An investigation into central nervous system involvement in distal symmetrical diabetic neuropathy in type 1 diabetes mellitus.

Diabetes is a leading cause of peripheral neuropathy. It is the main initiating factor for foot ulceration and amputation resulting in considerable morbidity and remarkable consumption of scarce medical resources. Relatively little is known about the pathophysiology underlying DPN. Research into DPN has focused mainly on the peripheral nervous system (PNS) with central nervous system (CNS) involvement relatively overlooked. The studies undertaken have been designed to investigate CNS involvement in DPN. 1. Before embarking on spinal cord studies, I reviewed and modified the techniques employed in the pilot study to improve the precision and accuracy of cord cross sectional area measurements. These modifications were patiented to quality control studies, which are reported in Chapter 2. 2. I performed in-vivo cross-sectional magnetic resonance imaging of the cervical spine and reported evidence of spinal cord shrinkage (atrophy) in Painless DPN (Chapter 3). This study showed spinal cord atrophy to be an early phenomenon, present even in subclinical DPN. As the spinal cord is the caudal portion of the CNS, its involvement made us question whether the brain too may be involved. 3. Using MR spectroscopy I examined thalamic involvement in Painless DPN (Chapter 4). This deep brain nucleus is considered the gateway to all somatosensory information entering the brain, and responsible for modulation of sensory information prior to presentation to the cerebral cortex. I demonstrated thalamic biochemical abnormalities consistent with possible neuronal dysfunction in patients with Painless DPN. 4. The demonstration of thalamic neuronal dysfunction in DPN suggests that CNS involvement is not limited to the spinal cord but other important areas, responsible for somatosensory perception, may also be involved. Although the pathogenesis of thalamic involvement is unknown, it is likely that both vascular and metabolic factors that have been implicated in the pathogenesis of DPN are involved. In Chapter 4, I examined the possible role of metabolic factors in the pathogenesis of thalamic neuronal dysfunction in DPN. Using MR spectroscopy, I demonstrated a significant elevation in thalamic glutamine/glutamate in patients with diabetes. Glutamate is the most abundant excitatory neurotransmitter and implicated in various models of neuronal cell death. Astrocytes, which play an important role in glutamate/glutamine metabolism, were impaired in the thalamus of diabetic patients in this study. The combination of elevated glutamate and impaired thalamic astrocytes may provide a pathophysiological explanation for thalamic dysfunction in DPN. 5. In Chapter 5, an alternative hypothesis for thalamic neuronal dysfunction in DPN was tested. Using dynamic contrast enhanced MR perfusion imaging, I demonstrated that Painful DPN is associated with unique thalamic perfusion abnormalities. Intriguingly, these abnormalities were present in patients with Painful but not Painless DPN. 6. Finally, in Chapter 6, I conducted a randomised, double blind and placebo-control trial (RCT) comparing the efficacy and tolerability of sativex, a cannabis based medicinal extract (CBME), with placebo in the symptomatic treatment of painful DPN. This is the first ever RCT using a CBME in painful DPN. We report no significant difference in the primary outcome measure due to a massive placebo effect and that depression is a potential major confounder in such clinical trials