Review and Evaluation of European National Clinical Practice Guidelines for the Treatment and Management of Active Charcot Neuro-Osteoarthropathy in Diabetes Using the AGREE-II Tool Identifies an Absence of Evidence-Based Recommendations.

Background: Charcot neuro-osteoarthropathy (CNO) is a rare but devastating complication of diabetes associated with high rates of morbidity; yet, many nonfoot specialists are unaware of it, resulting in missed and delayed diagnosis. Clinical practice guidelines (CPGs) have proven useful in improving quality of care and standardizing practice in diabetes and diabetic foot care. However, little is known about the consistency in recommendations for identification and management of active CNO. Aim: The aim of this study is to review European national diabetes CPGs for the diagnosis and management of active CNO and to assess their methodological rigor and transparency. Methods: A systematic search was performed to identify diabetes national CPGs across Europe. Guidelines in any language were reviewed to explore whether they provided a definition for active CNO and recommendations for diagnosis, monitoring, and management. Methodological rigor and transparency were assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE-II) tool, which comprises 23 key items organized within six domains with an overall guideline assessment score of ≥ 60% considered to be of adequate quality to recommend use. Each guideline was assessed by two reviewers, and inter-rater agreement (Kendall's W) was calculated for AGREE-II scores. Results: Seventeen CPGs met the inclusion criteria. Breadth of CNO content varied across guidelines (median (IQR) word count: 327; Q1 = 151; Q3 = 790), and 53% provided a definition for active CNO. Recommendations for diagnosis and monitoring were provided by 82% and 53%, respectively, with offloading being the most common management recommendation (88%). Four guidelines (24%) reached threshold for recommendation for use in clinical practice (≥ 60%) with the scope and purpose domain scoring highest (mean (SD): 67%, ± 23%). The remaining domains had average scores ranging between 19% and 53%. Inter-rater agreement was strong (W = 0.882; p < 0.001). Conclusions: European national CPGs for diabetes provide limited recommendations on active CNO. All guidelines showcased deficits in their methodology, suggesting that more rigorous methods should be employed for diabetes CPG development across Europe.

Infrared Thermography Shows That a Temperature Difference of 2.2°C (4°F) or Greater Between Corresponding Sites of Neuropathic Feet Does Not Always Lead to a Diabetic Foot Ulcer.

BACKGROUND: There is emerging interest in the application of foot temperature monitoring as means of diabetic foot ulcer (DFU) prevention. However, the variability in temperature readings of neuropathic feet remains unknown. The aim of this study was to analyze the long-term consistency of foot thermograms of diabetic feet at the risk of DFU. METHODS: A post-hoc analysis of thermal images of 15 participants who remained ulcer-free during a 12-month follow-up were unblinded at the end of the trial. Skin foot temperatures of 12 plantar, 15 dorsal, 3 lateral, and 3 medial regions of interests (ROIs) were derived on monthly thermograms. The temperature differences (∆Ts) of corresponding ROIs of both feet were calculated. RESULTS: Over the 12-month study period, out of the total 2026 plantar data points, 20.3% ROIs were rated as abnormal (absolute ∆T ≥ 2.2°C). There was a significant between-visit variability in the proportion of plantar ROIs with ∆T ≥ 2.2°C (range 7.6%-30.8%, chi-square test, P = .001). The proportion of patients presenting with hotspots (ROIs with ∆T ≥ 2.2°C), abnormal plantar foot temperature (mean ∆T of 12 plantar ROIs ≥ 2.2°C), and abnormal whole foot temperature (mean ∆T of 33 ROIs ≥ 2.2°C) varied between visits and showed no pattern (P > .05 for all comparisons). This variability was not related to the season of assessment. CONCLUSIONS: Despite the high rate of hotspots on monthly thermograms, all feet remained intact. This study underscores a significant between-visit inconsistency in thermal images of neuropathic feet which should be considered when planning DFU-prevention programs for self-testing and behavior modification.

HPV-associated oropharyngeal carcinomas in patients living with HIV on long-term antiretroviral therapy: Case reports.

In the 1970s, human papillomaviruses (HPV) were ascertained as the aetiologic agents of cervical carcinoma. Subsequently, an association with HPV was established in other epithelial tumours, including squamous cell carcinoma of the head and neck (HNSCC). HPV has demonstrated a high potential for inducing oropharyngeal tumours, with HPV-16 infection posing a significant oncogenic risk. People living with HIV (PLWH) are identified as being at a higher risk of HPV infection and the subsequent development of HPV-associated tumours of the oropharynx. We present two patients under the care of the Department of AIDS with long-term HIV infections who were newly diagnosed with HPV-associated carcinomas of the tonsils. Both patients had been on antiretroviral therapy (ART) for over 15 years, achieving optimal viral suppression for more than 10 years. Chemotherapy and radiation therapy were employed in the treatment of the carcinomas. Throughout the neoplastic disease treatment, both patients maintained optimal viral suppression for HIV. The presented cases underscore the fact that despite achieving long-term optimal viral suppression of HIV, people living with HIV remain susceptible to the development of HPV-associated neoplasms.

Autochthonous and Imported Visceral Leishmaniasis in Bulgaria-Clinical Experience and Treatment of Patients.

Visceral leishmaniasis (VL) is a severe endemic disease with a fatal outcome if left untreated. The symptoms of patients are diverse and atypical. Against the background of anemia and pancytopenia, the condition of the patients gradually worsens with marked cachexia. Through sharing our experience, we aim to draw attention to this deadly disease. Clinical and laboratory data for 58 patients with VL treated over a forty-five-year period are presented. The diagnosis was established within a duration of 1 to 28 months of illness. Continuous fever (38-42 °C), splenomegaly, hepatomegaly, severe anemia (decreased hemoglobin to lowest values of 31 g/L), leucopenia (lowest values of leucocytes et 0.5 g/L), and thrombocytopenia (reduced thrombocyte count to 29 g/L) were observed. The diagnosis was made on the basis of microscopic evidence of amastigote forms in bone marrow smears and serological tests. The patients were treated with Glucantime for 17 to 21 days. Relapses were observed in seven patients (12.1%) and fatal outcome was observed in two patients (3.5%) during treatment, who developed acute respiratory and cardiovascular failure. In Bulgaria, Visceral leishmaniasis is primarily endemic in the southern regions and should be suspected not only in patients who have returned from tropical and subtropical countries, but also in those who have not traveled abroad. The challenges associated with VL stem from delayed diagnosis of patients, as this disease remains unrecognized by physicians.

Guidelines on the diagnosis and treatment of active Charcot neuro-osteoarthropathy in persons with diabetes mellitus (IWGDF 2023).

The International Working Group on the Diabetic Foot (IWGDF) has published evidence-based guidelines on the prevention and management of diabetic foot disease since 1999. This is the first guideline on the diagnosis and treatment of active Charcot neuro-osteoarthropathy in persons with diabetes published by the IWGDF. We followed the GRADE Methodology to devise clinical questions in the PACO (Population, Assessment, Comparison, Outcome) and PICO (Population, Intervention, Comparison, Outcome) format, conducted a systematic review of the medical literature, and developed recommendations with the rationale. The recommendations are based on the evidence from our systematic review, expert opinion when evidence was not available, and also taking into account weighing of the benefits and harms, patient preferences, feasibility and applicability, and costs related to an intervention. We here present the 2023 Guidelines on the diagnosis and treatment of active Charcot neuro-osteoarthropathy in persons with diabetes mellitus and also suggest key future topics of research.

Diagnosis and treatment of active charcot neuro-osteoarthropathy in persons with diabetes mellitus: A systematic review.

BACKGROUND: There are uncertainties regarding the diagnostic criteria, optimal treatment methods, interventions, monitoring and determination of remission of Charcot neuro-osteoarthropathy (CNO) of the foot and ankle in people with diabetes mellitus (DM). The aims of this systematic review are to investigate the evidence for the diagnosis and subsequent treatment, to clarify the objective methods for determining remission and to evaluate the evidence for the prevention of re-activation in people with CNO, DM and intact skin. METHODS: We performed a systematic review based on clinical questions in the following categories: Diagnosis, Treatment, Identification of Remission and Prevention of Re-Activation in people with CNO, DM and intact skin. Included controlled studies were assessed for methodological quality and key data from all studies were extracted. RESULTS: We identified 37 studies for inclusion in this systematic review. Fourteen retrospective and observational studies relevant to the diagnosis of active CNO with respect to clinical examination, imaging and blood laboratory tests in patients with DM and intact skin were included. We identified 18 studies relevant to the treatment of active CNO. These studies included those focused on offloading (total contact cast, removable/non-removable knee high devices), medical treatment and surgical treatment in the setting of active CNO. Five observational studies were identified regarding the identification of remission in patients who had been treated for active CNO. We did not identify any studies that met our inclusion criteria for the prevention of re-activation in patients with DM and intact skin who had been previously treated for active CNO and were in remission. CONCLUSIONS: There is a paucity of high-quality data on the diagnosis, treatment, and prognosis of active CNO in people with DM and intact skin. Further research is warranted to address the issues surrounding this complex disease.

Molecular Analysis of Dihydropteroate Synthase Gene Mutations in Pneumocystis jirovecii Isolates among Bulgarian Patients with Pneumocystis Pneumonia.

Pneumocystis jirovecii pneumonia (PCP) is a significant cause of morbidity and mortality in immunocompromised people. The widespread use of trimethoprim-sulfamethoxazole (TMP-SMZ) for the treatment and prophylaxis of opportunistic infections (including PCP) has led to an increased selection of TMP-SMZ-resistant microorganisms. Sulfa/sulfone resistance has been demonstrated to result from specific point mutations in the DHPS gene. This study aims to investigate the presence of DHPS gene mutations among P. jirovecii isolates from Bulgarian patients with PCP. A total of 326 patients were examined via real-time PCR targeting the P. jirovecii mitochondrial large subunit rRNA gene and further at the DHPS locus. P. jirovecii DNA was detected in 50 (15.34%) specimens. A 370 bp DHPS locus fragment was successfully amplified in 21 samples from 19 PCP-positive patients, which was then purified, sequenced, and used for phylogenetic analysis. Based on the sequencing analysis, all (n = 21) P. jirovecii isolates showed DHPS genotype 1 (the wild type, with the nucleotide sequence ACA CGG CCT at codons 55, 56, and 57, respectively). In conclusion, infections caused by P. jirovecii mutants potentially resistant to sulfonamides are still rare events in Bulgaria. DHPS genotype 1 at codons 55 and 57 is the predominant P. jirovecii strain in the country.

Grading Fractures on Foot and Ankle X-rays and MRI Scans in the Active Charcot Foot in Diabetes: How Strong Is the Agreement Between Modalities?

OBJECTIVE: To compare X-ray and MRI as diagnostic tests of active Charcot neuro-osteoarthropathy (CNO) in diabetes. RESEARCH DESIGN AND METHODS: X-rays and MRI scans of 48 participants were rated for severity of fracture (0 = no fracture, 1 = fracture, 2 = collapse/fragmentation), and for absence/presence of bone marrow edema (BME) on MRI and absence/presence of bone injury on X-ray. The agreement between modalities was assessed with tests for symmetry, marginal homogeneity, and κ-coefficients. RESULTS: X-ray underscored MRI in grading fractures in the metatarsals (P = 0.05) and tarsals (P < 0.001) and reported as normal 79% of the bones with BME. The agreement between X-ray and MRI for grading severity of fracture was moderate to substantial (κ = 0.53; P < 0.001) and for detecting bone injury, slight to fair (κ = 0.17; P < 0.001). CONCLUSIONS: The significant underperformance of X-ray in the assessment of the hot, swollen foot in diabetes should be considered when confirming or refuting the diagnosis of active CNO.

Study on the Prevalence of Pneumocystis jirovecii as a Causative Agent of Lung Pathology in People with Different Immune Status.

BACKGROUND: Pneumocystis pneumonia (PCP) commonly affects immunocompromised individuals, whereas in immunocompetent persons, it occurs relatively rarely, and in most cases, the Pneumocystis infection is detected as an asymptomatic colonization. The present study aimed to establish the prevalence of Pneumocystis jirovecii infection in human hosts with different immune status (immunocompromised and immunocompetent), using molecular diagnostic methods, and to compare their diagnostic value with that of classical staining methods. METHODS: We used the collected-to-this-moment data from a prospective study on the prevalence of pneumocystosis among the Bulgarian population. Clinical specimens (including throat secretions, induced sputum, tracheal aspirates, and bronchoalveolar lavage) collected from 220 patients suspected of PCP (153 immunocompetent and 67 immunocompromised patients) were examined with microscopic staining methods and real-time PCR for detection of P. jirovecii. Results: DNA of the pathogen was detected in 38 (17%) specimens (32 immunocompromised patients and 6 immunocompetent subjects). From all 220 clinical samples examined by staining methods, only five (2%) P. jirovecii cysts were detected by the Gomori stain. All patients with PCP were treated with trimethoprim-sulfamethoxazole, but in ten of them (HIV-positive patients), the disease had a fatal outcome. CONCLUSIONS: This study is the first in Bulgaria including the main available laboratory methods for diagnosis of human pneumocystosis. Regarding the etiological diagnosis of PCP, in our study the sensitivity of real-time PCR was higher compared to the staining methods. The choice of a method for sample collection and examination has an important role in the efficiency of the laboratory diagnostics.

Onset of an Active Charcot Foot in a Person with Longstanding Type 1 Diabetes and Normal Vibration Perception Threshold-A Case Report.

Charcot neuro-osteoarthropathy (CNO), or Charcot foot, is a disabling complication of diabetes, which is poorly understood and frequently overlooked. We describe an atypical presentation of an active Charcot foot in a woman with a long-standing type 1 diabetes who did not exhibit loss of protective sensation (sensate to a 10-gram monofilament) or loss of vibration sensation. These standard measures of large nerve fibre function ruled out "classical" neuropathy. However, additional testing showed reduced sweat gland function most likely related to degeneration of c-fibres (small fibre neuropathy). This case raises the awareness that in addition to the "textbook" description, in diabetes, Charcot foot can develop in individuals with "minimal" or "no signs" of clinical neuropathy. The onset of active Charcot foot should be suspected in every person with diabetes and history of trauma even when foot and ankle x-rays are normal. Offloading should be initiated until the diagnosis is proven otherwise.

Stage 0 Charcot Neuroarthropathy in the Diabetic Foot: An Emerging Narrow Window of Opportunity?

In a world where popular culture and concepts can become the norm without all the rigors of normal scrutiny, our attention is focused on identifying Charcot neuroarthropathy (CN) at a stage before radiological bone destruction occurs. The rationale is that early recognition can prevent a destructive chain of events and thus potentially reduce the burden to patients and health care providers. In this article, we describe the evolution of stage 0 CN, and the use of modern imaging in characterizing the abnormalities recognized by these modalities and how they aid our understanding and supplement our knowledge. We review the potential of these imaging modalities, assessing how far we have come in characterizing stage 0 and if we have robust criteria for the identification of stage 0 in the natural history of CN.

People living with diabetes are unaware of their foot risk status or why they are referred to a multidisciplinary foot team.

AIM: People with active diabetic foot disease should be rapidly referred by health professionals along a pathway of care to a multidisciplinary foot team. The aim was to investigate patients' self-reported understanding of their foot risk status and reasons for their referral to a multidisciplinary foot team. METHOD: This seven-month service evaluation included consecutive newly referred patients. Participants completed a questionnaire which asked firstly about their understanding of their foot risk status, secondly about their pathway of care before presentation to the multidisciplinary foot team, and thirdly about their interest in diabetes-related foot education and preferred learning style. RESULTS: There were 202 participants; 65% were male, mean age was 64±15 years (mean±standard deviation (SD)), 86% had type 2 diabetes, and mean HbA1c was 65±23mmol/mol (8.3±3.7%). Only 4% of participants knew their current foot risk status and 52% did not know why their care had been escalated to a multidisciplinary foot clinic. Participants with type 2 diabetes more readily expressed an interest in further foot education compared with participants with type 1 diabetes, (70% versus 29%, p=0.001). CONCLUSIONS: These findings show that people with diabetes and foot disease are less aware of their foot risk status or why they are referred to a multidisciplinary team. Participants indicated a variable interest in further learning about foot complications. These findings indicate possible communication and educational barriers between patients and health professionals which may contribute to delayed presentation or suboptimal engagement.

Effect of Recombinant Human Parathyroid Hormone (1-84) on Resolution of Active Charcot Neuro-osteoarthropathy in Diabetes: A Randomized, Double-Blind, Placebo-Controlled Study.

OBJECTIVE: Fractures in Charcot neuro-osteoarthropathy (CN) often fail to heal despite prolonged immobilization with below-knee casting. The aim of the study was to assess the efficacy of recombinant human parathyroid hormone (PTH) in reducing time to resolution of CN and healing of fractures. RESEARCH DESIGN AND METHODS: People with diabetes and acute (active) Charcot foot were randomized (double-blind) to either full-length PTH (1-84) or placebo therapy, both in addition to below-knee casting and calcium and vitamin D3 supplementation. The primary outcome was resolution of CN, defined as a skin foot temperature difference >2°C at two consecutive monthly visits. RESULTS: Median time to resolution was 5 months (95% CI 4, 12) in intervention and 6 months (95% CI 2, 9) in control. On univariate mixed Cox and logistic regression, there was no significant difference in time to resolution between the groups (P = 0.64) or in the likelihood of resolution (P = 0.66). The hazard ratio of resolution was 0.84 (95% CI 0.41, 1.74; P = 0.64), and the odds ratio of resolution by 12 months was 0.80 (95% CI 0.3, 2.13; P = 0.66) (intervention vs. control). On linear regression analysis, there were no significant differences in the effect of treatment on fracture scores quantitated on MRI scans (coefficient 0.13 [95% CI -0.62, 0.88]; P = 0.73) and on foot and ankle X-rays (coefficient 0.30 [95% CI -0.03, 0.63]; P = 0.07). CONCLUSIONS: This double-blind placebo-controlled trial did not reduce time to resolution or enhance fracture healing of CN. There was no added benefit of daily intervention with PTH (1-84) to below-knee casting in achieving earlier resolution of CN.

The Role of Bone Scintigraphy with SPECT/CT in the Characterization and Early Diagnosis of Stage 0 Charcot Neuroarthropathy.

We describe the use of Single Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) in the investigation and diagnosis of Charcot neuroarthropathy (CN) in patients with a hot swollen foot but normal radiographs and clinical suspicion of CN, usually termed Stage 0. This was a retrospective cohort review of 46 diabetes patients who underwent 3 phase bone scintigraphy with "High Resolution" SPECT/CT. The imaging demonstrated that Stage 0 Charcot foot has a distinct bone pathology, which can be classified into three groups: (1) fractures on Computed Tomography (CT) with accompanying focal uptake of tracer on SPECT, (2) bony abnormalities apart from fracture on CT with focal uptake of tracer on SPECT, and (3) normal CT but focal bony uptake of tracer on SPECT. The CT component of SPECT/CT detected bony fractures in 59% of patients. Early treatment with below knee cast and follow-up for 24 months showed only 4 patients who developed Stage 1 Eichenholtz Charcot foot. Our findings support the use of 3 phase bone scintigraphy with SPECT/CT in the characterization and early diagnosis of CN. Stage 0 Charcot foot has a distinct bone pathology which requires urgent treatment to prevent progression to Stage 1 Eichenholtz Charcot foot. If SPECT/CT is unavailable, CT alone will detect bone fracture in 59% patients.

Between visit variability of thermal imaging of feet in people attending podiatric clinics with diabetic neuropathy at high risk of developing foot ulcers.

OBJECTIVE: People with diabetic neuropathy who have previously ulcerated are at high risk of re-ulceration. They should regularly attend podiatry clinics for surveillance and routine protective podiatric treatment. It has been suggested that inflammation prior to skin breakdown shows up as a hotspot on a thermal image even in the absence of clinical signs. The aim of this study is to quantify inter-patient and intra-patient thermal variations presented by diabetic feet at high risk of ulceration. APPROACH: Whole foot and spot temperatures were recorded for 96 patients who attended two successive podiatry appointments without ulceration 28 [28, 31] days apart, median [interquartile range]. This was a part of a longer study into whether thermal imaging in clinic can reduce the rate of re-ulceration. MAIN RESULTS: The variation in spot temperature right/left differences for single patients between visits was comparable to the variation observed between patients (0.8 [0.3, 1.5] °C compared with 0.9 [0.4, 1.7] °C). Similarly, whole foot temperature variation for a single patient between visits was comparable to the variation observed between patients (0.6 [0.2, 1.1] °C compared with 0.8 [0.2, 1.3] °C). SIGNIFICANCE: Thresholds which depend on thermal differences from visit to visit are unlikely to have sufficient specificity to effectively target treatment designed to prevent the development of foot ulcers.

Thermal symmetry of healthy feet: a precursor to a thermal study of diabetic feet prior to skin breakdown.

Early identification of areas of inflammation may aid prevention of diabetic foot ulcers. A new bespoke thermal camera system has been developed to thermally image feet at risk. Hotspots (areas at least 2.2 °C hotter than the contralateral site) may indicate areas of inflammation prior to any apparent visual signs. This article describes the thermal pattern and symmetry of 103 healthy pairs of feet. 68% of participants were thermally symmetric at the 33 foot sites measured. 32% of participants had at least one hotspot, but hotspots overall only accounted for 5% of the measurements made. Refinements to the definition of hotspots are proposed when considering feet at risk of ulceration.

Conservative and Pharmacologic Treatments for the Diabetic Charcot Foot.

Charcot neuroarthropathy is a disabling complication of diabetic neuropathy. Prolonged immobilization in a total contact cast (TCC) is among the main treatments. Education of health care professionals in the application of TCC together with well-conducted clinical trials are required to overcome its frequent underuse. There are no established pharmacologic therapies to treat this condition; however, there is an overwhelming need for a new therapeutic approach. Novel targeted drug delivery systems are required to prevent the pathologic bone and joint destruction of the Charcot neuroarthropathy and this may lead to an improved outcome in diabetic patients with this condition.

Inhibition of TNF-α Reverses the Pathological Resorption Pit Profile of Osteoclasts from Patients with Acute Charcot Osteoarthropathy.

We hypothesised that tumour necrosis factor-α (TNF-α) may enhance receptor activator of nuclear factor-κß ligand- (RANKL-) mediated osteoclastogenesis in acute Charcot osteoarthropathy. Peripheral blood monocytes were isolated from 10 acute Charcot patients, 8 diabetic patients, and 9 healthy control subjects and cultured in vitro on plastic and bone discs. Osteoclast formation and resorption were assessed after treatment with (1) macrophage-colony stimulating factor (M-CSF) and RANKL and (2) M-CSF, RANKL, and neutralising antibody to TNF-α (anti-TNF-α). Resorption was measured on the surface of bone discs by image analysis and under the surface using surface profilometry. Although osteoclast formation was similar in M-CSF + RANKL-treated cultures between the groups (p > 0.05), there was a significant increase in the area of resorption on the surface (p < 0.01) and under the surface (p < 0.01) in Charcot patients compared with diabetic patients and control subjects. The addition of anti-TNF-α resulted in a significant reduction in the area of resorption on the surface (p < 0.05) and under the surface (p < 0.05) only in Charcot patients as well as a normalisation of the aberrant erosion profile. We conclude that TNF-α modulates RANKL-mediated osteoclastic resorption in vitro in patients with acute Charcot osteoarthropathy.