Animal model detects early pathologic changes of Charcot neuropathic arthropathy.

Charcot neuropathic arthropathy is a degenerative, debilitating disease that affects the foot and ankle in patients with diabetes and peripheral neuropathy, often resulting in destruction, amputation. Proposed etiologies include neurotraumatic, inflammatory, and neurovascular. There has been no previous animal model for Charcot. This study proposes a novel rodent model of induced neuropathic arthropathy to understand the earliest progressive pathologic changes of human Charcot. High-fat-diet-induced obese (DIO) Wild-type C57BL/6J mice (n = 8, diabetic) and age-matched low-fat-diet controls (n = 6) were run on an inclined high-intensity treadmill protocol four times per week for 7 weeks to induce mechanical neurotrauma to the hind-paw, creating Charcot neuropathic arthropathy. Sensory function and radiologic correlation were assessed; animals were sacrificed to evaluate hindpaw soft tissue and joint pathology. With this model, Charcot-DIO mice reveals early pathologic features of Charcot neuropathic arthropathy, a distinctive subchondral microfracture callus, perichondral/subchondral osseous hypertrophy/osteosclerosis, that precedes fragmentation/destruction observed in human surgical pathology specimens. There is intraneural vacuolar-myxoid change and arteriolosclerosis. The DIO mice demonstrated significant hot plate sensory neuropathy compared (P < 0.01), radiographic collapse of the longitudinal arch in DIO mice (P < 0.001), and diminished bone density in DIO, compared with normal controls. Despite exercise, high-fat-DIO mice increased body weight and percentage of body fat (P < 0.001). This murine model of diet-induced obesity and peripheral neuropathy, combined with repetitive mechanical trauma, simulates the earliest changes observed in human Charcot neuropathic arthropathy, of vasculopathic-neuropathic etiology. An understanding of early pathophysiology may assist early diagnosis and intervention and reduce patient morbidity and mortality in Charcot neuropathic arthropathy.

Long-term foot outcomes following differential abatement of inflammation and osteoclastogenesis for active Charcot neuroarthropathy in diabetes mellitus.

AIMS: Inflammatory osteolysis is sine-qua-non of active Charcot neuroarthropathy (CN) causing decreased foot bone mineral density (BMD) and fractures. We aimed to explore the effect of anti-inflammatory or anti-resorptive agents for effect on foot bone mineral content (BMC) and consequent long-term outcomes of foot deformities, fractures and amputation. METHODS: Forty-three patients with active CN (temperature difference >2°C from normal foot) were evaluated. Patients were off-loaded with total contact cast and randomized to receive either methylprednisolone (1gm) (group A), zoledronate (5mg) (group B) or placebo (100ml normal saline) (group C) once monthly infusion for three consecutive months. Change in foot BMC was assessed at 6 months or at remission and followed subsequently up to 4 years for the incidence of new-onset fracture, deformities, or CN recurrence. RESULTS: Thirty-six participants (24 male, 12 female) were randomized (11 in group A, 12 group B, 13 group C). The mean age was 57.7± 9.9 years, duration of diabetes 12.3± 5.8 years and symptom duration 6.5± 2.8 weeks. BMC increased by 36% with zoledronate (p = 0.02) but reduced by 13% with methylprednisolone (p = 0.03) and 9% (p = 0.09) with placebo at remission. There were no incident foot fractures, however, two patients sustained ulcers, and 3 had new-onset or worsening deformities and none required amputation during 3.36 ± 0.89 years of follow-up. CONCLUSION: Bisphosphonate for active CN is associated with an increase in foot bone mineral content as compared to decrease with steroids or total contact cast but long-term outcomes of foot deformities, ulceration and amputation are similar. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03289338.

Syndrome of progressive deforming non-inflammatory arthritis of childhood: two patients of camptodactyly-arthropathy-coxa vara-pericarditis syndrome.

Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome is a rare familial arthropathy of childhood, commonly misdiagnosed as juvenile idiopathic arthritis. It is characterized by non-inflammatory arthropathy, coxa vara deformity, and sterile pericarditis. We describe two children with CACP syndrome who were referred to the rheumatology clinic for the suspicion of inflammatory arthritis. A literature search was carried out using PubMed/ Medline and Embase databases. English language reports of mutation-proven cases of CACP syndrome reported until 31 March 2020 were retrieved and analysed. Both the children had a delay in diagnosis (age at diagnosis- 12 and 13 years, respectively) and had received immunomodulatory therapy for suspected inflammatory arthritis. Presence of symmetrical arthropathy of large joints, camptodactyly, and normal inflammatory parameters are clues that indicated CACP syndrome. One child with a novel variant in PRG4 also had associated mitral valve prolapse and regurgitation. Both had severe constrictive pericarditis requiring pericardiectomy. On literature review, a total of 98 mutation-proven cases of CACP syndrome have been reported till date. Arthropathy in CACP syndrome mainly involves knees, wrists, ankles, and hips. Pericarditis is usually mild, however, can present rarely with severe symptoms requiring surgical intervention. CACP syndrome can closely mimic inflammatory arthritis and early clinical recognition is important to avoid misdiagnosis. Molecular confirmation is essential for early diagnosis and future genetic counselling for affected families.

Novel FEMASK-score, a histopathologic assessment for destructive Charcot neuropathic arthropathy, reveals intraneural vasculopathy and correlates with progression and best treatment.

BACKGROUND: Charcot neuropathic arthropathy is a debilitating, rapidly destructive degenerative joint disease that occurs in diabetic, neuropathic midfoot. Clinicoradiologic assessment for Charcot neuropathic arthropathy previously relied on Eichenholtz stage. There is limited histopathologic data on this entity. We wanted to independently develop a histopathologic scoring system for Charcot neuropathic arthropathy. DESIGN: Retrieval of surgical pathology midfoot specimens from Charcot patients (2012-2019) were analyzed to evaluate joint soft tissue and bone. Considering progression from large (≥half 40× hpf) to small (

[From cellulitis to arthrodesis]. / De la dermohypodermite à l'arthrodèse.

Neuropathic arthropathy is a pathology involving both upper and lower limbs. Different neurological diseases can cause this arthropathy. For instance, shoulder Charcot arthropathies are mostly associated to syringomyelia. The initial diagnosis of this arthropathy is difficult and often delayed in the presence of usually non specific symptoms. Since articular destruction is present in this disease, early diagnosis and primary management of the neurological condition is important, as it slows down the destruction of the joint.

L'arthropathie neuropathique est une pathologie touchant les membres supérieurs et inférieurs en lien avec différentes affections neurologiques. Dans le cadre de l'épaule, la syringomyélie est la cause la plus fréquente. La symptomatologie initiale est peu spécifique, peu douloureuse et conduit à la destruction articulaire. Le diagnostic est par conséquent difficile et souvent retardé. Une prise en charge optimale est nécessaire afin de traiter la pathologie neurologique sous-jacente, ce qui permet de ralentir la destruction articulaire.

Microscopic study of chronic charcot arthropathy foot bones contributes to understanding pathogenesis - A preliminary report.

INTRODUCTION: Charcot arthropathy (CA) is non-infective, chronic destructive condition affecting the pes architecture of long standing diabetic patients with neuropathy. Even though several theories have emerged to disclose its pathogenesis, inflammatory cytokine induced osteoclastogenesis stands as the chief culprit. Studies on micro-architecture of foot bones of acute stage CA patients, describes mainly destructive phase of bone remodelling. Increased osteoclast cell activity is reported in all studies communicated. No study has to the best of our knowledge detailed the microscopic structure of chronic stage CA foot bones. AIM: To study the microscopic structure of foot bones in patients with chronic CA. MATERIALS AND METHODS: Foot bones were collected from the feet of chronic CA patients (six in number) who underwent corrective foot surgery in the Department of Podiatric Surgery of a tertiary care hospital. Control samples were collected from the feet of age matched non-diabetic controls (2 in number). The samples were fixed in formalin, decalcified in 10% nitric acid, processed, sectioned and stained with haematoxylin and eosin. Histopathology and histomorphometry analysis were performed by two different pathologists. RESULTS: Trabeculae of chronic CA foot bones exhibited mainly a lamellar architecture, with reduced number of osteocytes and plenty of empty lacunae. Trabecular connectivity was lost and trabeculae showed considerable thinning. Trabecular osteoids lined by active osteoblast cells was a remarkable observation. Bone area was also considerably reduced in chronic CA foot bones. CONCLUSION: Chronic stage CA foot bones presented features of both healing and fragile bone. The compromised bone quality may be due to thin and fragmented trabecular structure and reduced cellularity.

Clinical features, radiological characteristics and offloading modalities in stage 0 Acute Charcot's neuroarthropathy - A single centre experience from South India.

AIMS: Stage 0 Acute Charcot's Neuroarthropathy (ACN)in Type 2 Diabetes patients is a challenging diagnosis with subtle clinical features and normal appearing plain radiographs of the affected foot. Delay in diagnosis can lead to progression of disease and irreversible deformities. There is a paucity of data on Stage 0 ACN from India. The aim of this study was to assess clinical and radiological characteristics and treatment outcomes in Indian Type 2 Diabetes patients with Stage 0 ACN. MATERIALS AND METHODS: A comparative, case-control study was carried out amongst patients attending the Integrated Diabetes Foot Clinic at a tertiary care South Indian hospital. During the 3-year study period, a total of 1811 patients with Type 2 Diabetes Mellitus were screened. Of these, n = 10 patients with stage 0 ACN Charcot's arthropathy were identified based on clinical features and MRI imaging of the foot for confirmation of diagnosis. These were compared with an age and duration of diabetes-matched group of n = 50 patients without ACN as controls. RESULTS: Our study identified 10 patients (0.5%) with Stage 0 Acute charcot neuroarthropathy (ACN) in the study population. Those with ACN had higher BMI, poorer glycaemic control and greater degree of peripheral neuropathy (p < 0.05). Clinically relative lack of pain and infrared thermometric temperature difference >2 °C in the affected foot were the most significant findings, while MRI foot was useful in early detection of active and severe stage 0 disease. Total contact cast was the preferred initial offloading modality, with delay in initiating complete immobilization leading to worse outcomes. CONCLUSIONS: This is the first study to highlight the characteristic features of Stage 0 ACN in Indian Type 2 Diabetes patients. Thorough clinical evaluation, infrared thermometry and radiological findigs on MRI foot leads to early disease detection. Complete offloading, preferably with total contact casts can prevent disease progression and chronic deformities.

Acute hot foot: Charcot neuroarthropathy or osteomyelitis? Untangling a diagnostic web.

A 55-year-old man with poorly controlled type 1 diabetes with microvascular and macrovascular complications presented with a 1-week history of painful erythematous swelling on the dorsum of the left foot with two areas of foot ulceration. Inflammatory markers were raised. MRI of the left foot revealed a soft tissue swelling on the dorsum of the left foot, marrow oedema and destruction of several small joints of the foot, indicating osteomyelitis and Charcot neuroarthropathy (CN). The soft tissue swelling on the dorsum of the left foot was debrided; per-operatively bone destruction of base of the fifth metatarsal was found. The patient received intravenous antibiotics for 6 weeks. The clinical features of CN including erythema, oedema and elevated temperature of the left foot settled with off-loading the foot in an air cast walker after 6 months. Our case highlights the need to recognise CN in an acutely inflamed foot of diabetic patients with neuropathy, even when other conditions like soft tissue infection and osteomyelitis can explain the clinical features.

[Neurogenic paraosteopathy of the elbow: results of surgical arthrolysis (a retrospective study of 37 cases)]. / La para-ostéopathie neurogène du coude: résultat de l'arthrolyse chirurgicale (étude rétrospective de 37 cas).

Neurogenic paraosteoarthropathies are ectopic ossifications which develop near the joints. They are a process of neo-ectopic osteogenesis occurring after central or peripheral neurological lesions, in some types of comas (oxygen carbon intoxication, prolonged sedation) and following peripheral traumas including burns. They inolve almost exclusively the large proximal joints of the limbs. Elbow is the second area of involvment. The purpose of our study was to analyze the results of surgical arthrolysis in 37 patients with elbow stiffness due to neurogenic osteoarthropathy of the elbow. We conducted a retrospective study of 35 patients and 37 elbows over a 25-year period. Preoperative assessment included clinical and radiological examination. Since 2003 the patients had undergone systematic elbow arthroscopy. The gold standard surgical treatment was arthrolysis. All patients underwent functional rehabilitation protocol. Outcomes were analyzed after a mean 5-year follow-up period (6 months - 10 years). Neurogenic paraosteoarthropathy was caused by head injury with coma in 58.8% of cases. Preoperative assessment showed bending stiffness in the majority of cases (88%), severe or very severe in 64.7% of cases. Intraoperatively functional elbow range of motion from -30° to 130° was obtained in 61.7% of cases and in 41% of cases in the long term. Ulnar nerve liberation was satisfactory in 92% of cases. No postoperative instability of the elbow was reported. Two patients with definitive neurological lesions had osteoma recurrence. The results were equivalent regardless surgical delay. Surgical arthrolysis is an effective treatment for neurogenic osteomas of the elbow.

Charcot Pathogenesis: A Study of In Vivo Gene Expression.

Charcot neuroarthropathy is a rare but often difficult to manage disease in the neuropathic patient. Early signs such as unremarkable edema, marginal trauma, or minor infection can activate a cascade of bony destruction and lead to gross prominence or deformity, with dire consequences. The exact molecular mechanism is poorly understood. Current theory states that an inflammatory reaction leads to the activation of osteoclasts mediated by specific cytokines. Our study sought to test the genetic expression of certain biomarkers in diabetic patients with and without Charcot neuroarthropathy compared with patients with and without diabetes or neuropathy. A total of 30 patients participated in the study, 17 (57%) males and 13 (43%) females. Peripheral blood samples were drawn, and gene expression was measured using real-time polymerase chain reaction. The expression levels of receptor activator of nuclear factor kappa-B ligand and osteoprotegerin showed no significant increase in the Charcot neuroarthropathy group compared with the healthy control group. We determined that the levels of receptor activator of nuclear factor kappa-B ligand and osteoprotegerin were not significantly increased in Charcot neuroarthropathy patients compared with healthy control patients. These results demonstrate a need for further investigation into alternative molecular pathways to determine the exact mechanism of the disease process.

Updates on Diabetic Foot and Charcot Osteopathic Arthropathy.

PURPOSE OF REVIEW: Diabetes mellitus affects approximately 30.8 million people currently living in the USA. Chronic diabetes complications, including diabetic foot complications, remain prevalent and challenging to treat. We review clinical diagnosis and challenges providers may encounter when managing diabetic foot ulcers and Charcot neuroarthropathy. RECENT FINDINGS: Mechanisms controlling these diseases are being elucidated and not fully understood. Offloading is paramount to heal and manage diabetic foot ulcers and Charcot neuroarthropathy. Diabetic foot ulcers recur and the importance of routine surveillance and multidisciplinary approach is essential. Several predictors of failure in Charcot foot include a related diabetic foot ulcer, midfoot or rearfoot location of the Charcot event, and progressive bony changes on interval radiographs. Patients with diabetic foot ulcer and/or Charcot neuroarthropathy are in need of consistent and regular special multidisciplinary care. If not diagnosed early and managed effectively, morbidity and mortality significantly increase.

Prevalence of active Charcot disease in the East Midlands of England.

AIMS: To undertake a prospective point prevalence study of the prevalence of active Charcot neuro-inflammatory osteoarthropathy (Charcot disease) in a circumscribed part of England and to audit the time elapsing between disease onset and first diagnosis. METHODS: The prevalence of active Charcot disease of the foot during a single month was assessed by specialist foot care teams at seven secondary care services in the East Midlands region of England. RESULTS: A total of 90 cases were identified, representing 4.3 per 10 000 of the 205 033 total diabetes population of the region. The time elapsed from first presentation to any healthcare professional until diagnosis was also assessed. While the diagnosis was suspected or confirmed in one-third of patients within 2 weeks, it was not made for 2 months or more in 23 patients (24%). CONCLUSIONS: Non-specialist professionals should have greater awareness of the existence of this uncommon complication of diabetes in the hope that earlier diagnosis will lead to lesser degrees of deformity.

Functionally compromised synovium-derived mesenchymal stem cells in Charcot neuroarthropathy.

Charcot neuroarthropathy (CNA) often presents as a diabetic foot complication. The role of synovial mesenchymal stem cells (syn-MSCs) in the pathogenesis of CNA is unclear. Synovial samples were collected, for isolation of syn-MSCs, from diabetic patients with CNA (n=7) and non-diabetic patients with intra-articular fracture or normal joints (non-CNA; n=7) during foot surgery. The syn-MSCs in the CNA and non-CNA groups were characterized comparatively. The average number of colonies formed in the CNA group was 6±3.5 per half plate (10mm in diameter), while it was 43±21.6 in the non-CNA group (p<0.05). The average size (pixels) of the colonies in the CNA group was smaller than that in the non-CNA group. When the colonies were stratified into high-, medium- and low-density subgroups, colonies in the high-density subgroup of the CNA group were reduced in density. Expression of PPAR-γ, RUNX2, Sox9 and type II collagen by syn-MSCs in the CNA group was decreased during adipogenic, osteogenic and chondrogenic differentiation as compared with the non-CNA group. In conclusion, syn-MSCs in CNA joints were reduced in number, with declined differentiation potentials. The high-density subpopulation of the syn-MSCs was particularly affected by the pathology of CNA.

Deformity and Clinical Outcomes Following Operative Correction of Charcot Foot: A New Classification With Implications for Treatment.

BACKGROUND: The historic treatment of Charcot foot arthropathy has been immobilization during the active phase of the disease process, followed by accommodative bracing of the acquired deformity. Evidence derived from modern patient-reported outcomes investigations has convinced many surgeons to attempt operative correction of the acquired deformity with a goal of improving quality of life. METHODS: Over a 12-year period, 214 patients (9 bilateral) underwent reconstruction of the acquired deformity associated with midtarsal Charcot foot arthropathy. Over time, 3 patterns of deformity were observed based on weight-bearing pattern, relationship of the forefoot to the hindfoot, and integrity of the talocalcaneal joint. A valgus deformity pattern was present in 138, varus in 48, and dislocation of the talocalcaneal joint in 37. A consistent operative strategy was employed. Surgery included percutaneous tendon-Achilles lengthening, resection of infection when present, attempted correction of the structural deformity by wedge resection at the apex of the deformity, and immobilization with a 3-level static circular external fixator. Additional deformity pattern-specific procedures were added over time. Clinical outcomes were based on the historic metrics of limb salvage and resolution of infection and the functional metric of the ability to walk with commercially available therapeutic footwear. RESULTS: Seven patients died within a year of surgery, and 15 underwent partial- or whole-foot amputation. Overall, 173 of 223 feet (77.6%) achieved a favorable clinical outcome. Patients with a valgus deformity pattern were most likely to achieve a favorable clinical outcome (120 of 138, 87.0%). Patients with a dislocation pattern were less likely to achieve a favorable clinical outcome (26 of 37, 70.3%), and those with a varus deformity pattern were least likely to achieve a favorable clinical outcome (27 of 48, 56.3%). CONCLUSIONS: Operative correction of the acquired deformity of Charcot foot arthropathy was performed with a goal of improving quality of life. Stratification of patients by deformity pattern allowed alterations of the basic surgery to afford improved outcomes. In addition to achieving historic goals of resolution of infection and limb salvage, almost 80% of the patients were able to achieve the functional goal of independent ambulation with commercially available therapeutic footwear. The clinical outcomes achieved in this retrospective case series appear to support the modern paradigm of operative correction of deformity in this complex patient population. This realistic appreciation of outcome expectations should both be helpful in counseling patients on the risk-benefit ratio associated with surgery and provide a benchmark to measure newer strategies of treatment. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Persistent inflammation with pedal osteolysis 1year after Charcot neuropathic osteoarthropathy.

AIMS: To determine local and systemic markers of inflammation and bone mineral density (BMD) in the foot and central sites in participants with diabetes mellitus and peripheral neuropathy (DMPN) with and without acute Charcot neuropathic osteoarthropathy (CN). METHODS: Eighteen participants with DMPN and CN and 19 participants without CN had foot temperature assessments, serum markers of inflammation [C-reactive protein, (CRP) and erythrocyte sedimentation rate, (ESR)] and BMD of the foot, hip and lumbar spine at baseline and 1year follow-up. RESULTS: CN foot temperature difference was higher compared to DMPN controls at baseline (4.2±1.9°F vs. 1.2±0.9°F, P<0.01) and after 1year (2.9±3.2°F vs. 0.9±1.1°F, P<0.01). Serum inflammatory markers in the CN group were greater at baseline and remained elevated 1year later compared to DMPN controls (CRP, P=0.02, ESR, P=0.03). All pedal bones' BMD decreased an average of 3% in the CN foot with no changes in hip or lumbar spine. DMPN controls' foot, hip and lumbar spine BMD remained unchanged. CONCLUSIONS: Local and systemic inflammation persists 1 year after CN with an accompanying pedal osteolysis that may contribute to mid foot deformity which is the hallmark of the chronic Charcot foot.

Multifocal neuropathic arthropathy in patient with undiagnosed neurosyphilis: A case report.

Although the prevalence of syphilis has decreased significantly, syphilis is still a common cause of neuropathic arthropathy. Tabetic arthropathy means progressive painless joint destruction that is related to neurosensory deficits caused by syphilis. In general, lower limb joints are involved and gradual swelling and instability of the involved joints are observed. Diagnosis of tabetic arthropathy is difficult as its clinical presentation is not specific and differential diagnosis is wide ranging. Hence, diagnosis of tabetic arthropathy requires clinical suspicion and an appropriate serological test. Laboratory tests for the diagnosis of syphilis include nontreponemal tests and treponemal tests. Conventionally, a nontreponemal test such as the Venereal Disease Research Laboratory test or the Rapid Plasma Reagin test is performed first as a screening test for syphilis, followed by a treponemal test to confirm the positive response found in the screening test. However, the sensitivity and specificity of the serum nontreponemal and treponemal tests for the diagnosis of syphilis are different based on the test type and the syphilis stages. We herein report a case of multifocal neuropathic arthropathy found in a patient whose syphilis was not diagnosed due to a nonreactive screening test result.

Soft Tissue Reconstruction Pyramid for the Diabetic Charcot Foot.

Foot and ankle ulcerations in patients with diabetic Charcot neuroarthropathy (DCN) occur frequently and can be challenging to address surgically when conservative care fails. Patients with acute or chronic diabetic foot ulcers (DFU) are at continued risk for development of osteomyelitis, septic arthritis, gas gangrene, and potential lower extremity amputation. Concurrent vasculopathy and peripheral neuropathy as well as uncontrolled medical comorbidities complicate the treatment approach. In addition, pathomechanical forces left untreated may contribute to DFU recurrence in this patient population. This article outlines in detail the stepwise approach and options available for durable soft tissue coverage in the DCN patient.

Revisional Surgery of the Diabetic Charcot Foot and Ankle.

Charcot neuroarthropathy (CN) is a difficult problem for the foot and ankle surgeon. If surgery is required, little is known or available regarding the best methods and timing. When the initial attempt of reconstruction fails, revision of CN is even more demanding. One must take in to account all aspects, including nutrition, vascular status, infection control, short- and long-term blood glucose management, as well as other factors requiring laboratory monitoring and consult services. Once optimized, the biomechanics of the deformity can be addressed and decisions can be made on fixation devices.