Charcot-Marie-Tooth Disease of the Foot and Ankle: Imaging Features and Pathophysiology.

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral polyneuropathy, resulting in length-dependent motor and sensory deficiencies. Asymmetric nerve involvement in the lower extremities creates a muscle imbalance, which manifests as a characteristic cavovarus deformity of the foot and ankle. This deformity is widely considered to be the most debilitating symptom of the disease, causing the patient to feel unstable and limiting mobility. Foot and ankle imaging in patients with CMT is critical for evaluation and treatment, as there is a wide range of phenotypic variation. Both radiography and weight-bearing CT should be used for assessment of this complex rotational deformity. Multimodality imaging including MRI and US is also important to help identify changes in the peripheral nerves, diagnose complications of abnormal alignment, and evaluate patients in the perioperative setting. The cavovarus foot is susceptible to distinctive pathologic conditions including soft-tissue calluses and ulceration, fractures of the fifth metatarsal, peroneal tendinopathy, and accelerated arthrosis of the tibiotalar joint. An externally applied brace can assist with balance and distribution of weight but may be appropriate for only a subset of patients. Many patients will require surgical correction, which may include soft-tissue releases, tendon transfers, osteotomies, and arthrodesis when necessary, with the goal of creating a more stable plantigrade foot. The authors focus on the cavovarus deformity of CMT. However, much of the information discussed may also be applied to a similar deformity that may result from idiopathic causes or other neuromuscular conditions. ©RSNA, 2023 Quiz questions for this article are available through the Online Learning Center.

Prevalence of sacroiliitis among patients referred for hip MR arthrography.

OBJECTIVE: To determine the prevalence of sacroiliitis among patients who have been referred for MR arthrography. MATERIALS AND METHODS: A retrospective search identified 130 consecutive MR arthrograms of the hip performed on a 1.5T Siemens Avanto at our institution from August 2013 to August 2014. Four studies were excluded due to the absence of a coronal short tau inversion recovery sequence of the pelvis, leaving 126 studies for analysis. A musculoskeletal radiology fellow and three attending musculoskeletal radiologists reviewed the images for the presence of bone marrow edema affecting the sacroiliac joints. Only cases of bone marrow edema meeting the Assessment of SpondyloArthritis international Society definition were considered positive. The two-tailed Fisher's exact test was used to compare the prevalence of positive MRI findings among age and gender groups. GraphPad InStat (GraphPad Software) was used for statistical calculations. RESULTS: Patients less than 40 years of age demonstrated a statistically higher prevalence of positive MRI findings of sacroiliitis when compared to patients older than 40 (p = 0.0082). No difference in prevalence was found between genders. Overall prevalence of MRI signal alteration suggestive of sacroiliitis as defined by the Assessment of SpondyloArthritis international Society was 4.8%. Among the six patients with positive findings, two were subsequently diagnosed with spondyloarthritis. CONCLUSION: Hip pain may be a presenting symptom of spondyloarthritis and attention should be paid to the sacroiliac joints during screening examinations, particularly in patients less than 40 years of age.

Squamous Cell Carcinoma Arising from a Morel-Lavallée Lesion: A Case Report.

CASE: A 72-year-old man presented 20 years after a Morel-Lavallée (ML) lesion with pain and drainage. Biopsies of the lesion and lymph nodes were positive for squamous cell carcinoma (SCC). There was no cutaneous involvement or distant metastasis. After chemotherapy and radiation, he underwent resection of the lesion and lymph nodes with flap closure. Two months postoperatively, he unfortunately developed malignant pleural effusions, hypercalcemia, and kidney injury and was eventually transferred to hospice care and died. CONCLUSION: This is the first report of SCC arising from a ML lesion. Chronic ML lesions should be treated aggressively and monitored for transformation into malignancy, even without cutaneous involvement.

Human iPSCs can be differentiated into notochordal cells that reduce intervertebral disc degeneration in a porcine model.

Introduction: As many as 80% of the adult population experience back pain at some point in their lifetimes. Previous studies have indicated a link between back pain and intervertebral disc (IVD) degeneration. Despite decades of research, there is an urgent need for robust stem cell therapy targeting underlying causes rather than symptoms. It has been proposed that notochordal cells (NCs) appear to be the ideal cell type to regenerate the IVD: these cells disappear in humans as they mature, are replaced by nucleus pulposus (NP) cells, and their disappearance correlates with the initiation of degeneration of the disc. Human NCs are in short supply, thus here aimed for generation of notochordal-like cells from induced pluripotent cells (iPSCs). Methods: Human iPSCs were generated from normal dermal fibroblasts by transfecting plasmids encoding for six factors: OCT4, SOX2, KLF4, L-MYC, LIN28, and p53 shRNA. Then the iPSCs were treated with GSK3i to induce differentiation towards Primitive Streak Mesoderm (PSM). The differentiation was confirmed by qRT-PCR and immunofluorescence. PSM cells were transfected with Brachyury (Br)-encoding plasmid and the cells were encapsulated in Tetronic-tetraacrylate-fibrinogen (TF) hydrogel that mimics the NP environment (G'=1kPa), cultured in hypoxic conditions (2% O2) and with specifically defined growth media. The cells were also tested in vivo in a large animal model. IVD degeneration was induced after an annular puncture in pigs, 4 weeks later the cells were injected and IVDs were analyzed at 12 weeks after the injury using MRI, gene expression analysis and histology. Results: After short-term exposure of iPSCs to GSK3i there was a significant change in cell morphology, Primitive Streak Mesoderm (PSM) markers (Brachyury, MIXL1, FOXF1) were upregulated and markers of pluripotency (Nanog, Oct4, Sox2) were downregulated, both compared to the control group. PSM cells nucleofected with Br (PSM-Br) cultured in TF hydrogels retained the NC phenotype consistently for up to 8 weeks, as seen in the gene expression analysis. PSM-Br cells were co-cultured with bone marrow (BM)-derived mesenchymal stem cells (MSCs) which, with time, expressed the NC markers in higher levels, however the levels of expression in BM-MSCs alone did not change. Higher expression of NC and NP marker genes in human BM-MSCs was found to be induced by iNC-condition media (iNC-CM) than porcine NC-CM. The annular puncture induced IVD degeneration as early as 2 weeks after the procedure. The injected iNCs were detected in the degenerated discs after 8 weeks in vivo. The iNC-treated discs were found protected from degeneration. This was evident in histological analysis and changes in the pH levels, indicative of degeneration state of the discs, observed using qCEST MRI. Immunofluorescence stains show that their phenotype was consistent with the in vitro study, namely they still expressed the notochordal markers Keratin 18, Keratin 19, Noto and Brachyury. Conclusion: In the present study, we report a stepwise differentiation method to generate notochordal cells from human iPSCs. These cells not only demonstrate a sustainable notochordal cell phenotype in vitro and in vivo, but also show the functionality of notochordal cells and have protective effect in case of induced disc degeneration and prevent the change in the pH level of the injected IVDs. The mechanism of this effect could be suggested via the paracrine effect on resident cells, as it was shown in the in vitro studies with MSCs.

Molecular pain markers correlate with pH-sensitive MRI signal in a pig model of disc degeneration.

Intervertebral disc (IVD) degeneration is a leading cause of chronic low back pain that affects millions of people every year. Yet identification of the specific IVD causing this pain is based on qualitative visual interpretation rather than objective findings. One possible approach to diagnosing pain-associated IVD could be to identify acidic IVDs, as decreased pH within an IVD has been postulated to mediate discogenic pain. We hypothesized that quantitative chemical exchange saturation transfer (qCEST) MRI could detect pH changes in IVDs, and thence be used to diagnose pathologically painful IVDs objectively and noninvasively. To test this hypothesis, a surgical model of IVD degeneration in Yucatan minipigs was used. Direct measurement of pH inside the degenerated IVDs revealed a significant drop in pH after degeneration, which correlated with a significant increase in the qCEST signal. Gene analysis of harvested degenerated IVDs revealed significant upregulation of pain-, nerve- and inflammatory-related markers after IVD degeneration. A strong positive correlation was observed between the expression of pain markers and the increase in the qCEST signal. Collectively, these findings suggest that this approach might be used to identify which IVD is causing low back pain, thereby providing valuable guidance for pain and surgical management.

Ultrasound-Mediated Gene Delivery Enhances Tendon Allograft Integration in Mini-Pig Ligament Reconstruction.

Ligament injuries occur frequently, substantially hindering routine daily activities and sports participation in patients. Surgical reconstruction using autogenous or allogeneic tissues is the gold standard treatment for ligament injuries. Although surgeons routinely perform ligament reconstructions, the integrity of these reconstructions largely depends on adequate biological healing of the interface between the ligament graft and the bone. We hypothesized that localized ultrasound-mediated, microbubble-enhanced therapeutic gene delivery to endogenous stem cells would lead to significantly improved ligament graft integration. To test this hypothesis, an anterior cruciate ligament reconstruction procedure was performed in Yucatan mini-pigs. A collagen scaffold was implanted in the reconstruction sites to facilitate recruitment of endogenous mesenchymal stem cells. Ultrasound-mediated reporter gene delivery successfully transfected 40% of cells recruited to the reconstruction sites. When BMP-6 encoding DNA was delivered, BMP-6 expression in the reconstruction sites was significantly enhanced. Micro-computed tomography and biomechanical analyses showed that ultrasound-mediated BMP-6 gene delivery led to significantly enhanced osteointegration in all animals 8 weeks after surgery. Collectively, these findings demonstrate that ultrasound-mediated gene delivery to endogenous mesenchymal progenitor cells can effectively improve ligament reconstruction in large animals, thereby addressing a major unmet orthopedic need and offering new possibilities for translation to the clinical setting.

Use of 3D Prints to Compare the Efficacy of Three Different Calcaneal Osteotomies for the Correction of Heel Varus.

BACKGROUND: Cavovarus deformity of the hindfoot is typically caused by neurologic disorders. Multiple osteotomies have been described for the correction of varus deformity but without clinical comparison. In this study, we used 18 identical 3-dimensional (3D) prints of a patient with heel varus to compare the operative correction obtained with Dwyer, oblique, and Z osteotomies. METHODS: A computed tomography (CT) scan of a patient with heel varus was used to create 18 identical 3D prints of the talus, calcaneus, and cuboid. Coordinate frames were added to the talus and calcaneus to evaluate rotation. The prints were then divided into 3 groups of 6 models each. A custom jig precisely and accurately replicated each osteotomy. Following the simulated operations, cut models were CT scanned and compared with 6 uncut models. Measurements were calculated using multiplanar reconstruction image processing. An analysis of variance (ANOVA) was performed on the initial data to determine significant differences among the measured variables. A Tukey Studentized range test was run to compare variables that showed statistically significant differences using the ANOVA. RESULTS: The coronal angle of the Dwyer and oblique osteotomies was significantly less than that of the Z osteotomy ( P < .05). The axial angle, lateral displacement, and calcaneal shortening of the uncut model and Z osteotomy were significantly less than the Dwyer and oblique osteotomies. CONCLUSIONS: Dwyer, oblique, and Z osteotomies did not create either lateral translation or coronal rotation without the addition of a lateralizing slide or rotation of the posterior tuberosity. CLINICAL RELEVANCE: Dwyer and oblique osteotomies would be best suited for mild deformity, yet the amount of calcaneal shortening must be acknowledged. A Z osteotomy is a complex procedure that has the capability of correcting moderate-severe coronal plane rotation but fails to provide lateralization of the pull of the Achilles insertion.

In situ bone tissue engineering via ultrasound-mediated gene delivery to endogenous progenitor cells in mini-pigs.

More than 2 million bone-grafting procedures are performed each year using autografts or allografts. However, both options carry disadvantages, and there remains a clear medical need for the development of new therapies for massive bone loss and fracture nonunions. We hypothesized that localized ultrasound-mediated, microbubble-enhanced therapeutic gene delivery to endogenous stem cells would induce efficient bone regeneration and fracture repair. To test this hypothesis, we surgically created a critical-sized bone fracture in the tibiae of Yucatán mini-pigs, a clinically relevant large animal model. A collagen scaffold was implanted in the fracture to facilitate recruitment of endogenous mesenchymal stem/progenitor cells (MSCs) into the fracture site. Two weeks later, transcutaneous ultrasound-mediated reporter gene delivery successfully transfected 40% of cells at the fracture site, and flow cytometry showed that 80% of the transfected cells expressed MSC markers. Human bone morphogenetic protein-6 (BMP-6) plasmid DNA was delivered using ultrasound in the same animal model, leading to transient expression and secretion of BMP-6 localized to the fracture area. Micro-computed tomography and biomechanical analyses showed that ultrasound-mediated BMP-6 gene delivery led to complete radiographic and functional fracture healing in all animals 6 weeks after treatment, whereas nonunion was evident in control animals. Collectively, these findings demonstrate that ultrasound-mediated gene delivery to endogenous mesenchymal progenitor cells can effectively treat nonhealing bone fractures in large animals, thereby addressing a major orthopedic unmet need and offering new possibilities for clinical translation.

Quantitative chemical exchange saturation transfer MRI of intervertebral disc in a porcine model.

PURPOSE: Previous studies have associated low pH in intervertebral discs (IVDs) with discogenic back pain. The purpose of this study was to determine whether quantitative CEST (qCEST) MRI can be used to detect pH changes in IVDs in vivo. METHODS: The exchange rate ksw between glycosaminoglycan (GAG) protons and water protons was determined from qCEST analysis. Its dependence on pH value was investigated in GAG phantoms with varying pH and concentrations. The relationship between ksw and pH was studied further in vivo in a porcine model on a 3T MR scanner and validated using a pH meter. Sodium lactate was injected into the IVDs to induce various pH values within the discs ranging from 5 to 7. RESULTS: Phantom and animal results revealed that ksw measured using qCEST MRI is highly correlated with pH level. In the animal studies, the relationship can be described as ksw =9.2 × 106 × 10-pH + 196.9, R2 = 0.7883. CONCLUSION: The exchange rate between GAG and water protons determined from qCEST MRI is closely correlated with pH value. This technique has the potential to noninvasively measure pH in the IVDs of patients with discogenic pain. Magn Reson Med 76:1677-1683, 2016. © 2016 International Society for Magnetic Resonance in Medicine.

CT-guided biopsy of bone and soft-tissue lesions: role of on-site immediate cytologic evaluation.

PURPOSE: To assess the impact of on-site immediate cytologic assessment (ICA) on the diagnostic success rate of computed tomography (CT)-guided percutaneous needle biopsy (PNB) of musculoskeletal lesions and the long-term outcome in inconclusive PNB findings. MATERIALS AND METHODS: A total of 299 CT-guided PNBs of musculoskeletal lesions performed between January 1997 and December 2009 were retrospectively reviewed. The lesions were categorized by their morphology, location, and size, and by biopsy type. The diagnostic success rates, impact of ICA, and outcome in inconclusive PNBs were studied, with final histopathologic findings and/or clinical follow-up as a reference. RESULTS: The overall diagnostic success rate of PNBs was 72.9% (218 of 299). The success rate increased with larger lesions (> 2 cm to 4 cm; P = .009). Biopsies performed with ICA had a higher success rate (77.0% vs 63.3%; P = .015). PNBs had inconclusive results in 109 of 299 cases (36.5%). In 66 of these, repeat open biopsy or clinical follow-up demonstrated 19 malignant/aggressive lesions (28.8%) and 47 benign/nonaggressive lesions (71.2%). CONCLUSIONS: CT-guided PNB had a satisfactory success rate, which significantly increased when performed with ICA. Inconclusive results in PNB were most frequently associated with benign findings during further workup.

Morbidity of direct MR arthrography.

OBJECTIVE: The purpose of this study was to determine the incidence and severity of arthrographic pain after intraarticular injection of a gadolinium mixture diluted in normal saline for direct MR arthrography. SUBJECTS AND METHODS: From March 2009 until January 2010, 155 consecutive patients underwent direct MR arthrography; 20 patients were lost to follow-up. Patients were contacted by telephone between 3 and 7 days after joint injection. Using an 11-point numeric pain rating scale, patients were asked to report if they had experienced joint pain that was different or more intense than their preinjection baseline, the severity of pain, the duration of pain, time to onset of pain, and eventual resolution of pain. RESULTS: The incidence of postarthrographic pain was 66% (89/135), with an average intensity of pain of 4.8 ± 2.4 (range, 1-10). Postarthrographic pain lasted an average of 44.4 ± 30.5 hours (range, 6-168 hours). The time to onset of pain after joint injection was on average 16.6 ± 13.1 hours (range, 4-72 hours). There was no significant difference regarding the severity or incidence of postarthrographic pain between groups on the basis of patient age (p = 0.20 and 0.26), patient sex (p = 0.20 and 0.86), contrast mixture contents (p = 0.83 and 0.49), or joint injected (p = 0.51 and 0.47). No patients experienced any other serious side effects. CONCLUSION: Sixty-six percent of patients who undergo direct MR arthrography will experience a fairly severe delayed onset of pain that completely resolves over the course of several days.

Stun gun induced myotendinous injury of the iliopsoas and gluteus minimus.

We report a 57-year-old man with a complete tear of his iliopsoas tendon at the distal myotendinous junction, a near complete tear of the iliopsoas tendon at the lesser trochanter of the femur, and a high-grade tear of his gluteus minimus tendon at the greater trochanter of the femur after being struck by a stun gun in the proximal left thigh. The stun gun discharge resulted in a forced contraction of the left hip flexor muscles, which resulted in pain, weakness and difficulty with active hip flexion. Three months after the being struck with the stun gun, the patient underwent magnetic resonance imaging (MRI) of the left hip. MRI of the left hip revealed a complete tear of the left iliopsoas tendon from the lesser trochanter with 4 cm of proximal retraction and a high-grade strain of the gluteus minimus tendon at the greater trochanter. The distal iliopsoas myotendinous junction and lesser trochanter tendon insertion were surgically repaired. This case illustrates that a stun gun can cause acute rupture of the iliopsoas tendon and tear of the gluteus minimus tendon, which is well visualized on MRI.

Anterior cruciate ligament graft reconstruction: clinical, technical, and imaging overview.

The anterior cruciate ligament (ACL) is one of the most frequently torn ligaments of the knee. With more than 100,000 ACL reconstructions performed yearly in the United States, evaluation of ACL grafts with magnetic resonance imaging is a common occurrence in daily clinical practice. Anterior cruciate ligament reconstructions vary from single bundle, double bundle, selective bundle, and physeal-sparing techniques. Complications of ACL graft reconstructions include graft tears, graft laxity, arthrofibrosis, and hardware failure or migration. This article offers a comprehensive review of ACL reconstruction for the consulting radiologist.