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International Perspectives On The Diabetic Foot
Edward Jude, MD, from the UK, a diabetologist and endocrinologist, shared his experience in creating a Charcot registry. He shared a study in which he participated where clinicians managing acute Charcot foot in the UK and Ireland registered details on 288 cases from 76 centers on a secure website anonymously. Researchers specifically looked at demographics, causative factors, time to resolution and effects of interventions chosen on time to resolution.1 Other relevant studies that looked at similar metrics showed high risk for ulceration in patients with Charcot, poor applications of offloading guidelines, better efficacy of non-removable offloading methods and a possible lack of benefits of bisphosphonates in this population.1-3
Dr. Jude hypothesizes that Charcot disease may actually be an “orphan disease.” He shares that an orphan disease is one not adopted by the pharmaceutical industry due to little financial incentive in the private sector to develop and market new therapeutic or preventative options.4 Similarly, a rare disease, by European Union (EU) criteria is one affecting less than five out of 10,000 individuals.5 He feels it is possible that Charcot meets these criteria and therefore may be eligible for special research funding under certain circumstances.
Overall, he commented that there is a continued need for clinician and patient participation in a Charcot registry. Challenges include cooperation with follow-up, monitoring accuracy of data collection, standardization of metrics across various countries and quality checks on any devices used. He points out that such a registry is not a clinical trial, and it provides real world evidence as opposed to data. Dr. Jude adds that most clinicians, in his experience, are not researchers, so treatments included in the registry may not be standardized among sites or providers. Lastly, due to the general rarity of the condition, many centers are needed for robust participation. Dr. Jude hopes to participate in the establishment of a prospective data registry in the near future.
Pertinent Pearls In Imaging For Charcot Neuroarthropathy
Ashu Rastogi, MD from India, presented on his experience as an Assistant Professor of Endocrinology on Charcot-related imaging. He recommends bilateral, weight-bearing radiographs when one suspects a Charcot process, including dorsoplantar, lateral and pronated oblique views, remembering that these studies can be normal in early stages. In his experience, he points out focal demineralization as a key early finding, along with absence of soft tissue involvement, a polyarticular distribution and subchondral or periarticular midfoot changes.
Dr. Rastogi shares that in his experience, MRI is best when plain X-rays are normal despite strong clinical suspicion, when there is an overlying ulcer, to differentiate from osteomyelitis and as a follow-up for remission. Advanced MRI techniques may prove helpful in complicated cases, such as diffusion-weighted imaging (DWI). Pure edema would not reveal a diffusion restriction, but pus and inflammatory cells would.6 Magnetic resonance spectroscopy (MRS) with poly unsaturation index (PUI) is another tool for following patients with Charcot. As the patient goes into remission, the PUI will decrease.7
Nuclear scans are not routinely required in Dr. Rastogi’s algorithm, but may have utility when there is skin ulceration, possible secondary osteomyelitis and as follow-up for quiescence of active Charcot. One option is PET/CT with labeled autologous leukocytes, as outlined in a paper in which Dr. Rastogi was the lead author.8 They evaluated 28 patients with Charcot deformity and active foot ulcer that had suspected osteomyelitis and/or acute-on-chronic Charcot. They found this modality to have 100 percent specificity for diagnosis of osteomyelitis in those with concurrent Charcot.8
In summary, Dr. Rastogi reminds the audience that Charcot foot is essentially a clinical diagnosis. Radiology can, however, support the diagnosis when there a strong index of suspicion.
How Can One Halt Acute Charcot?
Dr. Rastogi contends that stopping acute Charcot requires the best possible understanding of the process itself and at what physiologic points one can intervene. Many pharmacotherapeutic options exist. One study on bisphosphonates showed significant decreases in temperature differences from baseline throughout the study, but no significant differences in treatment versus placebo groups.9 Another study on intranasal calcitonin showed reduction in bone turnover markers as compared to placebo.10 However, some of these patients had renal failure, which could also exhibit this change, so overall results were inconclusive.10 Alendronate showed a significant reduction in bone resorption markers along with a slight increase in foot bone mineral density than in the control group.11 These patients also had improvement in the visual analog pain score, but the overall conclusions were again inconclusive due to no clear information on Charcot remission.11
A study of 39 patients receiving intravenous infusions of zoledronic acid looked at how long these patients stayed in a total contact cast.12 In Dr. Rastogi’s opinion, this is one of the most important patient-related outcome measures with respect to Charcot. Interestingly, the study found that those receiving zolendronate necessitated a mean of 27 weeks in total contact casts while the placebo group mean was 20 weeks.12 This likely means the zolendronate was not helpful for active Charcot.
Taking all of this and other research into account, consensus reports still say that offloading remains the gold standard strategy to arrest progression of active Charcot.13 And, overall, evidence is too weak for routine use of bisphosphonates for this same purpose.14 Denosumab, on the other hand, with one injection showed statistically significant improvements in both fracture resolution and total contact casting time.15
Newer insights suggest an inflammatory pathway in the Charcot process may benefit from anti-inflammatory treatment. A study randomized 36 patients to total contact casting with placebo, zoledronic acid or methylprednisolone. Inflammatory cytokines significantly reduced in all three groups. At the end of six months, however, methylprednisolone showed more reduction in TNF-alpha and IL-1beta than the other cohorts.16 Bone mineral content reduced by 13 percent with methylprednisolone, as expected with steroids. Zoledronate increased bone mineral content by 36 percent, however. Median time to remission of active Charcot was around 19.4 weeks with methylprednisolone, 14.6 weeks with zoledronate and 13.5 weeks with total contact cast alone. This supports the consensus statements that total contact cast alone is still best.16
In a systematic review, Dr. Rastogi shares that pharmacotherapy actually increased time to Charcot remission compared to total contact casting by about 0.5 weeks.17 These therapies did increase bone mineral content, caused a decrease in foot temperature and a decrease in alkaline phosphatase.17
What happens after remission of Charcot? Of note, Dr. Rastogi shares that bone mineral density (BMD) was 16 percent less on the foot with Charcot compared to the contralateral foot.18 Also, the bone quality revealed thinner and fewer trabeculae, disorganized, immature, more woven-like bone with more Howship’s lacunae and osteoclasts, similar to osteoporosis.19 So, he and his team conducted a randomized double-blind placebo-controlled study on teriparatide in 20 patients.20 They found that there was significant increase in BMD with teriparatide at three and 12 months. There was also improvement in bone modeling and stabilization of angles of the foot.20
What else can happen after remission of Charcot? In a study of 260 patients with Charcot and two-times matched controls, over five years, there was a fifteen percent mortality rate at five years for those with Charcot, however, patients without Charcot but with diabetes exhibited 9.8 percent mortality. Interestingly after adjustment, patients with Charcot had a 2.72 times risk of mortality compared to the control, most commonly from cardiac autonomic dysfunction.21
Key Considerations In Painful Diabetic Neuropathy
Andrew JM Boulton, MD, President of the International Diabetes Foundation, shares that distal symmetrical polyneuropathy occurs in about one-half of patients with diabetes and is the strongest risk factor for foot ulcer and amputation.
Although DPN is a clinical diagnosis, Dr. Boulton advocates for several points one can assess during screening. First is history of pain, usually presenting in a distal, symmetrical fashion with nocturnal exacerbation. One should assess severity and frequency of pain, along with screening for depression, sleep disturbance and functional deficits due to pain, says Dr. Boulton. One should exclude all other causes of pain as well. A consensus on diagnosing DPN recommends a simple, thorough history and exam with simple instrumentation such as tuning forks, monofilaments and reflex hammers.22 One should test reflexes, proprioception and vibration sense, along with thermal and pin-prick sensation in the clinical setting.
Regarding treatment, FDA-approved drugs for neuropathic pain include pregabalin, duloxetine and tapentadol (an opioid). A recently published study also looked at naltrexone, a competitive opioid receptor antagonist, compared with amitryptiline for DPN.23 This study included 67 subjects, with pain assessed by a visual analog scale. Researchers found similar efficacy, but a superior safety profile with naltrexone.23 Dr. Boulton shares, however, that more research is needed in this area. Opioids and related substances for DPN pain control must take into consideration the opioid crisis and patients should be selected appropriately.
In summary, Dr. Boulton suggests one follows the consensus to assess if pain is actually due to DPN, assess comorbidities, potential for adverse events, drug interaction and cost. Based on this, one selects the best therapy from: pregabalin or gabapentin; serotonin-norepinephrine reuptake inhibitors; or secondary amine tricyclic antidepressants. If there is no clinically meaningful improvement, one can switch agents, combine agents or add tramadol or tapentadol if the previous options fail. If these all do not work, or if pain is not clearly correlated with DPN, then he recommends referral to a pain clinic.30
A Closer Look At The Psychology Of Diabetic Foot Ulcers And Healing
Dr. Boulton stepped in to deliver this lecture originated from Loretta Vileikyte, MD, PhD, who was unable to present personally. He shares that DFUs affect more than just physical health and well-being. They can also affect social, psychological and economic aspects of one’s life.24,25 Specifically neuropathy can predict nonadherence to offloading protocols, delayed healing and reduced quality of life.26,27 Mobility and offloading are central to these issues, specifically showing improvement in quality of life with DFU healing, lower quality of life for DFU versus minor amputation, no difference in quality of life with major amputation vs DFU.28-30
Amputation is the most-feared complication of DFU.31 One-third of patients with a first DFU suffer from depression32, although DFUs themselves do not have an independent association with depression.33 However, clinical depression in those with DFU predicts major amputation and mortality.32 Results are not conclusive, however, on a relationship between depression and DFU healing.
Smart technologies may possibly empower patients to participate meaningfully in their own monitoring and care, creating a continuum between the clinic, provider and patient.34 A study of Australian podiatrists found that expectation of performance most predictive of podiatrist intent to adopt smart insoles into clinical practice. Benefits included better patient knowledge, engagement and self-efficacy. Concerns included potential cost, footwear-related issues and ability of use in the elderly and in remote populations.35
In summary, providers should be aware of the association of emotional distress and poor quality of life with DFU, including a predominant fear of amputation. While depression is a risk factor for first DFU, its role in healing is not conclusive. Foot self-care is shaped by DFU-specific patient beliefs and emotions. When it comes to smart technologies, it behooves the provider to address patient perception of barriers, benefits and challenges to use.
Examining Fall Risk In Patients With Diabetes
Dr. Boulton then changed topics to focus on fall risk in those with diabetes, sharing that patients with diabetic peripheral neuropathy are up to 15-times more likely to fall compared to their age-matched controls.36 Unsteadiness in general has significant ties to diabetes, including that lab tests of imbalance correlate strongly with a patient’s perception thereof.37 He then reviewed examples of various types of balance testing relevant in this population.
Could exercise training help prevent falls in patients with diabetes? There are some studies that exist that show this may be the case, especially with resistance- and balance-type exercise.38 He does caution providers to balance potential benefits of exercise training with possible risks of foot ulcer, and to strive to understand the higher metabolic cost of walking for those with diabetes.
Optimizing Options In Diabetic Footwear
Pt. CPO José Marcelo Carvalho, a physiotherapist and orthotics and prosthetics professional in Brazil, stresses that it is important for the treatment community to achieve consensus on footwear and orthosis characteristics for diabetic feet. He adds that patient education is also paramount, with specific shoe recommendations as opposed to a focus on comfort. Inappropriate shoes or orthotic devices can have significant impact on ulcerations that could lead to amputation, although he notes that there is debate regarding the indication of orthoses for those with diabetes.
In his experience, there is wide usage of flexible-soled shoes by patients with diabetes, which he points out may exacerbate malfunction and pressure from existing biomechanical deformities. He advocates for a comprehensive biomechanical evaluation for these patients, so as to identify the best types of insoles and footwear. He feels that heel height, “drop” of the sole and the angle of the forefoot is particularly important.
He shares several features of ideal diabetic footwear, with one particular point being keeping the foot at an ideal temperature of 29 to 30.5 degrees Celsius through materials that avoid and absorb excessive perspiration. Features that discourage overpronation and increased plantar pressures, along with using a rocker-type sole, are also preferrable in his experience. Appropriate selection of offloading shoes based on the patient case is also important to consider.
Pt. Carvalho goes on to share relevant case studies where footwear and orthoses made a difference in patients with diabetes.
What Do We Know About Microangiopathy In Limb Preservation?
Giacomo Clerici, MD, a diabetic foot surgeon in Milan, Italy, shares the importance of microangiopathy, specifically small arterial disease (SAD) and medial artery calcification in patients with diabetes. Showing angiographic examples of these conditions, he shares a study he participated in that showed that small arterial disease is a strong and independent association with critical limb ischemia, diabetes and dialysis.39 Large artery disease he characterizes as more of a transmission failure, whereas small arterial disease is a failure of distribution.54 Scoring of SAD angiographically carries challenges, requiring multiple injections of contrast, possible spasm or sluggish flow and movement artifacts, in his experience. Due to these issues, he feels that we need an easier, reproducible and universally feasible option for evaluation of this condition.
In his practice, Dr. Clerici sees a strong association between small arterial disease and medial artery calcification. He reinforces that medial arterial calcification and elevated ankle-brachial index (ABI) are associated with foot ulcer, PAD and amputation.40 In another study he participated in, they used a scoring system to evaluate medial arterial calcification based on specific anatomic areas seen on radiographs.56 In his experience and findings, he feels small arterial disease and medial arterial calcinosis are essentially the same disease, so he refers to them as one entity (SAD-MAC). A multivariate analysis in their study actually showed that diabetes alone did not correlate with repeat surgical intervention, major amputation or repeat MAC scoring strongly correlated with revisional foot and vascular intervention, along with major adverse limb events.41 He clarifies that this study garnered support in later research in multiple centers, as well. Dr. Clerici adds that these high-risk patients with chronic limb-threatening ischemia often must consider primary major amputation or palliative care, however he says that foot vein arterialization may represent the only true hope in these patients with no other options.
Understanding The Issues Surrounding Diabetic Foot Infection
Ammar Ibrahim, MD, FACS says that risk factors for diabetic foot infection (DFI) are multifactorial, including neuropathic, vascular, metabolic, behavioral and deformity-related issues, among others. Initially, diagnosis is clinical, with lab tests, vascular assessment, debridment and wound evaluation to quickly follow.42 Tissue specimens for culture are preferrable over swabs.42 DFI can be due to aerobic, Gram-positive cocci in a previously untreated case, or be polymicrobial in deep or chronic wounds.42 He shares common mistakes are failing to debride a wound before culture and culturing uninfected ulcers.
Dr. Ibrahim reminds the audience that plain film X-rays can assess for foreign bodies, soft tissue gas, arterial calcification, bone destruction (osteomyelitis) and deformity in DFI cases. He cautions, though, about X-rays being falsely negative sometimes in early osteomyelitis, along with Charcot neuroarthropathy producing similar radiographic findings to osteomyelitis. MRI can be useful as well.
In his experience, polymicrobial wounds may show three to five organisms on culture, each of potentially differing or unclear significance. One should assume that limb- or life-threatening infections are polymicrobial until proven otherwise, he says. He recommends the Saint Elian Wound Score/Infectious Disease Society of America system to classify DFI and determine severity.42 He explains that essentially all patients with “severe” infection under this system, and some “moderate,” require hospitalization. Accordingly, he feels most patients with “mild” infection can undergo outpatient treatment, but many other factors also contribute.
Regarding antibiotic therapy for osteomyelitis, determining agent of choice depends on infection severity and chronicity and local flora studies at one’s hospital center. One can base empiric treatment on studies such as that by Ghotaslou and colleagues in 2018.43 One should base surgical intervention on the clinical presentation, with an index of suspicion for urgent findings such as gas gangrene or abscess. Overall, he relates that antibiotic resistance is still a significant challenge due to many factors including knowledge being limited to culturable bacteria and that guidelines for DFI at individual institutions would be helpful.
All faculty in this lecture track relate no relevant disclosures.
