Perspectives in Circulation Today
Acute Painful Diabetic Neuritis, Retinopathy and the Circulator Boot
Anecdotal Cases and Pertinent Literature
The Chief of vascular surgery of a Philadelphia University Hospital referred a diabetic gentleman with inoperable leg ischemia to Bryn Mawr Hospital for therapy with the Circulator Boot. He arrived in a wheelchair with his “talking books”; he was functionally blind due to diabetic retinopathy. He did well with his therapy . His vascular surgeon came to check on him on perhaps the eighth hospital day and found him in his room reading a newspaper. Not only had he regained his ability to walk but he had regained his vision! It was apparent that there should be interest in the systemic effects of boot therapy and that patient baseline data might include documentation of all of the complications of diabetes: retinopathy, nephropathy and neuropathy.
Case 143: Peripheral Neuritis and Retinopathy Following Rapid Control of Diabetes . Here are presented the case history, retinal photographs, subcutaneous PO2 findings, EMG's, and NMR spectroscopy studies of a young diabetic women who developed painful peripheral neuritis and suffered a loss of vision when her previously uncontrolled diabetes was rapidly controlled. Salient points in her leg story include her palpable distal pulses, hypoxia documented by subcutaneous electrodes and her NMR studies. Her ophthalmology specialist noted 20/200+ vision and advanced background retinopathy. Associated with her boot therapy were loss of her neuritic pain, improvement in her vision (20/25 and 20/30) and normalization of her hypoxia.
Case 147: Acute Diabetic Papillopathy (?) Reversed in Association with Boot Therapy Twice Eight Years Apart. Here are presented the case history and retinal photographs of a now 65 year old diabetic lady who had episodes of loss of vision at age 43 and 51 associated with diabetic papillopathy both resolving with boot therapy. Now living in Boston, she is lost to her Philadephia physicians but admits to no problems with her vision to her Philadelphia friends.
Simplified view of pathophysiology of "acute" diabetic retinopathy and "acute" neuritis
Glycosylation is both time dependent and hyperglycemia dependent. The higher a blood glucose level and the longer it is elevated the more active the glycosylation process and the greater the accumulation of advanced glycosylation products. The integrity of the endothelium is lessened as pericytes decrease in number and the capillaries become more permeable. The capillary deficits may not be immediately apparent as changes in the blood may tend to compensate; at same time the blood becomes more viscous as erythrocytes tend to aggregate. Further the erythrocytes and the leukocytes stiffen. The serum proteins, platelets and clotting factors are all likewise compromised. The life span of these abnormal products and cells differ. When the glucose level is normalized, the fluidity of the blood may recover faster than the population of pericytes. In the eye and likely in the vasonervorum hemorrhage may develop along with local ischemia; the patient may experience loss of vision and neuritic pain. The increased arterial pulsations associated with Circulator Boot therapy increase circulating fibrinolysins, nitirc oxide and prostacyclin improving flow through the microcirculation.
More on Acute Painful Diabetic Neuritis and Retinopathy
Quadrini et al (2007) concluded that inappropriate local blood flow has a role in the pathogenesis of painful diabetic neuropathy finding an impairment of cutaneous endothelium-related vasodilation and C-fiber-mediated vasoconstriction. Tesfave et al studied 5 subjects with insulin neuritis and found severe abnormalities including arteriolar attenuation, tortuosity and arterio-venous shunting in all subjects. Proliferating neural 'new vessels' which bear striking similarities to those found in the retina and that were more leaky to fluorescein than normal vessels, were observed in three subjects. Venous distension and/or tortuosity was also observed in three subjects, especially in the subject with severe autonomic neuropathy. They suggested epineurial arterio-venous shunting and the fine network of vessels resembling the new vessels of the retina, may lead to a 'steal' effect rendering the endoneurium ischaemic. Kihara et al showed a fall in rat endoneurial oxygen tension in normal nerves with the administration of insulin falling from 26% at 0.04 U/kg insulin to 55% at 32 U/kg. The nerves of rats with streptozotocin-induced diabetes were resistant, but with control of hyperglycemia this susceptibility to the endoneurial hypoxic effect of insulin returned. The reduction in endoneurial oxygen tension regressed with glycosylated hemoglobin (Y = 53.8-2.7X, where Y = %reduction in endoneurial oxygen tension and X = HbA1; r = 0.87; P = < 0.001). Oomen et al,(2004) on the other hand could not show a detrimental effect on the microcirculation by either acute hyperglycemia or acute hyperinsulinemia in type 2 diabetic humans who have a resistance to insulin. Poulaki et al examined these issues further in rats and concluded that acute intensive insulin therapy produces a transient worsening of diabetic blood-retinal barrier breakdown via an HIF-1alpha-mediated increase in retinal VEGF expression. Insulin-induced VEGF expression requires p38 MAPK and PI 3-kinase, whereas hyperglycemia-induced VEGF expression is HIF-1alpha-independent and requires PKC and p42/p44 MAPK.
The Pericyte and Leukocyte
Pericytes are important cellular constituents of the capillaries and post capillary venules and are located abluminal to the endothelial cells and luminal to parenchymal cells. They deposit elements of the basal lamina and are totally surrounded by this vascular component. Pericytes are thought to be local regulatory cells and important to the maintenance of homeostasis and hemostasis. They are lost during incipient diabetic retinopathy. Pfister et al (2008) note hyperglycemia induces angiopoietin-2 (Ang-2) transcription, which modulates capillary pericyte coverage. They showed that changes in pericyte migration could explain the loss of pericytes in the retina and that the process was modulated by the angiopoietin transcription system. Cai et al (2008) likewise found the angiopoietin/Tie-2 system functional in pericytes and playing an important role in the progression of diabetic retinopathy, by regulating pericyte loss and influencing the activation state and recruitment of pericytes. Adding to the loss of pericytes and defects in the capillary wall is increased leukocyte-endothelial cell adhesion and entrapment in the retinal capillaries. Such "retinal leukostasis" is an early event associated with areas of vascular non-perfusion and the development of diabetic retinopathy (Chibber 2007).
The Literature on Boot Therapy and Cerebral and Retinal Vascular Disease
Yu and Zhen (1990) reported that ECP (external counterpulsation) was available in 1800 medical units in China where besides success in treating angina, it was more successful than medication in treating ischemic cerebral diseases. They also had success in treating thrombus of the retinal artery and serous central retinopathy. Such benefits were attributed to the increase in diastolic pressure generated by the treatment. However, hypertension is an important risk factor in the causation of cerebral vascular disease and is especially considered undesirable in cases of cerebral or retinal hemorrhage. Toyota (1999) showed that increases in coronary perfusion induced by the aortic balloon could be inhibited by blocking nitric oxide production. The shear forces generated by booting and increasing endothelial production of prostacyclin, nitric oxide and fibrinolysins were more important than the creation of diastolic hypertension. Werner et al in a series of studies have shown that ECP significantly decreases blood flow to the legs (2007), increases blood flow in the retinal artery in elderly arteriosclerotic patients (but not in younger healthy controls)(2001), and accelerates reperfusion of ischemic areas in the retina (2004). Han et al (2008) have reported a randomized, blinded, crossover trial in giving ECP to stroke patients with large artery occlusive disease. Of his three treatment groups (#1 treated weeks 1-7, #2 no treatment and #3 treated weeks 8-14), the early group had a significant improvement in the NIH Stroke Scale (p<0.042), a tendency for better cerebral blood flow, and a favorable outcome in 100% vs 76% in the late group (p<0.022).Abstracts of above references are found in our website library.