Conclusion
In patients with DM, chronic lower extremity wounds can generally be categorized as either neuropathic or neuroischemic. Wounds can be further stratified using the four factors of the WIfI threatened limb classification system: wound, ischemia, foot infection and function.21 22 Wounds arising in patients with peripheral neuropathy without signs of vascular disease are considered neuropathic, as loss of protective sensation and disruption of autonomic function are the primary causes of ulceration. In patients with vascular disease, reduced blood flow leads to necrosis of tissue in poorly perfused angiosomes. While patients with DM can develop purely ischemic wounds, chronic ulceration is most often neuropathic or neuroischemic, as purely ischemic wounds are relatively rare.23 These two patients were selected because their medical histories and clinical course are consistent with the classic presentation of neuropathic (1) and neuroischemic (2) wounds.
SFDI biomarkers provide an insight to the differing pathological processes of these two types of wounds. Previous studies have shown baseline perfusion differences between patients with DM and patients without DM, as well as statistically significant differences between PAD patients with and without DM.18 These differences are likely related to the microangiopathy and autonomic neuropathy seen in DM. As early as 91 days prior to the ulceration of patient 1’s right second MTPJ, a relative increase in StO2 and decrease in HbT1 was observed when compared with the contralateral foot’s corresponding region of interest—a finding consistent with the previous studies showing significant differences in both the global baseline and ulcer-preceding elevations of StO2 in patients with DM.14 18 This localized pattern of covariation (elevated StO2 and recessed HbT1) seems to signal at-risk sites due to mechanical stresses (ie, high plantar pressure and repetitive trauma) that precipitate pre-ulcer lesions and skin breakdown. This explanation is further supported by callus development at the left second MTPJ at week 13 following a similar, but less pronounced, focal StO2 and HbT1 appearance. Another corroborating detail is the anatomical shift in StO2 and HbT1 signatures over to the adjacent third MTPJ following right second MTPJ osteotomy, which may indicate plantar stress redistribution.
StO2 represents the ratio between oxy-Hb and total Hb (oxy-Hb+deoxy-Hb).24 Therefore, an increased StO2 in the presence of decreased HbT1 serves as a marker of dermal microcirculation dysfunction within the papillary dermis. Capillary basement membrane thickening from chronic hyperglycemia may reduce O2 diffusion into the surrounding tissue,25 thus causing a relative decrease in deoxy-Hb and consequentially elevating StO2. Another contributing factor to reduced deoxy-Hb is autonomic neuropathy, where loss of vasomotor tone on the dermal AV shunts allows blood to bypass the papillary plexus.26 27 The highest concentration of these dermal AV shunts are on the palmar and plantar surfaces of the hands and feet28; physiologically, autonomic regulation of these shunts allows the sympathetic nervous system to promote heat loss by increasing superficial dermal blood flow. Pathologically, this likely reduces the transport of O2 and nutrients to the dermal regenerative cells, inhibiting wound healing and exacerbating neuropathy by reducing perfusion of the vasa nervorum.28
Changes in microvascular function are well documented in patients with neuropathic foot ulcers. SFDI could potentially be used as a tool for functional assessment of microcirculatory changes, as patients with diabetes with foot ulcers demonstrate an impaired skin vasodilatory response to pressure, acetylcholine administration, lower extremity heating and ischemia-induced reactive hyperemia when compared with non-ulcer patients with diabetes and healthy controls.29 30 Given the notable differences in vasodilatory response between ulcer and non-ulcer patients with diabetes, the ability of SFDI to detect impaired microcirculatory responses to pressure and heat should be tested, as this may be an effective way of identifying patients at risk of ulceration.
The neuroischemic perfusion signatures from patient 2 show a different pre-ulcer microcirculatory environment to that of patient 1: elevated HbT1 and HbT2 at the eventual wound site and surrounding area. These features were apparent as early as 9 weeks prior to ulceration. On visible wound presentation, there is low tissue oxygenation; thus, the coinciding elevated HbT1 may indicate an accumulation of deoxy-Hb within the superficial dermis. While patient 1 had minimal differences in HbT2 between corresponding regions of interest, ulcers 2a and 2b both demonstrated increased HbT2 when compared with global foot perfusion. The combination of low StO2 with increased HbT1 and HbT2 may signify pooling of deoxy-Hb in the dermal microcirculation.
For patients with DM, neuroischemic wounds are more commonly found at the foot margins, while neuropathic ulcers tend to form on the plantar surface.31 In 2a, there were focal increases in StO2 and decreases in HbT1 at the initial pre-ulcerative sites on the distal hallux, briefly displaying signatures more consistent with neuropathic ulceration. Since the wound location and patient history is more consistent with a neuroischemic etiology, the transient perfusion changes may be indicative of an acute inflammatory response to tissue necrosis. Moreover, it is conceivable that the local circulation behavior in these cases is a function of the relative severity of PAD, neuropathy and their complex interaction within a given patient. Additional studies are required to investigate the contributory relationship between these component causes and SFDI biomarkers.
It is possible that iatrogenic causes contributed to the amputation of 2a. The addition of a highly vascularized SCIP flap to the patient’s heel may have induced a vascular steal syndrome in the forefoot, as low-pressure vessels in the forefoot were unable to compensate when a parallel circuit (ie, flap) was added. With monophasic flow in the AT and a toe pressure of 0 mm Hg, the patient was at risk for ischemic complications following reconstructive surgery. The patient’s forefoot had minimal collateral circulation, as there was bilateral hypoplasia of the PT, incomplete plantar arterial arches and minimal runoff into the medial plantar arteries on angiography. During the SCIP flap reconstruction, extensive calcification of the PT was noted and the flap was anastomosed with the artery in an end-side fashion; intraoperative flap assessment and follow-up indicated adequate arterial blood supply and venous drainage of the flap. While the treatment of the calcaneal ulcer was successful, 2a had far more tissue loss than 2b during this study. Perfusion changes following reconstructive surgery showed a precipitous drop in StO2 at the hallux and second digit, although global LLE changes were minimal for all biomarkers.
The DVAA was performed since a venous conduit was the only revascularization target; DVAA is reserved as a last resort treatment in limb salvage when severe PAD precludes bypassing to an arterial target, with complications like amputation being common following intervention.32 33 The gangrene rapidly worsened following the DVAA and a TMA was performed about 1 month later. Post-DVAA but pre-TMA, StO2 decreased and HbT2 increased rapidly; HbT1 changed minimally. These perfusion changes may be necrosis-related rather than a result of the venous arterialization, as the StO2 reduction and increased HbT2 seem to precede gross necrotic changes in areas associated with ischemia. This suggests SFDI circulation monitoring could potentially be used as an anatomical delimiting tool in strategizing amputations.
While recent studies using SFDI have attempted to develop statistical models for identifying high-risk pre-ulcerative perfusion signatures,14 classification and analysis of wounds by specific etiology has not been used. Since neuropathic and neuroischemic wounds can be differentiated clinically and occur in patients with particular comorbidities, subset analysis of SFDI data should divide wounds by clinical categorization to differentiate the dermal microcirculatory signals associated with the two most common DM-related wound etiologies. Although these cases demonstrate the proposed pathophysiological model of neuropathic and neuroischemic diabetic foot ulcers, there are inherent limitations given the small number of wounds presented. Going forward, the full dataset of SFDI data from the observational study will be analyzed, stratifying wounds by etiology and time (pre-ulcer, ulcerative, post-ulcer). Wounds with similar etiology and timing will be compared with contralateral controls, if present, and the differences will be pooled to demonstrate if there are statistically significant differences between etiology and time points throughout the healing process. Once larger SFDI datasets have been collected, stratified and analyzed, this technology can begin being tested as an ulcer-prevention tool, with physicians using the dermal microcirculation biomarkers to guide earlier prophylactic measures against lower extremity ulceration.