglycemic Agents/ therapeutic useInsulin/blood/ therapeutic useMaleMiddle AgedProspective StudiesRisk FactorsSulfonylurea Compounds/ therapeutic use1998Sep 129742976Partanen1995252517Partanen, J.Niskanen, L.Lehtinen, J.Mervaala, E.Siitonen, O.Uusitupa, M.Department of Clinical Neurophysiology, University Hospital, Kuopio, Finland.Natural history of peripheral neuropathy in patients with non-insulin-dependent diabetes mellitusN Engl J MedN Engl J Med89-943332Blood Glucose/metabolismC-Peptide/bloodCase-Control StudiesDiabetes Mellitus, Type 2/ complications/physiopathology/therapyDiabetic Neuropathies/epidemiology/ etiologyFemaleFollow-Up StudiesHumansInsulin/bloodMaleMiddle AgedMotor Neurons/physiologyNeural ConductionPeripheral Nerves/physiology/physiopathologyPrevalenceRisk Factors1995Jul 137777034UKPDS1998292917UKPDSIntensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) GroupLancetLancet837-533529131Blood Glucose/ analysisChlorpropamide/therapeutic useDiabetes Mellitus, Type 2/blood/complications/diet therapy/ drug therapyDiabetic Angiopathies/prevention & controlFemaleGlipizide/therapeutic useGlyburide/therapeutic useHemoglobin A, Glycosylated/analysisHumansHypoglycemic Agents/ therapeutic useInsulin/blood/ therapeutic useMaleMiddle AgedProspective StudiesRisk FactorsSulfonylurea Compounds/ therapeutic use1998Sep 129742976(UKPDS, 1998, Partanen et al., 1995) and is more common with increasing age and duration of diabetes.
One of the most definitive studies was the population-based Rochester Diabetic Neuropathy Study, which assessed neuropathy using a composite score based on clinical symptoms and signs, quantitative sensory testing, autonomic function tests and nerve conduction studies. The prevalence of some form of neuropathy was 66% in type 1 and 59% in type 2 diabetes ADDIN EN.CITE Dyck19939917Dyck, P. J.Kratz, K. M.Karnes, J. L.Litchy, W. J.Klein, R.Pach, J. M.Wilson, D. M.O'Brien, P. C.Melton, L. J., 3rdService, F. J.Department of Neurology, Mayo Clinic, Rochester, MN 55905.The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy StudyNeurologyNeurology817-24434AdultAgedCohort StudiesCreatinine/bloodCross-Sectional StudiesDiabetes Mellitus, Type 1/complicationsDiabetes Mellitus, Type 2/complicationsDiabetic Nephropathies/diagnosis/ epidemiology/etiologyDiabetic Neuropathies/diagnosis/ epidemiology/etiologyDiabetic Retinopathy/diagnosis/ epidemiology/etiologyElectrophysiologyFemaleHumansLongitudinal StudiesMaleMiddle AgedMinnesota/epidemiologyPrevalenceProspective Studies1993Apr8469345(Dyck et al., 1993a).
More recently, the Eurodiab study described a prevalence of neuropathy of 28% in 3250 subjects across Europe with type 1 diabetes ADDIN EN.CITE Tesfaye1996171717Tesfaye, S.Stevens, L. K.Stephenson, J. M.Fuller, J. H.Plater, M.Ionescu-Tirgoviste, C.Nuber, A.Pozza, G.Ward, J. D.Diabetes Unit, Royal Liverpool University Hospital, UK.Prevalence of diabetic peripheral neuropathy and its relation to glycaemic control and potential risk factors: the EURODIAB IDDM Complications StudyDiabetologiaDiabetologia1377-843911AdolescentAdultBlood PressureBody ConstitutionBody Mass IndexCardiovascular DiseasesDiabetes Mellitus, Type 1/ complications/epidemiology/physiopathologyDiabetic KetoacidosisDiabetic Neuropathies/blood/ epidemiology/physiopathologyDiabetic RetinopathyEurope/epidemiologyFemaleHumansHypoglycemiaLipids/bloodMaleMiddle AgedPeripheral Nervous System Diseases/ epidemiology/physiopathologyPrevalenceRegression AnalysisRisk FactorsSmoking1996Nov8933008(Tesfaye et al., 1996b). In those without neuropathy at baseline, the incidence was 24% over 7 years. In this study, neuropathy was diagnosed if there were more than two abnormalities amongst symptoms, lower limb reflexes, vibration perception threshold, and autonomic function tests (change in heart rate or blood pressure on standing). The incidence of neuropathy was related to the glycosylated haemoglobin (HbA1c) and duration of diabetes. After adjustment for these, they found that higher cholesterol, higher triglycerides, higher body mass index (BMI), higher urinary albumin excretion ratio (UAER), hypertension, and smoking were significantly associated with the cumulative incidence of neuropathy. After adjustment for other risk factors and other complications, the duration of diabetes, HbA1c, BMI, and smoking were all independently associated with the incidence of diabetic neuropathy. Cardiovascular disease at baseline was associated with double the risk of incident neuropathy ADDIN EN.CITE Tesfaye2005181817Tesfaye, S.Chaturvedi, N.Eaton, S. E.Ward, J. D.Manes, C.Ionescu-Tirgoviste, C.Witte, D. R.Fuller, J. H.Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield, United Kingdom. solomon.tesfaye@sth.nhs.uk.Vascular risk factors and diabetic neuropathyN Engl J MedN Engl J Med341-503524AdultBody Mass IndexCardiovascular Diseases/ complicationsCholesterol/bloodDiabetes Mellitus, Type 1/blood/ complicationsDiabetic Neuropathies/diagnosis/ etiologyFemaleFollow-Up StudiesHemoglobin A, Glycosylated/ metabolismHumansLogistic ModelsMaleMultivariate AnalysisProspective StudiesRisk FactorsSmoking/adverse effectsTriglycerides/blood2005Jan 2715673800(Tesfaye et al., 2005).
There have been relatively few epidemiological studies that have specifically examined the prevalence of painful DPN. In a recent study of a large cohort of diabetic patients receiving community-based health care in northwest England (n = 15,692), painful DPN assessed using neuropathy symptom and disability scores was found in 21% ADDIN EN.CITE Abbott201120120117Abbott, C. A.Malik, R. A.van Ross, E. R.Kulkarni, J.Boulton, A. J.Division of Cardiovascular Medicine, Core Technology Facility, University of Manchester, Manchester, UK. caroline.abbott@manchester.ac.ukPrevalence and characteristics of painful diabetic neuropathy in a large community-based diabetic population in the U.KDiabetes CareDiabetes Care2220-43410Administration, OralAdultAge DistributionAgedDiabetes Mellitus, Type 1/complications/drug therapy/epidemiologyDiabetes Mellitus, Type 2/complications/drug therapy/epidemiologyDiabetic Neuropathies/ epidemiology/ethnology/ pathologyFemaleGreat Britain/epidemiologyHumansHypoglycemic Agents/administration & dosage/therapeutic useMaleMiddle AgedSex Factors2011Oct21852677(Abbott et al., 2011). In one population-based study from Liverpool, UK, the prevalence of painful DPN assessed by a structured questionnaire and examination was estimated at 16% ADDIN EN.CITE Daousi200418418417Daousi, C.MacFarlane, I. A.Woodward, A.Nurmikko, T. J.Bundred, P. E.Benbow, S. J.Diabetes and Endocrinology Research Group, University Hospital Aintree, Liverpool, UK. c.daousi@ntlworld.comChronic painful peripheral neuropathy in an urban community: a controlled comparison of people with and without diabetesDiabet MedDiabet Med976-82219AdultAge DistributionAgedAged, 80 and overChronic DiseaseCross-Sectional StudiesDiabetic Neuropathies/drug therapy/ epidemiologyEngland/epidemiologyFemaleHumansMaleMiddle AgedPain Measurement/methodsPrevalenceSeverity of Illness IndexSex DistributionUrban Health2004Sep15317601(Daousi et al., 2004). Notably, it was found that 12.5% of these patients had never reported their symptoms to their doctor and 39% had never received treatment for their pain, indicating that there may be considerable under-diagnosis and under-treatment of painful neuropathic symptoms compared to other aspects of diabetes management such statin therapy and management of hypertension.
1.2.4 Pathogenesis
As outlined previously, it is clear that there is a complex cascade of vascular and metabolic factors that eventually results in end-organ damage such as DPN. It is still not clear why some people suffer from severe chronic pain, whilst others have no pain and the exact pathophysiological mechanisms of neuropathic pain in diabetes remain illusive. Although various mechanisms have been postulated ADDIN EN.CITE Tesfaye2005878717Tesfaye, S.Kempler, P.Diabetes Research Unit, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK. solomon.tesfaye@sth.nhs.ukPainful diabetic neuropathyDiabetologiaDiabetologia805-7485Diabetes Mellitus, Type 1/physiopathologyDiabetic Neuropathies/ physiopathologyHumansNeuralgia/etiology/ physiopathology2005May15834549(Tesfaye and Kempler, 2005), based on animal models of neuropathic pain (Table 5), studies in humans have been far from consistent. Part of the reason for this may be because much of the reported research has concentrated on changes within the peripheral nerve. It is increasingly being recognised that the generation and perception of pain is much more complex. For example, psychological and cultural factors strongly influence the perception and expression of pain ADDIN EN.CITE Tesfaye2005878717Tesfaye, S.Kempler, P.Diabetes Research Unit, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK. solomon.tesfaye@sth.nhs.ukPainful diabetic neuropathyDiabetologiaDiabetologia805-7485Diabetes Mellitus, Type 1/physiopathologyDiabetic Neuropathies/ physiopathologyHumansNeuralgia/etiology/ physiopathology2005May15834549(Tesfaye and Kempler, 2005). Diabetes is a global disorder and it is increasingly being recognised that all levels of the nervous system are involved.
Peripheral Mechanisms Changes in sodium channel distribution and expression
Changes in calcium channel distribution and expression
Altered neuro-peptide expression
Sympathetic sprouting
Peripheral sensitization
Altered peripheral blo o d f l o w
A x o n a l a t r o p h y , d e g e n e r a t i o n o r r e g e n e r a t i o n
D a m a g e t o s m a l l f i b r e s
I n c r e a s e d g l y c e m i c f l u x C e n t r a l M e c h a n i s m s C e n t r a l s e n s i t i z a t i o n
A f i b r e s p r o u t i n g i n t o A f i b r e s p r o u t i n g i n t o
R e d u c e d i n h i b i t i o n o f d e s c e n d i n g p a t h w a y s T a b l e S E Q T a b l e \ * ARABIC 5 Mechanisms of Neuropathic Pain
(Adapted from Tesfaye and Kempler 2005)
1.2.5 Management
The mainstay of treatment for neuropathy currently is prevention, mainly by delaying its onset. Once DPN is established, it is generally thought to be irreversible and progressive. Recently, there has been some evidence of improvements in small fibre morphology in the cornea following pancreas-kidney transplantation, using a technique called corneal confocal microscopy ADDIN EN.CITE Tavakoli19019017Tavakoli, M.Mitu-Pretorian, M.Petropoulos, I. N.Fadavi, H.Asghar, O.Alam, U.Ponirakis, G.Jeziorska, M.Marshall, A.Efron, N.Boulton, A. J.Augustine, T.Malik, R. A.Division of Cardiovascular Medicine, University of Manchester and Wellcome Trust Clinical Research Facility, Manchester, UK.Corneal confocal microscopy detects early nerve regeneration in diabetic neuropathy after simultaneous pancreas and kidney transplantationDiabetesDiabetes254-60621AdultCornea/ innervation/pathologyDiabetes Mellitus, Type 1/ complications/physiopathologyDiabetic Neuropathies/ physiopathology/surgeryFemaleHumansKidney TransplantationMaleMicroscopy, ConfocalMiddle AgedNerve RegenerationNeural ConductionPancreas Transplantation2013Jan23002037(Tavakoli et al., 2013). No improvement however has been demonstrated in large or small fibre numbers or function in peripheral nerves following transplantation. Although it has been suggested that changes seen on corneal confocal microscopy are surrogate markers of peripheral nerve function, the significance of these findings remain controversial. Aims of treatment should therefore be directed at reducing symptoms and slowing the progression of neuropathy.
There is good evidence that strict glycaemic control reduces the incidence of DPN. In type 1 diabetes, the DCCT showed that intensive insulin treatment reduced the incidence of DPN by as much as 50% in both the primary and secondary prevention cohorts ADDIN EN.CITE DCCT199517317317DCCTThe effect of intensive diabetes therapy on the development and progression of neuropathy. The Diabetes Control and Complications Trial Research GroupAnn Intern MedAnn Intern Med561-81228AdolescentAdultBlood Glucose/analysisDiabetes Mellitus, Type 1/ complications/ drug therapyDiabetic Neuropathies/etiology/physiopathology/ prevention & controlFollow-Up StudiesHumansInfusion PumpsInsulin Infusion SystemsNeural ConductionPatient ComplianceProspective StudiesRisk Factors1995Apr 157887548(DCCT, 1995). In type 2 diabetes, stricter control of blood glucose was associated with less deterioration in vibration perception threshold ADDIN EN.CITE UKPDS1998292917UKPDSIntensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) GroupLancetLancet837-533529131Blood Glucose/ analysisChlorpropamide/therapeutic useDiabetes Mellitus, Type 2/blood/complications/diet therapy/ drug therapyDiabetic Angiopathies/prevention & controlFemaleGlipizide/therapeutic useGlyburide/therapeutic useHemoglobin A, Glycosylated/analysisHumansHypoglycemic Agents/ therapeutic useInsulin/blood/ therapeutic useMaleMiddle AgedProspective StudiesRisk FactorsSulfonylurea Compounds/ therapeutic use1998Sep 129742976(UKPDS, 1998). This benefit was however, far less than that observed in the DCCT. In the STENO 2 study, type 2 diabetes patients were divided into two treatment cohorts ADDIN EN.CITE Gaede200816716717Gaede, P.Lund-Andersen, H.Parving, H. H.Pedersen, O.Steno Diabetes Center, Copenhagen, Denmark.Effect of a multifactorial intervention on mortality in type 2 diabetesN Engl J MedN Engl J Med580-913586AgedAngiotensin-Converting Enzyme Inhibitors/therapeutic useAspirin/therapeutic useBehavior TherapyCardiovascular Diseases/epidemiology/ mortality/prevention & controlCause of DeathCombined Modality TherapyDiabetes Mellitus, Type 2/complications/mortality/ therapyDiabetic Neuropathies/epidemiologyDrug Therapy, CombinationFollow-Up StudiesHumansHypoglycemic Agents/therapeutic useHypolipidemic Agents/therapeutic useKaplan-Meier EstimateMiddle AgedPlatelet Aggregation Inhibitors/therapeutic useRisk Factors2008Feb 718256393(Gaede et al., 2008). One cohort received conventional treatment and the other intensive treatment to tackle the multiple risk factors for DPN. This included antihypertensive drugs e.g. angiotensin converting enzyme inhibitors and calcium channel antagonist, hypoglycaemic agents, aspirin, lipid lowering agents and anti-oxidants. There was a 0.32 reduction in the odds ratio for developing autonomic neuropathy, but this study did not show a reduction in the risk of developing DPN.
Numerous treatments aimed at countering the proposed pathogenic mechanisms of DPN have been through rigourous clinical trials. Despite early promising results, many of these compounds have failed to make sufficient impact and hence are not widely licensed or available. There are however, a few treatments that have been granted licenses for use in certain countries e.g. alpha-lipoic acid in Germany and the aldose reductase inhibitor, epalerestat, in Japan.
Alpha-lipoic acid is an endogenous, sulphur-containing, free radical scavenger found in mitochondria. Free radicals can reduce nitric-oxide-mediated vasodilation and damage to the vascular endothelium ADDIN EN.CITE Cameron1997343417Cameron, N. E.Cotter, M. A.Department of Biomedical Sciences, University of Aberdeen, Scotland, U.K.Metabolic and vascular factors in the pathogenesis of diabetic neuropathyDiabetesDiabetesS31-746 Suppl 2AnimalsCarnitine/metabolismDiabetes Mellitus, Experimental/metabolismDiabetic Neuropathies/ etiology/metabolismEndothelium, Vascular/metabolismFatty Acids, Essential/metabolismGlycosylationHumansNerve Tissue/ blood supplyOxidation-ReductionRatsReactive Oxygen SpeciesRegional Blood FlowSugar Alcohols/metabolismVasodilator Agents/therapeutic use1997Sep9285496(Cameron and Cotter, 1997b). Alpha-lipoic acid also recycles other antioxidants, such as vitamins E and C. Clinical trials have shown that treatment with alpha-lipoic acid improves distal nerve conduction. A systemic review of 15 randomised clinical trials concluded that alpha-lipoic acid could be considered as a treatment option for diabetic patients with mild to moderate neuropathy, but many of the trials had poor methodology ADDIN EN.CITE Han201216816817Han, T.Bai, J.Liu, W.Hu, Y.Department of Endocrinology, Renji Hospital, Shanghai Jiaotong University, 200127 Shanghai, China.A systematic review and meta-analysis of alpha-lipoic acid in the treatment of diabetic peripheral neuropathyEur J EndocrinolEur J Endocrinol465-711674AdultAgedAntioxidants/administration & dosage/adverse effects/therapeutic useAsian Continental Ancestry Group/statistics & numerical dataDiabetic Neuropathies/ drug therapyHumansMiddle AgedRandomized Controlled Trials as Topic/statistics & numerical dataThioctic Acid/administration & dosage/adverse effects/ therapeutic useTreatment Outcome2012Oct22837391(Han et al., 2012). Intravenous administration is probably superior to oral administration.
Aldose reductase inhibitors reduce glucose flux through the polyol pathway and lower accumulation of toxic sorbitol. In a Cochrane review,19 trials, testing four different aldose reductase inhibitors between 4 208 weeks duration (median 24 weeks) were subjected to a meta-analysis ADDIN EN.CITE Airey200016916917Airey, M.Bennett, C.Nicolucci, A.Williams, R.Division of Public Health, Nuffield Institute for Health, University of Leeds, 71-75 Clarendon Rd, Leeds, UK, LS9 2PL. hssdrrw@leeds.ac.ukAldose reductase inhibitors for the prevention and treatment of diabetic peripheral neuropathyCochrane Database Syst RevCochrane Database Syst RevCD0021822Aldehyde Reductase/ antagonists & inhibitorsDiabetic Neuropathies/ drug therapy/prevention & controlEnzyme Inhibitors/ therapeutic useHumans200010796870(Airey et al., 2000). The review concluded that although aldose reductase inhibitors treatment diminished the reduction in motor nerve conduction velocity, the clinical relevance of such a change was uncertain.
The assessment and treatment of painful DPN is ideally done in the context of a multidisciplinary team (MDT). When treatment is started a realistic objective would be to achieve around 50% reduction in pain intensity. Secondary objectives should include restoration or improvement in functional measures, quality of life, sleep and mood. Management should include consideration of non-pharmacological therapies, such as psychological interventions. ADDIN EN.CITE Tesfaye201116616617Tesfaye, S.Vileikyte, L.Rayman, G.Sindrup, S.Perkins, B.Baconja, M.Vinik, A.Boulton, A.Diabetes Research Unit, Royal Hallamshire Hospital and University of Sheffield, Sheffield, UK.Painful Diabetic Peripheral Neuropathy: Consensus Recommendations on Diagnosis, Assessment and ManagementDiabetes Metab Res RevDiabetes Metab Res Rev629-38272011Jun 2121695762(Tesfaye et al., 2011)
Although strong evidence implicates poor glycemic control as a pathogenic mechanism in the aetiology of DPN, there is no proof from randomised, controlled trials that this is the case for neuropathic pain in diabetes. However, as increased blood glucose flux has been reported to contribute to pain in DPN ADDIN EN.CITE Oyibo200217417417Oyibo, S. O.Prasad, Y. D.Jackson, N. J.Jude, E. B.Boulton, A. J.Department of Diabetes, Manchester Royal Infirmary, Manchester, UK. samson@dc.cmht.nwest.nhs.ukThe relationship between blood glucose excursions and painful diabetic peripheral neuropathy: a pilot studyDiabet MedDiabet Med870-31910AdultBlood Glucose/ analysisDiabetic Neuropathies/ bloodFemaleHumansMaleMiddle AgedPain/blood/ etiologyPeripheral Nervous System Diseases/ bloodPilot Projects2002Oct12358878(Oyibo et al., 2002), there is a general consensus that good blood glucose control should, with the current level of knowledge, be the first step in the management of any form of diabetic neuropathy.
Pharmacological treatment of painful DPN is not entirely satisfactory as currently available drugs are often ineffective and complicated by adverse events. Tricyclic compounds have been used as first line agents for many years but many patients fail to respond to them and anti-cholinergic side effects including dry mouth, constipation, sweating, blurred vision, sedation, orthostatic hypotension (with the risk of falls particularly in elderly patients) are frequent ADDIN EN.CITE Tesfaye201116616617Tesfaye, S.Vileikyte, L.Rayman, G.Sindrup, S.Perkins, B.Baconja, M.Vinik, A.Boulton, A.Diabetes Research Unit, Royal Hallamshire Hospital and University of Sheffield, Sheffield, UK.Painful Diabetic Peripheral Neuropathy: Consensus Recommendations on Diagnosis, Assessment and ManagementDiabetes Metab Res RevDiabetes Metab Res Rev629-38272011Jun 2121695762(Tesfaye et al., 2011). Higher doses have been associated with an increased risk of sudden cardiac death thus caution should be taken in any patient with a history of cardiovascular disease ADDIN EN.CITE Ray200417517517Ray, W. A.Meredith, S.Thapa, P. B.Hall, K.Murray, K. T.Department of Preventive Medicine, Division of Pharmacoepidemiology, Vanderbilt University School of Medicine, A-1124 Medical Center North, Nashville, TN 37232, USA. wayne.ray@mcmail.vanderbilt.eduCyclic antidepressants and the risk of sudden cardiac deathClin Pharmacol TherClin Pharmacol Ther234-41753AdolescentAdultAgedAged, 80 and overAntidepressive Agents, Tricyclic/ administration & dosage/ adverse effectsCohort StudiesConfidence IntervalsDeath, Sudden, Cardiac/ epidemiology/prevention & controlFemaleFollow-Up StudiesHumansMaleMiddle AgedMultivariate AnalysisRetrospective StudiesRisk Factors2004Mar15001975(Ray et al., 2004).
The selective serotonin noradrenalin reuptake inhibitor (SNRI), duloxetine, has been used for the management of painful DPN. SNRIs relieve pain by increasing synaptic availability of 5-hydroxytryptamine and noradrenalin in the descending pathways that inhibit pain impulses ADDIN EN.CITE Tesfaye201116616617Tesfaye, S.Vileikyte, L.Rayman, G.Sindrup, S.Perkins, B.Baconja, M.Vinik, A.Boulton, A.Diabetes Research Unit, Royal Hallamshire Hospital and University of Sheffield, Sheffield, UK.Painful Diabetic Peripheral Neuropathy: Consensus Recommendations on Diagnosis, Assessment and ManagementDiabetes Metab Res RevDiabetes Metab Res Rev629-38272011Jun 2121695762(Tesfaye et al., 2011). The efficacy of Duloxetine in painful DPN has been investigated in three identical trials and pooled data from these shows that the 60 mg/day and 120 mg/day doses are effective in relieving painful symptoms, starting within a week and lasting the full treatment period of 12 weeks ADDIN EN.CITE Kajdasz200717017017Kajdasz, D. K.Iyengar, S.Desaiah, D.Backonja, M. M.Farrar, J. T.Fishbain, D. A.Jensen, T. S.Rowbotham, M. C.Sang, C. N.Ziegler, D.McQuay, H. J.Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. kaidasz_daniel_k@lilly.comDuloxetine for the management of diabetic peripheral neuropathic pain: evidence-based findings from post hoc analysis of three multicenter, randomized, double-blind, placebo-controlled, parallel-group studiesClin TherClin Ther2536-4629 SupplAdrenergic Uptake Inhibitors/ therapeutic useAdultAgedDiabetic Neuropathies/ drug therapyDouble-Blind MethodFemaleHumansMaleMiddle AgedNeuralgia/ drug therapyPeripheral Nervous System Diseases/ drug therapySerotonin Uptake Inhibitors/ therapeutic useThiophenes/ therapeutic use200718164920(Kajdasz et al., 2007). The main side effects include nausea, somnolence, dizziness, constipation, dry mouth and reduced appetite although these tend to be mild to moderate and are transient.
The anticonvulsant gabapentin, that binds to the - 2 - s u b u n i t o f t h e c a l c i u m c h a n n e l t h e r e b y r e d u c i n g n e u r o t r a n s m i t t e r r e l e a s e i n t h e h y p e r e x c i t e d n e u r o n e , i s a l s o e f f e c t i v e A D D I N E N . C I T E <