Spinal-cord involvement in diabetic peripheral neuropathy

Eaton, Simon; Harris, Nigel; Rajbhandari, Satyan; Greenwood, Pam; Wilkinson, Iain D.; Ward, John D.; Griffiths, Paul D.; Tesfaye, Solomon

doi:10.1016/s0140-6736(00)05268-5

Cited by 136 publications

(73 citation statements)

References 3 publications

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“…This adds to a growing list of neurochemical abnormalities found in the spinal cord of diabetic rodents that may have an impact on spinal nociceptive processing (43)(44)(45)(46)(47) and highlights a developing appreciation that the spinal cord is also a site of injury in diabetic patients (48,49). It also follows from these findings that COX inhibitors, particularly selective COX-2 inhibitors, may have a role in treating painful diabetic neuropathy.…”

Section: Discussionmentioning

confidence: 78%

Elevated Spinal Cyclooxygenase and Prostaglandin Release During Hyperalgesia in Diabetic Rats

et al. 2002

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Diabetic rats display exaggerated hyperalgesic behavior in response to noxious stimuli that may model aspects of painful diabetic neuropathy. This study examined the contribution of spinal prostaglandin production to this exaggerated hyperalgesic behavior. Rats were implanted with spinal dialysis probes and received noxious stimulation to the hind paw by subcutaneous injection of 0.5% formalin solution. Prostaglandin E 2 (PGE 2 ) was measured in dialysates of lumbar spinal cerebrospinal fluid concurrent with behavioral responses to formalin injection. In separate experiments, formalin-evoked behavioral responses were measured after intrathecal delivery of either a cyclooxygenase inhibitor or an EP 1 receptor antagonist, and cyclooxygenase protein was measured in spinal cord homogenates. Diabetic rats exhibited exaggerated behavioral responses to paw formalin injection and a concurrent prolongation of formalin-evoked PGE 2 release. Formalin-evoked behavioral responses were dose-dependently reduced in diabetic rats by spinal delivery of a cyclooxygenase inhibitor or an EP 1 receptor antagonist. Protein levels of cyclooxygenase-2 were elevated in the spinal cord of diabetic rats, whereas cyclooxygenase-1 protein was reduced. Hyperalgesic behavior in diabetic rats is associated with both increased cyclooxygenase-2 protein and cyclooxygenase-mediated PGE 2 release. Spinal delivery of selective inhibitors of cyclooxygenase-2 or antagonists of prostaglandin receptors may have therapeutic potential for treating painful diabetic neuropathy. Diabetes 51: 2249 -2255, 2002 A proportion of patients with diabetic neuropathy report aberrant sensations that may range from exaggerated perception of sensory stimuli to spontaneous paresthesias and pain. Morphometric analyses of peripheral nerves from patients with painful diabetic neuropathy have been unable to find clear associations with either nerve fiber degeneration or regeneration (1,2). In the absence of simple structural correlates in the peripheral nerves, it is plausible that neurochemical abnormalities at the peripheral, spinal, or supraspinal levels could contribute to painful diabetic neuropathy.Diabetic rats also display evidence of altered sensory processing, as illustrated by behavioral studies in which nocifensive responses to normally nonpainful stimuli (allodynia) and exaggerated responses to stimuli that usually produce mild nocifensive responses (hyperalgesia) were reported. Thus, allodynia to light touch (3) or mechanical pressure (4) and hyperalgesia after paw formalin injection (5,6) all develop within weeks of the onset of hyperglycemia and can be corrected by instituting a protracted period of tight glycemic control (3,7). Rats with short-term (4 weeks) experimental diabetes do not exhibit marked fiber degeneration or regeneration in their peripheral (8) or cutaneous (9) nerves. They may therefore allow investigation of the contribution of neurochemical disorders to the behavioral indexes of hyperalgesia and also provide a model for the assessment of p...

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Section: Discussionmentioning

confidence: 78%

Elevated Spinal Cyclooxygenase and Prostaglandin Release During Hyperalgesia in Diabetic Rats

et al. 2002

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“…We have previously demonstrated a clear reduction in cross-sectional area of the spinal cord in patients with established DPN (7). More recently, we reported that this reduction in spinal cord volume was found early in the neuropathic process in DPN, even in patients with subclinical DPN (8).…”

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confidence: 72%

Magnetic Resonance Neuroimaging Study of Brain Structural Differences in Diabetic Peripheral Neuropathy

et al. 2014

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OBJECTIVEDiabetic peripheral neuropathy (DPN) has hitherto been considered a disease of the peripheral nervous system only, with central nervous system (CNS) involvement largely overlooked. The aim of this study was to investigate any differences in brain structure in subjects with DPN. RESEARCH DESIGN AND METHODSThirty-six subjects with type 1 diabetes (No DPN [n = 18], Painful DPN [n = 9], Painless DPN [n = 9]) underwent neurophysiological assessment to quantify the severity of DPN. All subjects, including 18 healthy volunteers (HVs), underwent volumetric brain magnetic resonance imaging at 3 Tesla. RESULTSAdjusted peripheral gray matter volume was statistically significantly lower in subjects with painless and painful DPN (mean 599.6 mL [SEM 9.8 mL] and 585.4 mL [10.0 mL], respectively) compared with those with No DPN (626.5 mL [5.7 mL]) and HVs (639.9 mL [7.2 mL]; ANCOVA, P = 0.001). The difference in adjusted peripheral gray matter volume between subjects with No DPN and HVs and those with Painful DPN and Painless DPN was not statistically significant (P = 0.16 and 0.30, respectively). Voxel-based morphometry analyses revealed greater localized volume loss in the primary somatosensory cortex, supramarginal gyrus, and cingulate cortex (corrected P < 0.05) in DPN subjects. CONCLUSIONSThis is the first study to focus on structural changes in the brain associated with DPN. Our findings suggest increased peripheral gray matter volume loss, localized to regions involved with somatosensory perception in subjects with DPN. This may have important implications for the long-term prognosis of DPN.Diabetic peripheral neuropathy (DPN) is a common, debilitating, and distressing complication that develops in up to 30-50% of patients with diabetes (1). A painless distal symmetrical sensorimotor neuropathy, which increases the risk of foot ulceration and subsequent amputation, develops in most patients. In a significant proportion of patients, a chronic painful condition also develops, which can result in considerable disability and suffering. Although various vascular and metabolic factors (2) have been implicated, a complete understanding of the pathogenesis of DPN remains elusive (3,4). DPN has hitherto been considered a disease of the peripheral

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“…A possible explanation for the substantial number of negative trial stimulations might be the presence of permanent central changes in the spinal cord. Three observational studies reported a smaller mean spinal cord area index at the cervical and thoracic level in patients with diabetic peripheral neuropathy as compared with control patients without DM (38)(39)(40). Whether involvement of the spinal cord is a primary or secondary event in diabetic peripheral neuropathy is not yet clear (39).…”

Section: Discussionmentioning

confidence: 99%

Spinal Cord Stimulation and Pain Relief in Painful Diabetic Peripheral Neuropathy: A Prospective Two-Center Randomized Controlled Trial

et al. 2014

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OBJECTIVEPainful diabetic peripheral neuropathy (PDPN) is a common complication of diabetes mellitus. Unfortunately, pharmacological treatment is often partially effective or accompanied by unacceptable side effects, and new treatments are urgently needed. Small observational studies suggested that spinal cord stimulation (SCS) may have positive effects. RESEARCH DESIGN AND METHODSWe performed a multicenter randomized clinical trial in 36 PDPN patients with severe lower limb pain not responding to conventional therapy. Twenty-two patients were randomly assigned to SCS in combination with the best medical treatment (BMT) (SCS group) and 14 to BMT only (BMT group). The SCS system was implanted only if trial stimulation was successful. Treatment success was defined as ‡50% pain relief during daytime or nighttime or "(very) much improved" for pain and sleep on the patient global impression of change (PGIC) scale at 6 months. RESULTSTrial stimulation was successful in 77% of the SCS patients. Treatment success was observed in 59% of the SCS and in 7% of the BMT patients (P < 0.01). Pain relief during daytime and during nighttime was reported by 41 and 36% in the SCS group and 0 and 7% in the BMT group, respectively (P < 0.05). Pain and sleep were "(very) much improved" in 55 and 36% in the SCS group, whereas no changes were seen in the BMT group, respectively (P < 0.001 and P < 0.05). One SCS patient died because of a subdural hematoma. CONCLUSIONSTreatment success was shown in 59% of patients with PDPN who were treated with SCS over a 6-month period, although this treatment is not without risks.Painful diabetic peripheral neuropathy (PDPN) is a common complication of diabetes mellitus (DM), and prevalence of PDPN ranges from 10 to 26% (1-3). In many patients, the pain is of such intensity that it has a major impact on patients' health-related quality of life (HRQoL) and functional ability, including interference with general activity, mood, mobility, work, social relations, sleep, and enjoyment of life (4).

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Spinal-cord involvement in diabetic peripheral neuropathy

Cited by 136 publications

References 3 publications

Elevated Spinal Cyclooxygenase and Prostaglandin Release During Hyperalgesia in Diabetic Rats

Elevated Spinal Cyclooxygenase and Prostaglandin Release During Hyperalgesia in Diabetic Rats

Magnetic Resonance Neuroimaging Study of Brain Structural Differences in Diabetic Peripheral Neuropathy

Spinal Cord Stimulation and Pain Relief in Painful Diabetic Peripheral Neuropathy: A Prospective Two-Center Randomized Controlled Trial

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