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Title: Insights into the pathogenesis of painful and painless diabetic neuropathy
Author: Gandhi, Rajiv
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2013
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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.
Supervisor: Wilkinson, Iain Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available