Mechanisms and targeted treatments of cobalt-encephalopathy from cobalt-chromium orthopedic implants

5-10 million persons are living with cobalt-chromium joint or spinal implants therefore are systemically exposed to ionic and nanoparticulate cobalt-chromium metallosis degradation products from wear or corrosive mechanisms. Cobalt's toxidrome (cobaltism) is characterized by neurologic, cardiovascular, immune, and constitutional symptoms and findings. Orthopedic-Implant-Cobaltism (OIC) became recognized in 2010 related to metal-on-metal hip resurfacings and replacement of which two million were fitted before largely silent market recall. Recently the at-risk population has be expanded to any person with a cobalt-chromium orthopedic component of a hip, shoulder, knee, or spinal reconstruction. The Cobaltism- Symptom-Inventory (CSI) is a validated clinical screening tool for Orthopedic-Implant-Cobaltism. The CSI score increases when urinary cobalt exceeds 1 ppb or urine-cobalt-years exposed exceeds 10 ppb-years. This review explores the pathophysiology of cobalt encephalopathy focusing on cellular hypoxia, antioxidant imbalance, and mitochondrial damage. It also examines the role of microglia and oligodendrocytes in neurodegenerative diseases following cobalt exposure, m6A methylation modification, and proline isomerase Pin1 function. It further discusses current research on potential options for the treatment of cobalt toxicity, including glucagon-like peptide-1 and gastric inhibitory polypeptide, D-β-hydroxybutyrate, and inhibitors of NF-κB and p38 MAPK. Implant removal is currently the most effective method to reduce blood cobalt levels and halt the progression of OIC. However, revision joint and spinal operations are highly morbid and expensive though likely mandated in extreme cases. It is important to develop medical treatments that reduce systemic cobalt exposure from indwelling cobalt-chromium orthopedic implants and mitigate or reverse the cobalt related neurodegeneration.