Samuel Brown

Objective: To determine the incidence, presentation, and management of complex regional pain syndrome (CRPS) after total knee arthroplasty (TKA). Literature Survey: A Preferred Reporting Items for Systematic Reviews (PRISMA) compliant search was performed in February 2025 using PubMed, Embase, Ovid/MEDLINE, and Cochrane Central Register of Controlled Clinical Trials to identify TKA studies that describe CRPS. Case reports and non-English articles were included. Methodology: Two independent reviewers screened studies using specific eligibility criteria. Study characteristics, incidence, symptoms, physical exam findings, diagnostic modalities, therapies, and outcomes were extracted. Studies were evaluated according to the Newcastle-Ottawa scale and adherence to CARE case report guidelines. Synthesis: Fifteen studies comprising 125 TKA patients diagnosed with CRPS were included. The mean age was 64 7 years, 67.7% of patients were female, and mean follow-up was 16.9 15.9 months. The incidence of CRPS after TKA was 2.8% (83/2945). Mean time from surgery to diagnosis was 7 3.4 months (n=86). The most prevalent findings were edema (72.5%, 29/40), knee stiffness (62.5%, 25/40), hyperalgesia (62%, 43/69), allodynia (59%, 41/69), and skin temperature changes (50%, 20/40). Therapeutic sympathetic blocks were used in 75% (36/48) of cases, of which 42% (15/36) of patients had persistent symptoms after treatment. Manipulation under anesthesia was performed in 25% (n=11) of cases and resulted in an average increase in flexion of 29 (n=6). The average ROM at diagnosis was 3.4° - 66.1° (n=16) compared to 3.3° - 92.2° (n=12) at final follow-up. Conclusions: The archetypical CRPS TKA patient presents with disproportionate and unexplainable knee pain nine months postoperatively, often with burning and altered sensation, stiffness, edema, and temperature asymmetry on exam. Reported incidence varies significantly, likely due to evolving diagnostic criteria and a historical tendency to ascribe unexplainable pain to CRPS. However, the condition may be underdiagnosed after TKA given the multiple risk factors and prevalence of chronic unexplainable pain associated with knee replacement.

The development of periprosthetic soft tissue reactions is a well-documented complication in patients who have previously undergone metal-on-metal (MoM) total hip arthroplasty (THA). Adverse reactions resulting from the shedding of intraarticular metal ions have been broadly classified into several modes of failure, including pseudotumor development and aseptic lymphocyte-dominated vasculitis-associated lesion (ALVAL). We present a case report of a 76-year-old female with a history of MoM THA who presented with left thigh pain and swelling. Radiographic and histologic analysis were consistent with ALVAL and pseudotumor, despite normal serum metal ion levels. The patient underwent revision total hip arthroplasty with pseudotumor debridement of 3300 mL cystic fluid, and at nearly five years postoperatively, is functioning well with no recurrence of pain or swelling. Review of the literature demonstrates an average pseudotumor area of 73 cm2. Further literature review reveals that serum metal ion levels may not reliably exclude clinically significant pseudotumor formation. As such, this case report challenges the assumption of elevated serum metal ions as an indicator for MoM failure by demonstrating a massive pseudotumor in the context of normal serum levels. Clinicians should maintain a high index of suspicion for adverse local tissue reactions in patients with MoM THA, regardless of serum metal ion levels. Advanced imaging and clinical correlation remain essential for diagnosis and management.

Understanding the timing of fetal brain vulnerability to inflammatory changes in pregnancy complications is crucial for predicting neurodevelopmental risks. Beyond the placenta, the developing brain’s vascular system is believed to form a secondary defense, the blood–brain barrier (BBB), which restricts harmful substances that could disrupt neurodevelopment. However, the precise timing and mechanisms underlying BBB development are poorly understood. In this study, we examined the spatiotemporal expression of key BBB components and fetal brain vascularization in mice from gestational days (GD) 10 to 18. Fetal brain sections were immunostained to identify BBB components, including CD31, Factor VIII, NG2, and claudin-5. Our results showed that endothelial precursor cells form the primitive vascular network in a caudal-to-rostral gradient by GD10, with pericyte recruitment stabilizing vessels by GD12 in a lateral-to-medial gradient that aligns with neurogenesis, despite some regional exceptions. However, Factor VIII was not detected until GD15, and claudin-5 until GD18, suggesting a significant delay in endothelial maturation and tight junction formation. These findings highlight the critical timing of structural developments in the fetal brain vasculature and its vulnerability to placental diseases, laying the groundwork for future research on the impact of placental disorders on fetal brain development and potential therapeutic interventions.

The proliferation of trophoblast stem (TS) cells and their differentiation into multiple lineages are pivotal for placental development and functions. Various transcription factors (TFs), such as CDX2, EOMES, GATA3, TFAP2C, and TEAD4, along with their binding sites and cis-regulatory elements, have been studied for their roles in trophoblast cells. While previous studies have primarily focused on individual enhancer regions in trophoblast development and differentiation, recent attention has shifted towards investigating the role of super-enhancers (SEs) in different trophoblast cell lineages. SEs are clusters of regulatory elements enriched with transcriptional regulators, forming complex gene regulatory networks via differential binding patterns and the synchronized stimulation of multiple target genes. Although the exact role of SEs remains unclear, they are commonly found near master regulator genes for specific cell types and are implicated in the transcriptional regulation of tissue-specific stem cells and lineage determination. Additionally, super-enhancers play a crucial role in regulating cellular growth and differentiation in both normal development and disease pathologies. This review summarizes recent advances on SEs’ role in placental development and the pathophysiology of placental diseases, emphasizing the potential for identifying SE-driven networks in the placenta to provide valuable insights for developing therapeutic strategies to address placental dysfunctions.

Understanding the timing of fetal brain vulnerability to inflammatory changes in pregnancy complications is crucial for predicting neurodevelopmental risks. Beyond the placenta, the developing brain's vascular system is believed to form a secondary defense, the blood-brain barrier (BBB), which restricts harmful substances that could disrupt neurodevelopment. However, the precise timing and mechanisms underlying BBB development are poorly understood. In this study, we examined the spatiotemporal expression of key BBB components and fetal brain vascularization in mice from gestational days (GD) 10 to 18. Fetal brain sections were immunostained to identify BBB components, including CD31, Factor VIII, NG2, and claudin-5. Our results showed that endothelial precursor cells form the primitive vascular network in a caudal to rostral gradient by GD10, with pericyte recruitment stabilizing vessels by GD12 in a lateral-to-medial gradient that aligns with neurogenesis, despite some regional exceptions. However, Factor VIII was not detected until GD15, and claudin-5 until GD18, suggesting a significant delay in endothelial maturation and tight junction formation. These findings highlight the critical timing of structural developments in the fetal brain vasculature and its vulnerability to placental diseases, laying the groundwork for future research on the impact of placental disorders on fetal brain development and potential therapeutic interventions.