Systemic Cobalt Toxicity Secondary to Tibial Component Malpositioning in Bilateral Primary Total Knee Arthroplasties

Abstract

Metallosis and systemic metal toxicity are uncommon complications in modern total joint arthroplasty, typically linked to metal-on-metal hip articulations. We present a case of systemic cobalt toxicity following bilateral total knee arthroplasties (TKAs), where excessive posterior tibial slope caused flexion gap instability and polyethylene wear with subsequent metallic debris release. This patient developed cognitive impairment, neuropathy, and cardiac symptoms nearly a decade after surgery, with the highest serum cobalt and chromium levels reported in literature for primary TKAs. At revision, polyethylene and baseplate wear with metallic debris and bone loss were present. Surgeons should remain vigilant for metallosis and systemic toxicity in painful or unstable TKAs with polyethylene wear from component malalignment or instability. Further studies are needed to define surveillance strategies and management guidelines.

Introduction

Metallosis is a complication in joint arthroplasty in which corrosion or wear of metallic components leads to the accumulation of wear debris within periprosthetic tissues [1,2]. Due to advancements in implant design, clinically significant metallosis is rare within contemporary total knee arthroplasty (TKA), with most reported cases historically linked to older metal-on-metal hinge designs and megaprostheses [3,4]. Although this phenomenon has been described in total hip arthroplasty, where mechanically assisted crevice corrosion and fretting at modular junctions such as the head-neck or neck-stem interfaces generate metal ions and debris, analogous processes have increasingly been recognized in revision TKA [5,6]. In these knee revisions, modular junction corrosion and polyethylene wear can similarly produce metallic debris, potentially leading to adverse local tissue reaction, pseudotumor formation, osteolysis, and even elevated systemic metal ion concentrations [[7], [8], [9], [10], [11]]. Consequently, awareness and monitoring for these complications are essential in revision TKA, despite the absence of traditional metal-on-metal bearing surfaces [12].

The relative infrequency of this complication is primarily attributed to the widespread adoption of metal-on-polyethylene articulations in these modern TKA implants [13,14]. The precise incidence of metallosis remains unclear, as many cases are subclinical, but it is typically associated with severe polyethylene wear with metal-on-metal articulation resulting from severe instability, faulty polyethylene, or failure of the tibial polyethylene locking mechanisms in the current generation of implants [2,15,16]. Clinically, the condition manifests with nonspecific symptoms, including pain, swelling, instability, and reduced range of motion (ROM) [17]. Radiographically, early disease may present as subtle osteolysis, while classic findings such as the “cloud sign,” “bubble sign,” and “metal-line sign” are typically seen in more advanced cases and may not always be present [[18], [19], [20]]. Therefore, a definitive diagnosis requires intraoperative evaluation during revision surgery [2].

To support clinical suspicion and inform surgical planning, a comprehensive preoperative evaluation typically includes laboratory tests such as complete blood count (CBC), erythrocyte sedimentation rate, C-reactive protein, and serum metal ion concentrations, particularly cobalt, chromium, and titanium [11,17,21,22]. Routine inflammatory markers primarily help exclude infection, though their diagnostic utility in isolated metallosis remains limited [23,24]. Synovial fluid aspiration is especially informative, as elevated cobalt and chromium ion concentrations strongly suggest metallosis [[25], [26], [27]]. Additionally, ultrasound imaging can supplement radiographs by identifying joint effusions, synovitis, or metal debris, further reinforcing clinical suspicion before surgical intervention.

Although most patients with standard TKA designs may exhibit elevated serum metal ion concentrations that remain even after long-term follow-up, the progression to systemic toxicity is relatively uncommon [28,29]. In cases of implant wear or mechanical failure in TKA, metallic debris is primarily released from the cobalt-chromium femoral components and tibial components made from either cobalt-chromium or titanium alloy. Consequently, cobalt, chromium, and titanium are typically implicated in instances of metal toxicity [11,30]. The initial biological response to metallic debris includes local inflammation and osteolysis, which can progress to more severe multi-organ dysfunction in systemic cases which may not fully resolve even if the prosthesis is replaced [31]. Due to its highly variable and nonspecific clinical presentation, along with its rarity, the diagnosis of systemic metal toxicity is often delayed or missed completely [32]. This is further complicated by the absence of universally accepted blood ion levels that accurately predict toxicity, as well as an inconsistent correlation between measured blood levels and clinical symptoms [32].

Here, we present a case of severe metallosis with systemic metal toxicity, characterized by the highest serum metal ion levels reported in the literature. This complication developed nearly a decade after primary TKA and was precipitated by significant polyethylene wear secondary to an increased tibial slope. The patient provided written informed consent for the publication of their deidentified clinical data.

Case history

A 63-year-old female with a past medical history of rheumatoid arthritis presented with a 5-year history of progressively worsening bilateral knee pain and instability following TKAs performed at an outside hospital in 2015 for severe degenerative joint disease secondary to her underlying condition. While initially satisfied postoperatively, she began to experience chronic bilateral knee pain and instability, which progressively worsened over the previous 5 years. The patient described the pain as burning and stabbing in nature, which is exacerbated by physical activity. She reported her symptoms significantly impacted her functional status and often disrupted her sleep. Several months prior to her initial presentation, the patient reported intermittent episodes of blurry vision, confusion, tachycardia, memory impairment, brain fog, word-finding difficulties, and vertigo. She described these presyncopal episodes as “greying out,” resulting in falls without clear loss of consciousness, followed by immediate recovery to baseline. She also noted intermittent neuropathy predominantly affecting her arms bilaterally.

Physical examination revealed markedly unstable bilateral knees, despite excellent active ROM of 0° extension to 126-130° flexion bilaterally. Significant anteroposterior, medial-lateral, and varus-valgus laxity were noted. Preoperative lateral radiographs demonstrated bilateral cruciate-retaining TKAs with pronounced posterior polyethylene wear, anterior tibial subluxation, and significantly increased posterior tibial slopes (right knee: 16°, left knee: 15°) (Fig. 1A). Radiopaque specks of metal debris are present posterior to the tibia bilaterally. The “cloud sign,” or metal arthrogram, characterized by an amorphous, cloudy, or hazy area of radiodensity within the periprosthetic soft tissue, is observed on the right lateral radiograph posterior to the distal femur, surrounding the femoral component and extending into the infrapatellar region [33]. Similar radiodensities were observed primarily in the infrapatellar region on the left lateral radiograph. Areas of radiolucency are present along the anterior and lateral aspect of the tibial tray, suggestive of early osteolysis.

Figure 1.

Preoperative weight-bearing lateral (a) and anteroposterior (b) x-rays.

Laboratory analysis demonstrated markedly elevated serum cobalt and chromium levels of 127.9 μg/L and 64.7 μg/L levels, respectively, consistent with systemic metallosis and cobalt toxicity. Basic metabolic panel, CBC, thyroid-stimulating hormone (TSH), titanium, and iron levels were within normal limits. Although the patient had undergone a right reverse total shoulder arthroplasty 3 months prior to presentation, the shoulder was excluded as the source of metal toxicity given that systemic symptoms predated the procedure and knee radiographs already demonstrated extensive polyethylene wear with characteristic metallosis. She denied any history of total hip arthroplasty or other metal implants.

The patient underwent revision left TKA 4 days after presentation to our clinic. Intraoperatively, extensive metallic debris was evident, characterized by dark-stained synovium (Fig 2A). She had severe polyethylene wear extending into the tibial baseplate with metal erosion of the tibial component locking mechanism despite well-fixed implants, (Fig. 2B, C), femoral bone loss (Fig. 2D), and well-fixed tibial implant despite severe posterior tibial slope. Reconstruction required a tibial cone and femoral augments and bone-preserving hinged implants due to instability of ligaments after extensive synovectomy and erosion of femoral epicondyles further jeopardizing reliability of collaterals.

Figure 2.

Intraoperative images from the left knee demonstrate extensive metallic debris present on initial exposure of (a), severe bicompartmental tibial (b) and polyethylene wear (c), and femoral bone loss after removal of metallosis debris (d).

Postoperatively, she continued experiencing systemic symptoms, including tachycardia, dizziness, fatigue, bilateral numbness, cognitive impairment, and presyncope. On postoperative day 2, toxicology consultation confirmed systemic cobalt toxicity. Per their recommendation, 21-hour intravenous N-acetylcysteine therapy was initiated but resulted in minimal symptomatic improvement. On postoperative day 2, her serum cobalt and chromium levels decreased to 53.2 μg/L and 45.7 μg/L, respectively, and dropped even further to 42.9 μg/L and 20.3 μg/L the following day (Table 1). She was discharged on postoperative day 4, instructed on 50% weight-bearing with a walker and knee immobilizer for 2 weeks.

Table 1.

Plasma metal ion levels preoperatively to six-month follow-up.

Metal	Preop	POD #1	POD #2	Three-month postop	Six-month postop	Reference levels
Chromium (μg/L)	64.7	45.7	20.3	18.6	15.0	≤5.0
Cobalt (μg/L)	127.9	53.2	42.9	16.5	6.7	≤1.0
Titanium (μg/L)	2.5	-	-	7.3	6.3	Variable

POD, postoperative day.

Two weeks following her left revision TKA, she returned to clinic; her incision was healing, and she desired to proceed with her second knee revision within 2 months of her first due to satisfactory recovery and concerns about cobalt toxicity.

Her right knee was subsequently revised to a medial-lateral constrained revision prosthesis due to extensive metallic debris and polyethylene wear (Fig. 3A). Her implants were found to be well fixed but there was excessive tibial slope and tibial implant erosion including almost the entire posterior locking mechanism. There was central tibial bone loss after implant removal and femoral posterolateral condyle loss related to osteolysis (Fig. 3B); reconstruction included a tibial cone, femoral impaction grafting, and femoral augments. Concurrent manipulation under anesthesia improved left knee flexion from 90° preoperatively to 130° post-manipulation.

Figure 3.

Extensive right polyethylene wear (a) and femoral bone loss following debridement (b).

After a 3-day hospital stay, the patient was discharged without significant complications. By the 6-week follow-up, she reported fair pain control managed with oxycodone and tramadol. She and her family reported improved cognitive function, less word finding difficulty, no further fainting spells, and improved vision. She no longer required an assistive device for ambulation.

At the 6-month follow-up, the patient demonstrated substantial improvement, resuming activities such as hiking, gardening, and playing with grandchildren. Physical examination revealed bilateral knee ROM from 0 to 130˚, and stable gait (Fig. 4). She only complained of some mild left knee joint tenderness and occasional episodes of dizziness. Her radiographs confirmed stable, well-fixed, aligned bilateral revision knee prostheses without evidence of loosening or migration (Fig. 5). Cobalt and chromium levels further decreased to 16.5 μg/L and 18.6 μg/L, respectively. CBC, basic metabolic panel, TSH, and iron levels were all within normal limits. Routine 6-month follow-ups with periodic monitoring of metal ion levels, TSH, iron, CBC, and inflammatory markers were recommended to monitor ongoing recovery.

Figure 4.

Patient demonstrating full extension of the left (a) and right (b) and 130° of maximum knee flexion at 6-month follow-up (c).

Figure 5.

Postoperative lateral (a) and anteroposterior (b) radiographs and six-month follow-up.

Discussion

We present a rare case of severe metallosis with systemic cobalt and chromium toxicity developing nearly a decade after bilateral primary TKAs. This 63-year-old patient exhibited progressive bilateral knee pain and instability, accompanied by significant systemic manifestations, including cognitive impairment, visual disturbances, neuropathy, and tachycardia. Radiographs revealed markedly increased posterior tibial slopes, extensive polyethylene wear, anterior tibial subluxation, tibial tray erosion, and the characteristic cloud sign of metallosis. Serum cobalt and chromium ion levels in this patient were associated with severe symptoms and were among the highest documented in the primary TKA literature, prompting urgent bilateral revision surgery and highlighting critical lessons regarding implant alignment, polyethylene wear, and postoperative monitoring.

An optimal posterior tibial slope is essential for achieving proper knee biomechanics and stability following TKA. Typically, posterior tibial slope ranges from 0° to 7°, facilitating improved knee flexion, decreased quadriceps force requirements, lower patellofemoral stress, and ideal femoral condylar positioning [[34], [35], [36], [37], [38], [39], [40]]. However, slopes exceeding approximately 10° amplify these biomechanical effects, resulting in joint laxity, abnormal ligament tension, increased anterior tibial translation and shear forces on the polyethylene bearing, and ultimately premature wear and instability [[41], [42], [43]]. In our patient, slope angles significantly exceeded this recommended range, measuring approximately 15° and 16° on the right and left tibias, respectively. While intentional increases in tibial slope may sometimes be justified, bilateral occurrence of excessive slope suggests either a reproducible surgical error or underlying anatomical variation. Anterior cortex referencing methods are especially prone to substantial slope deviations, even with minor guide misalignment [42]. Improper fixation of the tibial cutting guide, such as using a single pin or short pins, may permit intraoperative drift, exacerbating these deviations, particularly in patients with excessive native tibial slope. Maintaining a postoperative tibial slope within 7° of the native tibial slope should be the goal, whether using robotics, navigation, personalized cutting guides, or standard mechanical instruments [44]. Given that implant malalignment is among the most frequent causes of severe polyethylene wear and subsequent metallosis in primary TKA, precise surgical technique remains imperative in preventing long-term complications. [32]. When addressing polyethylene wear in the setting of excessive tibial slope, surgeons should strongly consider tibial component revision rather than isolated polyethylene exchange; failure to correct the underlying malalignment may perpetuate abnormal biomechanics and predispose the new bearing surface to accelerated wear.

Cobalt, chromium, and titanium are the primary sources of metal ion release in TKA. In our patient, cobalt and chromium levels reached 127.9 μg/L and 64.7 μg/L, respectively, among the highest reported for primary TKA in the literature, suggesting massive debris generation from metal-on-metal abrasion following substantial polyethylene wear [29,45,46]. Cobalt toxicity has a well-established, highly morbid toxidrome that includes cardiomyopathy, arrhythmias, tachycardia, hypothyroidism, hearing and vision loss, peripheral neuropathy, emotional lability, and cognitive decline suggesting it is primarily the cause of the majority of our patient’s symptoms [31,[47], [48], [49]]. Chromium toxicity has less evidence of extensive organ involvement; however, it can similarly cause neurologic damage such as vision loss, hearing loss, cognitive decline, and peripheral neuropathy [31,50]. Though both metals have overlapping symptomology, cobalt has a higher predilection for the cerebrospinal fluid which causes a massive inflammatory response resulting in neuronal injury and subsequent neurotoxicity [50,51].

Titanium is considered relatively inert compared to cobalt and chromium, with a lower propensity to cause adverse local or systemic reactions [52,53]. While rare hypersensitivity reactions have been reported, there are no well-documented cases of titanium-induced systemic organ dysfunction or toxicity in the literature [46]. Although titanium is not directly toxic, it may stimulate cytokine release that activates osteoclasts, leading to local osteolysis [54,55]. Its synergistic interaction with polyethylene debris can further amplify the release of inflammatory mediators, exacerbating periarticular bone loss [56,57].

Taken together, the patient’s clinical presentation, imaging findings, and laboratory data pointed to an advanced stage of implant-associated metallosis with systemic involvement, necessitating prompt and definitive intervention. The management of systemic metal toxicity following TKA remains challenging, as there are limited clinical guidelines and revision surgery is often required in the absence of consistently effective treatment alternatives. [31,49]. In this patient, comprehensive synovectomy, extensive debridement, and bilateral revision to constrained implants with reconstruction using augments and metaphyseal cones were essential for addressing instability, polyethylene wear, and bone loss.

From a systemic toxicity standpoint, chelation agents may play a potential role in the management of cobalt toxicity; however, the data are often limited to animal model or singular case studies thus lacking standardized dosage and administration routes. For example, this patient received intravenous N-acetylcysteine, an amino acid-derived antioxidant, which has demonstrated efficacy in ameliorating cobalt ion toxicity in animal models but has no established studies in human subjects [58]. Therefore, the ideal dosage to potentially see effects in humans is not well established. Our patient experienced a 58% reduction in cobalt levels and a 29% reduction in chromium levels 2 days following surgery and 1 day following N-acetylcysteine administration. Interestingly, this rapid rate of decline contrasts sharply with the findings of Ball et al., who reported a 2% daily decline in metal ion levels during the first 6 weeks following revision surgery [59]. However, due to the observational nature of this report and the absence of serial metal ion measurements, it remains difficult to determine the individual contributions of each intervention.

The substantial postoperative decline in serum cobalt and chromium levels as well as rapid improvement in systemic symptoms highlights the effectiveness of timely surgical intervention (Fig. 6). Nevertheless, persistence of certain neurologic symptoms in this patient as well as the literature with arthroplasty sourced metallosis suggests that prolonged metal exposure may lead to irreversible central nervous system changes, emphasizing the critical importance of early recognition and prompt intervention [60]. Unlike previously reported cases involving early failures or modular junction corrosion, this patient experienced a prolonged interval of satisfactory implant function, demonstrating that systemic metal toxicity may develop insidiously and unpredictably with contemporary metal-on-polyethylene articulations [11,46,61]. Considering the delayed presentation observed here, long-term postoperative vigilance extending well beyond routine follow-up is critical. Regular clinical assessment, imaging, and appropriate metal ion screening should be implemented, particularly beyond 10 years postoperatively, to identify early signs of wear-related complications. Continued exploration into advanced polyethylene formulations and alternative bearing surface treatments may offer future prevention strategies, though current evidence for their long-term efficacy remains inconclusive. [15,46,61]

Figure 6.

Trend in plasma cobalt and chromium levels preoperatively to six-month follow-up.

In conclusion, this case expands clinical awareness regarding systemic metal toxicity following TKA. It highlights key considerations, including careful surgical planning, precise implant alignment, proactive long-term surveillance, and early intervention upon identification of systemic symptoms or radiographic abnormalities. Greater awareness of this rare yet significant complication in modern TKA can facilitate timely diagnosis and management, ultimately improve patient outcomes, and reduce morbidity associated with delayed intervention.

Summary

We present a severe case of systemic cobalt toxicity following bilateral primary TKAs with metal on polyethylene implants. The pathology was driven by excessive posterior tibial slope of the tibial baseplate, resulting in progressive flexion gap instability, polyethylene wear, metal-on-metal articulation, and then eventual release of metallic debris. The patient presented with a constellation of systemic symptoms, including cognitive decline, neuropathy, and cardiovascular disturbances, and was found to have the highest serum cobalt and chromium ion levels reported in the literature 10 years after her index procedures. This case illustrates how mechanical failure with polyethylene wear can lead to significant metal debris generation and systemic toxicity, even in modern primary implant designs. The patient’s clinical improvement and rapid decline in metal ion levels following staged bilateral revision with constrained components highlight the importance of early recognition and timely surgical management. Long-term postoperative surveillance is essential, particularly in patients presenting with unexplained systemic symptoms years after primary TKA. Increased clinical awareness and further research are necessary to establish evidence-based surveillance strategies and mitigate the serious consequences of delayed diagnosis in metal-induced toxicity.

Informed patient consent

The author(s) confirm that written informed consent has been obtained from the involved patient(s) or if appropriate from the parent, guardian, power of attorney of the involved patient(s); and, they have given approval for this information to be published in this case report (series).

CRediT authorship contribution statement

Nikhil Vallabhaneni: Writing – review & editing, Writing – original draft. Kayla Gates: Writing – review & editing, Writing – original draft, Conceptualization. Joshua P. Rainey: Writing – review & editing. Jeremy M. Gililland: Writing – review & editing, Conceptualization. Michael J. Archibeck: Writing – review & editing. Lucas A. Anderson: Writing – review & editing, Supervision, Conceptualization.

Conflicts of interest

J Gilliland receives royalties from Zimmer Biomet and Stryker; is a paid consultant for Stryker, Enovis, and Zimmer Biomet; possesses stock in CoNextions, MiCare Path, Sylke, Solenic, and OR Innovations; receives research support from Stryker, Zimmer Biomet, and Medacta; sits on the editorial board for the Journal of Arthroplasty; and is part of the American Association of Hip and Knee Surgeons program committee. M Archibeck is a paid consultant for and receives research support as a Principal Investigator from Zimmer Biomet; sits on the editorial board for the Journal of Arthroplasty. L Anderson has been a paid speaker for Medacta in addition to being a paid consultant; owns stock in OrthoGrid; received research support from Stryker and Zimmer Biomet; and is a section editor of the Société Internationale de Chirurgie Orthopédique et de Traumatologie for hip and knee arthroplasty; all other authors declare no potential conflicts of interest.