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.

A review of bone metabolism and developments in medical treatment of the diabetic Charcot foot.

Charcot foot is a rare but severe, and possibly limb-threatening, complication to neuropathy and diabetes mellitus. The current treatment consists of long-term off-loading, and has a large negative impact on the patient's life. Much research has gone into understanding the condition and its biochemical mechanisms, however, the underlying pathogenesis of a Charcot foot is not yet fully understood. In the recent decades several key advances in our understanding of the Charcot foot have been made, both in regards to the changes in bone metabolism and structure an acute Charcot foot can cause, and to the molecular pathways involved in this. This review summerizes the available research into the bone metabolism around a Charcot foot, with an emphasis on the biochemical profile. The existing data regarding attempts at medical treatment is also reviewed, including novel trials targetting specific inflammatory pathways upregulated in the acute diabetic Charcot foot.

Brothers with constrictive pericarditis - A novel mutation in a rare disease.

Familial constrictive pericarditis is extremely rare. We report a case of two brothers both suffering constrictive pericarditis along with having multiple painless joint deformities. Genetic workup confirmed the clinical diagnosis of camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome CACP syndrome and also revealed a rare mutation in the causative gene.

Pathological role of fibroblast-like synoviocytes in charcot neuroarthropathy.

This study was designed to characterize the synovium in the joints of Charcot neuroarthropathy (CNA) and investigate the potential role of fibroblast-like synoviocytes (FLS) in the pathology of CNA. Synovial samples were collected from CNA patients (n = 7) and non-CNA patients (n = 7), for control, during orthopaedic procedures and used for histology and isolation of FLS. Histological characterization of synovium included innervation and FLS localization. The isolated FLS from the CNA and non-CNA synovium were cultured, with or without tumor necrosis factor-α (TNF-α), for evaluation of invasiveness, gene expression, and cartilage degradation. Vasoactive intestinal peptide (VIP), a neuropeptide, was supplemented into the co-cultures of FLS and cartilage explants. Compared with the non-CNA synovium, CNA synovium was highly inflammatory, with reduced innervation and intense expression of cadherin-11. The FLS isolated from CNA synovium, particularly when activated with TNF-α, were more invasive, increased the expression of ADAMTS4, IL-6, and RANKL, and depleted proteoglycans from cartilage explants when they were co-cultured. Addition of VIP into the culture medium neutralized the catabolic effect of the CNA FLS on cartilage explants. In conclusion, FLS plays an important role in the pathology of CNA. Therapies targeting synovium and FLS may prevent or treat the joint destruction in CNA.

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.

Charcot osteoarthropathy in type 2 diabetes persons presenting to specialist diabetes clinic at a tertiary care hospital.

BACKGROUND: Charcot osteoarthropathy or charcot foot is a rare, chronic, non-communicable condition of bones and joints which may results into severe deformity and more prone to develop ulcers possibly leading to amputation. The purpose of this study was to determine the prevalence of Charcot osteoarthropathy and its association with age, BMI, gender, duration of diabetes, HBA1c and peripheral neuropathy. METHODS: A total of 1931 subjects with type 2 diabetes having mean age 50.72 ± 10.66 years presenting in a specialist diabetes clinic at shalamar hospital, Lahore, Pakistan were enrolled. The diagnosis of Charcot osteoarthropathy was made by examination of both dorsal and plantar surfaces of foot for swelling, erythema, increase in temperature and any musculoskeletal deformity which was later confirmed by radiographs. Assessment of neuropathy was carried out by checking the sense of pressure, joint position and vibration. BMI (Body Mass Index), fasting blood glucose (FBG) and HbA1C were determined. RESULTS: In all subjects including male 704 (36.45 %) and female 1227 (63.55 %), 0.4 % subjects had charcot deformity, while 0.2 %, 0.15 % and 0.05 % subjects having right, left and bilateral deformity respectively. Bilaterally symmetrical neuropathy was diagnosed in 25.4 % in subjects. There was a significant association (p < 0.05) of deformity with duration of diabetes, HbA1C and neuropathy, however no significant association (p > 0.05) was found with age, BMI, weight, height and gender. CONCLUSION: There is a need to have a special care of persons with diabetes regarding blood glucose control and development of peripheral neuropathy. Early identification and management of risk factors may prevent the occurrence of charcot deformity. Patients must be educated about the foot care.

A prospective study of calcaneal bone mineral density in acute Charcot osteoarthropathy.

OBJECTIVE: To measure prospectively bone mineral density (BMD) of the Charcot and non-Charcot foot in 36 diabetic patients presenting with acute Charcot osteoarthropathy. RESEARCH DESIGN AND METHODS: Calcaneal BMD was measured with quantitative ultrasound at presentation, at 3 months of casting, and at the time of the clinical resolution. RESULTS: BMD of the Charcot foot was significantly reduced compared with BMD of the non-Charcot foot at presentation (P = 0.001), at 3 months of casting (P < 0.001), and at the time of clinical resolution (P < 0.001). Overall, from the time of presentation to the time of resolution there was a significant fall of BMD of the Charcot foot (P < 0.001) but not of the non-Charcot foot (P = 0.439). CONCLUSIONS: Although the Charcot foot was treated with casting until clinical resolution, there was a significant fall of BMD only from presentation up until 3 months of casting.

Charcot's foot: newest findings on its pathophysiology, diagnosis and treatment.

Charcot neuro-osteoarthropathy (CNO) is one of the more devastating complications affecting diabetic patients with peripheral and/or autonomic neuropathy. The acute phase of the disease is often misdiagnosed, and can rapidly lead to deformity and amputation. The rapid progression towards foot deformation calls for early detection and intervention. Classical neurotraumatic and neurotrophic theories fail to explain all of the features of the condition, although recent advances that have clarified the mechanisms underlying the pathophysiology may make up for this lack. In particular, new data have emerged on the central role of the RANK/RANK-ligand (RANK-L)/osteoprotegerin (OPG) system in the pathogenesis of osteopenia. Also, it is now recognized that the acute phase of CNO can be triggered by any factor leading to local inflammation of the foot, especially in predisposed patients. As the cornerstone of treatment remains any method that avoids weight-bearing on the foot, the primary importance of the RANK/RANK-L/OPG signalling pathway is that it opens up the field to new treatment strategies for the future.

Levels of endothelial nitric oxide synthase and calcitonin gene-related peptide in the Charcot foot: a pilot study.

UNLABELLED: The pathogenesis of Charcot neuroarthropathy is unclear. To investigate the possibility that decreased levels of calcitonin gene-related peptide and endothelial nitric oxide synthase are involved in the process, we studied bone samples from healthy subjects (n = 4), subjects with diabetic neuropathy (n = 4), and subjects with Charcot neuroarthropathy (n = 4). A statistically significant difference was found in endothelial nitric oxide synthase expression between bone specimens in patients with diabetic neuropathy, Charcot neuroarthropathy, and normal bone (P = .008). A trend toward calcitonin gene-related peptide intensification was observed in normal bone as compared to diabetic neuropathy and Charcot neuroarthropathy bone specimens, but it did not reached statistical significance (P = .23). This pilot study suggests that abnormal calcitonin gene-related peptide and endothelial nitric oxide synthase activity may play a role in the development of Charcot neuroarthropathy. LEVEL OF CLINICAL EVIDENCE: 4.

Poly(ADP-ribose) polymerase inhibition alleviates experimental diabetic sensory neuropathy.

Poly(ADP-ribose) polymerase (PARP) activation is emerging as a fundamental mechanism in the pathogenesis of diabetes complications including diabetic neuropathy. This study evaluated the role of PARP in diabetic sensory neuropathy. The experiments were performed in control and streptozotocin-induced diabetic rats treated with or without the PARP inhibitor 1,5-isoquinolinediol (ISO; 3 mg x kg(-1) x day(-1) i.p.) for 2 weeks after 2 weeks without treatment. Diabetic rats developed thermal hyperalgesia (assessed by paw-withdrawal and tail-flick tests), mechanical hyperalgesia (von Frey anesthesiometer/rigid filaments and Randall-Sellito tests), tactile allodynia (flexible von Frey filaments), and increased flinching behavior in phases 1 and 2 of the 2% formalin pain test. They also had clearly manifest increase in nitrotyrosine and poly(ADP-ribose) immunoreactivities in the sciatic nerve and increased superoxide formation (hydroxyethidine method) and nitrotyrosine immunoreactivity in vasa nervorum. ISO treatment alleviated abnormal sensory responses, including thermal and mechanical hyperalgesia and tactile allodynia as well as exaggerated formalin flinching behavior in diabetic rats, without affecting the aforementioned variables in the control group. Poly(ADP-ribose) and, to a lesser extent, nitrotyrosine abundance in sciatic nerve, as well as superoxide and nitrotyrosine formation in vasa nervorum, were markedly reduced by ISO therapy. Apoptosis in dorsal root ganglion neurons (transferase-mediated dUTP nick-end labeling assay) was not detected in any of the groups. In conclusion, PARP activation contributes to early diabetic sensory neuropathy by mechanisms that may include oxidative stress but not neuronal apoptosis.

Cervical spine pseudogout with myelopathy and Charcot joints.

Myelopathy due to calcium pyrophosphate dihydrate (CPPD) crystals in the cervical spine is rare. Neuropathic-like joints are also uncommon manifestations of CPPD crystal disease. We describe a 79-year-old woman with multiple neuropathic joints containing CPPD crystals. She also had a large mass containing CPPD crystals impinging on the cervical spinal cord, causing a myelopathy. She appears to be the first patient with this combination of unusual clinical features with CPPD disease.

A neurogenic mechanism for symmetrical arthritis.

Human synovium is richly innervated by autonomic and sensory nerve fibres, many of which contain neuropeptides. The hypothesis is that, in addition to a sensory role, some of these fibres modulate the response of the synovial membrane to a variety of noxious stimuli by releasing these peptides. Synovial damage results in acute inflammation in the damaged joint and a neurogenically mediated infiltrate of inflammatory cells in the contralateral joint. These cells might protect the contralateral synovium from injury similar to that in the damaged joint. An increased response would lead to synovitis and symmetrical disease.

Neurogenic acceleration of degenerative joint lesions.

A severe form of degenerative joint lesion (neuropathic arthropathy) is known to complicate a variety of diseases that are associated with sensory abnormalities. We studied the relationship between sensory deficits and the development of degenerative joint lesions in dogs in two complementary experiments. In Experiment 1, dogs that were subjected to unilateral dorsal-root ganglionectomy (fourth lumbar to first sacral vertebra) failed to show biochemical, gross, or histological evidence of degenerative joint lesions in ipsilateral femoral condylar cartilage after sixteen months. In Experiment 2, five of six dogs that were subjected to transection of the anterior cruciate ligament two weeks after deafferentation of the ipsilateral limb showed striking gross or histological lesions, or both, of the femoral condylar cartilage three weeks after ligament transection (five weeks after ganglionectomy). We concluded that the neuromuscular mechanisms that protect normal joints from damage are inadequate to protect unstable joints from becoming rapidly and severely damaged.

[Crystalline calcium pyrophosphate dehydrate deposit disease]. / La malattia da depositi cristallini di pirofosfato diidrato di calcio.

Radiographic features of calcium pyrophosphate dihydrate (CPPD) crystal deposition disease are outlined in an investigation of 32 patients, with definite or probable disease (according to the diagnostic criteria previously utilized by McCarty). The crystal deposits within fibro- and hyaline cartilage (chondrocalcinosis) may produce an acute synovitis (pseudogout syndrome), and in some patients a radiographically distinctive degenerative arthropathy (pyrophosphate arthropathy). These abnormalities are most frequent in the knee, wrist and symphysis pubis, but often other joints may be affected. Although the alterations superficially resemble osteoarthritis, they are more severe and progressive (Charcot-like joint).