Imaging

Tourniquets are often used in total knee arthroplasty (TKA) to improve visualization of structures, shorten operative time, reduce intraoperative bleeding, and improve cementing technique. Despite these advantages, controversy remains regarding the safety of tourniquet use. Tourniquets have been associated with nerve palsies, vascular injury, and muscle damage.^1-5 Some have hypothesized they may cause venous stasis or direct endothelial damage that may develop into deep vein thrombosis (DVT). Abdel-Salam and Eyres⁶ found an increased incidence of postoperative wound complications and DVTs associated with tourniquet use.

Moreover, investigators have analyzed the role of tourniquets in populations at high risk for wound complications. DeLaurentis and colleagues⁷ performed a prospective and retrospective analysis of 1182 TKA patients, 24 (2%) of whom had preexisting peripheral vascular disease (PVD), defined as a history of arterial insufficiency, absent dorsalis pedis and/or absent posterior tibial pulsations, and arterial calcifications. A tourniquet was used in each case. Arterial complications occurred in 6 of the 24 patients with PVD. As expected, the authors found that a history of intermittent claudication, pain at rest, and arterial ulcers resulted in a high risk for vascular complications. Further studies have supported this finding and expanded the list of predisposing factors to include previous vascular surgery and absent and asymmetric pedal pulsations.^7-11 Of particular concern to total joint arthroplasty surgeons was the finding by DeLaurentis and colleagues⁷ that patients with radiographic evidence of calcification of the distal superficial femoral artery and/or popliteal artery were at risk for arterial complications. This finding is also supported by other studies.^8,11 In TKA, damage to arterial structures proximal to the surgical field could manifest as impaired postoperative wound healing or an ischemic limb. Wound healing depends on adequate blood flow to the healing tissue, and any damage to arterial or venous structures can theoretically compromise this process.

Added to vascular/wound complications as concerning complications in orthopedic surgery is venous thromboembolism (VTE). The role of tourniquets in the formation of VTEs is controversial. A tourniquet has the potential to increase the risk for DVT because of the stasis of venous blood in the lower limb or possible damage to calcified blood vessels. Callam and colleagues¹² studied the connection between artery disease and chronic leg ulcers and found that half the patients diagnosed with peripheral artery disease also had stigmata of chronic venous insufficiency. Therefore, the entities can occur in tandem, and surgeons should keep this in mind.

Here we report on a study we conducted to determine whether tourniquet use in TKA in patients with preexisting radiographic evidence of vascular disease increases the risk for wound complications or VTE.

Patients and Methods

We retrospectively reviewed 461 consecutive primary TKAs (373 patients) performed between January 2007 and June 2012 by 2 attending orthopedic surgeons specializing in adult reconstruction. Medical records and operative reports of 583 patients were examined after receiving institutional review board approval. Of these patients, 373 (64%) had a minimum of 12-month follow-up data available. Twelve months was deemed long enough to discover wound complications or DVTs secondary to the index procedure. Most of these outcomes manifest within the first 3 months after surgery and certainly by 12 months. Follow-up longer than 12 months may become a confounder, as wound complications outside the acute to subacute postoperative window could be related to patients’ underlying PVD and not directly to tourniquet use during surgery. Patient demographics and comorbidities were recorded. Comorbidities were obtained from preoperative medical evaluations and surgeons’ preoperative evaluations. All patients had preoperative palpable dorsalis pedis and posterior tibialis arterial pulses. No patient required preoperative vascular studies based on preoperative examination or comorbidities. No patient had prior vascular bypass surgery or stenting.

TKA was performed in a nonlaminar flow, positive-pressure, high-efficiency particulate air-filtered room with sterile toga/surgical helmet systems. For all patients, a pneumatic thigh tourniquet was applied, and the patient was prepared and draped. After limb exsanguination using a rubber bandage, the limb was elevated and the tourniquet inflated to a pressure of 250 to 300 mm Hg. The tourniquet was released either just before closure or immediately after closure in all cases; it was always let down before placement of final bandages.

Prophylactic chemical anticoagulation consisting of warfarin, aspirin, or enoxaparin was used in all patients and continued for 4 to 6 weeks after surgery. All patients received mechanical DVT prophylaxis with sequential compression devices, and all were mobilized out of bed beginning either the day of surgery or the next day. All patients received perioperative intravenous antibiotics, with the preoperative dose given before tourniquet inflation and the last postoperative dose stopped within 24 hours of surgery.

All patients who had primary TKA underwent preoperative medical evaluation and optimization. The patient’s hospital course was monitored closely, and complications noted by the orthopedic team were documented. Follow-up documentation was retrospectively reviewed for evidence of wound complications or VTE. Wound complications were defined as cellulitis, delayed wound healing, wound dehiscence, and/or periprosthetic joint infection. In the case of VTE, physical examination findings were not sufficient for inclusion. Venous duplex ultrasonography demonstrating the clot was reviewed before inclusion.

Preoperative radiographs were examined for arterial calcification (Figure). We refer to calcification seen above the knee joint as proximal calcification and to calcification observed below the joint as distal calcification. Patients exhibited calcification proximally only, distally only, or both proximally and distally. The 373 patients were placed into 2 groups based on whether they had preoperative arterial calcification on plain radiography of the knee. One group (285 patients with no radiographic evidence of preoperative knee arterial calcification) underwent 365 TKAs, and the other group (88 patients with radiographic evidence of preoperative knee arterial calcification) underwent 96 TKAs.

A sample size calculation was performed to determine how many patients were needed in each group with 80% power and an α of 0.05. With an estimated difference in VTE/wound complication rate between the calcification and no-calcification groups of 12%, we needed to review 316 TKAs total. This 12% difference was based on study findings of a 25% complication rate in PVD patients who underwent tourniquet-assisted TKA, and the rate of VTE/wound complication after TKA in patients overall, which can be up to 12%.^7,13,14 We exceeded minimal enrollment and had 461 TKAs. Descriptive statistics were reported, with means and ranges provided where appropriate. Independent t test was used to evaluate the differences in continuous data (age) between the groups. Univariate analysis (using Pearson χ² and Fisher exact tests) and multivariate logistic regression analysis were used to evaluate the effects of categorical variables (sex, comorbidity, calcification [presence, absence], and location of calcification [proximal only, distal only, both]) on wound complication and VTE rates. All tests were 2-tailed and performed with a type I error rate of 0.05. Data analysis was performed with SPSS Version 19.0 (SPSS).

Results

Patient characteristics are summarized in Table 1. Of the 373 patients, 285 lacked calcification, and 88 had calcification. Mean age was 67.73 years (range, 24-92 years) for all patients, 65.99 years (range, 24-89 years) for the no-calcification group, and 74.32 years (range, 54-92 years) for the calcification group; the calcification group demonstrated a trend toward older age, but the difference was not significantly different (P = .07). Of the 373 patients, 156 (41.82%) were male: 110 in the no-calcification group (38.60%) and 46 in the calcification group (52.27%); sex was significantly (P = .002) different between groups, with more males in the calcification group.

Data on total preoperative comorbidities are summarized in Table 2. Hypertension, hyperlipidemia, diabetes, and coronary artery disease (CAD) were the most common comorbidities, and they were all significantly (P ≤ .05) increased in the calcification group.

No patients had reported arterial complications, such as arterial bleeding, aneurysm, intimal tears, or loss of distal pulses. Wound complication after TKA was detected in 3.04% of all cases (Table 3). Rate of DVT after TKA was 2.60% of all cases, and rate of pulmonary embolism after TKA was 2.17% of all cases. Of the 96 TKAs with preoperative radiographic evidence of calcification, 47 (48.96%) had proximal calcification only, 11 (11.46%) had distal calcification only, and 38 (39.58%) had both proximal and distal calcification (Table 4). There was no significant difference between the rate of wound complication or VTE based on location of vascular calcification.

Univariate analysis demonstrated that presence of arterial knee calcification did not increase the risk for postoperative wound complication (odds ratio [OR], 1.04; 95% confidence interval [CI], 0.28-3.80; P > .05) (Table 5). Location of arterial knee calcification also did not increase the risk for postoperative wound complication. In addition, univariate analysis demonstrated that presence of arterial knee calcification did not increase the risk for postoperative VTE (OR, 1.20; 95% CI, 0.43-3.36; P > .05 (Table 6).

Of the 14 wound complications, the most common infections were cellulitis (5/14 cases; 35.71%) and infected hardware that required component revision (5/14 cases; 35.71%). Mean time from TKA to infection was 137.93 days (range, 5-783 days). The most common organism grown in culture from the wound was Staphylococcus (5/14 cases; 35.71%).

Additional univariate statistical analysis revealed that presence of diabetes, hypertension, prior VTE, CAD, and male sex was linked to higher incidence of wound complication (P < .05) (Table 5). When multivariate analysis was performed, hypertension, prior VTE, and male sex remained significant (P < .05) (Table 5).

Discussion

TKA is a safe and effective procedure used to treat osteoarthritis of the knee and improve patients’ quality of life.¹⁵ About 700,000 TKAs are performed annually in the United States.¹⁶ Because of improvements in preventive medicine and medical technology, life expectancy is increasing, and TKAs are now being performed in higher numbers and in an older patient population. Over the next few decades, these developments will lead to more postoperative complications. It is projected that, by 2030, the need for TKAs in the United States will increase by 673% to 3.48 million.¹⁷ Postoperative complications are rare but unfortunately often lead to poor outcomes or even mortality.¹⁸ To help minimize the number of postoperative complications, we must understand the safety of tourniquet use in TKA. Other investigators have concluded that tourniquet use is unsafe in patients with preoperative vascular calcifications on plain radiographs.^7,8,11 The present study, designed to elucidate whether preoperative evidence of knee arterial calcification may predispose TKA patients to postoperative wound complication or VTE, had some important findings.

In our study, wound complication and VTE occurred in a considerable number of patients after TKA. Despite exceeding the number of patients calculated by the power analysis, our population may have been inadequate to fully detect statistical significance. Thus, our conclusion of failing to reject the null hypothesis may have been because of sample size, a type II error. We found that, after primary TKA, 3.04% of patients developed wound complications and 4.77% VTE. According to the literature, the incidence of infection after primary TKA is between 0.5% and 12%, and that of VTE reported within 3 months after TKA is 1.3% to 10%.^13,14 Although we had 100% VTE prophylaxis, meeting the standard of care, VTE after TKA remains a postoperative complication.¹⁹ This study also found that a considerable percentage of primary TKA patients (23.59%) had preoperative calcification of the knee arteries. To our knowledge, this study was the first to quantify the incidence of knee arterial calcification in patients who underwent TKA.

Preoperative calcification of the knee arteries in patients who underwent TKA did not increase the risk for wound complication, VTE, or arterial damage. These calcifications, however, do pose an increased systemic vascular risk.²⁰ Calcification of the vascular wall predicts increased cardiovascular risk, independent of classical cardiovascular risk factors.^3,18,21-24 Clinically, patients who have both diabetes and calcifications are at significant excess risk for total mortality, stroke mortality, and cardiovascular mortality, compared with patients with diabetes but without such calcifications. They also had a significantly higher incidence of coronary heart disease events, stroke events, and lower extremity amputations.^25,26

All our patients underwent tourniquet-assisted TKA. Although previous studies have indicated that tourniquet use may increase arterial complications and wound complications or even limb loss in patients with calcified arteries, we did not find this link.^7,27 Our population had no reported arterial complications related to tourniquet use. Other, smaller studies have had similar findings. Vandenbussche and colleagues²⁸ prospectively studied 80 TKA cases randomized to tourniquet use or no tourniquet use and found no postoperative nerve palsies, wound infections, wound healing problems, or hematomas. Our study is also in accord with studies that have reported tourniquet use did not increase risk for DVT.²⁹ Therefore, unlike earlier data, our data demonstrated that tourniquet use in patients with knee arterial calcification was safe.^7,27,30,31

Patients with calcification were more likely to have the medical comorbidities of hypertension, diabetes, hyperlipidemia, and CAD. All these comorbidities are linked to the development of arterial calcification, or atherosclerotic occlusive disease.^32,33 As life expectancy and the need for TKA increase, it is likely that a larger percentage of TKA patients will have preoperative radiographic evidence of knee arterial calcification. Although current dogma is that tourniquet-assisted TKA is contraindicated for patients with preoperative radiographic evidence of femoral-popliteal calcification, our study results showed that this calcification should not affect preoperative TKA planning for these patients.

We divided our patients into 3 categories: those with proximal calcification (above the joint line), those with distal calcification (below the joint line), and those with both proximal and distal calcification. Location of arterial calcification did not have an effect on their rates of postoperative wound complication or VTE. We hypothesized that patients with proximal calcification would be at increased risk for direct arterial injury and subsequent wound complication because the tourniquet is placed proximally. Previous research has indicated that arterial occlusion and subsequent wound complication can occur because of low blood flow stemming from tourniquet use.⁷ Further, intraoperative manipulation (flexing) of a knee with calcified vessels causes arterial complications after TKA because these vessels are less elastic than nonatheromatous vessels.³¹ However, we found no such effect. At the same time, having arterial calcification might also be an indication of venous disease in this location,¹² which may be especially important for proximal calcifications. Proximal DVT more likely is a precursor to pulmonary embolic events than distal DVT is.^31,34 However, we found no difference in VTE rates among the 3 arterial location groups, which is supported by studies that have found that tourniquet use does not increase DVT incidence.^29,35-40

Risk for wound complications was higher in male patients and in patients with diabetes, prior VTE, hypertension, or CAD. This finding is important because, with the increasing age of patients who undergo TKA, those with serious medical comorbidities will continue to need and have this surgery.¹⁷ Diabetes may increase the rate of wound complication because patients with diabetes have poor microcirculation, poor collagen synthesis, and reduced wound strength.⁴¹ Malinzak and colleagues⁴² demonstrated that, compared with patients without diabetes, those with diabetes had a significantly higher risk for infection after TKA. Prior VTE, specifically DVT, may increase the rate of wound complication because after DVT the deep veins may be damaged and exhibit valvular dysfunction. Labropoulos and colleagues⁴³ showed that DVT history was strongly associated with ulcer nonhealing. Perhaps hypertension has been overlooked as a risk factor for wound complication in TKA. No previous studies have assessed the link between hypertension and wound complications after TKA. However, a study of wound healing after total hip arthroplasty found that, compared with normotensive patients, hypertensive patients had delayed wound healing, putting them at higher risk for infection.⁴⁴ In addition, we found that patients with CAD were at increased risk for wound complications—an unexpected finding, as CAD traditionally is not a risk factor for infection or poor wound healing. Recently, however, CAD was identified as an independent risk factor for surgical site infections in posterior lumbar–instrumented arthrodesis.⁴⁵ The etiology of this association is unknown. Also, male patients were at increased risk for wound complication. Male sex has been implicated as an independent risk factor for development of surgical site infections and has been established as an important predisposing factor for periprosthetic joint infections.⁴⁶

It is possible that patients who present with diabetes, VTE, hypertension, or CAD before TKA should have a consultation with a vascular surgeon or should have TKA performed without a tourniquet, but this conclusion cannot be considered definitive without a large prospective randomized trial or possibly registry data. Our data indicate that patients with these comorbidities have higher rates of wound complications irrespective of preoperative radiographic calcifications. On the basis of our study results, however, we certainly recommend that patients with these risk factors have preoperative medical optimization. Orthopedic surgeons should take a thorough history and perform a meticulous physical examination on these patients to look for evidence of PVD. We recommend that, if vascular claudication is elicited in the history, or if there is evidence of peripheral arterial disease—such as hair loss, skin discoloration, dystrophic nail changes, or absent or unequal peripheral pulses—the ankle-brachial index test should be performed. If the index value is less than 0.9, then a preoperative vascular surgery consultation should be obtained.

This study had some weaknesses. First, it was retrospective, so it is possible that some wound or VTE complications were not reported and thus not found in the paper charts or electronic medical records. Some patients may have had VTE diagnostic scans at other hospitals, and their results may not have been recorded across databases. Moreover, some patients may have seen wound specialists for wound infections or wound healing problems, and these may not have been reported to the orthopedic surgeons. Second, though our patient population was not small, it may not have been of adequate size to fully detect statistical significance. We met our enrollment numbers based on our sample size calculations from an a priori power analysis; however, we still draw conclusions with the possibility of committing a type II error in mind by failing to reject the null hypothesis when in reality a statistically significant difference does exist. Third, none of our consecutive patients carried the preoperative diagnosis of PVD, and none had preoperative vascular surgery. Therefore, though calcifications were noted on radiographs, clinically our patients were asymptomatic with respect to vascular health. Last, the 2 groups were not randomized. All patients underwent tourniquet-assisted TKA.           

Conclusion

To our knowledge, this is the largest study to examine the effect of preoperative knee arterial calcification on wound complication and VTE after tourniquet-assisted TKA. Contrary to previously published recommendations, we conclude that TKA can be safely performed with a tourniquet in the presence of preoperative radiographic evidence of such calcification. However, we recommend that patients with diabetes, hypertension, CAD, or prior VTE undergo an appropriate physical examination to elicit any signs or symptoms of vascular disease. If before surgery there is any question of vascular competence, a vascular surgeon should be consulted.

Tourniquets are often used in total knee arthroplasty (TKA) to improve visualization of structures, shorten operative time, reduce intraoperative bleeding, and improve cementing technique. Despite these advantages, controversy remains regarding the safety of tourniquet use. Tourniquets have been associated with nerve palsies, vascular injury, and muscle damage.^1-5 Some have hypothesized they may cause venous stasis or direct endothelial damage that may develop into deep vein thrombosis (DVT). Abdel-Salam and Eyres⁶ found an increased incidence of postoperative wound complications and DVTs associated with tourniquet use.

Moreover, investigators have analyzed the role of tourniquets in populations at high risk for wound complications. DeLaurentis and colleagues⁷ performed a prospective and retrospective analysis of 1182 TKA patients, 24 (2%) of whom had preexisting peripheral vascular disease (PVD), defined as a history of arterial insufficiency, absent dorsalis pedis and/or absent posterior tibial pulsations, and arterial calcifications. A tourniquet was used in each case. Arterial complications occurred in 6 of the 24 patients with PVD. As expected, the authors found that a history of intermittent claudication, pain at rest, and arterial ulcers resulted in a high risk for vascular complications. Further studies have supported this finding and expanded the list of predisposing factors to include previous vascular surgery and absent and asymmetric pedal pulsations.^7-11 Of particular concern to total joint arthroplasty surgeons was the finding by DeLaurentis and colleagues⁷ that patients with radiographic evidence of calcification of the distal superficial femoral artery and/or popliteal artery were at risk for arterial complications. This finding is also supported by other studies.^8,11 In TKA, damage to arterial structures proximal to the surgical field could manifest as impaired postoperative wound healing or an ischemic limb. Wound healing depends on adequate blood flow to the healing tissue, and any damage to arterial or venous structures can theoretically compromise this process.

Added to vascular/wound complications as concerning complications in orthopedic surgery is venous thromboembolism (VTE). The role of tourniquets in the formation of VTEs is controversial. A tourniquet has the potential to increase the risk for DVT because of the stasis of venous blood in the lower limb or possible damage to calcified blood vessels. Callam and colleagues¹² studied the connection between artery disease and chronic leg ulcers and found that half the patients diagnosed with peripheral artery disease also had stigmata of chronic venous insufficiency. Therefore, the entities can occur in tandem, and surgeons should keep this in mind.

Here we report on a study we conducted to determine whether tourniquet use in TKA in patients with preexisting radiographic evidence of vascular disease increases the risk for wound complications or VTE.

Patients and Methods

We retrospectively reviewed 461 consecutive primary TKAs (373 patients) performed between January 2007 and June 2012 by 2 attending orthopedic surgeons specializing in adult reconstruction. Medical records and operative reports of 583 patients were examined after receiving institutional review board approval. Of these patients, 373 (64%) had a minimum of 12-month follow-up data available. Twelve months was deemed long enough to discover wound complications or DVTs secondary to the index procedure. Most of these outcomes manifest within the first 3 months after surgery and certainly by 12 months. Follow-up longer than 12 months may become a confounder, as wound complications outside the acute to subacute postoperative window could be related to patients’ underlying PVD and not directly to tourniquet use during surgery. Patient demographics and comorbidities were recorded. Comorbidities were obtained from preoperative medical evaluations and surgeons’ preoperative evaluations. All patients had preoperative palpable dorsalis pedis and posterior tibialis arterial pulses. No patient required preoperative vascular studies based on preoperative examination or comorbidities. No patient had prior vascular bypass surgery or stenting.

TKA was performed in a nonlaminar flow, positive-pressure, high-efficiency particulate air-filtered room with sterile toga/surgical helmet systems. For all patients, a pneumatic thigh tourniquet was applied, and the patient was prepared and draped. After limb exsanguination using a rubber bandage, the limb was elevated and the tourniquet inflated to a pressure of 250 to 300 mm Hg. The tourniquet was released either just before closure or immediately after closure in all cases; it was always let down before placement of final bandages.

Prophylactic chemical anticoagulation consisting of warfarin, aspirin, or enoxaparin was used in all patients and continued for 4 to 6 weeks after surgery. All patients received mechanical DVT prophylaxis with sequential compression devices, and all were mobilized out of bed beginning either the day of surgery or the next day. All patients received perioperative intravenous antibiotics, with the preoperative dose given before tourniquet inflation and the last postoperative dose stopped within 24 hours of surgery.

All patients who had primary TKA underwent preoperative medical evaluation and optimization. The patient’s hospital course was monitored closely, and complications noted by the orthopedic team were documented. Follow-up documentation was retrospectively reviewed for evidence of wound complications or VTE. Wound complications were defined as cellulitis, delayed wound healing, wound dehiscence, and/or periprosthetic joint infection. In the case of VTE, physical examination findings were not sufficient for inclusion. Venous duplex ultrasonography demonstrating the clot was reviewed before inclusion.

Preoperative radiographs were examined for arterial calcification (Figure). We refer to calcification seen above the knee joint as proximal calcification and to calcification observed below the joint as distal calcification. Patients exhibited calcification proximally only, distally only, or both proximally and distally. The 373 patients were placed into 2 groups based on whether they had preoperative arterial calcification on plain radiography of the knee. One group (285 patients with no radiographic evidence of preoperative knee arterial calcification) underwent 365 TKAs, and the other group (88 patients with radiographic evidence of preoperative knee arterial calcification) underwent 96 TKAs.

A sample size calculation was performed to determine how many patients were needed in each group with 80% power and an α of 0.05. With an estimated difference in VTE/wound complication rate between the calcification and no-calcification groups of 12%, we needed to review 316 TKAs total. This 12% difference was based on study findings of a 25% complication rate in PVD patients who underwent tourniquet-assisted TKA, and the rate of VTE/wound complication after TKA in patients overall, which can be up to 12%.^7,13,14 We exceeded minimal enrollment and had 461 TKAs. Descriptive statistics were reported, with means and ranges provided where appropriate. Independent t test was used to evaluate the differences in continuous data (age) between the groups. Univariate analysis (using Pearson χ² and Fisher exact tests) and multivariate logistic regression analysis were used to evaluate the effects of categorical variables (sex, comorbidity, calcification [presence, absence], and location of calcification [proximal only, distal only, both]) on wound complication and VTE rates. All tests were 2-tailed and performed with a type I error rate of 0.05. Data analysis was performed with SPSS Version 19.0 (SPSS).

Results

Patient characteristics are summarized in Table 1. Of the 373 patients, 285 lacked calcification, and 88 had calcification. Mean age was 67.73 years (range, 24-92 years) for all patients, 65.99 years (range, 24-89 years) for the no-calcification group, and 74.32 years (range, 54-92 years) for the calcification group; the calcification group demonstrated a trend toward older age, but the difference was not significantly different (P = .07). Of the 373 patients, 156 (41.82%) were male: 110 in the no-calcification group (38.60%) and 46 in the calcification group (52.27%); sex was significantly (P = .002) different between groups, with more males in the calcification group.

Data on total preoperative comorbidities are summarized in Table 2. Hypertension, hyperlipidemia, diabetes, and coronary artery disease (CAD) were the most common comorbidities, and they were all significantly (P ≤ .05) increased in the calcification group.

No patients had reported arterial complications, such as arterial bleeding, aneurysm, intimal tears, or loss of distal pulses. Wound complication after TKA was detected in 3.04% of all cases (Table 3). Rate of DVT after TKA was 2.60% of all cases, and rate of pulmonary embolism after TKA was 2.17% of all cases. Of the 96 TKAs with preoperative radiographic evidence of calcification, 47 (48.96%) had proximal calcification only, 11 (11.46%) had distal calcification only, and 38 (39.58%) had both proximal and distal calcification (Table 4). There was no significant difference between the rate of wound complication or VTE based on location of vascular calcification.

Univariate analysis demonstrated that presence of arterial knee calcification did not increase the risk for postoperative wound complication (odds ratio [OR], 1.04; 95% confidence interval [CI], 0.28-3.80; P > .05) (Table 5). Location of arterial knee calcification also did not increase the risk for postoperative wound complication. In addition, univariate analysis demonstrated that presence of arterial knee calcification did not increase the risk for postoperative VTE (OR, 1.20; 95% CI, 0.43-3.36; P > .05 (Table 6).

Of the 14 wound complications, the most common infections were cellulitis (5/14 cases; 35.71%) and infected hardware that required component revision (5/14 cases; 35.71%). Mean time from TKA to infection was 137.93 days (range, 5-783 days). The most common organism grown in culture from the wound was Staphylococcus (5/14 cases; 35.71%).

Additional univariate statistical analysis revealed that presence of diabetes, hypertension, prior VTE, CAD, and male sex was linked to higher incidence of wound complication (P < .05) (Table 5). When multivariate analysis was performed, hypertension, prior VTE, and male sex remained significant (P < .05) (Table 5).

Discussion

TKA is a safe and effective procedure used to treat osteoarthritis of the knee and improve patients’ quality of life.¹⁵ About 700,000 TKAs are performed annually in the United States.¹⁶ Because of improvements in preventive medicine and medical technology, life expectancy is increasing, and TKAs are now being performed in higher numbers and in an older patient population. Over the next few decades, these developments will lead to more postoperative complications. It is projected that, by 2030, the need for TKAs in the United States will increase by 673% to 3.48 million.¹⁷ Postoperative complications are rare but unfortunately often lead to poor outcomes or even mortality.¹⁸ To help minimize the number of postoperative complications, we must understand the safety of tourniquet use in TKA. Other investigators have concluded that tourniquet use is unsafe in patients with preoperative vascular calcifications on plain radiographs.^7,8,11 The present study, designed to elucidate whether preoperative evidence of knee arterial calcification may predispose TKA patients to postoperative wound complication or VTE, had some important findings.

In our study, wound complication and VTE occurred in a considerable number of patients after TKA. Despite exceeding the number of patients calculated by the power analysis, our population may have been inadequate to fully detect statistical significance. Thus, our conclusion of failing to reject the null hypothesis may have been because of sample size, a type II error. We found that, after primary TKA, 3.04% of patients developed wound complications and 4.77% VTE. According to the literature, the incidence of infection after primary TKA is between 0.5% and 12%, and that of VTE reported within 3 months after TKA is 1.3% to 10%.^13,14 Although we had 100% VTE prophylaxis, meeting the standard of care, VTE after TKA remains a postoperative complication.¹⁹ This study also found that a considerable percentage of primary TKA patients (23.59%) had preoperative calcification of the knee arteries. To our knowledge, this study was the first to quantify the incidence of knee arterial calcification in patients who underwent TKA.

Preoperative calcification of the knee arteries in patients who underwent TKA did not increase the risk for wound complication, VTE, or arterial damage. These calcifications, however, do pose an increased systemic vascular risk.²⁰ Calcification of the vascular wall predicts increased cardiovascular risk, independent of classical cardiovascular risk factors.^3,18,21-24 Clinically, patients who have both diabetes and calcifications are at significant excess risk for total mortality, stroke mortality, and cardiovascular mortality, compared with patients with diabetes but without such calcifications. They also had a significantly higher incidence of coronary heart disease events, stroke events, and lower extremity amputations.^25,26

All our patients underwent tourniquet-assisted TKA. Although previous studies have indicated that tourniquet use may increase arterial complications and wound complications or even limb loss in patients with calcified arteries, we did not find this link.^7,27 Our population had no reported arterial complications related to tourniquet use. Other, smaller studies have had similar findings. Vandenbussche and colleagues²⁸ prospectively studied 80 TKA cases randomized to tourniquet use or no tourniquet use and found no postoperative nerve palsies, wound infections, wound healing problems, or hematomas. Our study is also in accord with studies that have reported tourniquet use did not increase risk for DVT.²⁹ Therefore, unlike earlier data, our data demonstrated that tourniquet use in patients with knee arterial calcification was safe.^7,27,30,31

Patients with calcification were more likely to have the medical comorbidities of hypertension, diabetes, hyperlipidemia, and CAD. All these comorbidities are linked to the development of arterial calcification, or atherosclerotic occlusive disease.^32,33 As life expectancy and the need for TKA increase, it is likely that a larger percentage of TKA patients will have preoperative radiographic evidence of knee arterial calcification. Although current dogma is that tourniquet-assisted TKA is contraindicated for patients with preoperative radiographic evidence of femoral-popliteal calcification, our study results showed that this calcification should not affect preoperative TKA planning for these patients.

We divided our patients into 3 categories: those with proximal calcification (above the joint line), those with distal calcification (below the joint line), and those with both proximal and distal calcification. Location of arterial calcification did not have an effect on their rates of postoperative wound complication or VTE. We hypothesized that patients with proximal calcification would be at increased risk for direct arterial injury and subsequent wound complication because the tourniquet is placed proximally. Previous research has indicated that arterial occlusion and subsequent wound complication can occur because of low blood flow stemming from tourniquet use.⁷ Further, intraoperative manipulation (flexing) of a knee with calcified vessels causes arterial complications after TKA because these vessels are less elastic than nonatheromatous vessels.³¹ However, we found no such effect. At the same time, having arterial calcification might also be an indication of venous disease in this location,¹² which may be especially important for proximal calcifications. Proximal DVT more likely is a precursor to pulmonary embolic events than distal DVT is.^31,34 However, we found no difference in VTE rates among the 3 arterial location groups, which is supported by studies that have found that tourniquet use does not increase DVT incidence.^29,35-40

Risk for wound complications was higher in male patients and in patients with diabetes, prior VTE, hypertension, or CAD. This finding is important because, with the increasing age of patients who undergo TKA, those with serious medical comorbidities will continue to need and have this surgery.¹⁷ Diabetes may increase the rate of wound complication because patients with diabetes have poor microcirculation, poor collagen synthesis, and reduced wound strength.⁴¹ Malinzak and colleagues⁴² demonstrated that, compared with patients without diabetes, those with diabetes had a significantly higher risk for infection after TKA. Prior VTE, specifically DVT, may increase the rate of wound complication because after DVT the deep veins may be damaged and exhibit valvular dysfunction. Labropoulos and colleagues⁴³ showed that DVT history was strongly associated with ulcer nonhealing. Perhaps hypertension has been overlooked as a risk factor for wound complication in TKA. No previous studies have assessed the link between hypertension and wound complications after TKA. However, a study of wound healing after total hip arthroplasty found that, compared with normotensive patients, hypertensive patients had delayed wound healing, putting them at higher risk for infection.⁴⁴ In addition, we found that patients with CAD were at increased risk for wound complications—an unexpected finding, as CAD traditionally is not a risk factor for infection or poor wound healing. Recently, however, CAD was identified as an independent risk factor for surgical site infections in posterior lumbar–instrumented arthrodesis.⁴⁵ The etiology of this association is unknown. Also, male patients were at increased risk for wound complication. Male sex has been implicated as an independent risk factor for development of surgical site infections and has been established as an important predisposing factor for periprosthetic joint infections.⁴⁶

It is possible that patients who present with diabetes, VTE, hypertension, or CAD before TKA should have a consultation with a vascular surgeon or should have TKA performed without a tourniquet, but this conclusion cannot be considered definitive without a large prospective randomized trial or possibly registry data. Our data indicate that patients with these comorbidities have higher rates of wound complications irrespective of preoperative radiographic calcifications. On the basis of our study results, however, we certainly recommend that patients with these risk factors have preoperative medical optimization. Orthopedic surgeons should take a thorough history and perform a meticulous physical examination on these patients to look for evidence of PVD. We recommend that, if vascular claudication is elicited in the history, or if there is evidence of peripheral arterial disease—such as hair loss, skin discoloration, dystrophic nail changes, or absent or unequal peripheral pulses—the ankle-brachial index test should be performed. If the index value is less than 0.9, then a preoperative vascular surgery consultation should be obtained.

This study had some weaknesses. First, it was retrospective, so it is possible that some wound or VTE complications were not reported and thus not found in the paper charts or electronic medical records. Some patients may have had VTE diagnostic scans at other hospitals, and their results may not have been recorded across databases. Moreover, some patients may have seen wound specialists for wound infections or wound healing problems, and these may not have been reported to the orthopedic surgeons. Second, though our patient population was not small, it may not have been of adequate size to fully detect statistical significance. We met our enrollment numbers based on our sample size calculations from an a priori power analysis; however, we still draw conclusions with the possibility of committing a type II error in mind by failing to reject the null hypothesis when in reality a statistically significant difference does exist. Third, none of our consecutive patients carried the preoperative diagnosis of PVD, and none had preoperative vascular surgery. Therefore, though calcifications were noted on radiographs, clinically our patients were asymptomatic with respect to vascular health. Last, the 2 groups were not randomized. All patients underwent tourniquet-assisted TKA.           

Conclusion

To our knowledge, this is the largest study to examine the effect of preoperative knee arterial calcification on wound complication and VTE after tourniquet-assisted TKA. Contrary to previously published recommendations, we conclude that TKA can be safely performed with a tourniquet in the presence of preoperative radiographic evidence of such calcification. However, we recommend that patients with diabetes, hypertension, CAD, or prior VTE undergo an appropriate physical examination to elicit any signs or symptoms of vascular disease. If before surgery there is any question of vascular competence, a vascular surgeon should be consulted.

Tourniquets are often used in total knee arthroplasty (TKA) to improve visualization of structures, shorten operative time, reduce intraoperative bleeding, and improve cementing technique. Despite these advantages, controversy remains regarding the safety of tourniquet use. Tourniquets have been associated with nerve palsies, vascular injury, and muscle damage.^1-5 Some have hypothesized they may cause venous stasis or direct endothelial damage that may develop into deep vein thrombosis (DVT). Abdel-Salam and Eyres⁶ found an increased incidence of postoperative wound complications and DVTs associated with tourniquet use.

Moreover, investigators have analyzed the role of tourniquets in populations at high risk for wound complications. DeLaurentis and colleagues⁷ performed a prospective and retrospective analysis of 1182 TKA patients, 24 (2%) of whom had preexisting peripheral vascular disease (PVD), defined as a history of arterial insufficiency, absent dorsalis pedis and/or absent posterior tibial pulsations, and arterial calcifications. A tourniquet was used in each case. Arterial complications occurred in 6 of the 24 patients with PVD. As expected, the authors found that a history of intermittent claudication, pain at rest, and arterial ulcers resulted in a high risk for vascular complications. Further studies have supported this finding and expanded the list of predisposing factors to include previous vascular surgery and absent and asymmetric pedal pulsations.^7-11 Of particular concern to total joint arthroplasty surgeons was the finding by DeLaurentis and colleagues⁷ that patients with radiographic evidence of calcification of the distal superficial femoral artery and/or popliteal artery were at risk for arterial complications. This finding is also supported by other studies.^8,11 In TKA, damage to arterial structures proximal to the surgical field could manifest as impaired postoperative wound healing or an ischemic limb. Wound healing depends on adequate blood flow to the healing tissue, and any damage to arterial or venous structures can theoretically compromise this process.

Added to vascular/wound complications as concerning complications in orthopedic surgery is venous thromboembolism (VTE). The role of tourniquets in the formation of VTEs is controversial. A tourniquet has the potential to increase the risk for DVT because of the stasis of venous blood in the lower limb or possible damage to calcified blood vessels. Callam and colleagues¹² studied the connection between artery disease and chronic leg ulcers and found that half the patients diagnosed with peripheral artery disease also had stigmata of chronic venous insufficiency. Therefore, the entities can occur in tandem, and surgeons should keep this in mind.

Here we report on a study we conducted to determine whether tourniquet use in TKA in patients with preexisting radiographic evidence of vascular disease increases the risk for wound complications or VTE.

Patients and Methods

We retrospectively reviewed 461 consecutive primary TKAs (373 patients) performed between January 2007 and June 2012 by 2 attending orthopedic surgeons specializing in adult reconstruction. Medical records and operative reports of 583 patients were examined after receiving institutional review board approval. Of these patients, 373 (64%) had a minimum of 12-month follow-up data available. Twelve months was deemed long enough to discover wound complications or DVTs secondary to the index procedure. Most of these outcomes manifest within the first 3 months after surgery and certainly by 12 months. Follow-up longer than 12 months may become a confounder, as wound complications outside the acute to subacute postoperative window could be related to patients’ underlying PVD and not directly to tourniquet use during surgery. Patient demographics and comorbidities were recorded. Comorbidities were obtained from preoperative medical evaluations and surgeons’ preoperative evaluations. All patients had preoperative palpable dorsalis pedis and posterior tibialis arterial pulses. No patient required preoperative vascular studies based on preoperative examination or comorbidities. No patient had prior vascular bypass surgery or stenting.

TKA was performed in a nonlaminar flow, positive-pressure, high-efficiency particulate air-filtered room with sterile toga/surgical helmet systems. For all patients, a pneumatic thigh tourniquet was applied, and the patient was prepared and draped. After limb exsanguination using a rubber bandage, the limb was elevated and the tourniquet inflated to a pressure of 250 to 300 mm Hg. The tourniquet was released either just before closure or immediately after closure in all cases; it was always let down before placement of final bandages.

Prophylactic chemical anticoagulation consisting of warfarin, aspirin, or enoxaparin was used in all patients and continued for 4 to 6 weeks after surgery. All patients received mechanical DVT prophylaxis with sequential compression devices, and all were mobilized out of bed beginning either the day of surgery or the next day. All patients received perioperative intravenous antibiotics, with the preoperative dose given before tourniquet inflation and the last postoperative dose stopped within 24 hours of surgery.

All patients who had primary TKA underwent preoperative medical evaluation and optimization. The patient’s hospital course was monitored closely, and complications noted by the orthopedic team were documented. Follow-up documentation was retrospectively reviewed for evidence of wound complications or VTE. Wound complications were defined as cellulitis, delayed wound healing, wound dehiscence, and/or periprosthetic joint infection. In the case of VTE, physical examination findings were not sufficient for inclusion. Venous duplex ultrasonography demonstrating the clot was reviewed before inclusion.

Preoperative radiographs were examined for arterial calcification (Figure). We refer to calcification seen above the knee joint as proximal calcification and to calcification observed below the joint as distal calcification. Patients exhibited calcification proximally only, distally only, or both proximally and distally. The 373 patients were placed into 2 groups based on whether they had preoperative arterial calcification on plain radiography of the knee. One group (285 patients with no radiographic evidence of preoperative knee arterial calcification) underwent 365 TKAs, and the other group (88 patients with radiographic evidence of preoperative knee arterial calcification) underwent 96 TKAs.

A sample size calculation was performed to determine how many patients were needed in each group with 80% power and an α of 0.05. With an estimated difference in VTE/wound complication rate between the calcification and no-calcification groups of 12%, we needed to review 316 TKAs total. This 12% difference was based on study findings of a 25% complication rate in PVD patients who underwent tourniquet-assisted TKA, and the rate of VTE/wound complication after TKA in patients overall, which can be up to 12%.^7,13,14 We exceeded minimal enrollment and had 461 TKAs. Descriptive statistics were reported, with means and ranges provided where appropriate. Independent t test was used to evaluate the differences in continuous data (age) between the groups. Univariate analysis (using Pearson χ² and Fisher exact tests) and multivariate logistic regression analysis were used to evaluate the effects of categorical variables (sex, comorbidity, calcification [presence, absence], and location of calcification [proximal only, distal only, both]) on wound complication and VTE rates. All tests were 2-tailed and performed with a type I error rate of 0.05. Data analysis was performed with SPSS Version 19.0 (SPSS).

Results

Patient characteristics are summarized in Table 1. Of the 373 patients, 285 lacked calcification, and 88 had calcification. Mean age was 67.73 years (range, 24-92 years) for all patients, 65.99 years (range, 24-89 years) for the no-calcification group, and 74.32 years (range, 54-92 years) for the calcification group; the calcification group demonstrated a trend toward older age, but the difference was not significantly different (P = .07). Of the 373 patients, 156 (41.82%) were male: 110 in the no-calcification group (38.60%) and 46 in the calcification group (52.27%); sex was significantly (P = .002) different between groups, with more males in the calcification group.

Data on total preoperative comorbidities are summarized in Table 2. Hypertension, hyperlipidemia, diabetes, and coronary artery disease (CAD) were the most common comorbidities, and they were all significantly (P ≤ .05) increased in the calcification group.

No patients had reported arterial complications, such as arterial bleeding, aneurysm, intimal tears, or loss of distal pulses. Wound complication after TKA was detected in 3.04% of all cases (Table 3). Rate of DVT after TKA was 2.60% of all cases, and rate of pulmonary embolism after TKA was 2.17% of all cases. Of the 96 TKAs with preoperative radiographic evidence of calcification, 47 (48.96%) had proximal calcification only, 11 (11.46%) had distal calcification only, and 38 (39.58%) had both proximal and distal calcification (Table 4). There was no significant difference between the rate of wound complication or VTE based on location of vascular calcification.

Univariate analysis demonstrated that presence of arterial knee calcification did not increase the risk for postoperative wound complication (odds ratio [OR], 1.04; 95% confidence interval [CI], 0.28-3.80; P > .05) (Table 5). Location of arterial knee calcification also did not increase the risk for postoperative wound complication. In addition, univariate analysis demonstrated that presence of arterial knee calcification did not increase the risk for postoperative VTE (OR, 1.20; 95% CI, 0.43-3.36; P > .05 (Table 6).

Of the 14 wound complications, the most common infections were cellulitis (5/14 cases; 35.71%) and infected hardware that required component revision (5/14 cases; 35.71%). Mean time from TKA to infection was 137.93 days (range, 5-783 days). The most common organism grown in culture from the wound was Staphylococcus (5/14 cases; 35.71%).

Additional univariate statistical analysis revealed that presence of diabetes, hypertension, prior VTE, CAD, and male sex was linked to higher incidence of wound complication (P < .05) (Table 5). When multivariate analysis was performed, hypertension, prior VTE, and male sex remained significant (P < .05) (Table 5).

Discussion

TKA is a safe and effective procedure used to treat osteoarthritis of the knee and improve patients’ quality of life.¹⁵ About 700,000 TKAs are performed annually in the United States.¹⁶ Because of improvements in preventive medicine and medical technology, life expectancy is increasing, and TKAs are now being performed in higher numbers and in an older patient population. Over the next few decades, these developments will lead to more postoperative complications. It is projected that, by 2030, the need for TKAs in the United States will increase by 673% to 3.48 million.¹⁷ Postoperative complications are rare but unfortunately often lead to poor outcomes or even mortality.¹⁸ To help minimize the number of postoperative complications, we must understand the safety of tourniquet use in TKA. Other investigators have concluded that tourniquet use is unsafe in patients with preoperative vascular calcifications on plain radiographs.^7,8,11 The present study, designed to elucidate whether preoperative evidence of knee arterial calcification may predispose TKA patients to postoperative wound complication or VTE, had some important findings.

In our study, wound complication and VTE occurred in a considerable number of patients after TKA. Despite exceeding the number of patients calculated by the power analysis, our population may have been inadequate to fully detect statistical significance. Thus, our conclusion of failing to reject the null hypothesis may have been because of sample size, a type II error. We found that, after primary TKA, 3.04% of patients developed wound complications and 4.77% VTE. According to the literature, the incidence of infection after primary TKA is between 0.5% and 12%, and that of VTE reported within 3 months after TKA is 1.3% to 10%.^13,14 Although we had 100% VTE prophylaxis, meeting the standard of care, VTE after TKA remains a postoperative complication.¹⁹ This study also found that a considerable percentage of primary TKA patients (23.59%) had preoperative calcification of the knee arteries. To our knowledge, this study was the first to quantify the incidence of knee arterial calcification in patients who underwent TKA.

Preoperative calcification of the knee arteries in patients who underwent TKA did not increase the risk for wound complication, VTE, or arterial damage. These calcifications, however, do pose an increased systemic vascular risk.²⁰ Calcification of the vascular wall predicts increased cardiovascular risk, independent of classical cardiovascular risk factors.^3,18,21-24 Clinically, patients who have both diabetes and calcifications are at significant excess risk for total mortality, stroke mortality, and cardiovascular mortality, compared with patients with diabetes but without such calcifications. They also had a significantly higher incidence of coronary heart disease events, stroke events, and lower extremity amputations.^25,26

All our patients underwent tourniquet-assisted TKA. Although previous studies have indicated that tourniquet use may increase arterial complications and wound complications or even limb loss in patients with calcified arteries, we did not find this link.^7,27 Our population had no reported arterial complications related to tourniquet use. Other, smaller studies have had similar findings. Vandenbussche and colleagues²⁸ prospectively studied 80 TKA cases randomized to tourniquet use or no tourniquet use and found no postoperative nerve palsies, wound infections, wound healing problems, or hematomas. Our study is also in accord with studies that have reported tourniquet use did not increase risk for DVT.²⁹ Therefore, unlike earlier data, our data demonstrated that tourniquet use in patients with knee arterial calcification was safe.^7,27,30,31

Patients with calcification were more likely to have the medical comorbidities of hypertension, diabetes, hyperlipidemia, and CAD. All these comorbidities are linked to the development of arterial calcification, or atherosclerotic occlusive disease.^32,33 As life expectancy and the need for TKA increase, it is likely that a larger percentage of TKA patients will have preoperative radiographic evidence of knee arterial calcification. Although current dogma is that tourniquet-assisted TKA is contraindicated for patients with preoperative radiographic evidence of femoral-popliteal calcification, our study results showed that this calcification should not affect preoperative TKA planning for these patients.

We divided our patients into 3 categories: those with proximal calcification (above the joint line), those with distal calcification (below the joint line), and those with both proximal and distal calcification. Location of arterial calcification did not have an effect on their rates of postoperative wound complication or VTE. We hypothesized that patients with proximal calcification would be at increased risk for direct arterial injury and subsequent wound complication because the tourniquet is placed proximally. Previous research has indicated that arterial occlusion and subsequent wound complication can occur because of low blood flow stemming from tourniquet use.⁷ Further, intraoperative manipulation (flexing) of a knee with calcified vessels causes arterial complications after TKA because these vessels are less elastic than nonatheromatous vessels.³¹ However, we found no such effect. At the same time, having arterial calcification might also be an indication of venous disease in this location,¹² which may be especially important for proximal calcifications. Proximal DVT more likely is a precursor to pulmonary embolic events than distal DVT is.^31,34 However, we found no difference in VTE rates among the 3 arterial location groups, which is supported by studies that have found that tourniquet use does not increase DVT incidence.^29,35-40

Risk for wound complications was higher in male patients and in patients with diabetes, prior VTE, hypertension, or CAD. This finding is important because, with the increasing age of patients who undergo TKA, those with serious medical comorbidities will continue to need and have this surgery.¹⁷ Diabetes may increase the rate of wound complication because patients with diabetes have poor microcirculation, poor collagen synthesis, and reduced wound strength.⁴¹ Malinzak and colleagues⁴² demonstrated that, compared with patients without diabetes, those with diabetes had a significantly higher risk for infection after TKA. Prior VTE, specifically DVT, may increase the rate of wound complication because after DVT the deep veins may be damaged and exhibit valvular dysfunction. Labropoulos and colleagues⁴³ showed that DVT history was strongly associated with ulcer nonhealing. Perhaps hypertension has been overlooked as a risk factor for wound complication in TKA. No previous studies have assessed the link between hypertension and wound complications after TKA. However, a study of wound healing after total hip arthroplasty found that, compared with normotensive patients, hypertensive patients had delayed wound healing, putting them at higher risk for infection.⁴⁴ In addition, we found that patients with CAD were at increased risk for wound complications—an unexpected finding, as CAD traditionally is not a risk factor for infection or poor wound healing. Recently, however, CAD was identified as an independent risk factor for surgical site infections in posterior lumbar–instrumented arthrodesis.⁴⁵ The etiology of this association is unknown. Also, male patients were at increased risk for wound complication. Male sex has been implicated as an independent risk factor for development of surgical site infections and has been established as an important predisposing factor for periprosthetic joint infections.⁴⁶

It is possible that patients who present with diabetes, VTE, hypertension, or CAD before TKA should have a consultation with a vascular surgeon or should have TKA performed without a tourniquet, but this conclusion cannot be considered definitive without a large prospective randomized trial or possibly registry data. Our data indicate that patients with these comorbidities have higher rates of wound complications irrespective of preoperative radiographic calcifications. On the basis of our study results, however, we certainly recommend that patients with these risk factors have preoperative medical optimization. Orthopedic surgeons should take a thorough history and perform a meticulous physical examination on these patients to look for evidence of PVD. We recommend that, if vascular claudication is elicited in the history, or if there is evidence of peripheral arterial disease—such as hair loss, skin discoloration, dystrophic nail changes, or absent or unequal peripheral pulses—the ankle-brachial index test should be performed. If the index value is less than 0.9, then a preoperative vascular surgery consultation should be obtained.

This study had some weaknesses. First, it was retrospective, so it is possible that some wound or VTE complications were not reported and thus not found in the paper charts or electronic medical records. Some patients may have had VTE diagnostic scans at other hospitals, and their results may not have been recorded across databases. Moreover, some patients may have seen wound specialists for wound infections or wound healing problems, and these may not have been reported to the orthopedic surgeons. Second, though our patient population was not small, it may not have been of adequate size to fully detect statistical significance. We met our enrollment numbers based on our sample size calculations from an a priori power analysis; however, we still draw conclusions with the possibility of committing a type II error in mind by failing to reject the null hypothesis when in reality a statistically significant difference does exist. Third, none of our consecutive patients carried the preoperative diagnosis of PVD, and none had preoperative vascular surgery. Therefore, though calcifications were noted on radiographs, clinically our patients were asymptomatic with respect to vascular health. Last, the 2 groups were not randomized. All patients underwent tourniquet-assisted TKA.           

Conclusion

To our knowledge, this is the largest study to examine the effect of preoperative knee arterial calcification on wound complication and VTE after tourniquet-assisted TKA. Contrary to previously published recommendations, we conclude that TKA can be safely performed with a tourniquet in the presence of preoperative radiographic evidence of such calcification. However, we recommend that patients with diabetes, hypertension, CAD, or prior VTE undergo an appropriate physical examination to elicit any signs or symptoms of vascular disease. If before surgery there is any question of vascular competence, a vascular surgeon should be consulted.

Perilunate injuries typically stem from a high-energy insult to the carpus. Because of their relative infrequency and often subtle radiographic and physical examination findings, these injuries are often undetected in the emergency department setting.¹ Early anatomic reduction of any carpal malalignment is essential. Even with optimal treatment, complications such as generalized wrist stiffness, diminished grip strength, and posttraumatic arthritis, commonly develop; however, recent studies suggest these issues are often well tolerated.^1-5 In this article, the diagnosis, treatment, and outcomes after perilunate injuries are examined. 

History and Physical Examination

Perilunate injuries result from high-energy trauma to the carpus. Patients with these injuries often present with vague wrist pain and loss of wrist motion. Their fingers are frequently held in slight flexion. The patient may complain of numbness and tingling in the median nerve distribution. An acute carpal tunnel syndrome can rapidly develop. The general belief is that acute carpal tunnel syndrome occurs more commonly in pure volar lunate dislocations than in dorsal perilunate dislocations. However, no studies compare the incidence of acute carpal tunnel syndrome in lunate versus perilunate dislocations.

Radiographic Evaluation

Standard radiographic evaluation of a potential perilunate injury includes posteroanterior (PA), lateral, and oblique views of the wrist (Figure 1). A scaphoid view (ie, PA view with the wrist in ulnar deviation) may also be helpful. The PA view is particularly helpful because it enables assessment of Gilula lines, which are imaginary lines drawn across the proximal and distal aspects of the proximal carpal row and the proximal aspect of the distal carpal row. These lines should appear as 3 smooth arcs running nearly parallel to each other.⁶ Any disruption in these lines suggests carpal incongruity. It may be possible to note a triangular-shaped lunate on the PA view, which is a sign of lunate dislocation.⁷ 

While the PA view is certainly useful, the lateral view is the most important in diagnosing a perilunate injury. The lateral view allows assessment of the collinearity of radius, lunate, and capitate. Any disruption in this collinearity strongly suggests a perilunate dislocation.^7,8 

Classification

Mayfield and colleagues^9,10 described 4 stages of perilunate instability proceeding from a radial to an ulnar direction around the lunate. Stage I involves disruption of the scapholunate joint, while stage II involves both the scapholunate and capitolunate joints. In stage III, the scapholunate, capitolunate, and lunotriquetral ligaments are disrupted, and the result is a perilunate dislocation, usually dorsal. Finally, in stage IV, all the ligaments surrounding the lunate are disrupted and the lunate dislocates, most often volarly.

Lastly, perilunate injuries can be classified as greater-arc injuries if concomitant fracture of the carpus occurs, lesser-arc injuries if the injury is purely ligamentous, or inferior-arc injuries if there is an associated fracture of the volar rim of the distal radius.⁸

Treatment

Closed Reduction

All acute perilunate dislocations should be managed initially with an attempted closed reduction.¹¹ If the injury is older than 72 hours, such an attempt may be futile. For any closed reduction performed in the emergency department setting, intravenous sedation is generally advised for muscle relaxation. Gentle traction with finger traps can also be used prior to the reduction attempt. For a dorsal perilunate dislocation, longitudinal traction followed by volar flexion of the wrist with volar pressure on the lunate and dorsal pressure on the capitate (ie, Tavernier’s maneuver) is required. Once reduction is complete, PA and lateral views of the wrist should be obtained to assess carpal alignment. If closed reduction is unsuccessful, an open reduction is required, although the timing of said procedure is an area of debate, which we will discuss later.^1,3 Restoration of anatomic carpal alignment is essential to optimizing outcome, although it does not guarantee a good overall result.

Open Reduction

If successful closed reduction is achieved, the patient can be immobilized temporarily in a short-arm plaster splint. However, open reduction and either pinning or internal fixation will be required to maintain this alignment. The exact timing of open reduction and fixation is debatable and often dictated by the absence or presence of median nerve symptoms.^1,3 If a patient with no median nerve symptoms undergoes a successful closed reduction, he or she may be stabilized surgically within 3 to 5 days (or longer) with either pins or headless screws. If closed reduction is unsuccessful, an open reduction should be done within 2 to 3 days. However, if the patient has progressive numbness in the median nerve distribution upon presentation that fails to improve or worsens despite a successful closed reduction, an urgent open reduction (within 24 hours) and carpal tunnel release should be performed to prevent permanent damage to the median nerve.

Once open reduction is undertaken, a dorsal, volar, and combined approach can be used.^2-4 In most cases the dorsal approach is selected first. A longitudinal incision is made over the dorsum of the wrist, centered on the Lister tubercle. Dissection occurs between the third and fourth dorsal compartments. After the capsule is exposed, reduction of the lunate to the capitate is confirmed. If any fractures are present in the carpus (eg, scaphoid), they are internally fixed. The scapholunate articulation is then addressed. In general, the scapholunate ligament is not disrupted with a transscaphoid perilunate dislocation. However, if the scapholunate ligament is disrupted, the joint should be reduced and pinned. Repair or reconstruction of the scapholunate ligament is performed. Finally, the lunotriquetral articulation is reduced and stabilized with pins. There are no studies that specifically suggest direct repair of the lunotriquetral ligament versus pinning of the lunotriquetral articulation, but the lunotriquetral ligament could be repaired in similar fashion to the scapholunate ligament at the surgeon’s discretion.

As an alternative to percutaneous pinning, intercarpal screw fixation can be used to stabilize the carpus. A 2007 study by Souer and colleagues¹² showed no substantial difference in outcome between the 2 methods of fixation. However, a second procedure is required to remove the screws.

The volar approach, if selected, is typically done second and performed via an extended carpal tunnel incision. It allows decompression of the carpal tunnel and enables repair of volar capsular ligaments (ie, long and short radiolunate ligaments, volar scapholunate ligament, and volar lunotriquetral ligament), which increases overall carpal stability. Currently, many surgeons favor a combined dorsal-volar approach for its efficacy.^2,3 Some use a dorsal approach in all patients and perform a volar procedure only if the patient has median nerve symptoms.⁴ However, Başar and colleagues¹³ report use of only the volar approach for treatment of perilunate injuries. The authors repaired the long and short radiolunate ligaments, volar scapholunate ligament, and volar lunotriquetral ligament. They reported reasonably good outcomes, which are equivalent to those reported in similar studies using dorsal or combined dorsal-volar approaches. However, no studies in the literature directly compare any of the different approaches with each other.

Postoperatively, patients are placed in a long-arm thumb-spica cast for 4 weeks, and then in a short-arm cast for 4 to 8 weeks (Figure 2). If present, pins are removed in 3 to 12 weeks, with most authors recommending removal at 8 weeks.^2,14

Lastly, carpal tunnel symptoms can develop late and even after a successful reduction and surgical stabilization. One theory is that a significant perilunate injury can create slightly higher baseline carpal tunnel pressures, which can compromise the blood flow to the median nerve and cause carpal tunnel symptoms. Additionally, it is possible that direct median nerve contusion and/or traction injury via a displaced lunate can also cause these symptoms. Whatever the inciting cause of median-nerve irritation, a delayed carpal tunnel release is sometimes required.

Conclusion

Outcomes after either perilunate or lunate dislocation are fair to good at best but can be optimized with prompt, appropriate treatment. Closed reduction and casting as definitive treatment has been abandoned because of frequent loss of reduction.¹² Early open reduction (ie, less than 3 days after injury) has been shown to be beneficial.^1,2 However, even those treated early and with anatomic restoration of carpal alignment can expect a loss of grip strength and a range of motion of approximately 70% compared with the contralateral side.^2-5 A recent study has suggested that lesser-arc injures generally have a poorer overall outcome than their greater-arc counterparts.¹⁵

More than half of all patients with perilunate injuries will develop radiographic signs of osteoarthritis, and some will require additional salvage procedures.3-5 Kremer and colleagues4 showed that overall results after perilunate injuries deteriorate with time. However, according to a paper by Forli and colleagues5 in which patients were followed a minimum of 10 years after their injuries, the authors found that, despite radiographic progression of arthritis, most patients maintained reasonable hand function.

Perilunate injuries typically stem from a high-energy insult to the carpus. Because of their relative infrequency and often subtle radiographic and physical examination findings, these injuries are often undetected in the emergency department setting.¹ Early anatomic reduction of any carpal malalignment is essential. Even with optimal treatment, complications such as generalized wrist stiffness, diminished grip strength, and posttraumatic arthritis, commonly develop; however, recent studies suggest these issues are often well tolerated.^1-5 In this article, the diagnosis, treatment, and outcomes after perilunate injuries are examined. 

History and Physical Examination

Perilunate injuries result from high-energy trauma to the carpus. Patients with these injuries often present with vague wrist pain and loss of wrist motion. Their fingers are frequently held in slight flexion. The patient may complain of numbness and tingling in the median nerve distribution. An acute carpal tunnel syndrome can rapidly develop. The general belief is that acute carpal tunnel syndrome occurs more commonly in pure volar lunate dislocations than in dorsal perilunate dislocations. However, no studies compare the incidence of acute carpal tunnel syndrome in lunate versus perilunate dislocations.

Radiographic Evaluation

Standard radiographic evaluation of a potential perilunate injury includes posteroanterior (PA), lateral, and oblique views of the wrist (Figure 1). A scaphoid view (ie, PA view with the wrist in ulnar deviation) may also be helpful. The PA view is particularly helpful because it enables assessment of Gilula lines, which are imaginary lines drawn across the proximal and distal aspects of the proximal carpal row and the proximal aspect of the distal carpal row. These lines should appear as 3 smooth arcs running nearly parallel to each other.⁶ Any disruption in these lines suggests carpal incongruity. It may be possible to note a triangular-shaped lunate on the PA view, which is a sign of lunate dislocation.⁷ 

While the PA view is certainly useful, the lateral view is the most important in diagnosing a perilunate injury. The lateral view allows assessment of the collinearity of radius, lunate, and capitate. Any disruption in this collinearity strongly suggests a perilunate dislocation.^7,8 

Classification

Mayfield and colleagues^9,10 described 4 stages of perilunate instability proceeding from a radial to an ulnar direction around the lunate. Stage I involves disruption of the scapholunate joint, while stage II involves both the scapholunate and capitolunate joints. In stage III, the scapholunate, capitolunate, and lunotriquetral ligaments are disrupted, and the result is a perilunate dislocation, usually dorsal. Finally, in stage IV, all the ligaments surrounding the lunate are disrupted and the lunate dislocates, most often volarly.

Lastly, perilunate injuries can be classified as greater-arc injuries if concomitant fracture of the carpus occurs, lesser-arc injuries if the injury is purely ligamentous, or inferior-arc injuries if there is an associated fracture of the volar rim of the distal radius.⁸

Treatment

Closed Reduction

All acute perilunate dislocations should be managed initially with an attempted closed reduction.¹¹ If the injury is older than 72 hours, such an attempt may be futile. For any closed reduction performed in the emergency department setting, intravenous sedation is generally advised for muscle relaxation. Gentle traction with finger traps can also be used prior to the reduction attempt. For a dorsal perilunate dislocation, longitudinal traction followed by volar flexion of the wrist with volar pressure on the lunate and dorsal pressure on the capitate (ie, Tavernier’s maneuver) is required. Once reduction is complete, PA and lateral views of the wrist should be obtained to assess carpal alignment. If closed reduction is unsuccessful, an open reduction is required, although the timing of said procedure is an area of debate, which we will discuss later.^1,3 Restoration of anatomic carpal alignment is essential to optimizing outcome, although it does not guarantee a good overall result.

Open Reduction

If successful closed reduction is achieved, the patient can be immobilized temporarily in a short-arm plaster splint. However, open reduction and either pinning or internal fixation will be required to maintain this alignment. The exact timing of open reduction and fixation is debatable and often dictated by the absence or presence of median nerve symptoms.^1,3 If a patient with no median nerve symptoms undergoes a successful closed reduction, he or she may be stabilized surgically within 3 to 5 days (or longer) with either pins or headless screws. If closed reduction is unsuccessful, an open reduction should be done within 2 to 3 days. However, if the patient has progressive numbness in the median nerve distribution upon presentation that fails to improve or worsens despite a successful closed reduction, an urgent open reduction (within 24 hours) and carpal tunnel release should be performed to prevent permanent damage to the median nerve.

Once open reduction is undertaken, a dorsal, volar, and combined approach can be used.^2-4 In most cases the dorsal approach is selected first. A longitudinal incision is made over the dorsum of the wrist, centered on the Lister tubercle. Dissection occurs between the third and fourth dorsal compartments. After the capsule is exposed, reduction of the lunate to the capitate is confirmed. If any fractures are present in the carpus (eg, scaphoid), they are internally fixed. The scapholunate articulation is then addressed. In general, the scapholunate ligament is not disrupted with a transscaphoid perilunate dislocation. However, if the scapholunate ligament is disrupted, the joint should be reduced and pinned. Repair or reconstruction of the scapholunate ligament is performed. Finally, the lunotriquetral articulation is reduced and stabilized with pins. There are no studies that specifically suggest direct repair of the lunotriquetral ligament versus pinning of the lunotriquetral articulation, but the lunotriquetral ligament could be repaired in similar fashion to the scapholunate ligament at the surgeon’s discretion.

As an alternative to percutaneous pinning, intercarpal screw fixation can be used to stabilize the carpus. A 2007 study by Souer and colleagues¹² showed no substantial difference in outcome between the 2 methods of fixation. However, a second procedure is required to remove the screws.

The volar approach, if selected, is typically done second and performed via an extended carpal tunnel incision. It allows decompression of the carpal tunnel and enables repair of volar capsular ligaments (ie, long and short radiolunate ligaments, volar scapholunate ligament, and volar lunotriquetral ligament), which increases overall carpal stability. Currently, many surgeons favor a combined dorsal-volar approach for its efficacy.^2,3 Some use a dorsal approach in all patients and perform a volar procedure only if the patient has median nerve symptoms.⁴ However, Başar and colleagues¹³ report use of only the volar approach for treatment of perilunate injuries. The authors repaired the long and short radiolunate ligaments, volar scapholunate ligament, and volar lunotriquetral ligament. They reported reasonably good outcomes, which are equivalent to those reported in similar studies using dorsal or combined dorsal-volar approaches. However, no studies in the literature directly compare any of the different approaches with each other.

Postoperatively, patients are placed in a long-arm thumb-spica cast for 4 weeks, and then in a short-arm cast for 4 to 8 weeks (Figure 2). If present, pins are removed in 3 to 12 weeks, with most authors recommending removal at 8 weeks.^2,14

Lastly, carpal tunnel symptoms can develop late and even after a successful reduction and surgical stabilization. One theory is that a significant perilunate injury can create slightly higher baseline carpal tunnel pressures, which can compromise the blood flow to the median nerve and cause carpal tunnel symptoms. Additionally, it is possible that direct median nerve contusion and/or traction injury via a displaced lunate can also cause these symptoms. Whatever the inciting cause of median-nerve irritation, a delayed carpal tunnel release is sometimes required.

Conclusion

Outcomes after either perilunate or lunate dislocation are fair to good at best but can be optimized with prompt, appropriate treatment. Closed reduction and casting as definitive treatment has been abandoned because of frequent loss of reduction.¹² Early open reduction (ie, less than 3 days after injury) has been shown to be beneficial.^1,2 However, even those treated early and with anatomic restoration of carpal alignment can expect a loss of grip strength and a range of motion of approximately 70% compared with the contralateral side.^2-5 A recent study has suggested that lesser-arc injures generally have a poorer overall outcome than their greater-arc counterparts.¹⁵

More than half of all patients with perilunate injuries will develop radiographic signs of osteoarthritis, and some will require additional salvage procedures.3-5 Kremer and colleagues4 showed that overall results after perilunate injuries deteriorate with time. However, according to a paper by Forli and colleagues5 in which patients were followed a minimum of 10 years after their injuries, the authors found that, despite radiographic progression of arthritis, most patients maintained reasonable hand function.

Perilunate injuries typically stem from a high-energy insult to the carpus. Because of their relative infrequency and often subtle radiographic and physical examination findings, these injuries are often undetected in the emergency department setting.¹ Early anatomic reduction of any carpal malalignment is essential. Even with optimal treatment, complications such as generalized wrist stiffness, diminished grip strength, and posttraumatic arthritis, commonly develop; however, recent studies suggest these issues are often well tolerated.^1-5 In this article, the diagnosis, treatment, and outcomes after perilunate injuries are examined. 

History and Physical Examination

Perilunate injuries result from high-energy trauma to the carpus. Patients with these injuries often present with vague wrist pain and loss of wrist motion. Their fingers are frequently held in slight flexion. The patient may complain of numbness and tingling in the median nerve distribution. An acute carpal tunnel syndrome can rapidly develop. The general belief is that acute carpal tunnel syndrome occurs more commonly in pure volar lunate dislocations than in dorsal perilunate dislocations. However, no studies compare the incidence of acute carpal tunnel syndrome in lunate versus perilunate dislocations.

Radiographic Evaluation

Standard radiographic evaluation of a potential perilunate injury includes posteroanterior (PA), lateral, and oblique views of the wrist (Figure 1). A scaphoid view (ie, PA view with the wrist in ulnar deviation) may also be helpful. The PA view is particularly helpful because it enables assessment of Gilula lines, which are imaginary lines drawn across the proximal and distal aspects of the proximal carpal row and the proximal aspect of the distal carpal row. These lines should appear as 3 smooth arcs running nearly parallel to each other.⁶ Any disruption in these lines suggests carpal incongruity. It may be possible to note a triangular-shaped lunate on the PA view, which is a sign of lunate dislocation.⁷ 

While the PA view is certainly useful, the lateral view is the most important in diagnosing a perilunate injury. The lateral view allows assessment of the collinearity of radius, lunate, and capitate. Any disruption in this collinearity strongly suggests a perilunate dislocation.^7,8 

Classification

Mayfield and colleagues^9,10 described 4 stages of perilunate instability proceeding from a radial to an ulnar direction around the lunate. Stage I involves disruption of the scapholunate joint, while stage II involves both the scapholunate and capitolunate joints. In stage III, the scapholunate, capitolunate, and lunotriquetral ligaments are disrupted, and the result is a perilunate dislocation, usually dorsal. Finally, in stage IV, all the ligaments surrounding the lunate are disrupted and the lunate dislocates, most often volarly.

Lastly, perilunate injuries can be classified as greater-arc injuries if concomitant fracture of the carpus occurs, lesser-arc injuries if the injury is purely ligamentous, or inferior-arc injuries if there is an associated fracture of the volar rim of the distal radius.⁸

Treatment

Closed Reduction

All acute perilunate dislocations should be managed initially with an attempted closed reduction.¹¹ If the injury is older than 72 hours, such an attempt may be futile. For any closed reduction performed in the emergency department setting, intravenous sedation is generally advised for muscle relaxation. Gentle traction with finger traps can also be used prior to the reduction attempt. For a dorsal perilunate dislocation, longitudinal traction followed by volar flexion of the wrist with volar pressure on the lunate and dorsal pressure on the capitate (ie, Tavernier’s maneuver) is required. Once reduction is complete, PA and lateral views of the wrist should be obtained to assess carpal alignment. If closed reduction is unsuccessful, an open reduction is required, although the timing of said procedure is an area of debate, which we will discuss later.^1,3 Restoration of anatomic carpal alignment is essential to optimizing outcome, although it does not guarantee a good overall result.

Open Reduction

If successful closed reduction is achieved, the patient can be immobilized temporarily in a short-arm plaster splint. However, open reduction and either pinning or internal fixation will be required to maintain this alignment. The exact timing of open reduction and fixation is debatable and often dictated by the absence or presence of median nerve symptoms.^1,3 If a patient with no median nerve symptoms undergoes a successful closed reduction, he or she may be stabilized surgically within 3 to 5 days (or longer) with either pins or headless screws. If closed reduction is unsuccessful, an open reduction should be done within 2 to 3 days. However, if the patient has progressive numbness in the median nerve distribution upon presentation that fails to improve or worsens despite a successful closed reduction, an urgent open reduction (within 24 hours) and carpal tunnel release should be performed to prevent permanent damage to the median nerve.

Once open reduction is undertaken, a dorsal, volar, and combined approach can be used.^2-4 In most cases the dorsal approach is selected first. A longitudinal incision is made over the dorsum of the wrist, centered on the Lister tubercle. Dissection occurs between the third and fourth dorsal compartments. After the capsule is exposed, reduction of the lunate to the capitate is confirmed. If any fractures are present in the carpus (eg, scaphoid), they are internally fixed. The scapholunate articulation is then addressed. In general, the scapholunate ligament is not disrupted with a transscaphoid perilunate dislocation. However, if the scapholunate ligament is disrupted, the joint should be reduced and pinned. Repair or reconstruction of the scapholunate ligament is performed. Finally, the lunotriquetral articulation is reduced and stabilized with pins. There are no studies that specifically suggest direct repair of the lunotriquetral ligament versus pinning of the lunotriquetral articulation, but the lunotriquetral ligament could be repaired in similar fashion to the scapholunate ligament at the surgeon’s discretion.

As an alternative to percutaneous pinning, intercarpal screw fixation can be used to stabilize the carpus. A 2007 study by Souer and colleagues¹² showed no substantial difference in outcome between the 2 methods of fixation. However, a second procedure is required to remove the screws.

The volar approach, if selected, is typically done second and performed via an extended carpal tunnel incision. It allows decompression of the carpal tunnel and enables repair of volar capsular ligaments (ie, long and short radiolunate ligaments, volar scapholunate ligament, and volar lunotriquetral ligament), which increases overall carpal stability. Currently, many surgeons favor a combined dorsal-volar approach for its efficacy.^2,3 Some use a dorsal approach in all patients and perform a volar procedure only if the patient has median nerve symptoms.⁴ However, Başar and colleagues¹³ report use of only the volar approach for treatment of perilunate injuries. The authors repaired the long and short radiolunate ligaments, volar scapholunate ligament, and volar lunotriquetral ligament. They reported reasonably good outcomes, which are equivalent to those reported in similar studies using dorsal or combined dorsal-volar approaches. However, no studies in the literature directly compare any of the different approaches with each other.

Postoperatively, patients are placed in a long-arm thumb-spica cast for 4 weeks, and then in a short-arm cast for 4 to 8 weeks (Figure 2). If present, pins are removed in 3 to 12 weeks, with most authors recommending removal at 8 weeks.^2,14

Lastly, carpal tunnel symptoms can develop late and even after a successful reduction and surgical stabilization. One theory is that a significant perilunate injury can create slightly higher baseline carpal tunnel pressures, which can compromise the blood flow to the median nerve and cause carpal tunnel symptoms. Additionally, it is possible that direct median nerve contusion and/or traction injury via a displaced lunate can also cause these symptoms. Whatever the inciting cause of median-nerve irritation, a delayed carpal tunnel release is sometimes required.

Conclusion

Outcomes after either perilunate or lunate dislocation are fair to good at best but can be optimized with prompt, appropriate treatment. Closed reduction and casting as definitive treatment has been abandoned because of frequent loss of reduction.¹² Early open reduction (ie, less than 3 days after injury) has been shown to be beneficial.^1,2 However, even those treated early and with anatomic restoration of carpal alignment can expect a loss of grip strength and a range of motion of approximately 70% compared with the contralateral side.^2-5 A recent study has suggested that lesser-arc injures generally have a poorer overall outcome than their greater-arc counterparts.¹⁵

More than half of all patients with perilunate injuries will develop radiographic signs of osteoarthritis, and some will require additional salvage procedures.3-5 Kremer and colleagues4 showed that overall results after perilunate injuries deteriorate with time. However, according to a paper by Forli and colleagues5 in which patients were followed a minimum of 10 years after their injuries, the authors found that, despite radiographic progression of arthritis, most patients maintained reasonable hand function.

A 20-year-old woman with Gaucher disease presents with pain in her right ankle and in her back. She has had the ankle pain for the past 12 months and the back pain for the past 2 years. She describes the ankle pain as stabbing and moderately severe. It is constant, present both at rest and during physical activity, but aggravated by walking and twisting movements. She has noticed grinding and clicking sounds as she moves her ankle. The ankle pain has worsened over the past several months.

She says her back pain is similar to her ankle pain but less severe. She also reports generalized mild aches and bone pain. No other joints are involved. She has no history of fever, chills, or trauma.

A COMPLICATED MEDICAL HISTORY

Her Gaucher disease was diagnosed at age 4 when she presented with failure to thrive and with thrombocytopenia and splenomegaly. She and was found to have an N370S/IVS2+1 mutation of the GBA gene. She underwent removal of 90% of her spleen at the time of diagnosis and was on enzyme replacement therapy with imiglucerase until 3 years ago, when the treatment was stopped because the drug had become unavailable (because of a temporary closure of the manufacturing facility), and because she had developed neutralizing antibodies to it. Despite a dosage as high as 120 U/kg every 2 weeks (the recommended range is 2.5 U/kg three times a week up to 60 U/kg every 2 weeks), her anemia and thrombocytopenia worsened to the point that she became dependent on transfusion of red blood cells and platelets. She has also taken glucocorticoids at various times in the past as a premedication before enzyme replacement therapy.

About 3 years ago, she developed dryness of the skin, pruritus, shiny skin, hardening of the skin, and decreased oral aperture, which was diagnosed as scleroderma.

During the past 5 years, she has had multiple episodes of pale coloration of her skin on exposure to cold, suggestive of Raynaud phenomenon. And for the past 5 months, she has noticed a burning sensation in her throat and retrosternal pain, suggestive of gastroesophageal reflux disease.

She is a college student, with no history of smoking or use of alcohol or recreational drugs. She is sexually active, with no history of sexually transmitted disease, and she uses condoms and oral contraceptives for contraception.

Her father and mother are both carriers of Gaucher disease. She is not of Ashkenazi Jewish descent.

FINDINGS ON PHYSICAL EXAMINATION

On physical examination, her temperature, blood pressure, pulse, and respiratory rate are within normal limits. She has extensive tattooing on her upper chest to hide scarring from previous cannulation ports. The right ankle joint is moderately swollen but shows no other signs of inflammation; its range of motion is limited by severe pain. She has tenderness of the spinous processes and paraspinal area, in addition to multiple tender points in the thoracolumbar area. Palpation of the right hip reveals tenderness of the groin and trochanteric bursa.

No lymphadenopathy, hepatomegaly, splenomegaly, or abdominal masses are noted. Neurologic examination is essentially nonfocal.

Her current medications include omeprazole, ergocalciferol, calcium carbonate, gabapentin, citalopram, and celecoxib. She also takes a multivitamin daily.

1. Which is the most likely underlying cause of her ankle pain?

• Rheumatoid arthritis
• Gaucher disease
• Septic arthritis
• Avascular necrosis secondary to steroid use

Rheumatoid arthritis varies in its presentation. It is usually insidious in onset, migratory, and intermittent, with polyarticular or even monoarticular involvement, and it presents with pain, stiffness, and swelling of the joint.¹ Most often affected are the metacarpophalangeal, proximal interphalangeal, wrist, and metatarsophalangeal joints. Involvement of large joints of the upper and lower limbs is also common.² This is not the most likely cause of this patient’s symptoms, based on the history and the current presentation.

Gaucher disease is a lipidosis caused by accumulation of cellular glycolipids, especially glucocerebrosides, due to deficiency of the enzyme beta-glucosidase. Clinical manifestations include hepatomegaly, splenomegaly, and bone marrow disease presenting as anemia, thrombocytopenia, or skeletal disease.³ Skeletal involvement in Gaucher disease includes bone pain, bone infarcts, and lytic lesions.

Whether splenectomy predisposes the patient to bone manifestations is controversial. Some believe that splenectomy decreases the total body reservoir for the storage of glycolipids and predisposes to their deposition in bone, which in turn results in cortical thinning, impaired remodeling, and decreased intraosseous blood flow, leading to osteonecrosis and fractures.⁴ This is more common in patients with type 1 Gaucher disease who have undergone splenectomy. (Types 2 and 3 are much rarer, occurring mainly in children; central nervous system involvement is a key feature. A discussion of these types is beyond the focus of this paper.) However, some studies suggest that the increase in bone manifestations after splenectomy may be simply because of severe disease.⁵ It should be noted that, since the advent of enzyme replacement therapy for Gaucher disease, splenectomy is now rarely performed.⁶

Anemia is also considered an independent risk factor for the development of avascular necrosis in type 1 Gaucher disease.⁷ Osteonecrosis due to Gaucher disease is relatively common in the femur, tibia, and humerus and uncommon in the ankle joints.⁸

Septic arthritis is unlikely in this patient in the absence of fever or signs of inflammation of the joint. Her long-standing history of ankle pain would also be unusual for infection, but a superimposed infectious process should always be suspected in an arthritic joint.

Avascular necrosis secondary to steroid use. Glucocorticoids are notorious for their adverse effects on bone. They induce osteocyte apoptosis and a decrease in bone remodeling, potentially predisposing to osteonecrosis.⁹ There is a high incidence of osteoporosis, osteonecrosis, and fracture risk with glucocorticoid therapy, and the incidence is dose-dependent. Discontinuation of the drug only partially restores fracture risk to baseline levels.^10,11

A meta-analysis of cohort studies with a total sample size of about 42,000 reported an increased risk of fracture at all ages with the use of glucocorticoids.¹² Because the minimum dosage and duration of therapy to prevent glucocorticoid-induced osteoporosis are not known, the only recommendation is to keep the dosage as low as possible.¹³

Glucocorticoid therapy is the most common cause of nontraumatic avascular necrosis. The risk of osteonecrosis in patients on long-term glucocorticoid therapy may be as high as 40%.¹⁴ The risk is increased with prolonged treatment and with high doses, but it can also occur with short-term exposure to high doses. The increased risk has been shown to persist for as long as 2 years after the drugs are discontinued.¹⁵ Glucocorticoid-induced bone disease commonly affects the hip and vertebrae.

At this stage of the workup, we cannot completely rule out glucocorticoid use as the cause. However, after considering this patient’s presentation and the key features of the other diagnoses, her ankle pain and back pain are more likely caused by her preexisting Gaucher disease.

CONTINUED EVALUATION


Initial laboratory tests (Table 1) reveal severe anemia and thrombocytopenia. Bone marrow biopsy of the iliac crest done as part of the workup for these conditions shows extensive bone marrow space replacement by histiocytic infiltrate, consistent with Gaucher disease. No other marrow process is observed.

Radiography of the ankle (Figure 1) shows a subtle lucency in the talar dome with minimal subarticular collapse seen on the lateral view, suggestive of avascular necrosis and diffuse osteopenia. Joint spaces are maintained.

Magnetic resonance imaging (MRI) of the ankle shows numerous bone infarcts with an approximately 15-mm region of mild articular surface collapse in the central and lateral aspect of the talar dome.

MRI of the back shows extensive abnormal bone marrow signal intensity throughout the spine, compatible with a marrow replacement process. Patchy nonexpansile T2/stir hyperintensity with serpiginous enhancement within the T9, T11, T12, L2, and L3 vertebral bodies as well as throughout the entire sacrum is consistent with bone infarct.

2. Based on the results of radiographic studies, which is most likely the immediate cause of her ankle pain?

• Talar avascular necrosis secondary to rheumatoid arthritis
• Talar avascular necrosis secondary to Gaucher disease
• Trauma-induced fracture of the talus
• Plantar fasciitis

Of the bones of the feet, the talus is unique. It is the second largest of the tarsal bones and does not have muscular or tendinous attachments. Sixty percent of the talus bone is covered by articular cartilage,¹⁶ so only a limited area is available for penetration of blood vessels. Also, small nutrient vessels and variations of intraosseous anastomoses with a lack of collateral circulation predispose the talus to osteonecrosis when the vascular supply is compromised.¹⁶

Radiographic evidence of avascular necrosis is the presence of bone that is more radiopaque than normal bone; this is necrotic bone surrounded by osteopenic bone. Avascular necrosis causes hyperemia and resorption of bone. The resorption does not take place in necrotic bone because of the lack of a vascular supply, and so it appears radiopaque, whereas the bone surrounding the necrotic bone becomes osteopenic and radiolucent.

The sclerotic rim of a bone infarct is also enhanced by an attempted healing process in which new bone forms on the surface of necrotic trabeculae, a process known as “creeping substitution.” This gives a typical sclerotic picture of the talus.

MRI is the most sensitive technique for detecting osteonecrosis. A characteristic radiographic pattern is seen with osteonecrosis of the talus starting with talar dome opacity, followed by deformity and, in severe cases, articular collapse and bone fragmentation.¹⁷

The radiograph in our patient’s case is not consistent with features of rheumatoid arthritis or traumatic fracture of the talus. In plantar fasciitis, radiographs are used to rule out other pathologies of the foot, and the only finding may be a bone spur seen at the site of pain. The bone spur is not the cause of pain in plantar fasciitis but may be a result of the plantar fasciitis itself.

Therefore, avascular necrosis secondary to Gaucher disease is most likely the immediate cause of her ankle pain.

THE COURSE OF TREATMENT

The patient is started on enzyme replacement therapy with taliglucerase alfa (see discussion of enzyme replacement below). For the ankle pain, conservative management is prescribed, with application of a splint and a boot.

After 4 months of conservative management, radiography (Figure 2) and magnetic resonance imaging (Figure 3) show progressive deterioration of the talus body, and her ankle pain has worsened. A 6-week trial of an ankle brace also proves futile. Her pain continues to worsen and is not controllable with high doses of pain medication. She requests below-the-knee amputation.

Given the complexity of this patient’s medical condition, fusion of the ankle and hindfoot—which in some patients is preferable to amputation—is not considered because of her extensive bone involvement and ongoing thrombocytopenia, which would impede healing after the procedure. Below-the-knee amputation is performed without complications.

Study of the specimen after amputation reveals talar bone necrosis and bone marrow infiltration by foamy macrophages, consistent with Gaucher disease (Figures 4–6).

GAUCHER DISEASE

Pharmacologic treatments, effective only for type 1 Gaucher disease, target hepatosplenomegaly, cytopenia, and bone manifestations. Two approaches are enzyme replacement therapy—ie, to replace the defective enzyme—and substrate reduction therapy—ie, to reduce the production and thus the accumulation of glucocerebroside. Enzyme replacement is the first choice of therapy; substrate reduction is reserved for patients unable to tolerate enzyme replacement therapy.

Enzyme replacement

Current drugs for enzyme replacement therapy are imiglucerase, taliglucerase alfa, and velaglucerase alfa. The drugs are given by intravenous infusion over 1 to 2 hours in an outpatient clinic or office every 2 weeks.

These drugs are extremely expensive. Currently, the estimated cost of therapy for 1 year would be $432,978 for imiglucerase, $324,870 for taliglucerase alfa, and $368,550 for velaglucerase alfa. (The estimated costs are for 1 year of treatment for a 70-kg patient at 60 U/kg every 2 weeks.)¹⁸ Taliglucerase alfa is less expensive than the other two because it is plant-derived and thus can be more readily produced on a large scale.¹⁹

Substrate reduction

Current drugs for substrate reduction therapy are eliglustat and miglustat. They are given orally. Eliglustat is the first oral drug approved as a first-line treatment for Gaucher disease.²⁰ Miglustat is approved only for mild to moderate disease when enzyme replacement fails or is not tolerated.

Patients can develop antibodies to any of the enzyme replacement drugs. It is not known whether this antibody response differs among the three drugs.²¹

Avascular necrosis of bone can occur in many clinical settings especially after a fracture, particularly of the head of the femur, which leads to interruption of blood supply to the area. Patients with sickle cell disease, those on corticosteroids or bisphosphonates (the latter causing osteonecrosis of the jaw), and those who have pancreatitis or human immunodeficiency virus infection are more prone to this bone complication.

In Gaucher disease, osteonecrosis is associated with splenectomy and severe disease and tends to occur at a younger age than in patients with other diagnoses.⁸ The plasma chitotriosidase activity and pulmonary and activation-regulated chemokines (PARC/CCL18), which are 10 to 40 times higher than normal in symptomatic patients with Gaucher disease, can be used as a biomarker of disease activity.⁸ Only plasma chitotriosidase is clinically available and used on a routine basis.

Bone involvement is seen in approximately 75% of the patients with type 1 Gaucher disease,²² and osteonecrosis is a severe form of bone involvement. Monitoring of patients for bone involvement is recommended. Enzyme replacement therapy for Gaucher disease needs to be started even if visceral disease is absent if the patient has evidence of bone involvement in the form of avascular necrosis.⁷ Prospective studies have shown that enzyme replacement therapy reduces the incidence of osteonecrosis.²³

FOLLOW-UP MANAGEMENT OF OUR PATIENT

Avascular necrosis in Gaucher disease more typically involves the hips and shoulders. In the case of our patient, the talus was the most affected bone. Other contributing factors may have been the use of steroids as a premedication (often unnecessary) for her enzyme replacement therapy, as well as the coexistent scleroderma.²⁴

The decision to switch from imiglucerase, to which she developed antibodies, to taliglucerase was made in the hope that the antibodies would not cross-react. After she started taliglucerase, her complete blood count values improved steadily. She did not require transfusions for more than 1 year. Her platelet count rose to 90 × 10⁹/L, and her hemoglobin to 12 g/dL.

A multidisciplinary approach with regular monitoring and appropriate initiation of therapy is necessary to prevent disastrous complications in patients with Gaucher disease.

A 20-year-old woman with Gaucher disease presents with pain in her right ankle and in her back. She has had the ankle pain for the past 12 months and the back pain for the past 2 years. She describes the ankle pain as stabbing and moderately severe. It is constant, present both at rest and during physical activity, but aggravated by walking and twisting movements. She has noticed grinding and clicking sounds as she moves her ankle. The ankle pain has worsened over the past several months.

She says her back pain is similar to her ankle pain but less severe. She also reports generalized mild aches and bone pain. No other joints are involved. She has no history of fever, chills, or trauma.

A COMPLICATED MEDICAL HISTORY

Her Gaucher disease was diagnosed at age 4 when she presented with failure to thrive and with thrombocytopenia and splenomegaly. She and was found to have an N370S/IVS2+1 mutation of the GBA gene. She underwent removal of 90% of her spleen at the time of diagnosis and was on enzyme replacement therapy with imiglucerase until 3 years ago, when the treatment was stopped because the drug had become unavailable (because of a temporary closure of the manufacturing facility), and because she had developed neutralizing antibodies to it. Despite a dosage as high as 120 U/kg every 2 weeks (the recommended range is 2.5 U/kg three times a week up to 60 U/kg every 2 weeks), her anemia and thrombocytopenia worsened to the point that she became dependent on transfusion of red blood cells and platelets. She has also taken glucocorticoids at various times in the past as a premedication before enzyme replacement therapy.

About 3 years ago, she developed dryness of the skin, pruritus, shiny skin, hardening of the skin, and decreased oral aperture, which was diagnosed as scleroderma.

During the past 5 years, she has had multiple episodes of pale coloration of her skin on exposure to cold, suggestive of Raynaud phenomenon. And for the past 5 months, she has noticed a burning sensation in her throat and retrosternal pain, suggestive of gastroesophageal reflux disease.

She is a college student, with no history of smoking or use of alcohol or recreational drugs. She is sexually active, with no history of sexually transmitted disease, and she uses condoms and oral contraceptives for contraception.

Her father and mother are both carriers of Gaucher disease. She is not of Ashkenazi Jewish descent.

FINDINGS ON PHYSICAL EXAMINATION

On physical examination, her temperature, blood pressure, pulse, and respiratory rate are within normal limits. She has extensive tattooing on her upper chest to hide scarring from previous cannulation ports. The right ankle joint is moderately swollen but shows no other signs of inflammation; its range of motion is limited by severe pain. She has tenderness of the spinous processes and paraspinal area, in addition to multiple tender points in the thoracolumbar area. Palpation of the right hip reveals tenderness of the groin and trochanteric bursa.

No lymphadenopathy, hepatomegaly, splenomegaly, or abdominal masses are noted. Neurologic examination is essentially nonfocal.

Her current medications include omeprazole, ergocalciferol, calcium carbonate, gabapentin, citalopram, and celecoxib. She also takes a multivitamin daily.

1. Which is the most likely underlying cause of her ankle pain?

• Rheumatoid arthritis
• Gaucher disease
• Septic arthritis
• Avascular necrosis secondary to steroid use

Rheumatoid arthritis varies in its presentation. It is usually insidious in onset, migratory, and intermittent, with polyarticular or even monoarticular involvement, and it presents with pain, stiffness, and swelling of the joint.¹ Most often affected are the metacarpophalangeal, proximal interphalangeal, wrist, and metatarsophalangeal joints. Involvement of large joints of the upper and lower limbs is also common.² This is not the most likely cause of this patient’s symptoms, based on the history and the current presentation.

Gaucher disease is a lipidosis caused by accumulation of cellular glycolipids, especially glucocerebrosides, due to deficiency of the enzyme beta-glucosidase. Clinical manifestations include hepatomegaly, splenomegaly, and bone marrow disease presenting as anemia, thrombocytopenia, or skeletal disease.³ Skeletal involvement in Gaucher disease includes bone pain, bone infarcts, and lytic lesions.

Whether splenectomy predisposes the patient to bone manifestations is controversial. Some believe that splenectomy decreases the total body reservoir for the storage of glycolipids and predisposes to their deposition in bone, which in turn results in cortical thinning, impaired remodeling, and decreased intraosseous blood flow, leading to osteonecrosis and fractures.⁴ This is more common in patients with type 1 Gaucher disease who have undergone splenectomy. (Types 2 and 3 are much rarer, occurring mainly in children; central nervous system involvement is a key feature. A discussion of these types is beyond the focus of this paper.) However, some studies suggest that the increase in bone manifestations after splenectomy may be simply because of severe disease.⁵ It should be noted that, since the advent of enzyme replacement therapy for Gaucher disease, splenectomy is now rarely performed.⁶

Anemia is also considered an independent risk factor for the development of avascular necrosis in type 1 Gaucher disease.⁷ Osteonecrosis due to Gaucher disease is relatively common in the femur, tibia, and humerus and uncommon in the ankle joints.⁸

Septic arthritis is unlikely in this patient in the absence of fever or signs of inflammation of the joint. Her long-standing history of ankle pain would also be unusual for infection, but a superimposed infectious process should always be suspected in an arthritic joint.

Avascular necrosis secondary to steroid use. Glucocorticoids are notorious for their adverse effects on bone. They induce osteocyte apoptosis and a decrease in bone remodeling, potentially predisposing to osteonecrosis.⁹ There is a high incidence of osteoporosis, osteonecrosis, and fracture risk with glucocorticoid therapy, and the incidence is dose-dependent. Discontinuation of the drug only partially restores fracture risk to baseline levels.^10,11

A meta-analysis of cohort studies with a total sample size of about 42,000 reported an increased risk of fracture at all ages with the use of glucocorticoids.¹² Because the minimum dosage and duration of therapy to prevent glucocorticoid-induced osteoporosis are not known, the only recommendation is to keep the dosage as low as possible.¹³

Glucocorticoid therapy is the most common cause of nontraumatic avascular necrosis. The risk of osteonecrosis in patients on long-term glucocorticoid therapy may be as high as 40%.¹⁴ The risk is increased with prolonged treatment and with high doses, but it can also occur with short-term exposure to high doses. The increased risk has been shown to persist for as long as 2 years after the drugs are discontinued.¹⁵ Glucocorticoid-induced bone disease commonly affects the hip and vertebrae.

At this stage of the workup, we cannot completely rule out glucocorticoid use as the cause. However, after considering this patient’s presentation and the key features of the other diagnoses, her ankle pain and back pain are more likely caused by her preexisting Gaucher disease.

CONTINUED EVALUATION


Initial laboratory tests (Table 1) reveal severe anemia and thrombocytopenia. Bone marrow biopsy of the iliac crest done as part of the workup for these conditions shows extensive bone marrow space replacement by histiocytic infiltrate, consistent with Gaucher disease. No other marrow process is observed.

Radiography of the ankle (Figure 1) shows a subtle lucency in the talar dome with minimal subarticular collapse seen on the lateral view, suggestive of avascular necrosis and diffuse osteopenia. Joint spaces are maintained.

Magnetic resonance imaging (MRI) of the ankle shows numerous bone infarcts with an approximately 15-mm region of mild articular surface collapse in the central and lateral aspect of the talar dome.

MRI of the back shows extensive abnormal bone marrow signal intensity throughout the spine, compatible with a marrow replacement process. Patchy nonexpansile T2/stir hyperintensity with serpiginous enhancement within the T9, T11, T12, L2, and L3 vertebral bodies as well as throughout the entire sacrum is consistent with bone infarct.

2. Based on the results of radiographic studies, which is most likely the immediate cause of her ankle pain?

• Talar avascular necrosis secondary to rheumatoid arthritis
• Talar avascular necrosis secondary to Gaucher disease
• Trauma-induced fracture of the talus
• Plantar fasciitis

Of the bones of the feet, the talus is unique. It is the second largest of the tarsal bones and does not have muscular or tendinous attachments. Sixty percent of the talus bone is covered by articular cartilage,¹⁶ so only a limited area is available for penetration of blood vessels. Also, small nutrient vessels and variations of intraosseous anastomoses with a lack of collateral circulation predispose the talus to osteonecrosis when the vascular supply is compromised.¹⁶

Radiographic evidence of avascular necrosis is the presence of bone that is more radiopaque than normal bone; this is necrotic bone surrounded by osteopenic bone. Avascular necrosis causes hyperemia and resorption of bone. The resorption does not take place in necrotic bone because of the lack of a vascular supply, and so it appears radiopaque, whereas the bone surrounding the necrotic bone becomes osteopenic and radiolucent.

The sclerotic rim of a bone infarct is also enhanced by an attempted healing process in which new bone forms on the surface of necrotic trabeculae, a process known as “creeping substitution.” This gives a typical sclerotic picture of the talus.

MRI is the most sensitive technique for detecting osteonecrosis. A characteristic radiographic pattern is seen with osteonecrosis of the talus starting with talar dome opacity, followed by deformity and, in severe cases, articular collapse and bone fragmentation.¹⁷

The radiograph in our patient’s case is not consistent with features of rheumatoid arthritis or traumatic fracture of the talus. In plantar fasciitis, radiographs are used to rule out other pathologies of the foot, and the only finding may be a bone spur seen at the site of pain. The bone spur is not the cause of pain in plantar fasciitis but may be a result of the plantar fasciitis itself.

Therefore, avascular necrosis secondary to Gaucher disease is most likely the immediate cause of her ankle pain.

THE COURSE OF TREATMENT

The patient is started on enzyme replacement therapy with taliglucerase alfa (see discussion of enzyme replacement below). For the ankle pain, conservative management is prescribed, with application of a splint and a boot.

After 4 months of conservative management, radiography (Figure 2) and magnetic resonance imaging (Figure 3) show progressive deterioration of the talus body, and her ankle pain has worsened. A 6-week trial of an ankle brace also proves futile. Her pain continues to worsen and is not controllable with high doses of pain medication. She requests below-the-knee amputation.

Given the complexity of this patient’s medical condition, fusion of the ankle and hindfoot—which in some patients is preferable to amputation—is not considered because of her extensive bone involvement and ongoing thrombocytopenia, which would impede healing after the procedure. Below-the-knee amputation is performed without complications.

Study of the specimen after amputation reveals talar bone necrosis and bone marrow infiltration by foamy macrophages, consistent with Gaucher disease (Figures 4–6).

GAUCHER DISEASE

Pharmacologic treatments, effective only for type 1 Gaucher disease, target hepatosplenomegaly, cytopenia, and bone manifestations. Two approaches are enzyme replacement therapy—ie, to replace the defective enzyme—and substrate reduction therapy—ie, to reduce the production and thus the accumulation of glucocerebroside. Enzyme replacement is the first choice of therapy; substrate reduction is reserved for patients unable to tolerate enzyme replacement therapy.

Enzyme replacement

Current drugs for enzyme replacement therapy are imiglucerase, taliglucerase alfa, and velaglucerase alfa. The drugs are given by intravenous infusion over 1 to 2 hours in an outpatient clinic or office every 2 weeks.

These drugs are extremely expensive. Currently, the estimated cost of therapy for 1 year would be $432,978 for imiglucerase, $324,870 for taliglucerase alfa, and $368,550 for velaglucerase alfa. (The estimated costs are for 1 year of treatment for a 70-kg patient at 60 U/kg every 2 weeks.)¹⁸ Taliglucerase alfa is less expensive than the other two because it is plant-derived and thus can be more readily produced on a large scale.¹⁹

Substrate reduction

Current drugs for substrate reduction therapy are eliglustat and miglustat. They are given orally. Eliglustat is the first oral drug approved as a first-line treatment for Gaucher disease.²⁰ Miglustat is approved only for mild to moderate disease when enzyme replacement fails or is not tolerated.

Patients can develop antibodies to any of the enzyme replacement drugs. It is not known whether this antibody response differs among the three drugs.²¹

Avascular necrosis of bone can occur in many clinical settings especially after a fracture, particularly of the head of the femur, which leads to interruption of blood supply to the area. Patients with sickle cell disease, those on corticosteroids or bisphosphonates (the latter causing osteonecrosis of the jaw), and those who have pancreatitis or human immunodeficiency virus infection are more prone to this bone complication.

In Gaucher disease, osteonecrosis is associated with splenectomy and severe disease and tends to occur at a younger age than in patients with other diagnoses.⁸ The plasma chitotriosidase activity and pulmonary and activation-regulated chemokines (PARC/CCL18), which are 10 to 40 times higher than normal in symptomatic patients with Gaucher disease, can be used as a biomarker of disease activity.⁸ Only plasma chitotriosidase is clinically available and used on a routine basis.

Bone involvement is seen in approximately 75% of the patients with type 1 Gaucher disease,²² and osteonecrosis is a severe form of bone involvement. Monitoring of patients for bone involvement is recommended. Enzyme replacement therapy for Gaucher disease needs to be started even if visceral disease is absent if the patient has evidence of bone involvement in the form of avascular necrosis.⁷ Prospective studies have shown that enzyme replacement therapy reduces the incidence of osteonecrosis.²³

FOLLOW-UP MANAGEMENT OF OUR PATIENT

Avascular necrosis in Gaucher disease more typically involves the hips and shoulders. In the case of our patient, the talus was the most affected bone. Other contributing factors may have been the use of steroids as a premedication (often unnecessary) for her enzyme replacement therapy, as well as the coexistent scleroderma.²⁴

The decision to switch from imiglucerase, to which she developed antibodies, to taliglucerase was made in the hope that the antibodies would not cross-react. After she started taliglucerase, her complete blood count values improved steadily. She did not require transfusions for more than 1 year. Her platelet count rose to 90 × 10⁹/L, and her hemoglobin to 12 g/dL.

A multidisciplinary approach with regular monitoring and appropriate initiation of therapy is necessary to prevent disastrous complications in patients with Gaucher disease.

A 20-year-old woman with Gaucher disease presents with pain in her right ankle and in her back. She has had the ankle pain for the past 12 months and the back pain for the past 2 years. She describes the ankle pain as stabbing and moderately severe. It is constant, present both at rest and during physical activity, but aggravated by walking and twisting movements. She has noticed grinding and clicking sounds as she moves her ankle. The ankle pain has worsened over the past several months.

She says her back pain is similar to her ankle pain but less severe. She also reports generalized mild aches and bone pain. No other joints are involved. She has no history of fever, chills, or trauma.

A COMPLICATED MEDICAL HISTORY

Her Gaucher disease was diagnosed at age 4 when she presented with failure to thrive and with thrombocytopenia and splenomegaly. She and was found to have an N370S/IVS2+1 mutation of the GBA gene. She underwent removal of 90% of her spleen at the time of diagnosis and was on enzyme replacement therapy with imiglucerase until 3 years ago, when the treatment was stopped because the drug had become unavailable (because of a temporary closure of the manufacturing facility), and because she had developed neutralizing antibodies to it. Despite a dosage as high as 120 U/kg every 2 weeks (the recommended range is 2.5 U/kg three times a week up to 60 U/kg every 2 weeks), her anemia and thrombocytopenia worsened to the point that she became dependent on transfusion of red blood cells and platelets. She has also taken glucocorticoids at various times in the past as a premedication before enzyme replacement therapy.

About 3 years ago, she developed dryness of the skin, pruritus, shiny skin, hardening of the skin, and decreased oral aperture, which was diagnosed as scleroderma.

During the past 5 years, she has had multiple episodes of pale coloration of her skin on exposure to cold, suggestive of Raynaud phenomenon. And for the past 5 months, she has noticed a burning sensation in her throat and retrosternal pain, suggestive of gastroesophageal reflux disease.

She is a college student, with no history of smoking or use of alcohol or recreational drugs. She is sexually active, with no history of sexually transmitted disease, and she uses condoms and oral contraceptives for contraception.

Her father and mother are both carriers of Gaucher disease. She is not of Ashkenazi Jewish descent.

FINDINGS ON PHYSICAL EXAMINATION

On physical examination, her temperature, blood pressure, pulse, and respiratory rate are within normal limits. She has extensive tattooing on her upper chest to hide scarring from previous cannulation ports. The right ankle joint is moderately swollen but shows no other signs of inflammation; its range of motion is limited by severe pain. She has tenderness of the spinous processes and paraspinal area, in addition to multiple tender points in the thoracolumbar area. Palpation of the right hip reveals tenderness of the groin and trochanteric bursa.

No lymphadenopathy, hepatomegaly, splenomegaly, or abdominal masses are noted. Neurologic examination is essentially nonfocal.

Her current medications include omeprazole, ergocalciferol, calcium carbonate, gabapentin, citalopram, and celecoxib. She also takes a multivitamin daily.

1. Which is the most likely underlying cause of her ankle pain?

• Rheumatoid arthritis
• Gaucher disease
• Septic arthritis
• Avascular necrosis secondary to steroid use

Rheumatoid arthritis varies in its presentation. It is usually insidious in onset, migratory, and intermittent, with polyarticular or even monoarticular involvement, and it presents with pain, stiffness, and swelling of the joint.¹ Most often affected are the metacarpophalangeal, proximal interphalangeal, wrist, and metatarsophalangeal joints. Involvement of large joints of the upper and lower limbs is also common.² This is not the most likely cause of this patient’s symptoms, based on the history and the current presentation.

Gaucher disease is a lipidosis caused by accumulation of cellular glycolipids, especially glucocerebrosides, due to deficiency of the enzyme beta-glucosidase. Clinical manifestations include hepatomegaly, splenomegaly, and bone marrow disease presenting as anemia, thrombocytopenia, or skeletal disease.³ Skeletal involvement in Gaucher disease includes bone pain, bone infarcts, and lytic lesions.

Whether splenectomy predisposes the patient to bone manifestations is controversial. Some believe that splenectomy decreases the total body reservoir for the storage of glycolipids and predisposes to their deposition in bone, which in turn results in cortical thinning, impaired remodeling, and decreased intraosseous blood flow, leading to osteonecrosis and fractures.⁴ This is more common in patients with type 1 Gaucher disease who have undergone splenectomy. (Types 2 and 3 are much rarer, occurring mainly in children; central nervous system involvement is a key feature. A discussion of these types is beyond the focus of this paper.) However, some studies suggest that the increase in bone manifestations after splenectomy may be simply because of severe disease.⁵ It should be noted that, since the advent of enzyme replacement therapy for Gaucher disease, splenectomy is now rarely performed.⁶

Anemia is also considered an independent risk factor for the development of avascular necrosis in type 1 Gaucher disease.⁷ Osteonecrosis due to Gaucher disease is relatively common in the femur, tibia, and humerus and uncommon in the ankle joints.⁸

Septic arthritis is unlikely in this patient in the absence of fever or signs of inflammation of the joint. Her long-standing history of ankle pain would also be unusual for infection, but a superimposed infectious process should always be suspected in an arthritic joint.

Avascular necrosis secondary to steroid use. Glucocorticoids are notorious for their adverse effects on bone. They induce osteocyte apoptosis and a decrease in bone remodeling, potentially predisposing to osteonecrosis.⁹ There is a high incidence of osteoporosis, osteonecrosis, and fracture risk with glucocorticoid therapy, and the incidence is dose-dependent. Discontinuation of the drug only partially restores fracture risk to baseline levels.^10,11

A meta-analysis of cohort studies with a total sample size of about 42,000 reported an increased risk of fracture at all ages with the use of glucocorticoids.¹² Because the minimum dosage and duration of therapy to prevent glucocorticoid-induced osteoporosis are not known, the only recommendation is to keep the dosage as low as possible.¹³

Glucocorticoid therapy is the most common cause of nontraumatic avascular necrosis. The risk of osteonecrosis in patients on long-term glucocorticoid therapy may be as high as 40%.¹⁴ The risk is increased with prolonged treatment and with high doses, but it can also occur with short-term exposure to high doses. The increased risk has been shown to persist for as long as 2 years after the drugs are discontinued.¹⁵ Glucocorticoid-induced bone disease commonly affects the hip and vertebrae.

At this stage of the workup, we cannot completely rule out glucocorticoid use as the cause. However, after considering this patient’s presentation and the key features of the other diagnoses, her ankle pain and back pain are more likely caused by her preexisting Gaucher disease.

CONTINUED EVALUATION


Initial laboratory tests (Table 1) reveal severe anemia and thrombocytopenia. Bone marrow biopsy of the iliac crest done as part of the workup for these conditions shows extensive bone marrow space replacement by histiocytic infiltrate, consistent with Gaucher disease. No other marrow process is observed.

Radiography of the ankle (Figure 1) shows a subtle lucency in the talar dome with minimal subarticular collapse seen on the lateral view, suggestive of avascular necrosis and diffuse osteopenia. Joint spaces are maintained.

Magnetic resonance imaging (MRI) of the ankle shows numerous bone infarcts with an approximately 15-mm region of mild articular surface collapse in the central and lateral aspect of the talar dome.

MRI of the back shows extensive abnormal bone marrow signal intensity throughout the spine, compatible with a marrow replacement process. Patchy nonexpansile T2/stir hyperintensity with serpiginous enhancement within the T9, T11, T12, L2, and L3 vertebral bodies as well as throughout the entire sacrum is consistent with bone infarct.

2. Based on the results of radiographic studies, which is most likely the immediate cause of her ankle pain?

• Talar avascular necrosis secondary to rheumatoid arthritis
• Talar avascular necrosis secondary to Gaucher disease
• Trauma-induced fracture of the talus
• Plantar fasciitis

Of the bones of the feet, the talus is unique. It is the second largest of the tarsal bones and does not have muscular or tendinous attachments. Sixty percent of the talus bone is covered by articular cartilage,¹⁶ so only a limited area is available for penetration of blood vessels. Also, small nutrient vessels and variations of intraosseous anastomoses with a lack of collateral circulation predispose the talus to osteonecrosis when the vascular supply is compromised.¹⁶

Radiographic evidence of avascular necrosis is the presence of bone that is more radiopaque than normal bone; this is necrotic bone surrounded by osteopenic bone. Avascular necrosis causes hyperemia and resorption of bone. The resorption does not take place in necrotic bone because of the lack of a vascular supply, and so it appears radiopaque, whereas the bone surrounding the necrotic bone becomes osteopenic and radiolucent.

The sclerotic rim of a bone infarct is also enhanced by an attempted healing process in which new bone forms on the surface of necrotic trabeculae, a process known as “creeping substitution.” This gives a typical sclerotic picture of the talus.

MRI is the most sensitive technique for detecting osteonecrosis. A characteristic radiographic pattern is seen with osteonecrosis of the talus starting with talar dome opacity, followed by deformity and, in severe cases, articular collapse and bone fragmentation.¹⁷

The radiograph in our patient’s case is not consistent with features of rheumatoid arthritis or traumatic fracture of the talus. In plantar fasciitis, radiographs are used to rule out other pathologies of the foot, and the only finding may be a bone spur seen at the site of pain. The bone spur is not the cause of pain in plantar fasciitis but may be a result of the plantar fasciitis itself.

Therefore, avascular necrosis secondary to Gaucher disease is most likely the immediate cause of her ankle pain.

THE COURSE OF TREATMENT

The patient is started on enzyme replacement therapy with taliglucerase alfa (see discussion of enzyme replacement below). For the ankle pain, conservative management is prescribed, with application of a splint and a boot.

After 4 months of conservative management, radiography (Figure 2) and magnetic resonance imaging (Figure 3) show progressive deterioration of the talus body, and her ankle pain has worsened. A 6-week trial of an ankle brace also proves futile. Her pain continues to worsen and is not controllable with high doses of pain medication. She requests below-the-knee amputation.

Given the complexity of this patient’s medical condition, fusion of the ankle and hindfoot—which in some patients is preferable to amputation—is not considered because of her extensive bone involvement and ongoing thrombocytopenia, which would impede healing after the procedure. Below-the-knee amputation is performed without complications.

Study of the specimen after amputation reveals talar bone necrosis and bone marrow infiltration by foamy macrophages, consistent with Gaucher disease (Figures 4–6).

GAUCHER DISEASE

Pharmacologic treatments, effective only for type 1 Gaucher disease, target hepatosplenomegaly, cytopenia, and bone manifestations. Two approaches are enzyme replacement therapy—ie, to replace the defective enzyme—and substrate reduction therapy—ie, to reduce the production and thus the accumulation of glucocerebroside. Enzyme replacement is the first choice of therapy; substrate reduction is reserved for patients unable to tolerate enzyme replacement therapy.

Enzyme replacement

Current drugs for enzyme replacement therapy are imiglucerase, taliglucerase alfa, and velaglucerase alfa. The drugs are given by intravenous infusion over 1 to 2 hours in an outpatient clinic or office every 2 weeks.

These drugs are extremely expensive. Currently, the estimated cost of therapy for 1 year would be $432,978 for imiglucerase, $324,870 for taliglucerase alfa, and $368,550 for velaglucerase alfa. (The estimated costs are for 1 year of treatment for a 70-kg patient at 60 U/kg every 2 weeks.)¹⁸ Taliglucerase alfa is less expensive than the other two because it is plant-derived and thus can be more readily produced on a large scale.¹⁹

Substrate reduction

Current drugs for substrate reduction therapy are eliglustat and miglustat. They are given orally. Eliglustat is the first oral drug approved as a first-line treatment for Gaucher disease.²⁰ Miglustat is approved only for mild to moderate disease when enzyme replacement fails or is not tolerated.

Patients can develop antibodies to any of the enzyme replacement drugs. It is not known whether this antibody response differs among the three drugs.²¹

Avascular necrosis of bone can occur in many clinical settings especially after a fracture, particularly of the head of the femur, which leads to interruption of blood supply to the area. Patients with sickle cell disease, those on corticosteroids or bisphosphonates (the latter causing osteonecrosis of the jaw), and those who have pancreatitis or human immunodeficiency virus infection are more prone to this bone complication.

In Gaucher disease, osteonecrosis is associated with splenectomy and severe disease and tends to occur at a younger age than in patients with other diagnoses.⁸ The plasma chitotriosidase activity and pulmonary and activation-regulated chemokines (PARC/CCL18), which are 10 to 40 times higher than normal in symptomatic patients with Gaucher disease, can be used as a biomarker of disease activity.⁸ Only plasma chitotriosidase is clinically available and used on a routine basis.

Bone involvement is seen in approximately 75% of the patients with type 1 Gaucher disease,²² and osteonecrosis is a severe form of bone involvement. Monitoring of patients for bone involvement is recommended. Enzyme replacement therapy for Gaucher disease needs to be started even if visceral disease is absent if the patient has evidence of bone involvement in the form of avascular necrosis.⁷ Prospective studies have shown that enzyme replacement therapy reduces the incidence of osteonecrosis.²³

FOLLOW-UP MANAGEMENT OF OUR PATIENT

Avascular necrosis in Gaucher disease more typically involves the hips and shoulders. In the case of our patient, the talus was the most affected bone. Other contributing factors may have been the use of steroids as a premedication (often unnecessary) for her enzyme replacement therapy, as well as the coexistent scleroderma.²⁴

The decision to switch from imiglucerase, to which she developed antibodies, to taliglucerase was made in the hope that the antibodies would not cross-react. After she started taliglucerase, her complete blood count values improved steadily. She did not require transfusions for more than 1 year. Her platelet count rose to 90 × 10⁹/L, and her hemoglobin to 12 g/dL.

A multidisciplinary approach with regular monitoring and appropriate initiation of therapy is necessary to prevent disastrous complications in patients with Gaucher disease.

This has been a boom year for Parkinson disease, with the US Food and Drug Administration (FDA) approving two new therapies, and with others in the pipeline.

This article details clinical signs of Parkinson disease, discusses functional imaging, provides an update on current thinking on disease pathogenesis, and gives an overview of managing parkinsonian symptoms and dyskinesias.

DIAGNOSIS REMAINS CLINICAL

Although a better understanding of Parkinson disease has been gained in recent years, with the recognition of several premotor features and potential biomarkers, its diagnosis is still primarily based on clinical motor findings. The four cardinal motor features have the mnemonic TRAP:

• Tremor at rest can be subtle, involving just the thumb, best observed when the patient is sitting with the hand resting on the lap; or it can be obvious, involving the entire hand, arm, feet, lips, and chin.
• Rigidity can be felt rather than seen, by slowly passively rotating the patient’s wrist or elbow and feeling resistance. The right and left sides often differ.
• Akinesia or bradykinesia (slowness or lack of movement) can be observed by having the patient walk down a hallway. One may observe reduced arm swing and hesitation in initiating movement.
• Postural instability usually develops later rather than sooner in the disease progression. The patient may need to hold onto someone to maintain balance when getting up or walking.

At least two features must be present to make the diagnosis of parkinsonism. One feature must be tremor or rigidity.

The TRAP features of Parkinson disease:
• Tremor
• Rigidity
• Akinesia
• Postural instabilityAlthough the criteria for parkinsonism appear simple, the diagnosis of Parkinson disease is not always clear-cut. For example, shaking can be secondary to a dopamine receptor-blocking medication, to anxiety, or to essential tremor; rigidity and slowness may be due to arthritis; and postural instability can result from a neuropathy. Moreover, other neurodegenerative parkinsonian disorders may respond to levodopa (at least initially) and may present with levodopa-induced dyskinesias. Robust response to levodopa and the occurrence of dyskinesias are two additional features that strongly suggest the diagnosis of Parkinson disease.

Supporting parkinsonian features include stooped posture, masked facies, micrographia (small handwriting), drooling, speech changes (eg, hypophonia or soft speech, stuttering, slurring, monotonic speech), and a shuffling, festinating gait (quick short steps as if falling forward).

PARKINSON MIMICS

Parkinsonism is a broader term than Parkinson disease or idiopathic Parkinson disease. It is characterized by akinetic rigidity and impaired motor activity that leads to reduced function and falls; behavioral changes also may occur.

In the United States, Parkinson disease is the most common cause of parkinsonism. Other nonneurodegenerative causes are drug-induced parkinsonism (due to dopamine receptor antagonists such as antipsychotic or antiemetic drugs), stroke (in the basal ganglia or frontal lobe), and normal-pressure hydrocephalus (causing lower-body parkinsonism). Mimics of parkinsonism include essential tremor and psychogenic parkinsonism.

Parkinsonism can also be caused by Parkinson-plus disorders, ie, neurodegenerative conditions characterized by parkinsonism along with additional signs and symptoms, as listed below. Parkinson-plus disorders include progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, and Lewy body disease.

Clinical features that suggest a diagnosis other than Parkinson disease include¹:

• Poor response to adequate dosages of levodopa
• Early onset of postural instability and falls
• Axial rigidity (eg, stiff neck) more than appendicular rigidity
• Early dementia
• Supranuclear gaze palsy
• Unusual movements besides tremor, eg, limb dystonia, myoclonus, limb levitation or alien limb syndrome
• Profound autonomic dysfunction
• Psychotic symptoms before taking levodopa or dopaminergic medication.

The precise diagnosis of Parkinson-plus disorders is not critical, as the treatment is generally the same for all of them: ie, levodopa (if it shows some efficacy and is well tolerated), with additional symptomatic treatment for features such as depression, cognitive impairment, and autonomic dysfunction, and supportive therapy including physical, occupational, speech, and swallowing therapy.

IMAGING MAY ASSIST IN THE DIAGNOSIS

Dopamine transporter single-photon emission computed tomography (SPECT) is a functional imaging technique that supposedly reflects dopamine uptake by surviving presynaptic dopaminergic neurons in the striate bodies of the basal ganglia. Normal uptake shows distinct cashew-shaped enhancement bilaterally. In Parkinson disease, the enhanced areas are smaller and asymmetric, first with diminution of the tail (representing the putamen), then later involving the head (representing the caudate) along with the other striate bodies (Figure 1).

Dopamine transporter SPECT does not distinguish one neurodegenerative parkinsonian disorder from another. Therefore, it should not be used to distinguish Parkinson disease from other Parkinson-plus syndromes. But it does distinguish neurodegenerative parkinsonian disorders from nonneurodegenerative conditions and mimics, which have a normal result on dopamine transporter SPECT (Table 1).

SLOWING DISEASE PROGRESSION

Current treatments for Parkinson disease can significantly improve symptoms but, unfortunately, do not cure the disease or slow its progression. Testing whether agents modify the disease course is particularly difficult with Parkinson disease, because it affects individuals differently, has a wide spectrum of symptoms, has a long time course, and lacks definitive markers to monitor progression. Some agents have shown promise:

Caffeine. People who drink coffee are less likely to develop Parkinson disease, with the risk declining with the number of cups per day.² For those who have the disease, drinking coffee is associated with reduced symptoms.

Exercise improves Parkinson disease and may prevent it, and some studies suggest that it can delay its progression.³ Exercise has been shown in an animal model to reduce the vulnerability of dopamine neurons to the toxic agent 6-hydroxydopamine.⁴ Functional magnetic resonance imaging studies have shown blood flow patterns before and after exercise that are similar to those seen in patients with and without Parkinson medication.³

Rasagiline, a monoamine oxidase B (MAO-B) inhibitor used for symptomatic treatment of Parkinson disease, had conflicting results in a neuroprotective clinical trial. Patients who received rasagiline 1 mg daily—but not those who received 2 mg daily—at the beginning of the trial had better Parkinson motor scores compared with patients who received rasagiline 9 months later.⁵

Inosine is a urate precursor that elevates urate levels in serum and the central nervous system. For unknown reasons, patients with Parkinson disease tend to have a low uric acid level, and higher levels are associated with milder disease. It is hoped that raising the uric acid level to a “pre-gout level” may slow the progression of Parkinson disease.

Isradipine, a calcium channel blocker, was found in an epidemiologic study of elderly patients to be associated with reduced likelihood of developing Parkinson disease.⁶ The drug is now undergoing clinical trials.

Smoking. Although cigarette smokers have long been recognized as having a very low risk of developing Parkinson disease, smoking is not recommended.

Agents found ineffective. Agents that have been tested and found ineffective in modifying the course of Parkinson disease include vitamin E, coenzyme Q10, riluzole, GPI-1485, pramipexole, cogane, CEP-1347, TCH-346, and creatine.

NOT JUST DOPAMINE—OR TREMORS

Dopamine deficiency is central to the current understanding of the pathogenesis of Parkinson disease and the focus of treatment efforts, but if dopamine deficiency were the only problem, replacing it should completely ameliorate all parkinsonian features. Other neurotransmitters also play roles: norepinephrine is implicated in orthostatic symptoms and apathy, acetylcholine in cognitive behaviors, glutamate in dyskinesias, and serotonin in depression, anxiety, and sleep abnormalities.

The most recognized area of involvement in the brain has traditionally been the substantia nigra in the midbrain. However, current thinking is that the disease starts lower in the caudal area of the brainstem (along with the olfactory tubercle), moves through the pons to the midbrain, then spreads across the cerebrum with extensive neocortical involvement.

Early premotor indicators are now recognized to occur 15 to 20 years before a tremor appears. The first signs are often hyposmia (diminished sense of smell, reflecting involvement of the olfactory tubercle) and constipation (reflecting involvement of the medulla and the vagus nucleus). With pons involvement, the patient can develop rapid eye movement sleep behavior disorder, depression, or anxiety. Only then does the disease spread to the midbrain and cause resting tremor, rigidity, and bradykinesia.⁷

Identifying the preclinical stages and starting disease-modifying treatments before the onset of motor symptoms may one day prove important, but at this point, the premotor symptoms (anosmia, constipation, depression) are too nonspecific to be useful, and such treatments have not yet been identified.

TREATMENT: LEVODOPA STILL PRIMARY

When gait problems develop, treatment should be startedWhen to start drug treatment depends primarily on how much the symptoms bother the patient. Regardless of the clinician’s (or patient’s) belief in the benefits of delaying symptomatic treatment, it is universally considered necessary to start medication when gait problems develop because of the danger of a fall and resulting disability.

Carbidopa-levodopa combination therapy remains the most effective treatment; if it is not effective, another diagnosis may need to be considered. Carbidopa-levodopa improves tremor, rigidity, and bradykinesia, particularly in the early stages of Parkinson disease. It is well tolerated, has rapid onset, reduces the risk of death, and is the least expensive of the medications for Parkinson disease.

Immediate-release and continued-release formulations are available, as well as one that dissolves rapidly on the tongue and can be taken without water. An oral extended-release carbidopa-levodopa formulation (Rytary) was approved by the FDA in January 2015. Tablets are filled with drug-containing microbeads that dissolve at different rates to achieve therapeutic levodopa levels as quickly as the immediate-release formulation and maintain them for an extended time.⁸

The development of dyskinesias is the major psychological drawback of levodopa, occurring in 80% of patients after 5 to 10 years of treatment. Although many patients fear this side effect, most patients who develop it find it preferable to the rigidity and bradykinesia of Parkinson disease. In most cases, bothersome dyskinesias can be controlled by adjusting medications.^9,10

Dopamine agonists include pramipexole, ropinirole, and rotigotine. They are available in generic form as three-times-daily dosing; once-daily dosing is also available, but not as a generic formulation. Dopamine agonists have the advantage of potentially improving depression and delaying the onset of dyskinesias.

However, dopamine agonists have a number of disadvantages compared with levodopa: they have a longer titration period, are less effective, and are less well tolerated, especially in the elderly. Side effects occur more frequently than with levodopa and include general and peripheral edema, hallucinations, nausea, lightheadedness, and sleepiness.^11,12 These drugs are also associated with “sleep attacks” (sudden falling asleep while active, such as while driving or eating) and with compulsive and impulsive behaviors such as hypersexuality, buying, binge eating, and gambling. Although these behaviors occur in fewer than 10% of patients, they can be devastating, leading to marital, financial, and legal problems. A bothersome clinical state termed dopamine agonist withdrawal syndrome is characterized by anxiety, depression, jitteriness, and palpitations when dopamine agonists are tapered or discontinued because of a side effect.¹³

MAO-B inhibitors delay the breakdown of dopamine, allowing it to “stay” in the brain for a longer period of time. Rasagiline for early monotherapy has the advantages of once-daily dosing, no titration, and excellent tolerability, even in the elderly. Potential drug interactions should be considered when using this drug. Early warnings about interactions with tyramine-rich foods were lifted after trials showed that this was not a problem.¹⁴

Amantadine is an N-methyl-d-aspartate (NMDA) receptor antagonist often used in early Parkinson disease and for treatment of dyskinesias and fatigue. It is the only drug that is intrinsically antidyskinetic and also improves Parkinson symptoms.¹⁵ Side effects include leg swelling, livedo reticularis, and neuropsychiatric and anticholinergic effects.

Anticholinergic agents (eg, trihexyphenidyl) improve tremor but are not as useful for bradykinesia or rigidity, and often have anticholinergic effects such as mental dullness, dry mouth, dry eye, and urinary hesitancy, especially in the elderly, so they have a limited role in Parkinson treatment.

MOTOR COMPLICATIONS: FLUCTUATIONS AND DYSKINESIAS

Motor fluctuations are changes between the akinetic and mobile phases of Parkinson disease, or the off-periods and on-periods of drug treatment. A patient who is “off” is generally rigid and feels that the medication is not working. A patient who is “on” feels loose and mobile and that the medication is working. Variants of motor fluctuations include:

• End-of-dose deterioration
• Delayed onset of response (more than half an hour after taking medication)
• Drug-resistant offs—medication has become ineffective
• Random oscillation—on-off phenomenon
• Freezing—unpredictable inability to start or finish a movement.

Dyskinesias are abnormal involuntary movements such as writhing and twisting. They are associated with dopaminergic therapy at peak dose, when the drug starts to turn on or wear off (termed diphasic dyskinesias).¹⁶

The storage hypothesis provides a plausible explanation for the development of motor complications as the disease progresses. Although the half-life of levodopa is only 60 to 90 minutes, it is effective in early disease when given three times a day. It is believed that at this stage of the disease, enough dopaminergic neurons survive to “store” dopamine and release it as needed. As the disease progresses and dopaminergic neurons die, storage capacity diminishes, and the clinical effect slowly starts to approximate the pharmacokinetic profile of the drug. Upon taking the medication, the patient gets a surge of drug, causing dyskinesias, followed later by rigidity as the effect wears off since there are fewer surviving dopaminergic cells to store dopamine.

MANAGING DYSKINESIAS

Patients with dyskinesias should first be asked if they are bothered by them; not all patients are troubled by dyskinesias. If the movements only bother others (eg, family members), then education is often the only treatment needed. If the patient is uncomfortable, the following measures can be tried:

• Taking lower, more frequent doses of levodopa (however, risk of wearing off becomes a problem)
• Adding a dopamine agonist or MAO-B inhibitor while lowering the levodopa dose (however, MAO-B inhibitors pose a risk of side effects in elderly patients)
• Adding clozapine (periodic laboratory testing is required to monitor blood levels and liver and kidney function)
• Adding amantadine (however, this poses a risk of cognitive side effects).

Deep-brain-stimulation surgery is appropriate for select patients who are generally physically healthy, cognitively intact, and emotionally stable, with a strong family support system, but who are bothered by symptoms of parkinsonism (such as tremors), motor fluctuations, or dyskinesias.¹⁷

Infusion pump. In January 2015, the FDA approved a new system that continuously delivers levodopa-carbidopa in a 4:1 ratio in gel suspension for 16 hours directly into the small intestine, minimizing motor fluctuations. The patient changes the cartridge daily and turns it off at bedtime.

*Dr. Fernandez has received research support from AbbVie, Acadia, Auspex, Biotie Therapies, Civitas, Kyowa/ProStrakan, Michael J. Fox Foundation, Movement Disorders Society, NIH/NINDS, Parkinson Study Group, Rhythm, Synosia, and Teva. He also has received honoraria from Carling Communications, International Parkinson and Movement Disorders Society, The Ohio State University, and PRIME Education, Inc as a speaker in CME events. He has received honoraria from Biogen, GE Health Care, Lundbeck, Merz Pharmaceuticals, and Pfizer as a consultant. He has received royalty payments from Demos Publishing for serving as a book author/editor. Cleveland Clinic has contracts with AbbVie and Merz Pharmaceuticals for Dr. Fernandez’s role as a member of the Global Steering Committee for LCIG studies and as a consultant or speaker, and as Head Principal Investigator for the Xeomin Registry Study. Dr. Fernandez has received a stipend from International Parkinson and Movement Disorders Society for serving as medical editor of the Movement Disorders Society website.
 

This has been a boom year for Parkinson disease, with the US Food and Drug Administration (FDA) approving two new therapies, and with others in the pipeline.

This article details clinical signs of Parkinson disease, discusses functional imaging, provides an update on current thinking on disease pathogenesis, and gives an overview of managing parkinsonian symptoms and dyskinesias.

DIAGNOSIS REMAINS CLINICAL

Although a better understanding of Parkinson disease has been gained in recent years, with the recognition of several premotor features and potential biomarkers, its diagnosis is still primarily based on clinical motor findings. The four cardinal motor features have the mnemonic TRAP:

• Tremor at rest can be subtle, involving just the thumb, best observed when the patient is sitting with the hand resting on the lap; or it can be obvious, involving the entire hand, arm, feet, lips, and chin.
• Rigidity can be felt rather than seen, by slowly passively rotating the patient’s wrist or elbow and feeling resistance. The right and left sides often differ.
• Akinesia or bradykinesia (slowness or lack of movement) can be observed by having the patient walk down a hallway. One may observe reduced arm swing and hesitation in initiating movement.
• Postural instability usually develops later rather than sooner in the disease progression. The patient may need to hold onto someone to maintain balance when getting up or walking.

At least two features must be present to make the diagnosis of parkinsonism. One feature must be tremor or rigidity.

The TRAP features of Parkinson disease:
• Tremor
• Rigidity
• Akinesia
• Postural instabilityAlthough the criteria for parkinsonism appear simple, the diagnosis of Parkinson disease is not always clear-cut. For example, shaking can be secondary to a dopamine receptor-blocking medication, to anxiety, or to essential tremor; rigidity and slowness may be due to arthritis; and postural instability can result from a neuropathy. Moreover, other neurodegenerative parkinsonian disorders may respond to levodopa (at least initially) and may present with levodopa-induced dyskinesias. Robust response to levodopa and the occurrence of dyskinesias are two additional features that strongly suggest the diagnosis of Parkinson disease.

Supporting parkinsonian features include stooped posture, masked facies, micrographia (small handwriting), drooling, speech changes (eg, hypophonia or soft speech, stuttering, slurring, monotonic speech), and a shuffling, festinating gait (quick short steps as if falling forward).

PARKINSON MIMICS

Parkinsonism is a broader term than Parkinson disease or idiopathic Parkinson disease. It is characterized by akinetic rigidity and impaired motor activity that leads to reduced function and falls; behavioral changes also may occur.

In the United States, Parkinson disease is the most common cause of parkinsonism. Other nonneurodegenerative causes are drug-induced parkinsonism (due to dopamine receptor antagonists such as antipsychotic or antiemetic drugs), stroke (in the basal ganglia or frontal lobe), and normal-pressure hydrocephalus (causing lower-body parkinsonism). Mimics of parkinsonism include essential tremor and psychogenic parkinsonism.

Parkinsonism can also be caused by Parkinson-plus disorders, ie, neurodegenerative conditions characterized by parkinsonism along with additional signs and symptoms, as listed below. Parkinson-plus disorders include progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, and Lewy body disease.

Clinical features that suggest a diagnosis other than Parkinson disease include¹:

• Poor response to adequate dosages of levodopa
• Early onset of postural instability and falls
• Axial rigidity (eg, stiff neck) more than appendicular rigidity
• Early dementia
• Supranuclear gaze palsy
• Unusual movements besides tremor, eg, limb dystonia, myoclonus, limb levitation or alien limb syndrome
• Profound autonomic dysfunction
• Psychotic symptoms before taking levodopa or dopaminergic medication.

The precise diagnosis of Parkinson-plus disorders is not critical, as the treatment is generally the same for all of them: ie, levodopa (if it shows some efficacy and is well tolerated), with additional symptomatic treatment for features such as depression, cognitive impairment, and autonomic dysfunction, and supportive therapy including physical, occupational, speech, and swallowing therapy.

IMAGING MAY ASSIST IN THE DIAGNOSIS

Dopamine transporter single-photon emission computed tomography (SPECT) is a functional imaging technique that supposedly reflects dopamine uptake by surviving presynaptic dopaminergic neurons in the striate bodies of the basal ganglia. Normal uptake shows distinct cashew-shaped enhancement bilaterally. In Parkinson disease, the enhanced areas are smaller and asymmetric, first with diminution of the tail (representing the putamen), then later involving the head (representing the caudate) along with the other striate bodies (Figure 1).

Dopamine transporter SPECT does not distinguish one neurodegenerative parkinsonian disorder from another. Therefore, it should not be used to distinguish Parkinson disease from other Parkinson-plus syndromes. But it does distinguish neurodegenerative parkinsonian disorders from nonneurodegenerative conditions and mimics, which have a normal result on dopamine transporter SPECT (Table 1).

SLOWING DISEASE PROGRESSION

Current treatments for Parkinson disease can significantly improve symptoms but, unfortunately, do not cure the disease or slow its progression. Testing whether agents modify the disease course is particularly difficult with Parkinson disease, because it affects individuals differently, has a wide spectrum of symptoms, has a long time course, and lacks definitive markers to monitor progression. Some agents have shown promise:

Caffeine. People who drink coffee are less likely to develop Parkinson disease, with the risk declining with the number of cups per day.² For those who have the disease, drinking coffee is associated with reduced symptoms.

Exercise improves Parkinson disease and may prevent it, and some studies suggest that it can delay its progression.³ Exercise has been shown in an animal model to reduce the vulnerability of dopamine neurons to the toxic agent 6-hydroxydopamine.⁴ Functional magnetic resonance imaging studies have shown blood flow patterns before and after exercise that are similar to those seen in patients with and without Parkinson medication.³

Rasagiline, a monoamine oxidase B (MAO-B) inhibitor used for symptomatic treatment of Parkinson disease, had conflicting results in a neuroprotective clinical trial. Patients who received rasagiline 1 mg daily—but not those who received 2 mg daily—at the beginning of the trial had better Parkinson motor scores compared with patients who received rasagiline 9 months later.⁵

Inosine is a urate precursor that elevates urate levels in serum and the central nervous system. For unknown reasons, patients with Parkinson disease tend to have a low uric acid level, and higher levels are associated with milder disease. It is hoped that raising the uric acid level to a “pre-gout level” may slow the progression of Parkinson disease.

Isradipine, a calcium channel blocker, was found in an epidemiologic study of elderly patients to be associated with reduced likelihood of developing Parkinson disease.⁶ The drug is now undergoing clinical trials.

Smoking. Although cigarette smokers have long been recognized as having a very low risk of developing Parkinson disease, smoking is not recommended.

Agents found ineffective. Agents that have been tested and found ineffective in modifying the course of Parkinson disease include vitamin E, coenzyme Q10, riluzole, GPI-1485, pramipexole, cogane, CEP-1347, TCH-346, and creatine.

NOT JUST DOPAMINE—OR TREMORS

Dopamine deficiency is central to the current understanding of the pathogenesis of Parkinson disease and the focus of treatment efforts, but if dopamine deficiency were the only problem, replacing it should completely ameliorate all parkinsonian features. Other neurotransmitters also play roles: norepinephrine is implicated in orthostatic symptoms and apathy, acetylcholine in cognitive behaviors, glutamate in dyskinesias, and serotonin in depression, anxiety, and sleep abnormalities.

The most recognized area of involvement in the brain has traditionally been the substantia nigra in the midbrain. However, current thinking is that the disease starts lower in the caudal area of the brainstem (along with the olfactory tubercle), moves through the pons to the midbrain, then spreads across the cerebrum with extensive neocortical involvement.

Early premotor indicators are now recognized to occur 15 to 20 years before a tremor appears. The first signs are often hyposmia (diminished sense of smell, reflecting involvement of the olfactory tubercle) and constipation (reflecting involvement of the medulla and the vagus nucleus). With pons involvement, the patient can develop rapid eye movement sleep behavior disorder, depression, or anxiety. Only then does the disease spread to the midbrain and cause resting tremor, rigidity, and bradykinesia.⁷

Identifying the preclinical stages and starting disease-modifying treatments before the onset of motor symptoms may one day prove important, but at this point, the premotor symptoms (anosmia, constipation, depression) are too nonspecific to be useful, and such treatments have not yet been identified.

TREATMENT: LEVODOPA STILL PRIMARY

When gait problems develop, treatment should be startedWhen to start drug treatment depends primarily on how much the symptoms bother the patient. Regardless of the clinician’s (or patient’s) belief in the benefits of delaying symptomatic treatment, it is universally considered necessary to start medication when gait problems develop because of the danger of a fall and resulting disability.

Carbidopa-levodopa combination therapy remains the most effective treatment; if it is not effective, another diagnosis may need to be considered. Carbidopa-levodopa improves tremor, rigidity, and bradykinesia, particularly in the early stages of Parkinson disease. It is well tolerated, has rapid onset, reduces the risk of death, and is the least expensive of the medications for Parkinson disease.

Immediate-release and continued-release formulations are available, as well as one that dissolves rapidly on the tongue and can be taken without water. An oral extended-release carbidopa-levodopa formulation (Rytary) was approved by the FDA in January 2015. Tablets are filled with drug-containing microbeads that dissolve at different rates to achieve therapeutic levodopa levels as quickly as the immediate-release formulation and maintain them for an extended time.⁸

The development of dyskinesias is the major psychological drawback of levodopa, occurring in 80% of patients after 5 to 10 years of treatment. Although many patients fear this side effect, most patients who develop it find it preferable to the rigidity and bradykinesia of Parkinson disease. In most cases, bothersome dyskinesias can be controlled by adjusting medications.^9,10

Dopamine agonists include pramipexole, ropinirole, and rotigotine. They are available in generic form as three-times-daily dosing; once-daily dosing is also available, but not as a generic formulation. Dopamine agonists have the advantage of potentially improving depression and delaying the onset of dyskinesias.

However, dopamine agonists have a number of disadvantages compared with levodopa: they have a longer titration period, are less effective, and are less well tolerated, especially in the elderly. Side effects occur more frequently than with levodopa and include general and peripheral edema, hallucinations, nausea, lightheadedness, and sleepiness.^11,12 These drugs are also associated with “sleep attacks” (sudden falling asleep while active, such as while driving or eating) and with compulsive and impulsive behaviors such as hypersexuality, buying, binge eating, and gambling. Although these behaviors occur in fewer than 10% of patients, they can be devastating, leading to marital, financial, and legal problems. A bothersome clinical state termed dopamine agonist withdrawal syndrome is characterized by anxiety, depression, jitteriness, and palpitations when dopamine agonists are tapered or discontinued because of a side effect.¹³

MAO-B inhibitors delay the breakdown of dopamine, allowing it to “stay” in the brain for a longer period of time. Rasagiline for early monotherapy has the advantages of once-daily dosing, no titration, and excellent tolerability, even in the elderly. Potential drug interactions should be considered when using this drug. Early warnings about interactions with tyramine-rich foods were lifted after trials showed that this was not a problem.¹⁴

Amantadine is an N-methyl-d-aspartate (NMDA) receptor antagonist often used in early Parkinson disease and for treatment of dyskinesias and fatigue. It is the only drug that is intrinsically antidyskinetic and also improves Parkinson symptoms.¹⁵ Side effects include leg swelling, livedo reticularis, and neuropsychiatric and anticholinergic effects.

Anticholinergic agents (eg, trihexyphenidyl) improve tremor but are not as useful for bradykinesia or rigidity, and often have anticholinergic effects such as mental dullness, dry mouth, dry eye, and urinary hesitancy, especially in the elderly, so they have a limited role in Parkinson treatment.

MOTOR COMPLICATIONS: FLUCTUATIONS AND DYSKINESIAS

Motor fluctuations are changes between the akinetic and mobile phases of Parkinson disease, or the off-periods and on-periods of drug treatment. A patient who is “off” is generally rigid and feels that the medication is not working. A patient who is “on” feels loose and mobile and that the medication is working. Variants of motor fluctuations include:

• End-of-dose deterioration
• Delayed onset of response (more than half an hour after taking medication)
• Drug-resistant offs—medication has become ineffective
• Random oscillation—on-off phenomenon
• Freezing—unpredictable inability to start or finish a movement.

Dyskinesias are abnormal involuntary movements such as writhing and twisting. They are associated with dopaminergic therapy at peak dose, when the drug starts to turn on or wear off (termed diphasic dyskinesias).¹⁶

The storage hypothesis provides a plausible explanation for the development of motor complications as the disease progresses. Although the half-life of levodopa is only 60 to 90 minutes, it is effective in early disease when given three times a day. It is believed that at this stage of the disease, enough dopaminergic neurons survive to “store” dopamine and release it as needed. As the disease progresses and dopaminergic neurons die, storage capacity diminishes, and the clinical effect slowly starts to approximate the pharmacokinetic profile of the drug. Upon taking the medication, the patient gets a surge of drug, causing dyskinesias, followed later by rigidity as the effect wears off since there are fewer surviving dopaminergic cells to store dopamine.

MANAGING DYSKINESIAS

Patients with dyskinesias should first be asked if they are bothered by them; not all patients are troubled by dyskinesias. If the movements only bother others (eg, family members), then education is often the only treatment needed. If the patient is uncomfortable, the following measures can be tried:

• Taking lower, more frequent doses of levodopa (however, risk of wearing off becomes a problem)
• Adding a dopamine agonist or MAO-B inhibitor while lowering the levodopa dose (however, MAO-B inhibitors pose a risk of side effects in elderly patients)
• Adding clozapine (periodic laboratory testing is required to monitor blood levels and liver and kidney function)
• Adding amantadine (however, this poses a risk of cognitive side effects).

Deep-brain-stimulation surgery is appropriate for select patients who are generally physically healthy, cognitively intact, and emotionally stable, with a strong family support system, but who are bothered by symptoms of parkinsonism (such as tremors), motor fluctuations, or dyskinesias.¹⁷

Infusion pump. In January 2015, the FDA approved a new system that continuously delivers levodopa-carbidopa in a 4:1 ratio in gel suspension for 16 hours directly into the small intestine, minimizing motor fluctuations. The patient changes the cartridge daily and turns it off at bedtime.

*Dr. Fernandez has received research support from AbbVie, Acadia, Auspex, Biotie Therapies, Civitas, Kyowa/ProStrakan, Michael J. Fox Foundation, Movement Disorders Society, NIH/NINDS, Parkinson Study Group, Rhythm, Synosia, and Teva. He also has received honoraria from Carling Communications, International Parkinson and Movement Disorders Society, The Ohio State University, and PRIME Education, Inc as a speaker in CME events. He has received honoraria from Biogen, GE Health Care, Lundbeck, Merz Pharmaceuticals, and Pfizer as a consultant. He has received royalty payments from Demos Publishing for serving as a book author/editor. Cleveland Clinic has contracts with AbbVie and Merz Pharmaceuticals for Dr. Fernandez’s role as a member of the Global Steering Committee for LCIG studies and as a consultant or speaker, and as Head Principal Investigator for the Xeomin Registry Study. Dr. Fernandez has received a stipend from International Parkinson and Movement Disorders Society for serving as medical editor of the Movement Disorders Society website.
 

This has been a boom year for Parkinson disease, with the US Food and Drug Administration (FDA) approving two new therapies, and with others in the pipeline.

This article details clinical signs of Parkinson disease, discusses functional imaging, provides an update on current thinking on disease pathogenesis, and gives an overview of managing parkinsonian symptoms and dyskinesias.

DIAGNOSIS REMAINS CLINICAL

Although a better understanding of Parkinson disease has been gained in recent years, with the recognition of several premotor features and potential biomarkers, its diagnosis is still primarily based on clinical motor findings. The four cardinal motor features have the mnemonic TRAP:

• Tremor at rest can be subtle, involving just the thumb, best observed when the patient is sitting with the hand resting on the lap; or it can be obvious, involving the entire hand, arm, feet, lips, and chin.
• Rigidity can be felt rather than seen, by slowly passively rotating the patient’s wrist or elbow and feeling resistance. The right and left sides often differ.
• Akinesia or bradykinesia (slowness or lack of movement) can be observed by having the patient walk down a hallway. One may observe reduced arm swing and hesitation in initiating movement.
• Postural instability usually develops later rather than sooner in the disease progression. The patient may need to hold onto someone to maintain balance when getting up or walking.

At least two features must be present to make the diagnosis of parkinsonism. One feature must be tremor or rigidity.

The TRAP features of Parkinson disease:
• Tremor
• Rigidity
• Akinesia
• Postural instabilityAlthough the criteria for parkinsonism appear simple, the diagnosis of Parkinson disease is not always clear-cut. For example, shaking can be secondary to a dopamine receptor-blocking medication, to anxiety, or to essential tremor; rigidity and slowness may be due to arthritis; and postural instability can result from a neuropathy. Moreover, other neurodegenerative parkinsonian disorders may respond to levodopa (at least initially) and may present with levodopa-induced dyskinesias. Robust response to levodopa and the occurrence of dyskinesias are two additional features that strongly suggest the diagnosis of Parkinson disease.

Supporting parkinsonian features include stooped posture, masked facies, micrographia (small handwriting), drooling, speech changes (eg, hypophonia or soft speech, stuttering, slurring, monotonic speech), and a shuffling, festinating gait (quick short steps as if falling forward).

PARKINSON MIMICS

Parkinsonism is a broader term than Parkinson disease or idiopathic Parkinson disease. It is characterized by akinetic rigidity and impaired motor activity that leads to reduced function and falls; behavioral changes also may occur.

In the United States, Parkinson disease is the most common cause of parkinsonism. Other nonneurodegenerative causes are drug-induced parkinsonism (due to dopamine receptor antagonists such as antipsychotic or antiemetic drugs), stroke (in the basal ganglia or frontal lobe), and normal-pressure hydrocephalus (causing lower-body parkinsonism). Mimics of parkinsonism include essential tremor and psychogenic parkinsonism.

Parkinsonism can also be caused by Parkinson-plus disorders, ie, neurodegenerative conditions characterized by parkinsonism along with additional signs and symptoms, as listed below. Parkinson-plus disorders include progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, and Lewy body disease.

Clinical features that suggest a diagnosis other than Parkinson disease include¹:

• Poor response to adequate dosages of levodopa
• Early onset of postural instability and falls
• Axial rigidity (eg, stiff neck) more than appendicular rigidity
• Early dementia
• Supranuclear gaze palsy
• Unusual movements besides tremor, eg, limb dystonia, myoclonus, limb levitation or alien limb syndrome
• Profound autonomic dysfunction
• Psychotic symptoms before taking levodopa or dopaminergic medication.

The precise diagnosis of Parkinson-plus disorders is not critical, as the treatment is generally the same for all of them: ie, levodopa (if it shows some efficacy and is well tolerated), with additional symptomatic treatment for features such as depression, cognitive impairment, and autonomic dysfunction, and supportive therapy including physical, occupational, speech, and swallowing therapy.

IMAGING MAY ASSIST IN THE DIAGNOSIS

Dopamine transporter single-photon emission computed tomography (SPECT) is a functional imaging technique that supposedly reflects dopamine uptake by surviving presynaptic dopaminergic neurons in the striate bodies of the basal ganglia. Normal uptake shows distinct cashew-shaped enhancement bilaterally. In Parkinson disease, the enhanced areas are smaller and asymmetric, first with diminution of the tail (representing the putamen), then later involving the head (representing the caudate) along with the other striate bodies (Figure 1).

Dopamine transporter SPECT does not distinguish one neurodegenerative parkinsonian disorder from another. Therefore, it should not be used to distinguish Parkinson disease from other Parkinson-plus syndromes. But it does distinguish neurodegenerative parkinsonian disorders from nonneurodegenerative conditions and mimics, which have a normal result on dopamine transporter SPECT (Table 1).

SLOWING DISEASE PROGRESSION

Current treatments for Parkinson disease can significantly improve symptoms but, unfortunately, do not cure the disease or slow its progression. Testing whether agents modify the disease course is particularly difficult with Parkinson disease, because it affects individuals differently, has a wide spectrum of symptoms, has a long time course, and lacks definitive markers to monitor progression. Some agents have shown promise:

Caffeine. People who drink coffee are less likely to develop Parkinson disease, with the risk declining with the number of cups per day.² For those who have the disease, drinking coffee is associated with reduced symptoms.

Exercise improves Parkinson disease and may prevent it, and some studies suggest that it can delay its progression.³ Exercise has been shown in an animal model to reduce the vulnerability of dopamine neurons to the toxic agent 6-hydroxydopamine.⁴ Functional magnetic resonance imaging studies have shown blood flow patterns before and after exercise that are similar to those seen in patients with and without Parkinson medication.³

Rasagiline, a monoamine oxidase B (MAO-B) inhibitor used for symptomatic treatment of Parkinson disease, had conflicting results in a neuroprotective clinical trial. Patients who received rasagiline 1 mg daily—but not those who received 2 mg daily—at the beginning of the trial had better Parkinson motor scores compared with patients who received rasagiline 9 months later.⁵

Inosine is a urate precursor that elevates urate levels in serum and the central nervous system. For unknown reasons, patients with Parkinson disease tend to have a low uric acid level, and higher levels are associated with milder disease. It is hoped that raising the uric acid level to a “pre-gout level” may slow the progression of Parkinson disease.

Isradipine, a calcium channel blocker, was found in an epidemiologic study of elderly patients to be associated with reduced likelihood of developing Parkinson disease.⁶ The drug is now undergoing clinical trials.

Smoking. Although cigarette smokers have long been recognized as having a very low risk of developing Parkinson disease, smoking is not recommended.

Agents found ineffective. Agents that have been tested and found ineffective in modifying the course of Parkinson disease include vitamin E, coenzyme Q10, riluzole, GPI-1485, pramipexole, cogane, CEP-1347, TCH-346, and creatine.

NOT JUST DOPAMINE—OR TREMORS

Dopamine deficiency is central to the current understanding of the pathogenesis of Parkinson disease and the focus of treatment efforts, but if dopamine deficiency were the only problem, replacing it should completely ameliorate all parkinsonian features. Other neurotransmitters also play roles: norepinephrine is implicated in orthostatic symptoms and apathy, acetylcholine in cognitive behaviors, glutamate in dyskinesias, and serotonin in depression, anxiety, and sleep abnormalities.

The most recognized area of involvement in the brain has traditionally been the substantia nigra in the midbrain. However, current thinking is that the disease starts lower in the caudal area of the brainstem (along with the olfactory tubercle), moves through the pons to the midbrain, then spreads across the cerebrum with extensive neocortical involvement.

Early premotor indicators are now recognized to occur 15 to 20 years before a tremor appears. The first signs are often hyposmia (diminished sense of smell, reflecting involvement of the olfactory tubercle) and constipation (reflecting involvement of the medulla and the vagus nucleus). With pons involvement, the patient can develop rapid eye movement sleep behavior disorder, depression, or anxiety. Only then does the disease spread to the midbrain and cause resting tremor, rigidity, and bradykinesia.⁷

Identifying the preclinical stages and starting disease-modifying treatments before the onset of motor symptoms may one day prove important, but at this point, the premotor symptoms (anosmia, constipation, depression) are too nonspecific to be useful, and such treatments have not yet been identified.

TREATMENT: LEVODOPA STILL PRIMARY

When gait problems develop, treatment should be startedWhen to start drug treatment depends primarily on how much the symptoms bother the patient. Regardless of the clinician’s (or patient’s) belief in the benefits of delaying symptomatic treatment, it is universally considered necessary to start medication when gait problems develop because of the danger of a fall and resulting disability.

Carbidopa-levodopa combination therapy remains the most effective treatment; if it is not effective, another diagnosis may need to be considered. Carbidopa-levodopa improves tremor, rigidity, and bradykinesia, particularly in the early stages of Parkinson disease. It is well tolerated, has rapid onset, reduces the risk of death, and is the least expensive of the medications for Parkinson disease.

Immediate-release and continued-release formulations are available, as well as one that dissolves rapidly on the tongue and can be taken without water. An oral extended-release carbidopa-levodopa formulation (Rytary) was approved by the FDA in January 2015. Tablets are filled with drug-containing microbeads that dissolve at different rates to achieve therapeutic levodopa levels as quickly as the immediate-release formulation and maintain them for an extended time.⁸

The development of dyskinesias is the major psychological drawback of levodopa, occurring in 80% of patients after 5 to 10 years of treatment. Although many patients fear this side effect, most patients who develop it find it preferable to the rigidity and bradykinesia of Parkinson disease. In most cases, bothersome dyskinesias can be controlled by adjusting medications.^9,10

Dopamine agonists include pramipexole, ropinirole, and rotigotine. They are available in generic form as three-times-daily dosing; once-daily dosing is also available, but not as a generic formulation. Dopamine agonists have the advantage of potentially improving depression and delaying the onset of dyskinesias.

However, dopamine agonists have a number of disadvantages compared with levodopa: they have a longer titration period, are less effective, and are less well tolerated, especially in the elderly. Side effects occur more frequently than with levodopa and include general and peripheral edema, hallucinations, nausea, lightheadedness, and sleepiness.^11,12 These drugs are also associated with “sleep attacks” (sudden falling asleep while active, such as while driving or eating) and with compulsive and impulsive behaviors such as hypersexuality, buying, binge eating, and gambling. Although these behaviors occur in fewer than 10% of patients, they can be devastating, leading to marital, financial, and legal problems. A bothersome clinical state termed dopamine agonist withdrawal syndrome is characterized by anxiety, depression, jitteriness, and palpitations when dopamine agonists are tapered or discontinued because of a side effect.¹³

MAO-B inhibitors delay the breakdown of dopamine, allowing it to “stay” in the brain for a longer period of time. Rasagiline for early monotherapy has the advantages of once-daily dosing, no titration, and excellent tolerability, even in the elderly. Potential drug interactions should be considered when using this drug. Early warnings about interactions with tyramine-rich foods were lifted after trials showed that this was not a problem.¹⁴

Amantadine is an N-methyl-d-aspartate (NMDA) receptor antagonist often used in early Parkinson disease and for treatment of dyskinesias and fatigue. It is the only drug that is intrinsically antidyskinetic and also improves Parkinson symptoms.¹⁵ Side effects include leg swelling, livedo reticularis, and neuropsychiatric and anticholinergic effects.

Anticholinergic agents (eg, trihexyphenidyl) improve tremor but are not as useful for bradykinesia or rigidity, and often have anticholinergic effects such as mental dullness, dry mouth, dry eye, and urinary hesitancy, especially in the elderly, so they have a limited role in Parkinson treatment.

MOTOR COMPLICATIONS: FLUCTUATIONS AND DYSKINESIAS

Motor fluctuations are changes between the akinetic and mobile phases of Parkinson disease, or the off-periods and on-periods of drug treatment. A patient who is “off” is generally rigid and feels that the medication is not working. A patient who is “on” feels loose and mobile and that the medication is working. Variants of motor fluctuations include:

• End-of-dose deterioration
• Delayed onset of response (more than half an hour after taking medication)
• Drug-resistant offs—medication has become ineffective
• Random oscillation—on-off phenomenon
• Freezing—unpredictable inability to start or finish a movement.

Dyskinesias are abnormal involuntary movements such as writhing and twisting. They are associated with dopaminergic therapy at peak dose, when the drug starts to turn on or wear off (termed diphasic dyskinesias).¹⁶

The storage hypothesis provides a plausible explanation for the development of motor complications as the disease progresses. Although the half-life of levodopa is only 60 to 90 minutes, it is effective in early disease when given three times a day. It is believed that at this stage of the disease, enough dopaminergic neurons survive to “store” dopamine and release it as needed. As the disease progresses and dopaminergic neurons die, storage capacity diminishes, and the clinical effect slowly starts to approximate the pharmacokinetic profile of the drug. Upon taking the medication, the patient gets a surge of drug, causing dyskinesias, followed later by rigidity as the effect wears off since there are fewer surviving dopaminergic cells to store dopamine.

MANAGING DYSKINESIAS

Patients with dyskinesias should first be asked if they are bothered by them; not all patients are troubled by dyskinesias. If the movements only bother others (eg, family members), then education is often the only treatment needed. If the patient is uncomfortable, the following measures can be tried:

• Taking lower, more frequent doses of levodopa (however, risk of wearing off becomes a problem)
• Adding a dopamine agonist or MAO-B inhibitor while lowering the levodopa dose (however, MAO-B inhibitors pose a risk of side effects in elderly patients)
• Adding clozapine (periodic laboratory testing is required to monitor blood levels and liver and kidney function)
• Adding amantadine (however, this poses a risk of cognitive side effects).

Deep-brain-stimulation surgery is appropriate for select patients who are generally physically healthy, cognitively intact, and emotionally stable, with a strong family support system, but who are bothered by symptoms of parkinsonism (such as tremors), motor fluctuations, or dyskinesias.¹⁷

Infusion pump. In January 2015, the FDA approved a new system that continuously delivers levodopa-carbidopa in a 4:1 ratio in gel suspension for 16 hours directly into the small intestine, minimizing motor fluctuations. The patient changes the cartridge daily and turns it off at bedtime.

*Dr. Fernandez has received research support from AbbVie, Acadia, Auspex, Biotie Therapies, Civitas, Kyowa/ProStrakan, Michael J. Fox Foundation, Movement Disorders Society, NIH/NINDS, Parkinson Study Group, Rhythm, Synosia, and Teva. He also has received honoraria from Carling Communications, International Parkinson and Movement Disorders Society, The Ohio State University, and PRIME Education, Inc as a speaker in CME events. He has received honoraria from Biogen, GE Health Care, Lundbeck, Merz Pharmaceuticals, and Pfizer as a consultant. He has received royalty payments from Demos Publishing for serving as a book author/editor. Cleveland Clinic has contracts with AbbVie and Merz Pharmaceuticals for Dr. Fernandez’s role as a member of the Global Steering Committee for LCIG studies and as a consultant or speaker, and as Head Principal Investigator for the Xeomin Registry Study. Dr. Fernandez has received a stipend from International Parkinson and Movement Disorders Society for serving as medical editor of the Movement Disorders Society website.
 

Total hip arthroplasty (THA) is an excellent option for the treatment of osteoarthritis of the hip. In numerous studies, modern implants have shown survivorship of more than 90% at 10 years.^1,2 Polyethylene wear and subsequent osteolysis are major obstacles to the long-term success of THA.^3-5 Polyethylene wear particles are phagocytized by macrophages, inducing an inflammatory response that can ultimately lead to osteolysis of the bony architecture surrounding the bone–implant interface.^6,7 As modern implants often rely on direct implant-to-bone ingrowth to maintain fixation, wear at this junction can lead to aseptic component loosening and ultimately require revision surgery.^8-10 Osteolysis can be diagnosed with plain radiography or computed tomography (CT).¹¹ CT is more sensitive than plain radiography for the diagnosis of osteolysis and is better able to determine the size and location of osteolytic lesions.^12,13

Although diagnosis of osteolysis is well defined in the literature, what is more challenging is radiographic diagnosis of a loose acetabular component.¹¹ The most commonly described criteria for loosening are presence of a complete radiolucent line of more than 2 mm in width at the bone–implant interface and any progressive tilting or migration of the component.^14,15 CT-based criteria for component loosening remain largely undefined, though Egawa and colleagues¹⁶ showed that acetabular osteolysis involving less than 40% of the total cup surface is not associated with component loosening. Although a patient may show signs of osteolysis on postoperative imaging, this finding does not necessitate immediate revision surgery.¹⁷ Osteolysis may be monitored clinically and followed radiographically to determine when intervention is necessary.¹³

The goals of revision surgery are to eliminate the wear generator and bone-graft lytic lesions where needed to help maintain the bone–implant interface.¹⁷ The timing of such surgery is important, as the surgeon must balance the risk for gross component migration against the morbidity and mortality associated with acetabular component revision.¹⁸ This is in contrast to the settings of infection, periprosthetic fracture, recurrent instability, and component fracture/loosening, in which revision is urgently indicated and the case cannot be managed conservatively.

We conducted a study to determine the incidence of loose acetabular components without radiographic or clinical findings that would necessitate urgent revision THA. Radiographically silent loosening (RSL) was defined as an acetabular component that was loose at time of revision surgery but that did not show frank signs of loosening on either plain radiography or CT. Although these patients make up a small minority of the revision population, knowing the incidence of RSL can help raise surgeon awareness of this potentially dangerous situation. We further sought to determine whether patients with RSL present with different demographic characteristics or clinical symptoms than patients with stable acetabular components.

Materials and Methods

In this retrospective, case–control, institutional review board–approved study, we evaluated patients who had undergone revision THA and had preoperative plain radiographs and CT images. We identified patients by International Classification of Diseases, Ninth Revision (ICD‑9) codes (00.70, 00.71, 00.72, 00.73, 80.05, 81.53, 84.56, 84.57) and searched for those cases treated between 2000 and 2012.

Inclusion criteria were confirmed revision THA and confirmed plain radiography and CT of the THA performed before revision. When osteolysis was diagnosed by plain radiography, CT was ordered to determine the extent of bony lesions or to evaluate for eccentric head position or component malposition. Last, all patients included in the study had a detailed operative report clearly indicating acetabular component stability at time of revision. Acetabular component stability at time of surgery was determined according to the criteria defined by Berger and colleagues.¹⁹ Cups were evaluated for gross motion during both hip dislocation and during edge loading of the component after thorough scar and capsular débridement.

Patients who did not have CT performed before revision surgery were excluded from the study. These patients had been diagnosed by clinical history and/or plain radiography. Cases revised for periprosthetic infection or periprosthetic fracture were also excluded. Patients with metal-on-metal bearings were excluded, as were any cases revised from hemiarthroplasty to THA, as well as cases revised for recurrent dislocations or component malposition.

All plain radiographs and CT images were evaluated by the orthopedic surgeon who performed the revision and by a radiologist. Images were inspected for signs of gross component migration, tilting, and concentric lucency of the bone–implant interface. Patients with imaging that showed signs of component movement or migration (as seen by the attending surgeon or the radiologist) were excluded. Patients with radiographic evidence of femoral stem loosening were also excluded, as they had an indication to undergo revision arthroplasty. The remaining patients were then stratified into 2 groups: those with stable acetabular components at time of revision and those with loose acetabular components. Stable acetabular shells showed no gross motion of the implant with dislocation, edge loading with an impactor, or pulling with a Kocher clamp after débridement and screw removal.^15,19 The 2 groups were then compared with respect to age, sex, and most common presenting symptoms and diagnoses. Fischer exact test and Student t test were used to statistically compare the groups.

Results

Overall, 393 patients underwent revision arthroplasty for the diagnoses (ICD-9 codes) indicated (Figure). One hundred eighty-nine patients (48.1%) had CT performed before revision. Of these 189 patients, 85 were excluded for diagnoses that were evident on either plain radiography or CT, that necessitated urgent revision, or for procedures beyond the scope of the study (Table 1). CT showed a loose cup in 28 patients; 6 of these cups were also seen on CT. Thirteen patients were diagnosed with a loose femoral stem, 10 with a periprosthetic infection, and 8 with a periprosthetic fracture.

One hundred four patients (54 men, 50 women) met the study inclusion criteria. Mean age was 65.1 years. Of these 104 patients, 87 (83.7%) had a stable acetabular shell at time of revision surgery; the other 17 (16.3%) were diagnosed with RSL of the acetabular shell. Osteolysis was the most common diagnosis (89.4%) in the overall population, and pain was the most common complaint at time of presentation (66.6%). Lack of symptoms was the second most common presentation at time of revision (19.2%) (Table 2). Patients without symptoms underwent revision surgery because of concern about impending compromise of the bone–implant interface and progressive osteolysis.

The 2 groups (stable vs unstable acetabular shells) were not significantly different with respect to age (P = .961) or sex distribution (P = .185). All patients in the RSL group were diagnosed with osteolysis radiographically, and 15 (88%) of 17 patients presented with pain as the primary complaint, compared with only 54 (62%) of 87 patients in the group with stable shells. Patients with RSL were significantly more likely to present with pain as the primary complaint (P = .0487). Nineteen patients in the stable implant group and only 1 patient in the RSL group were asymptomatic, but this was not statistically significant (P = .185) when compared against all other diagnoses.

Discussion

We defined RSL as an acetabular component that was loose at time of revision surgery but that did not show frank signs of loosening on either plain radiography or CT. Patients with RSL and the surgeons who treat them are in a difficult position. In the setting of osteolysis, patients can be treated with serial radiographic imaging and clinical monitoring to determine if and when revision arthroplasty should be performed.¹⁷ However, given the complexity and risks associated with revision THA, surgeons should be aware that the acetabular shell may necessitate revision even if it does not appear to be frankly unstable on radiographic imaging.¹⁸

Of the 393 patients who underwent revision THA at our institution, 48.1% were evaluated with CT. Eighty-five of the 189 patients who underwent CT were diagnosed with radiographic loosening, or were diagnosed as needing urgent revision THA in the setting of loose components, periprosthetic infection, periprosthetic fracture, or catastrophic implant failure. Of the remaining 104 patients, 17 (16.3%) met the diagnosis of RSL of the acetabular component. The most common complaint was pain, and the most common diagnoses were osteolysis and polyethylene wear. Age and sex were not associated with increased likelihood of RSL.

Our study has several limitations. We defined the radiographic diagnosis of loose acetabular components as components showing frank migration, tilting, or a 2-mm concentric lucency on plain radiography or CT. Although these are common definitions of loose acetabular components, more sensitive radiographic measures have been described.¹⁶ We also excluded patients with recurrent dislocations and metal-on-metal prostheses, as these cases increase the metal artifact on CT and limit the ability to evaluate the bone–implant interface. Metal artifact remains an ongoing challenge to use of CT for post-THA imaging. However, tailored imaging protocols are helping to eliminate metal artifact. Bone scan was not used to evaluate for possible component loosening. Although sensitivity and specificity are about 67% and 76%, respectively,²⁰ Temmerman and colleagues²¹ also found poor intraobserver reliability (0.53) for bone scans in the setting of uncemented acetabular components. Last, our study did not evaluate the bony ingrowth patterns that corresponded to stable or unstable fixation and did not evaluate the volumetric size or anatomical location of the osteolytic lesions on CT. Careful assessment of these variables is clinically relevant when trying to determine if revision arthroplasty is warranted.

Although we used relatively simple radiographic criteria to define loose components, more sensitive and specific techniques have been described for both plain radiography and CT. Moore and colleagues²² described 5 radiographic signs of bony ingrowth; when 3 or more were present, sensitivity was 89.6% and specificity 76.9%. Mehin and colleagues²³ suggested that osteolysis involving more than 50% of the circumference of the shell on a standard pelvic radiograph might require revision arthroplasty. However, more recent studies have found that anteroposterior and lateral radiographs are less able to evaluate the anterior and posterior rims of the bone–implant interface, and it is this ingrowth area that may be the most crucial for stable osseointegration.^12,16

CT has expanded our ability to evaluate the bone–implant interface in 3 dimensions. Egawa and colleagues¹⁶ described using CT to evaluate the surface area involved with osteolysis and found that less than 40% involvement of the surface area generally corresponded to well-fixed components. Furthermore, they found that osteolysis generally creates lesions inferior and superior to the acetabular component and less often involves the anterior and posterior rims, which may be more important for stable fixation. The authors noted that volumetric analysis and CT were not as cost-effective as plain radiography and were more time- and skill-intensive.

Osteolysis itself remains a common indication for revision THA. However, the most appropriate procedure remains controversial. Mallory and colleagues²⁴ recommended explanting all acetabular shells in the setting of revision arthroplasty. They indicated that full assessment of the bony pelvis and any lytic defects was possible only with the wide exposure gained by acetabular component removal. More recent studies have begun to justify isolated component revision in the setting of well-fixed acetabular shells. Studies by Maloney and colleagues,¹⁰ Park and colleagues,¹⁵ and Beaulé and colleagues²⁵ have shown excellent outcomes with retention of well-fixed acetabular shells and removal of the wear generator in the setting of osteolysis. Haidukewych¹⁷ wrote that the goals in addressing osteolysis in revision THA are to eliminate the wear generator, débride osteolytic lesions, and restore bone stock. Surgeons should weigh the benefits of component retention and isolated liner exchange against the morbidity associated with explantation and preparation for implanting a new component. Good outcomes have been achieved with isolated component exchange, but surgeons should be aware that instability remains the most common complication after isolated liner exchange.⁸

The majority of our patients with RSL presented with complaints of pain and the diagnosis of osteolysis. One patient who had the diagnosis but was clinically asymptomatic was found to have a loose acetabular shell at time of revision surgery. Given the increased morbidity associated with acetabular component revision, this patient’s condition represents a dangerous combination of RSL and clinically asymptomatic component loosening. By raising awareness about RSL and its incidence, we should be able to increase our ability to detect RSL. A surgeon who detects RSL before gross migration or movement of the acetabular component may be better able to plan for revision arthroplasty before a catastrophic event that may necessitate a larger, more complex procedure. With the number of patients who require revision THA continuing to rise, surgeons should be aware of the incidence of RSL and the potential of RSL to affect patient care and potential surgical options.

Total hip arthroplasty (THA) is an excellent option for the treatment of osteoarthritis of the hip. In numerous studies, modern implants have shown survivorship of more than 90% at 10 years.^1,2 Polyethylene wear and subsequent osteolysis are major obstacles to the long-term success of THA.^3-5 Polyethylene wear particles are phagocytized by macrophages, inducing an inflammatory response that can ultimately lead to osteolysis of the bony architecture surrounding the bone–implant interface.^6,7 As modern implants often rely on direct implant-to-bone ingrowth to maintain fixation, wear at this junction can lead to aseptic component loosening and ultimately require revision surgery.^8-10 Osteolysis can be diagnosed with plain radiography or computed tomography (CT).¹¹ CT is more sensitive than plain radiography for the diagnosis of osteolysis and is better able to determine the size and location of osteolytic lesions.^12,13

Although diagnosis of osteolysis is well defined in the literature, what is more challenging is radiographic diagnosis of a loose acetabular component.¹¹ The most commonly described criteria for loosening are presence of a complete radiolucent line of more than 2 mm in width at the bone–implant interface and any progressive tilting or migration of the component.^14,15 CT-based criteria for component loosening remain largely undefined, though Egawa and colleagues¹⁶ showed that acetabular osteolysis involving less than 40% of the total cup surface is not associated with component loosening. Although a patient may show signs of osteolysis on postoperative imaging, this finding does not necessitate immediate revision surgery.¹⁷ Osteolysis may be monitored clinically and followed radiographically to determine when intervention is necessary.¹³

The goals of revision surgery are to eliminate the wear generator and bone-graft lytic lesions where needed to help maintain the bone–implant interface.¹⁷ The timing of such surgery is important, as the surgeon must balance the risk for gross component migration against the morbidity and mortality associated with acetabular component revision.¹⁸ This is in contrast to the settings of infection, periprosthetic fracture, recurrent instability, and component fracture/loosening, in which revision is urgently indicated and the case cannot be managed conservatively.

We conducted a study to determine the incidence of loose acetabular components without radiographic or clinical findings that would necessitate urgent revision THA. Radiographically silent loosening (RSL) was defined as an acetabular component that was loose at time of revision surgery but that did not show frank signs of loosening on either plain radiography or CT. Although these patients make up a small minority of the revision population, knowing the incidence of RSL can help raise surgeon awareness of this potentially dangerous situation. We further sought to determine whether patients with RSL present with different demographic characteristics or clinical symptoms than patients with stable acetabular components.

Materials and Methods

In this retrospective, case–control, institutional review board–approved study, we evaluated patients who had undergone revision THA and had preoperative plain radiographs and CT images. We identified patients by International Classification of Diseases, Ninth Revision (ICD‑9) codes (00.70, 00.71, 00.72, 00.73, 80.05, 81.53, 84.56, 84.57) and searched for those cases treated between 2000 and 2012.

Inclusion criteria were confirmed revision THA and confirmed plain radiography and CT of the THA performed before revision. When osteolysis was diagnosed by plain radiography, CT was ordered to determine the extent of bony lesions or to evaluate for eccentric head position or component malposition. Last, all patients included in the study had a detailed operative report clearly indicating acetabular component stability at time of revision. Acetabular component stability at time of surgery was determined according to the criteria defined by Berger and colleagues.¹⁹ Cups were evaluated for gross motion during both hip dislocation and during edge loading of the component after thorough scar and capsular débridement.

Patients who did not have CT performed before revision surgery were excluded from the study. These patients had been diagnosed by clinical history and/or plain radiography. Cases revised for periprosthetic infection or periprosthetic fracture were also excluded. Patients with metal-on-metal bearings were excluded, as were any cases revised from hemiarthroplasty to THA, as well as cases revised for recurrent dislocations or component malposition.

All plain radiographs and CT images were evaluated by the orthopedic surgeon who performed the revision and by a radiologist. Images were inspected for signs of gross component migration, tilting, and concentric lucency of the bone–implant interface. Patients with imaging that showed signs of component movement or migration (as seen by the attending surgeon or the radiologist) were excluded. Patients with radiographic evidence of femoral stem loosening were also excluded, as they had an indication to undergo revision arthroplasty. The remaining patients were then stratified into 2 groups: those with stable acetabular components at time of revision and those with loose acetabular components. Stable acetabular shells showed no gross motion of the implant with dislocation, edge loading with an impactor, or pulling with a Kocher clamp after débridement and screw removal.^15,19 The 2 groups were then compared with respect to age, sex, and most common presenting symptoms and diagnoses. Fischer exact test and Student t test were used to statistically compare the groups.

Results

Overall, 393 patients underwent revision arthroplasty for the diagnoses (ICD-9 codes) indicated (Figure). One hundred eighty-nine patients (48.1%) had CT performed before revision. Of these 189 patients, 85 were excluded for diagnoses that were evident on either plain radiography or CT, that necessitated urgent revision, or for procedures beyond the scope of the study (Table 1). CT showed a loose cup in 28 patients; 6 of these cups were also seen on CT. Thirteen patients were diagnosed with a loose femoral stem, 10 with a periprosthetic infection, and 8 with a periprosthetic fracture.

One hundred four patients (54 men, 50 women) met the study inclusion criteria. Mean age was 65.1 years. Of these 104 patients, 87 (83.7%) had a stable acetabular shell at time of revision surgery; the other 17 (16.3%) were diagnosed with RSL of the acetabular shell. Osteolysis was the most common diagnosis (89.4%) in the overall population, and pain was the most common complaint at time of presentation (66.6%). Lack of symptoms was the second most common presentation at time of revision (19.2%) (Table 2). Patients without symptoms underwent revision surgery because of concern about impending compromise of the bone–implant interface and progressive osteolysis.

The 2 groups (stable vs unstable acetabular shells) were not significantly different with respect to age (P = .961) or sex distribution (P = .185). All patients in the RSL group were diagnosed with osteolysis radiographically, and 15 (88%) of 17 patients presented with pain as the primary complaint, compared with only 54 (62%) of 87 patients in the group with stable shells. Patients with RSL were significantly more likely to present with pain as the primary complaint (P = .0487). Nineteen patients in the stable implant group and only 1 patient in the RSL group were asymptomatic, but this was not statistically significant (P = .185) when compared against all other diagnoses.

Discussion

We defined RSL as an acetabular component that was loose at time of revision surgery but that did not show frank signs of loosening on either plain radiography or CT. Patients with RSL and the surgeons who treat them are in a difficult position. In the setting of osteolysis, patients can be treated with serial radiographic imaging and clinical monitoring to determine if and when revision arthroplasty should be performed.¹⁷ However, given the complexity and risks associated with revision THA, surgeons should be aware that the acetabular shell may necessitate revision even if it does not appear to be frankly unstable on radiographic imaging.¹⁸

Of the 393 patients who underwent revision THA at our institution, 48.1% were evaluated with CT. Eighty-five of the 189 patients who underwent CT were diagnosed with radiographic loosening, or were diagnosed as needing urgent revision THA in the setting of loose components, periprosthetic infection, periprosthetic fracture, or catastrophic implant failure. Of the remaining 104 patients, 17 (16.3%) met the diagnosis of RSL of the acetabular component. The most common complaint was pain, and the most common diagnoses were osteolysis and polyethylene wear. Age and sex were not associated with increased likelihood of RSL.

Our study has several limitations. We defined the radiographic diagnosis of loose acetabular components as components showing frank migration, tilting, or a 2-mm concentric lucency on plain radiography or CT. Although these are common definitions of loose acetabular components, more sensitive radiographic measures have been described.¹⁶ We also excluded patients with recurrent dislocations and metal-on-metal prostheses, as these cases increase the metal artifact on CT and limit the ability to evaluate the bone–implant interface. Metal artifact remains an ongoing challenge to use of CT for post-THA imaging. However, tailored imaging protocols are helping to eliminate metal artifact. Bone scan was not used to evaluate for possible component loosening. Although sensitivity and specificity are about 67% and 76%, respectively,²⁰ Temmerman and colleagues²¹ also found poor intraobserver reliability (0.53) for bone scans in the setting of uncemented acetabular components. Last, our study did not evaluate the bony ingrowth patterns that corresponded to stable or unstable fixation and did not evaluate the volumetric size or anatomical location of the osteolytic lesions on CT. Careful assessment of these variables is clinically relevant when trying to determine if revision arthroplasty is warranted.

Although we used relatively simple radiographic criteria to define loose components, more sensitive and specific techniques have been described for both plain radiography and CT. Moore and colleagues²² described 5 radiographic signs of bony ingrowth; when 3 or more were present, sensitivity was 89.6% and specificity 76.9%. Mehin and colleagues²³ suggested that osteolysis involving more than 50% of the circumference of the shell on a standard pelvic radiograph might require revision arthroplasty. However, more recent studies have found that anteroposterior and lateral radiographs are less able to evaluate the anterior and posterior rims of the bone–implant interface, and it is this ingrowth area that may be the most crucial for stable osseointegration.^12,16

CT has expanded our ability to evaluate the bone–implant interface in 3 dimensions. Egawa and colleagues¹⁶ described using CT to evaluate the surface area involved with osteolysis and found that less than 40% involvement of the surface area generally corresponded to well-fixed components. Furthermore, they found that osteolysis generally creates lesions inferior and superior to the acetabular component and less often involves the anterior and posterior rims, which may be more important for stable fixation. The authors noted that volumetric analysis and CT were not as cost-effective as plain radiography and were more time- and skill-intensive.

Osteolysis itself remains a common indication for revision THA. However, the most appropriate procedure remains controversial. Mallory and colleagues²⁴ recommended explanting all acetabular shells in the setting of revision arthroplasty. They indicated that full assessment of the bony pelvis and any lytic defects was possible only with the wide exposure gained by acetabular component removal. More recent studies have begun to justify isolated component revision in the setting of well-fixed acetabular shells. Studies by Maloney and colleagues,¹⁰ Park and colleagues,¹⁵ and Beaulé and colleagues²⁵ have shown excellent outcomes with retention of well-fixed acetabular shells and removal of the wear generator in the setting of osteolysis. Haidukewych¹⁷ wrote that the goals in addressing osteolysis in revision THA are to eliminate the wear generator, débride osteolytic lesions, and restore bone stock. Surgeons should weigh the benefits of component retention and isolated liner exchange against the morbidity associated with explantation and preparation for implanting a new component. Good outcomes have been achieved with isolated component exchange, but surgeons should be aware that instability remains the most common complication after isolated liner exchange.⁸

The majority of our patients with RSL presented with complaints of pain and the diagnosis of osteolysis. One patient who had the diagnosis but was clinically asymptomatic was found to have a loose acetabular shell at time of revision surgery. Given the increased morbidity associated with acetabular component revision, this patient’s condition represents a dangerous combination of RSL and clinically asymptomatic component loosening. By raising awareness about RSL and its incidence, we should be able to increase our ability to detect RSL. A surgeon who detects RSL before gross migration or movement of the acetabular component may be better able to plan for revision arthroplasty before a catastrophic event that may necessitate a larger, more complex procedure. With the number of patients who require revision THA continuing to rise, surgeons should be aware of the incidence of RSL and the potential of RSL to affect patient care and potential surgical options.

Total hip arthroplasty (THA) is an excellent option for the treatment of osteoarthritis of the hip. In numerous studies, modern implants have shown survivorship of more than 90% at 10 years.^1,2 Polyethylene wear and subsequent osteolysis are major obstacles to the long-term success of THA.^3-5 Polyethylene wear particles are phagocytized by macrophages, inducing an inflammatory response that can ultimately lead to osteolysis of the bony architecture surrounding the bone–implant interface.^6,7 As modern implants often rely on direct implant-to-bone ingrowth to maintain fixation, wear at this junction can lead to aseptic component loosening and ultimately require revision surgery.^8-10 Osteolysis can be diagnosed with plain radiography or computed tomography (CT).¹¹ CT is more sensitive than plain radiography for the diagnosis of osteolysis and is better able to determine the size and location of osteolytic lesions.^12,13

Although diagnosis of osteolysis is well defined in the literature, what is more challenging is radiographic diagnosis of a loose acetabular component.¹¹ The most commonly described criteria for loosening are presence of a complete radiolucent line of more than 2 mm in width at the bone–implant interface and any progressive tilting or migration of the component.^14,15 CT-based criteria for component loosening remain largely undefined, though Egawa and colleagues¹⁶ showed that acetabular osteolysis involving less than 40% of the total cup surface is not associated with component loosening. Although a patient may show signs of osteolysis on postoperative imaging, this finding does not necessitate immediate revision surgery.¹⁷ Osteolysis may be monitored clinically and followed radiographically to determine when intervention is necessary.¹³

The goals of revision surgery are to eliminate the wear generator and bone-graft lytic lesions where needed to help maintain the bone–implant interface.¹⁷ The timing of such surgery is important, as the surgeon must balance the risk for gross component migration against the morbidity and mortality associated with acetabular component revision.¹⁸ This is in contrast to the settings of infection, periprosthetic fracture, recurrent instability, and component fracture/loosening, in which revision is urgently indicated and the case cannot be managed conservatively.

We conducted a study to determine the incidence of loose acetabular components without radiographic or clinical findings that would necessitate urgent revision THA. Radiographically silent loosening (RSL) was defined as an acetabular component that was loose at time of revision surgery but that did not show frank signs of loosening on either plain radiography or CT. Although these patients make up a small minority of the revision population, knowing the incidence of RSL can help raise surgeon awareness of this potentially dangerous situation. We further sought to determine whether patients with RSL present with different demographic characteristics or clinical symptoms than patients with stable acetabular components.

Materials and Methods

In this retrospective, case–control, institutional review board–approved study, we evaluated patients who had undergone revision THA and had preoperative plain radiographs and CT images. We identified patients by International Classification of Diseases, Ninth Revision (ICD‑9) codes (00.70, 00.71, 00.72, 00.73, 80.05, 81.53, 84.56, 84.57) and searched for those cases treated between 2000 and 2012.

Inclusion criteria were confirmed revision THA and confirmed plain radiography and CT of the THA performed before revision. When osteolysis was diagnosed by plain radiography, CT was ordered to determine the extent of bony lesions or to evaluate for eccentric head position or component malposition. Last, all patients included in the study had a detailed operative report clearly indicating acetabular component stability at time of revision. Acetabular component stability at time of surgery was determined according to the criteria defined by Berger and colleagues.¹⁹ Cups were evaluated for gross motion during both hip dislocation and during edge loading of the component after thorough scar and capsular débridement.

Patients who did not have CT performed before revision surgery were excluded from the study. These patients had been diagnosed by clinical history and/or plain radiography. Cases revised for periprosthetic infection or periprosthetic fracture were also excluded. Patients with metal-on-metal bearings were excluded, as were any cases revised from hemiarthroplasty to THA, as well as cases revised for recurrent dislocations or component malposition.

All plain radiographs and CT images were evaluated by the orthopedic surgeon who performed the revision and by a radiologist. Images were inspected for signs of gross component migration, tilting, and concentric lucency of the bone–implant interface. Patients with imaging that showed signs of component movement or migration (as seen by the attending surgeon or the radiologist) were excluded. Patients with radiographic evidence of femoral stem loosening were also excluded, as they had an indication to undergo revision arthroplasty. The remaining patients were then stratified into 2 groups: those with stable acetabular components at time of revision and those with loose acetabular components. Stable acetabular shells showed no gross motion of the implant with dislocation, edge loading with an impactor, or pulling with a Kocher clamp after débridement and screw removal.^15,19 The 2 groups were then compared with respect to age, sex, and most common presenting symptoms and diagnoses. Fischer exact test and Student t test were used to statistically compare the groups.

Results

Overall, 393 patients underwent revision arthroplasty for the diagnoses (ICD-9 codes) indicated (Figure). One hundred eighty-nine patients (48.1%) had CT performed before revision. Of these 189 patients, 85 were excluded for diagnoses that were evident on either plain radiography or CT, that necessitated urgent revision, or for procedures beyond the scope of the study (Table 1). CT showed a loose cup in 28 patients; 6 of these cups were also seen on CT. Thirteen patients were diagnosed with a loose femoral stem, 10 with a periprosthetic infection, and 8 with a periprosthetic fracture.

One hundred four patients (54 men, 50 women) met the study inclusion criteria. Mean age was 65.1 years. Of these 104 patients, 87 (83.7%) had a stable acetabular shell at time of revision surgery; the other 17 (16.3%) were diagnosed with RSL of the acetabular shell. Osteolysis was the most common diagnosis (89.4%) in the overall population, and pain was the most common complaint at time of presentation (66.6%). Lack of symptoms was the second most common presentation at time of revision (19.2%) (Table 2). Patients without symptoms underwent revision surgery because of concern about impending compromise of the bone–implant interface and progressive osteolysis.

The 2 groups (stable vs unstable acetabular shells) were not significantly different with respect to age (P = .961) or sex distribution (P = .185). All patients in the RSL group were diagnosed with osteolysis radiographically, and 15 (88%) of 17 patients presented with pain as the primary complaint, compared with only 54 (62%) of 87 patients in the group with stable shells. Patients with RSL were significantly more likely to present with pain as the primary complaint (P = .0487). Nineteen patients in the stable implant group and only 1 patient in the RSL group were asymptomatic, but this was not statistically significant (P = .185) when compared against all other diagnoses.

Discussion

We defined RSL as an acetabular component that was loose at time of revision surgery but that did not show frank signs of loosening on either plain radiography or CT. Patients with RSL and the surgeons who treat them are in a difficult position. In the setting of osteolysis, patients can be treated with serial radiographic imaging and clinical monitoring to determine if and when revision arthroplasty should be performed.¹⁷ However, given the complexity and risks associated with revision THA, surgeons should be aware that the acetabular shell may necessitate revision even if it does not appear to be frankly unstable on radiographic imaging.¹⁸

Of the 393 patients who underwent revision THA at our institution, 48.1% were evaluated with CT. Eighty-five of the 189 patients who underwent CT were diagnosed with radiographic loosening, or were diagnosed as needing urgent revision THA in the setting of loose components, periprosthetic infection, periprosthetic fracture, or catastrophic implant failure. Of the remaining 104 patients, 17 (16.3%) met the diagnosis of RSL of the acetabular component. The most common complaint was pain, and the most common diagnoses were osteolysis and polyethylene wear. Age and sex were not associated with increased likelihood of RSL.

Our study has several limitations. We defined the radiographic diagnosis of loose acetabular components as components showing frank migration, tilting, or a 2-mm concentric lucency on plain radiography or CT. Although these are common definitions of loose acetabular components, more sensitive radiographic measures have been described.¹⁶ We also excluded patients with recurrent dislocations and metal-on-metal prostheses, as these cases increase the metal artifact on CT and limit the ability to evaluate the bone–implant interface. Metal artifact remains an ongoing challenge to use of CT for post-THA imaging. However, tailored imaging protocols are helping to eliminate metal artifact. Bone scan was not used to evaluate for possible component loosening. Although sensitivity and specificity are about 67% and 76%, respectively,²⁰ Temmerman and colleagues²¹ also found poor intraobserver reliability (0.53) for bone scans in the setting of uncemented acetabular components. Last, our study did not evaluate the bony ingrowth patterns that corresponded to stable or unstable fixation and did not evaluate the volumetric size or anatomical location of the osteolytic lesions on CT. Careful assessment of these variables is clinically relevant when trying to determine if revision arthroplasty is warranted.

Although we used relatively simple radiographic criteria to define loose components, more sensitive and specific techniques have been described for both plain radiography and CT. Moore and colleagues²² described 5 radiographic signs of bony ingrowth; when 3 or more were present, sensitivity was 89.6% and specificity 76.9%. Mehin and colleagues²³ suggested that osteolysis involving more than 50% of the circumference of the shell on a standard pelvic radiograph might require revision arthroplasty. However, more recent studies have found that anteroposterior and lateral radiographs are less able to evaluate the anterior and posterior rims of the bone–implant interface, and it is this ingrowth area that may be the most crucial for stable osseointegration.^12,16

CT has expanded our ability to evaluate the bone–implant interface in 3 dimensions. Egawa and colleagues¹⁶ described using CT to evaluate the surface area involved with osteolysis and found that less than 40% involvement of the surface area generally corresponded to well-fixed components. Furthermore, they found that osteolysis generally creates lesions inferior and superior to the acetabular component and less often involves the anterior and posterior rims, which may be more important for stable fixation. The authors noted that volumetric analysis and CT were not as cost-effective as plain radiography and were more time- and skill-intensive.

Osteolysis itself remains a common indication for revision THA. However, the most appropriate procedure remains controversial. Mallory and colleagues²⁴ recommended explanting all acetabular shells in the setting of revision arthroplasty. They indicated that full assessment of the bony pelvis and any lytic defects was possible only with the wide exposure gained by acetabular component removal. More recent studies have begun to justify isolated component revision in the setting of well-fixed acetabular shells. Studies by Maloney and colleagues,¹⁰ Park and colleagues,¹⁵ and Beaulé and colleagues²⁵ have shown excellent outcomes with retention of well-fixed acetabular shells and removal of the wear generator in the setting of osteolysis. Haidukewych¹⁷ wrote that the goals in addressing osteolysis in revision THA are to eliminate the wear generator, débride osteolytic lesions, and restore bone stock. Surgeons should weigh the benefits of component retention and isolated liner exchange against the morbidity associated with explantation and preparation for implanting a new component. Good outcomes have been achieved with isolated component exchange, but surgeons should be aware that instability remains the most common complication after isolated liner exchange.⁸

The majority of our patients with RSL presented with complaints of pain and the diagnosis of osteolysis. One patient who had the diagnosis but was clinically asymptomatic was found to have a loose acetabular shell at time of revision surgery. Given the increased morbidity associated with acetabular component revision, this patient’s condition represents a dangerous combination of RSL and clinically asymptomatic component loosening. By raising awareness about RSL and its incidence, we should be able to increase our ability to detect RSL. A surgeon who detects RSL before gross migration or movement of the acetabular component may be better able to plan for revision arthroplasty before a catastrophic event that may necessitate a larger, more complex procedure. With the number of patients who require revision THA continuing to rise, surgeons should be aware of the incidence of RSL and the potential of RSL to affect patient care and potential surgical options.

The Food and Drug Administration is investigating the risk of brain deposits after recurring use of gadolinium-based contrast agents for MRI, the agency announced in a statement.

Studies suggest that gadolinium-based contrast agent (GBCA) deposits may stay in the brains of patients who have four or more contrast MRI scans, though it is unknown whether these deposits cause adverse effects, the FDA said.

GBCAs are usually expelled through the kidneys, but may remain in the brain after repeated exposure. FDA’s National Center for Toxicological

Research will further investigate safety risks in consultation with researchers and industry, the statement said.

The FDA is not requiring manufacturers to change the labels of GBCA products until more information is known. The agency is, however, recommending that clinicians limit GBCA use to situations in which it would be necessary for patient care.

“Health care professionals are also urged to reassess the necessity of repetitive GBCA MRIs in established treatment protocols,” the FDA said.

Patients may report side effects and adverse events to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.

[email protected]

The Food and Drug Administration is investigating the risk of brain deposits after recurring use of gadolinium-based contrast agents for MRI, the agency announced in a statement.

Studies suggest that gadolinium-based contrast agent (GBCA) deposits may stay in the brains of patients who have four or more contrast MRI scans, though it is unknown whether these deposits cause adverse effects, the FDA said.

GBCAs are usually expelled through the kidneys, but may remain in the brain after repeated exposure. FDA’s National Center for Toxicological

Research will further investigate safety risks in consultation with researchers and industry, the statement said.

The FDA is not requiring manufacturers to change the labels of GBCA products until more information is known. The agency is, however, recommending that clinicians limit GBCA use to situations in which it would be necessary for patient care.

“Health care professionals are also urged to reassess the necessity of repetitive GBCA MRIs in established treatment protocols,” the FDA said.

Patients may report side effects and adverse events to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.

[email protected]

The Food and Drug Administration is investigating the risk of brain deposits after recurring use of gadolinium-based contrast agents for MRI, the agency announced in a statement.

Studies suggest that gadolinium-based contrast agent (GBCA) deposits may stay in the brains of patients who have four or more contrast MRI scans, though it is unknown whether these deposits cause adverse effects, the FDA said.

GBCAs are usually expelled through the kidneys, but may remain in the brain after repeated exposure. FDA’s National Center for Toxicological

Research will further investigate safety risks in consultation with researchers and industry, the statement said.

The FDA is not requiring manufacturers to change the labels of GBCA products until more information is known. The agency is, however, recommending that clinicians limit GBCA use to situations in which it would be necessary for patient care.

“Health care professionals are also urged to reassess the necessity of repetitive GBCA MRIs in established treatment protocols,” the FDA said.

Patients may report side effects and adverse events to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.

[email protected]