Premature birth after preeclampsia: $23.1M verdict

When a woman saw her ObGyn on August 16 at 24 weeks’ gestation, test results showed proteinuria and high blood pressure (BP). The following day, she was hospitalized for a 24-hour urine test and BP evaluation supervised by an on-call ObGyn and her ObGyn. Test results confirmed preeclampsia. She was released from the hospital. A few days later, she was found to have continued high BP and increased proteinuria, and restricted fetal growth was detected. On August 29 at 26 weeks’ gestation, the baby girl was born with severe cystic periventricular leukomalacia by emergency cesarean delivery. She cannot perform basic tasks and will need 24-hour care for the rest of her life.

PARENTS' CLAIM:

The hospital staff and 2 ObGyns failed to timely diagnose and treat preeclampsia. The treating ObGyn neither prescribed medication to treat preeclampsia nor administered antenatal corticosteroids to enhance fetal lung and brain development, both of which should have been started on August 17. Hospital health care providers failed to transfer her to a Level III facility equipped to handle a premature birth of less than 33 weeks’ gestation.

DEFENDANTS' DEFENSE:

The hospital and ObGyn denied negligence.

VERDICT:

Prior to trial, the mother settled with the on-call ObGyn for an undisclosed amount. A $23.15 million Florida verdict was returned, apportioning 70% liability to the treating ObGyn and 30% to the hospital.

Related article:
For the management of labor, patience is a virtue

Shoulder dystocia, paralysis: $950,000 settlement

During delivery, shoulder dystocia was encountered. The ObGyn used maneuvers to release the shoulder and completed the delivery. The child has a brachial plexus injury. Despite nerve graft surgery, her right arm, shoulder, and hand are paralyzed.

PARENTS' CLAIM:

The ObGyn failed to properly manage the delivery. Shoulder dystocia had been encountered during the delivery of a sibling, but the ObGyn failed to communicate the need for cesarean delivery in future pregnancies.

DEFENDANTS' DEFENSE:

There was no negligence. The case settled during trial.

VERDICT:

A $950,000 California settlement was reached with the hospital and ObGyn.

Related article:
Shoulder dystocia: Taking the fear out of management

Child has brachial plexus injury

A mother was admitted to the hospital shortly after her membranes broke. Meconium was detected but the fetal heart-rate (FHR) monitor results were normal. About 15 minutes after admission, she was seen by an attending ObGyn, who started oxytocin to induce labor. FHR monitoring results were acceptable throughout the day, and by midafternoon, the mother was ready to deliver. A fetal baseline heart rate of less than 110 bpm was detected as staff prepared for the delivery. Less than an hour later, the baby’s head crowned and the ObGyn quickly identified shoulder dystocia. Nurses repositioned the mother, the baby rotated, and was delivered. Apgar scores were normal despite a shoulder injury.

PARENTS' CLAIM:

The ObGyn caused the injury by using excessive force during delivery. After attempting gentle traction, the ObGyn should have changed strategies.

DEFENDANTS' DEFENSE:

The ObGyn asserted that she used gentle traction that prevented twisting or stretching the baby’s nerves. The birth was normal and she followed all protocols, resulting in the birth of a cognitively intact baby, as evidenced by the child’s Apgar scores. The baby was large and labor and delivery went very quickly, both factors that could have led to the baby’s injuries. The ObGyn’s actions did not cause the injuries.

VERDICT:

A Pennsylvania defense verdict was returned.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Premature birth after preeclampsia: $23.1M verdict

When a woman saw her ObGyn on August 16 at 24 weeks’ gestation, test results showed proteinuria and high blood pressure (BP). The following day, she was hospitalized for a 24-hour urine test and BP evaluation supervised by an on-call ObGyn and her ObGyn. Test results confirmed preeclampsia. She was released from the hospital. A few days later, she was found to have continued high BP and increased proteinuria, and restricted fetal growth was detected. On August 29 at 26 weeks’ gestation, the baby girl was born with severe cystic periventricular leukomalacia by emergency cesarean delivery. She cannot perform basic tasks and will need 24-hour care for the rest of her life.

PARENTS' CLAIM:

The hospital staff and 2 ObGyns failed to timely diagnose and treat preeclampsia. The treating ObGyn neither prescribed medication to treat preeclampsia nor administered antenatal corticosteroids to enhance fetal lung and brain development, both of which should have been started on August 17. Hospital health care providers failed to transfer her to a Level III facility equipped to handle a premature birth of less than 33 weeks’ gestation.

DEFENDANTS' DEFENSE:

The hospital and ObGyn denied negligence.

VERDICT:

Prior to trial, the mother settled with the on-call ObGyn for an undisclosed amount. A $23.15 million Florida verdict was returned, apportioning 70% liability to the treating ObGyn and 30% to the hospital.

Related article:
For the management of labor, patience is a virtue

Shoulder dystocia, paralysis: $950,000 settlement

During delivery, shoulder dystocia was encountered. The ObGyn used maneuvers to release the shoulder and completed the delivery. The child has a brachial plexus injury. Despite nerve graft surgery, her right arm, shoulder, and hand are paralyzed.

PARENTS' CLAIM:

The ObGyn failed to properly manage the delivery. Shoulder dystocia had been encountered during the delivery of a sibling, but the ObGyn failed to communicate the need for cesarean delivery in future pregnancies.

DEFENDANTS' DEFENSE:

There was no negligence. The case settled during trial.

VERDICT:

A $950,000 California settlement was reached with the hospital and ObGyn.

Related article:
Shoulder dystocia: Taking the fear out of management

Child has brachial plexus injury

A mother was admitted to the hospital shortly after her membranes broke. Meconium was detected but the fetal heart-rate (FHR) monitor results were normal. About 15 minutes after admission, she was seen by an attending ObGyn, who started oxytocin to induce labor. FHR monitoring results were acceptable throughout the day, and by midafternoon, the mother was ready to deliver. A fetal baseline heart rate of less than 110 bpm was detected as staff prepared for the delivery. Less than an hour later, the baby’s head crowned and the ObGyn quickly identified shoulder dystocia. Nurses repositioned the mother, the baby rotated, and was delivered. Apgar scores were normal despite a shoulder injury.

PARENTS' CLAIM:

The ObGyn caused the injury by using excessive force during delivery. After attempting gentle traction, the ObGyn should have changed strategies.

DEFENDANTS' DEFENSE:

The ObGyn asserted that she used gentle traction that prevented twisting or stretching the baby’s nerves. The birth was normal and she followed all protocols, resulting in the birth of a cognitively intact baby, as evidenced by the child’s Apgar scores. The baby was large and labor and delivery went very quickly, both factors that could have led to the baby’s injuries. The ObGyn’s actions did not cause the injuries.

VERDICT:

A Pennsylvania defense verdict was returned.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Premature birth after preeclampsia: $23.1M verdict

When a woman saw her ObGyn on August 16 at 24 weeks’ gestation, test results showed proteinuria and high blood pressure (BP). The following day, she was hospitalized for a 24-hour urine test and BP evaluation supervised by an on-call ObGyn and her ObGyn. Test results confirmed preeclampsia. She was released from the hospital. A few days later, she was found to have continued high BP and increased proteinuria, and restricted fetal growth was detected. On August 29 at 26 weeks’ gestation, the baby girl was born with severe cystic periventricular leukomalacia by emergency cesarean delivery. She cannot perform basic tasks and will need 24-hour care for the rest of her life.

PARENTS' CLAIM:

The hospital staff and 2 ObGyns failed to timely diagnose and treat preeclampsia. The treating ObGyn neither prescribed medication to treat preeclampsia nor administered antenatal corticosteroids to enhance fetal lung and brain development, both of which should have been started on August 17. Hospital health care providers failed to transfer her to a Level III facility equipped to handle a premature birth of less than 33 weeks’ gestation.

DEFENDANTS' DEFENSE:

The hospital and ObGyn denied negligence.

VERDICT:

Prior to trial, the mother settled with the on-call ObGyn for an undisclosed amount. A $23.15 million Florida verdict was returned, apportioning 70% liability to the treating ObGyn and 30% to the hospital.

Related article:
For the management of labor, patience is a virtue

Shoulder dystocia, paralysis: $950,000 settlement

During delivery, shoulder dystocia was encountered. The ObGyn used maneuvers to release the shoulder and completed the delivery. The child has a brachial plexus injury. Despite nerve graft surgery, her right arm, shoulder, and hand are paralyzed.

PARENTS' CLAIM:

The ObGyn failed to properly manage the delivery. Shoulder dystocia had been encountered during the delivery of a sibling, but the ObGyn failed to communicate the need for cesarean delivery in future pregnancies.

DEFENDANTS' DEFENSE:

There was no negligence. The case settled during trial.

VERDICT:

A $950,000 California settlement was reached with the hospital and ObGyn.

Related article:
Shoulder dystocia: Taking the fear out of management

Child has brachial plexus injury

A mother was admitted to the hospital shortly after her membranes broke. Meconium was detected but the fetal heart-rate (FHR) monitor results were normal. About 15 minutes after admission, she was seen by an attending ObGyn, who started oxytocin to induce labor. FHR monitoring results were acceptable throughout the day, and by midafternoon, the mother was ready to deliver. A fetal baseline heart rate of less than 110 bpm was detected as staff prepared for the delivery. Less than an hour later, the baby’s head crowned and the ObGyn quickly identified shoulder dystocia. Nurses repositioned the mother, the baby rotated, and was delivered. Apgar scores were normal despite a shoulder injury.

PARENTS' CLAIM:

The ObGyn caused the injury by using excessive force during delivery. After attempting gentle traction, the ObGyn should have changed strategies.

DEFENDANTS' DEFENSE:

The ObGyn asserted that she used gentle traction that prevented twisting or stretching the baby’s nerves. The birth was normal and she followed all protocols, resulting in the birth of a cognitively intact baby, as evidenced by the child’s Apgar scores. The baby was large and labor and delivery went very quickly, both factors that could have led to the baby’s injuries. The ObGyn’s actions did not cause the injuries.

VERDICT:

A Pennsylvania defense verdict was returned.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Take-Home Points

• The author had a 90% success rate with no complications in treating almost 600 trigger digits.
• All digits can be safely treated, including multiple fingers on one hand, all in an office setting.
• Percutaneous trigger release appears to be a safe and reliable alternative to open surgery.
• Success rate, discomfort, and cost may make a percutaneous trigger release preferable to even a trial of corticosteroid injection.
• A failed percutaneous release can be successfully treated with an open release, if needed.

Trigger finger, or stenosing flexor tenosynovitis, is a condition characterized by clicking or locking during finger movement, sometimes resulting in the freezing of a digit in flexion or extension¹ (Figure 1). [[{"fid":"202300","view_mode":"medstat_image_flush_left","attributes":{"class":"media-element file-medstat-image-flush-left","data-delta":"1"},"fields":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 1.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"1":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 1.","field_file_image_credit[und][0][value]":""}}}]]Tendon inflammation is thought to cause constriction of the tendon sheath and bunching of the fibrous bundles of the first annular (A1) pulley, often creating a palpable nodule at the base of the digit.^2,3 Many patients experience intermittent joint pain and swelling, which may progress to triggering or complete locking of the digit.¹ One of the most common conditions treated by hand surgeons, trigger finger is most often reported in the dominant hand of women in their sixth decade of life and has been associated with several conditions, including diabetes and rheumatoid arthritis.^4-6 Other researchers have indicated the thumb and ring finger are most commonly affected, though all fingers can potentially trigger.^7,8

Initial treatment often involves injecting corticosteroid into the flexor tendon sheath, at or proximal to the annular pulley system, to reduce inflammation and the fibrous nodule.³ Another injection study found an initial success rate of 57% with a single injection, and 86% with a second injection, but patients were monitored for only 6 months, a period that may have been too short for symptom recurrence.⁷

On failure of steroid injections, patients typically are treated with open tendon sheath incision.⁹ This procedure, usually performed in a hospital or outpatient surgery setting, requires postoperative wound care, including dressing changes, suture removal, possible hand therapy, and follow-up physician visits. Operative treatment involves making a 1-cm to 2-cm incision, releasing the A1 pulley, and skin suturing.^7,8,10 The most common postoperative complaint is incisional tenderness, though long-term scar pain, infection, nerve injury, and disease recurrence have been reported.⁸ Overall, the procedure is very successful, providing up to 100% symptom relief.^7,8,10

Endoscopic release of trigger finger has also been described as an effective operative treatment. This technique involves passing a small cannula through a palmar incision—using an endoscope and retrograde knife within this 2.7-mm tunnel.¹⁰ With this treatment, reduced visibility may increase the risk of nerve injury.¹⁰ Although generally successful, endoscopic release requires anesthesia and expensive instruments and has a significant learning curve.^8,10

More recently, percutaneous release of trigger finger has been described as a definitive, in-office treatment.^5,6,11,12 Percutaneous release has the obvious advantages of no open incision, less scarring, less discomfort, and shorter recovery. Several studies have found comparable success rates for open and percutaneous procedures but consistently shorter recovery with the percutaneous technique.^7,8,12 Given its lower recurrence rate (vs steroid injections) and shorter recovery and lower cost (vs a surgical procedure), percutaneous treatment of stenosing tenosynovitis appears to be a safe, highly successful, and minimally invasive treatment method.⁸ This study represents a single surgeon’s experience with percutaneous tendon sheath incision over a 10-year period.

Methods

Patients presented with symptoms of stenosing flexor tenosynovitis with severity ranging from intermittent triggering to frank locking of the digit. Most patients underwent prior conservative treatment, including corticosteroid injections and hand therapy. With each patient, the senior author discussed the pathophysiology of trigger digit; treatment options, including observation, hand therapy, corticosteroid injection, percutaneous release, and open release; and potential risks and complications. The treatment path—initial corticosteroid injection, percutaneous release, or open release—was left up to the patient. The only exclusion criterion was prior surgery to the involved digit, and there was no discrimination by finger, symptomatic period, or severity. Each released digit was recorded independently. In no case was anticoagulant therapy discontinued.
A complete medical history was obtained for each patient.

Over a 10-year period (March 2003-December 2013), percutaneous release was performed on 596 trigger fingers in 429 patients, 18 years old or older. Of these patients, 279 were female. Mean age was 62 years (range, 26-97 years). Of the 531 releases with handedness recorded, 56.3% were performed on trigger digits on dominant hands (Table 1). [[{"fid":"202302","view_mode":"medstat_image_flush_right","attributes":{"class":"media-element file-medstat-image-flush-right","data-delta":"2"},"fields":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Table 1.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"2":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Table 1.","field_file_image_credit[und][0][value]":""}}}]]Mean duration of symptoms before percutaneous release was 9.7 months (range, 0.5-132 months). Of the 596 digits, 69 were reported to have previously sustained trauma, and 161 had been unsuccessfully treated with one or more cortisone injections before undergoing release. Of the suspected comorbidities examined, carpal tunnel syndrome was previously diagnosed in 79 patients and diabetes in 56 patients.¹

Of the 429 patients, 313 had a single digit released and 116 had multiple digits released. Of the 116 patients in the multiple-release group, 80 had 2 fingers released, 24 had 3 released, 7 had 4 released, and 5 had 5 released. The 596 released trigger fingers consisted of 188 thumbs, 41 index fingers, 185 middle fingers, 140 ring fingers, and 42 small fingers.

Surgical Technique

In-office percutaneous trigger finger releases were performed with a local anesthetic. One milliliter of lidocaine 1% injection was used to anesthetize the skin, the subcutaneous tissues, and the flexor tendon sheath at the level of the A1 pulley. As described by Pandey and colleagues,⁶ the proper location of the pulley was confirmed using specific surface landmarks on each digit. After waiting several minutes to allow the anesthetic to take effect, the surgeon inserted an 18-gauge needle into the center of the pulley with the digit held in extension (Figure 2). [[{"fid":"202303","view_mode":"medstat_image_flush_left","attributes":{"class":"media-element file-medstat-image-flush-left","data-delta":"3"},"fields":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 2.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"3":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 2.","field_file_image_credit[und][0][value]":""}}}]]The needle was carefully moved longitudinally along the length of the pulley with the bevel of the needle parallel to the tendon. A grating sensation was felt as the fibers of the pulley were cut. Several needle passes were made until the pulley was felt to have been released. Complete release was determined by loss of the grating sensation, along with complete relief of any further symptoms of triggering. The puncture site was cleaned and covered with a light sterile dressing (watch the Video online). There was no postoperative immobilization, and patients were encouraged to immediately return to normal use of the digit. Hand therapy was not prescribed, and pain medications were not dispensed. A 1-week follow-up appointment was scheduled, and patients were advised to return for evaluation in the event of any recurring symptoms (eg, triggering, swelling, stiffness, pain).

Results

were successfully released with 1 percutaneous procedure (recurrence or failure rate, 9.9%). The thumb was the digit most reliably released (success rate, 94.7%) (Table 2). [[{"fid":"202306","view_mode":"medstat_image_flush_right","attributes":{"class":"media-element file-medstat-image-flush-right","data-delta":"4"},"fields":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Table 2.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"4":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Table 2.","field_file_image_credit[und][0][value]":""}}}]]Patients with recurrent or unresolved symptoms were given the options of a second percutaneous release or an open surgical procedure. Of the 59 digits unsuccessfully released, as identified by persistent triggering or locking of the digit, 17 were treated with a second percutaneous release (15 were successful), and 40 underwent open tendon sheath incision as a second procedure (success rate, 100%); triggering persisted in the remaining 2 digits, and these were considered failures (the 2 patients did not pursue further treatment).

There were no complications: infection; nerve, artery, or tendon injury; or chronic pain. Some patients had mild stiffness, swelling, or pain for a few days after the procedure, and these effects typically resolved without treatment. In 29 digits, persistent pain or swelling without triggering was successfully treated with a corticosteroid injection.

Discussion

[[{"fid":"202307","view_mode":"medstat_image_flush_left","attributes":{"class":"media-element file-medstat-image-flush-left","data-delta":"5"},"fields":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Table 3.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"5":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Table 3.","field_file_image_credit[und][0][value]":""}}}]]Over a 10-year period, 596 percutaneous trigger finger releases were sequentially performed by a single surgeon. The 90% success rate compares favorably with rates found in other studies (Table 3).^5-9,12-14 The surgeon’s success rates for individual years vary and demonstrate no clear trend or learning curve with the procedure (Figure 3). There were no significant complications. Patient satisfaction with the procedure was high.[[{"fid":"202308","view_mode":"medstat_image_flush_right","attributes":{"class":"media-element file-medstat-image-flush-right","data-delta":"6"},"fields":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Figure 3.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"6":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Figure 3.","field_file_image_credit[und][0][value]":""}}}]]

There were no injuries to digital nerves, arteries, or flexor tendons, either early or late, and no reports of infections or long-term pain or loss of motion. Although it is quite probable that in some procedures the longitudinal passes of the 18-gauge needle may have also slightly cut into the flexor tendon after passing through the A1 pulley, the direction of the needle passes was in line with the direction of the collagen fibers of the tendon, and thus any inadvertent superficial abrasion would not have structurally weakened the tendon. Of the 40 digits that underwent open release after incomplete or failed percutaneous release, none showed significant longitudinal lacerations of the superficialis tendon. During these revision surgeries, the typical intraoperative finding was incomplete release of the A1 pulley, usually at the distal end. Although loss of the grating sensation or relief of further triggering symptoms was considered adequate evidence of a successful release in this study, small tendon attachments could remain and potentially could lead to recurrent triggering. Given the high success rate achieved with the large sample, however, these 2 factors are considered appropriate indicators of successful release.

It is unclear why there was a relatively consistent 10% failure rate and why it did not decrease over the 10-year study period. Although the technique used does not have a significant learning curve, it appears that digits are not actively triggering at time of procedure have a higher failure rate. When a patient’s digit is actively triggering, assessment of the success of the procedure is relatively straightforward, whereas when a digit intermittently triggers and locks and is not symptomatic in the office, success cannot be immediately determined.

No specific digit was significantly more prone to failed releases, though the small finger had the lowest success rate (85.7%). Given that only 56.4% of patients experienced triggering on the dominant hand, there is not enough evidence to suggest a significant relationship between likelihood of a trigger digit and a patient’s hand dominance. Similarly, there was no correlation between the duration of symptoms and the success of the percutaneous procedure.

Investigation of the relationship between the previously suggested comorbidities of carpal tunnel syndrome and diabetes was also inconclusive. Only 79 (18%) of 429 patients reported having carpal tunnel syndrome, and even fewer, 56 (13.0%), reported having diabetes. Only 69 of the 596 treated digits reportedly had sustained trauma before developing triggering symptoms, and only 12 of the 69 were unsuccessfully released. In addition, of the 161 digits in which one or more steroid injections failed to resolve triggering symptoms, 158 (87.3%) were successfully released with 1 percutaneous procedure. Collectively, these data show percutaneous release can effectively eliminate triggering symptoms in a digit that has sustained injury or that has been unsuccessfully treated with nonoperative methods. Failed percutaneous release subsequently can be reliably treated with an open procedure, and results are excellent.

This study had several limitations. It was retrospective, nonblinded, and did not compare outcomes of percutaneous release with those of an open procedure. Data are presented to support the efficacy and safety of percutaneous release as a treatment option. Another limitation is that pre-release treatment was not controlled. Patients had been treated with a variety of nonoperative methods, including use of anti-inflammatory medication, hand therapy, splinting, and one or more corticosteroid injections, both at our office and elsewhere.

Percutaneous release appears to have an advantage in terms of pain relief, but the study did not evaluate or control for procedure discomfort. However, patients who had been treated with a corticosteroid injection before percutaneous release consistently refused corticosteroid injections for subsequent trigger digits, citing the dramatic pain reduction achieved with release relative to injection. Similarly, all patients who had a trigger digit treated with open tendon sheath incision in the past indicated a strong preference for the percutaneous release.

Follow-up on this patient population was inconsistent and incomplete. Many patients did not return, presumably because they considered the procedure a success and thought follow-up was unnecessary. However, some patients may have had a recurrence or an incomplete release and gone elsewhere for treatment.

The results of this study, to date the largest study on percutaneous release of trigger finger, provide more evidence of the safety and efficacy of this procedure as a treatment option. The success rate of percutaneous release is high, surpasses that of nonoperative treatments such as steroid injections, and approaches that of open and endoscopic surgical alternatives. Some of the obvious advantages of percutaneous release are less visible scarring, fewer incision-related complications, and shorter rehabilitation.¹⁰ In addition, post-procedure pain is possibly reduced, symptom relief is comparable, operative time is significantly shorter,⁸ and percutaneous release is easily performed in the office setting.

Percutaneous release is a viable treatment option for stenosing flexor tenosynovitis, regardless of previously used nonoperative treatment methods, duration or severity of symptoms, or trigger digit treated.

Take-Home Points

• The author had a 90% success rate with no complications in treating almost 600 trigger digits.
• All digits can be safely treated, including multiple fingers on one hand, all in an office setting.
• Percutaneous trigger release appears to be a safe and reliable alternative to open surgery.
• Success rate, discomfort, and cost may make a percutaneous trigger release preferable to even a trial of corticosteroid injection.
• A failed percutaneous release can be successfully treated with an open release, if needed.

Trigger finger, or stenosing flexor tenosynovitis, is a condition characterized by clicking or locking during finger movement, sometimes resulting in the freezing of a digit in flexion or extension¹ (Figure 1). [[{"fid":"202300","view_mode":"medstat_image_flush_left","attributes":{"class":"media-element file-medstat-image-flush-left","data-delta":"1"},"fields":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 1.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"1":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 1.","field_file_image_credit[und][0][value]":""}}}]]Tendon inflammation is thought to cause constriction of the tendon sheath and bunching of the fibrous bundles of the first annular (A1) pulley, often creating a palpable nodule at the base of the digit.^2,3 Many patients experience intermittent joint pain and swelling, which may progress to triggering or complete locking of the digit.¹ One of the most common conditions treated by hand surgeons, trigger finger is most often reported in the dominant hand of women in their sixth decade of life and has been associated with several conditions, including diabetes and rheumatoid arthritis.^4-6 Other researchers have indicated the thumb and ring finger are most commonly affected, though all fingers can potentially trigger.^7,8

Initial treatment often involves injecting corticosteroid into the flexor tendon sheath, at or proximal to the annular pulley system, to reduce inflammation and the fibrous nodule.³ Another injection study found an initial success rate of 57% with a single injection, and 86% with a second injection, but patients were monitored for only 6 months, a period that may have been too short for symptom recurrence.⁷

On failure of steroid injections, patients typically are treated with open tendon sheath incision.⁹ This procedure, usually performed in a hospital or outpatient surgery setting, requires postoperative wound care, including dressing changes, suture removal, possible hand therapy, and follow-up physician visits. Operative treatment involves making a 1-cm to 2-cm incision, releasing the A1 pulley, and skin suturing.^7,8,10 The most common postoperative complaint is incisional tenderness, though long-term scar pain, infection, nerve injury, and disease recurrence have been reported.⁸ Overall, the procedure is very successful, providing up to 100% symptom relief.^7,8,10

Endoscopic release of trigger finger has also been described as an effective operative treatment. This technique involves passing a small cannula through a palmar incision—using an endoscope and retrograde knife within this 2.7-mm tunnel.¹⁰ With this treatment, reduced visibility may increase the risk of nerve injury.¹⁰ Although generally successful, endoscopic release requires anesthesia and expensive instruments and has a significant learning curve.^8,10

More recently, percutaneous release of trigger finger has been described as a definitive, in-office treatment.^5,6,11,12 Percutaneous release has the obvious advantages of no open incision, less scarring, less discomfort, and shorter recovery. Several studies have found comparable success rates for open and percutaneous procedures but consistently shorter recovery with the percutaneous technique.^7,8,12 Given its lower recurrence rate (vs steroid injections) and shorter recovery and lower cost (vs a surgical procedure), percutaneous treatment of stenosing tenosynovitis appears to be a safe, highly successful, and minimally invasive treatment method.⁸ This study represents a single surgeon’s experience with percutaneous tendon sheath incision over a 10-year period.

Methods

Patients presented with symptoms of stenosing flexor tenosynovitis with severity ranging from intermittent triggering to frank locking of the digit. Most patients underwent prior conservative treatment, including corticosteroid injections and hand therapy. With each patient, the senior author discussed the pathophysiology of trigger digit; treatment options, including observation, hand therapy, corticosteroid injection, percutaneous release, and open release; and potential risks and complications. The treatment path—initial corticosteroid injection, percutaneous release, or open release—was left up to the patient. The only exclusion criterion was prior surgery to the involved digit, and there was no discrimination by finger, symptomatic period, or severity. Each released digit was recorded independently. In no case was anticoagulant therapy discontinued.
A complete medical history was obtained for each patient.

Over a 10-year period (March 2003-December 2013), percutaneous release was performed on 596 trigger fingers in 429 patients, 18 years old or older. Of these patients, 279 were female. Mean age was 62 years (range, 26-97 years). Of the 531 releases with handedness recorded, 56.3% were performed on trigger digits on dominant hands (Table 1). [[{"fid":"202302","view_mode":"medstat_image_flush_right","attributes":{"class":"media-element file-medstat-image-flush-right","data-delta":"2"},"fields":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Table 1.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"2":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Table 1.","field_file_image_credit[und][0][value]":""}}}]]Mean duration of symptoms before percutaneous release was 9.7 months (range, 0.5-132 months). Of the 596 digits, 69 were reported to have previously sustained trauma, and 161 had been unsuccessfully treated with one or more cortisone injections before undergoing release. Of the suspected comorbidities examined, carpal tunnel syndrome was previously diagnosed in 79 patients and diabetes in 56 patients.¹

Of the 429 patients, 313 had a single digit released and 116 had multiple digits released. Of the 116 patients in the multiple-release group, 80 had 2 fingers released, 24 had 3 released, 7 had 4 released, and 5 had 5 released. The 596 released trigger fingers consisted of 188 thumbs, 41 index fingers, 185 middle fingers, 140 ring fingers, and 42 small fingers.

Surgical Technique

In-office percutaneous trigger finger releases were performed with a local anesthetic. One milliliter of lidocaine 1% injection was used to anesthetize the skin, the subcutaneous tissues, and the flexor tendon sheath at the level of the A1 pulley. As described by Pandey and colleagues,⁶ the proper location of the pulley was confirmed using specific surface landmarks on each digit. After waiting several minutes to allow the anesthetic to take effect, the surgeon inserted an 18-gauge needle into the center of the pulley with the digit held in extension (Figure 2). [[{"fid":"202303","view_mode":"medstat_image_flush_left","attributes":{"class":"media-element file-medstat-image-flush-left","data-delta":"3"},"fields":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 2.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"3":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 2.","field_file_image_credit[und][0][value]":""}}}]]The needle was carefully moved longitudinally along the length of the pulley with the bevel of the needle parallel to the tendon. A grating sensation was felt as the fibers of the pulley were cut. Several needle passes were made until the pulley was felt to have been released. Complete release was determined by loss of the grating sensation, along with complete relief of any further symptoms of triggering. The puncture site was cleaned and covered with a light sterile dressing (watch the Video online). There was no postoperative immobilization, and patients were encouraged to immediately return to normal use of the digit. Hand therapy was not prescribed, and pain medications were not dispensed. A 1-week follow-up appointment was scheduled, and patients were advised to return for evaluation in the event of any recurring symptoms (eg, triggering, swelling, stiffness, pain).

Results

were successfully released with 1 percutaneous procedure (recurrence or failure rate, 9.9%). The thumb was the digit most reliably released (success rate, 94.7%) (Table 2). [[{"fid":"202306","view_mode":"medstat_image_flush_right","attributes":{"class":"media-element file-medstat-image-flush-right","data-delta":"4"},"fields":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Table 2.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"4":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Table 2.","field_file_image_credit[und][0][value]":""}}}]]Patients with recurrent or unresolved symptoms were given the options of a second percutaneous release or an open surgical procedure. Of the 59 digits unsuccessfully released, as identified by persistent triggering or locking of the digit, 17 were treated with a second percutaneous release (15 were successful), and 40 underwent open tendon sheath incision as a second procedure (success rate, 100%); triggering persisted in the remaining 2 digits, and these were considered failures (the 2 patients did not pursue further treatment).

There were no complications: infection; nerve, artery, or tendon injury; or chronic pain. Some patients had mild stiffness, swelling, or pain for a few days after the procedure, and these effects typically resolved without treatment. In 29 digits, persistent pain or swelling without triggering was successfully treated with a corticosteroid injection.

Discussion

[[{"fid":"202307","view_mode":"medstat_image_flush_left","attributes":{"class":"media-element file-medstat-image-flush-left","data-delta":"5"},"fields":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Table 3.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"5":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Table 3.","field_file_image_credit[und][0][value]":""}}}]]Over a 10-year period, 596 percutaneous trigger finger releases were sequentially performed by a single surgeon. The 90% success rate compares favorably with rates found in other studies (Table 3).^5-9,12-14 The surgeon’s success rates for individual years vary and demonstrate no clear trend or learning curve with the procedure (Figure 3). There were no significant complications. Patient satisfaction with the procedure was high.[[{"fid":"202308","view_mode":"medstat_image_flush_right","attributes":{"class":"media-element file-medstat-image-flush-right","data-delta":"6"},"fields":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Figure 3.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"6":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Figure 3.","field_file_image_credit[und][0][value]":""}}}]]

There were no injuries to digital nerves, arteries, or flexor tendons, either early or late, and no reports of infections or long-term pain or loss of motion. Although it is quite probable that in some procedures the longitudinal passes of the 18-gauge needle may have also slightly cut into the flexor tendon after passing through the A1 pulley, the direction of the needle passes was in line with the direction of the collagen fibers of the tendon, and thus any inadvertent superficial abrasion would not have structurally weakened the tendon. Of the 40 digits that underwent open release after incomplete or failed percutaneous release, none showed significant longitudinal lacerations of the superficialis tendon. During these revision surgeries, the typical intraoperative finding was incomplete release of the A1 pulley, usually at the distal end. Although loss of the grating sensation or relief of further triggering symptoms was considered adequate evidence of a successful release in this study, small tendon attachments could remain and potentially could lead to recurrent triggering. Given the high success rate achieved with the large sample, however, these 2 factors are considered appropriate indicators of successful release.

It is unclear why there was a relatively consistent 10% failure rate and why it did not decrease over the 10-year study period. Although the technique used does not have a significant learning curve, it appears that digits are not actively triggering at time of procedure have a higher failure rate. When a patient’s digit is actively triggering, assessment of the success of the procedure is relatively straightforward, whereas when a digit intermittently triggers and locks and is not symptomatic in the office, success cannot be immediately determined.

No specific digit was significantly more prone to failed releases, though the small finger had the lowest success rate (85.7%). Given that only 56.4% of patients experienced triggering on the dominant hand, there is not enough evidence to suggest a significant relationship between likelihood of a trigger digit and a patient’s hand dominance. Similarly, there was no correlation between the duration of symptoms and the success of the percutaneous procedure.

Investigation of the relationship between the previously suggested comorbidities of carpal tunnel syndrome and diabetes was also inconclusive. Only 79 (18%) of 429 patients reported having carpal tunnel syndrome, and even fewer, 56 (13.0%), reported having diabetes. Only 69 of the 596 treated digits reportedly had sustained trauma before developing triggering symptoms, and only 12 of the 69 were unsuccessfully released. In addition, of the 161 digits in which one or more steroid injections failed to resolve triggering symptoms, 158 (87.3%) were successfully released with 1 percutaneous procedure. Collectively, these data show percutaneous release can effectively eliminate triggering symptoms in a digit that has sustained injury or that has been unsuccessfully treated with nonoperative methods. Failed percutaneous release subsequently can be reliably treated with an open procedure, and results are excellent.

This study had several limitations. It was retrospective, nonblinded, and did not compare outcomes of percutaneous release with those of an open procedure. Data are presented to support the efficacy and safety of percutaneous release as a treatment option. Another limitation is that pre-release treatment was not controlled. Patients had been treated with a variety of nonoperative methods, including use of anti-inflammatory medication, hand therapy, splinting, and one or more corticosteroid injections, both at our office and elsewhere.

Percutaneous release appears to have an advantage in terms of pain relief, but the study did not evaluate or control for procedure discomfort. However, patients who had been treated with a corticosteroid injection before percutaneous release consistently refused corticosteroid injections for subsequent trigger digits, citing the dramatic pain reduction achieved with release relative to injection. Similarly, all patients who had a trigger digit treated with open tendon sheath incision in the past indicated a strong preference for the percutaneous release.

Follow-up on this patient population was inconsistent and incomplete. Many patients did not return, presumably because they considered the procedure a success and thought follow-up was unnecessary. However, some patients may have had a recurrence or an incomplete release and gone elsewhere for treatment.

The results of this study, to date the largest study on percutaneous release of trigger finger, provide more evidence of the safety and efficacy of this procedure as a treatment option. The success rate of percutaneous release is high, surpasses that of nonoperative treatments such as steroid injections, and approaches that of open and endoscopic surgical alternatives. Some of the obvious advantages of percutaneous release are less visible scarring, fewer incision-related complications, and shorter rehabilitation.¹⁰ In addition, post-procedure pain is possibly reduced, symptom relief is comparable, operative time is significantly shorter,⁸ and percutaneous release is easily performed in the office setting.

Percutaneous release is a viable treatment option for stenosing flexor tenosynovitis, regardless of previously used nonoperative treatment methods, duration or severity of symptoms, or trigger digit treated.

Take-Home Points

• The author had a 90% success rate with no complications in treating almost 600 trigger digits.
• All digits can be safely treated, including multiple fingers on one hand, all in an office setting.
• Percutaneous trigger release appears to be a safe and reliable alternative to open surgery.
• Success rate, discomfort, and cost may make a percutaneous trigger release preferable to even a trial of corticosteroid injection.
• A failed percutaneous release can be successfully treated with an open release, if needed.

Trigger finger, or stenosing flexor tenosynovitis, is a condition characterized by clicking or locking during finger movement, sometimes resulting in the freezing of a digit in flexion or extension¹ (Figure 1). [[{"fid":"202300","view_mode":"medstat_image_flush_left","attributes":{"class":"media-element file-medstat-image-flush-left","data-delta":"1"},"fields":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 1.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"1":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 1.","field_file_image_credit[und][0][value]":""}}}]]Tendon inflammation is thought to cause constriction of the tendon sheath and bunching of the fibrous bundles of the first annular (A1) pulley, often creating a palpable nodule at the base of the digit.^2,3 Many patients experience intermittent joint pain and swelling, which may progress to triggering or complete locking of the digit.¹ One of the most common conditions treated by hand surgeons, trigger finger is most often reported in the dominant hand of women in their sixth decade of life and has been associated with several conditions, including diabetes and rheumatoid arthritis.^4-6 Other researchers have indicated the thumb and ring finger are most commonly affected, though all fingers can potentially trigger.^7,8

Initial treatment often involves injecting corticosteroid into the flexor tendon sheath, at or proximal to the annular pulley system, to reduce inflammation and the fibrous nodule.³ Another injection study found an initial success rate of 57% with a single injection, and 86% with a second injection, but patients were monitored for only 6 months, a period that may have been too short for symptom recurrence.⁷

On failure of steroid injections, patients typically are treated with open tendon sheath incision.⁹ This procedure, usually performed in a hospital or outpatient surgery setting, requires postoperative wound care, including dressing changes, suture removal, possible hand therapy, and follow-up physician visits. Operative treatment involves making a 1-cm to 2-cm incision, releasing the A1 pulley, and skin suturing.^7,8,10 The most common postoperative complaint is incisional tenderness, though long-term scar pain, infection, nerve injury, and disease recurrence have been reported.⁸ Overall, the procedure is very successful, providing up to 100% symptom relief.^7,8,10

Endoscopic release of trigger finger has also been described as an effective operative treatment. This technique involves passing a small cannula through a palmar incision—using an endoscope and retrograde knife within this 2.7-mm tunnel.¹⁰ With this treatment, reduced visibility may increase the risk of nerve injury.¹⁰ Although generally successful, endoscopic release requires anesthesia and expensive instruments and has a significant learning curve.^8,10

More recently, percutaneous release of trigger finger has been described as a definitive, in-office treatment.^5,6,11,12 Percutaneous release has the obvious advantages of no open incision, less scarring, less discomfort, and shorter recovery. Several studies have found comparable success rates for open and percutaneous procedures but consistently shorter recovery with the percutaneous technique.^7,8,12 Given its lower recurrence rate (vs steroid injections) and shorter recovery and lower cost (vs a surgical procedure), percutaneous treatment of stenosing tenosynovitis appears to be a safe, highly successful, and minimally invasive treatment method.⁸ This study represents a single surgeon’s experience with percutaneous tendon sheath incision over a 10-year period.

Methods

Patients presented with symptoms of stenosing flexor tenosynovitis with severity ranging from intermittent triggering to frank locking of the digit. Most patients underwent prior conservative treatment, including corticosteroid injections and hand therapy. With each patient, the senior author discussed the pathophysiology of trigger digit; treatment options, including observation, hand therapy, corticosteroid injection, percutaneous release, and open release; and potential risks and complications. The treatment path—initial corticosteroid injection, percutaneous release, or open release—was left up to the patient. The only exclusion criterion was prior surgery to the involved digit, and there was no discrimination by finger, symptomatic period, or severity. Each released digit was recorded independently. In no case was anticoagulant therapy discontinued.
A complete medical history was obtained for each patient.

Over a 10-year period (March 2003-December 2013), percutaneous release was performed on 596 trigger fingers in 429 patients, 18 years old or older. Of these patients, 279 were female. Mean age was 62 years (range, 26-97 years). Of the 531 releases with handedness recorded, 56.3% were performed on trigger digits on dominant hands (Table 1). [[{"fid":"202302","view_mode":"medstat_image_flush_right","attributes":{"class":"media-element file-medstat-image-flush-right","data-delta":"2"},"fields":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Table 1.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"2":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Table 1.","field_file_image_credit[und][0][value]":""}}}]]Mean duration of symptoms before percutaneous release was 9.7 months (range, 0.5-132 months). Of the 596 digits, 69 were reported to have previously sustained trauma, and 161 had been unsuccessfully treated with one or more cortisone injections before undergoing release. Of the suspected comorbidities examined, carpal tunnel syndrome was previously diagnosed in 79 patients and diabetes in 56 patients.¹

Of the 429 patients, 313 had a single digit released and 116 had multiple digits released. Of the 116 patients in the multiple-release group, 80 had 2 fingers released, 24 had 3 released, 7 had 4 released, and 5 had 5 released. The 596 released trigger fingers consisted of 188 thumbs, 41 index fingers, 185 middle fingers, 140 ring fingers, and 42 small fingers.

Surgical Technique

In-office percutaneous trigger finger releases were performed with a local anesthetic. One milliliter of lidocaine 1% injection was used to anesthetize the skin, the subcutaneous tissues, and the flexor tendon sheath at the level of the A1 pulley. As described by Pandey and colleagues,⁶ the proper location of the pulley was confirmed using specific surface landmarks on each digit. After waiting several minutes to allow the anesthetic to take effect, the surgeon inserted an 18-gauge needle into the center of the pulley with the digit held in extension (Figure 2). [[{"fid":"202303","view_mode":"medstat_image_flush_left","attributes":{"class":"media-element file-medstat-image-flush-left","data-delta":"3"},"fields":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 2.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"3":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 2.","field_file_image_credit[und][0][value]":""}}}]]The needle was carefully moved longitudinally along the length of the pulley with the bevel of the needle parallel to the tendon. A grating sensation was felt as the fibers of the pulley were cut. Several needle passes were made until the pulley was felt to have been released. Complete release was determined by loss of the grating sensation, along with complete relief of any further symptoms of triggering. The puncture site was cleaned and covered with a light sterile dressing (watch the Video online). There was no postoperative immobilization, and patients were encouraged to immediately return to normal use of the digit. Hand therapy was not prescribed, and pain medications were not dispensed. A 1-week follow-up appointment was scheduled, and patients were advised to return for evaluation in the event of any recurring symptoms (eg, triggering, swelling, stiffness, pain).

Results

were successfully released with 1 percutaneous procedure (recurrence or failure rate, 9.9%). The thumb was the digit most reliably released (success rate, 94.7%) (Table 2). [[{"fid":"202306","view_mode":"medstat_image_flush_right","attributes":{"class":"media-element file-medstat-image-flush-right","data-delta":"4"},"fields":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Table 2.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"4":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Table 2.","field_file_image_credit[und][0][value]":""}}}]]Patients with recurrent or unresolved symptoms were given the options of a second percutaneous release or an open surgical procedure. Of the 59 digits unsuccessfully released, as identified by persistent triggering or locking of the digit, 17 were treated with a second percutaneous release (15 were successful), and 40 underwent open tendon sheath incision as a second procedure (success rate, 100%); triggering persisted in the remaining 2 digits, and these were considered failures (the 2 patients did not pursue further treatment).

There were no complications: infection; nerve, artery, or tendon injury; or chronic pain. Some patients had mild stiffness, swelling, or pain for a few days after the procedure, and these effects typically resolved without treatment. In 29 digits, persistent pain or swelling without triggering was successfully treated with a corticosteroid injection.

Discussion

[[{"fid":"202307","view_mode":"medstat_image_flush_left","attributes":{"class":"media-element file-medstat-image-flush-left","data-delta":"5"},"fields":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Table 3.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"5":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Table 3.","field_file_image_credit[und][0][value]":""}}}]]Over a 10-year period, 596 percutaneous trigger finger releases were sequentially performed by a single surgeon. The 90% success rate compares favorably with rates found in other studies (Table 3).^5-9,12-14 The surgeon’s success rates for individual years vary and demonstrate no clear trend or learning curve with the procedure (Figure 3). There were no significant complications. Patient satisfaction with the procedure was high.[[{"fid":"202308","view_mode":"medstat_image_flush_right","attributes":{"class":"media-element file-medstat-image-flush-right","data-delta":"6"},"fields":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Figure 3.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"6":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Figure 3.","field_file_image_credit[und][0][value]":""}}}]]

There were no injuries to digital nerves, arteries, or flexor tendons, either early or late, and no reports of infections or long-term pain or loss of motion. Although it is quite probable that in some procedures the longitudinal passes of the 18-gauge needle may have also slightly cut into the flexor tendon after passing through the A1 pulley, the direction of the needle passes was in line with the direction of the collagen fibers of the tendon, and thus any inadvertent superficial abrasion would not have structurally weakened the tendon. Of the 40 digits that underwent open release after incomplete or failed percutaneous release, none showed significant longitudinal lacerations of the superficialis tendon. During these revision surgeries, the typical intraoperative finding was incomplete release of the A1 pulley, usually at the distal end. Although loss of the grating sensation or relief of further triggering symptoms was considered adequate evidence of a successful release in this study, small tendon attachments could remain and potentially could lead to recurrent triggering. Given the high success rate achieved with the large sample, however, these 2 factors are considered appropriate indicators of successful release.

It is unclear why there was a relatively consistent 10% failure rate and why it did not decrease over the 10-year study period. Although the technique used does not have a significant learning curve, it appears that digits are not actively triggering at time of procedure have a higher failure rate. When a patient’s digit is actively triggering, assessment of the success of the procedure is relatively straightforward, whereas when a digit intermittently triggers and locks and is not symptomatic in the office, success cannot be immediately determined.

No specific digit was significantly more prone to failed releases, though the small finger had the lowest success rate (85.7%). Given that only 56.4% of patients experienced triggering on the dominant hand, there is not enough evidence to suggest a significant relationship between likelihood of a trigger digit and a patient’s hand dominance. Similarly, there was no correlation between the duration of symptoms and the success of the percutaneous procedure.

Investigation of the relationship between the previously suggested comorbidities of carpal tunnel syndrome and diabetes was also inconclusive. Only 79 (18%) of 429 patients reported having carpal tunnel syndrome, and even fewer, 56 (13.0%), reported having diabetes. Only 69 of the 596 treated digits reportedly had sustained trauma before developing triggering symptoms, and only 12 of the 69 were unsuccessfully released. In addition, of the 161 digits in which one or more steroid injections failed to resolve triggering symptoms, 158 (87.3%) were successfully released with 1 percutaneous procedure. Collectively, these data show percutaneous release can effectively eliminate triggering symptoms in a digit that has sustained injury or that has been unsuccessfully treated with nonoperative methods. Failed percutaneous release subsequently can be reliably treated with an open procedure, and results are excellent.

This study had several limitations. It was retrospective, nonblinded, and did not compare outcomes of percutaneous release with those of an open procedure. Data are presented to support the efficacy and safety of percutaneous release as a treatment option. Another limitation is that pre-release treatment was not controlled. Patients had been treated with a variety of nonoperative methods, including use of anti-inflammatory medication, hand therapy, splinting, and one or more corticosteroid injections, both at our office and elsewhere.

Percutaneous release appears to have an advantage in terms of pain relief, but the study did not evaluate or control for procedure discomfort. However, patients who had been treated with a corticosteroid injection before percutaneous release consistently refused corticosteroid injections for subsequent trigger digits, citing the dramatic pain reduction achieved with release relative to injection. Similarly, all patients who had a trigger digit treated with open tendon sheath incision in the past indicated a strong preference for the percutaneous release.

Follow-up on this patient population was inconsistent and incomplete. Many patients did not return, presumably because they considered the procedure a success and thought follow-up was unnecessary. However, some patients may have had a recurrence or an incomplete release and gone elsewhere for treatment.

The results of this study, to date the largest study on percutaneous release of trigger finger, provide more evidence of the safety and efficacy of this procedure as a treatment option. The success rate of percutaneous release is high, surpasses that of nonoperative treatments such as steroid injections, and approaches that of open and endoscopic surgical alternatives. Some of the obvious advantages of percutaneous release are less visible scarring, fewer incision-related complications, and shorter rehabilitation.¹⁰ In addition, post-procedure pain is possibly reduced, symptom relief is comparable, operative time is significantly shorter,⁸ and percutaneous release is easily performed in the office setting.

Percutaneous release is a viable treatment option for stenosing flexor tenosynovitis, regardless of previously used nonoperative treatment methods, duration or severity of symptoms, or trigger digit treated.

Take-Home Points

• GCT of bones of the wrist is rare. This article is the only report of a wrist GCT during pregnancy that we could identify.
• Routine treatment usually consists of surgical excision with local adjuvant, and in the wrist, often results in reduced wrist motion.
• GCT of the wrist is more aggressive than the more common locations in long bones, with higher local recurrence rates if treated with surgery alone.
• Diagnosis is often delayed for GCT of the wrist, due to insufficient imaging, which should include CT or MRI.
• For pregnant women with GCT, local adjuvant treatments can be used in addition to surgery. Following pregnancy, denosumab can be used systemically, and can be effective with metastatic or unresectable disease.

Giant cell tumor (GCT) of bone accounts for about 5% of primary bone tumors.^1-3 Only 3% to 5% of GCTs occur in the hand.^4,5 Wrist involvement, which is rare, most often involves the hamate bone.^5-7 Capitate bone involvement is exceedingly rare.^8-11 Although histologically benign, GCT can recur locally after treatment with curettage alone, and lung metastases are found in 2% to 5% of cases.^2,12-14 Therefore, en bloc tumor excision is preferred in the setting of cortical erosion or soft-tissue involvement.^1,4,8 Wrist joint motion is inevitably reduced, and bone graft donor-site morbidity is significant.^6-8

In the unusual case reported here, GCT presented in the capitate bone and, after the patient became pregnant, recurred in the hamate and trapezoid bones with soft-tissue extension and lung metastases. The capitate was excised en bloc and reconstructed with an interposition of polymethylmethacrylate bone cement. Pulmonary metastases developed, and the GCT expanded to involve multiple carpal bones and the bases of the second through fourth metacarpals. A 10-month course of systemic chemotherapy with the RANK ligand (RANKL) inhibitor denosumab was started after the pregnancy. After this treatment, the patient underwent both tumor resection and reconstruction with autogenous bicortical iliac crest bone graft (ICBG) carefully designed to preserve range of motion and maintain the fingers in anatomical position. Treatment with denosumab was continued after surgery. Although this case offers no endpoint for postoperative chemotherapy with denosumab, preoperative treatment dramatically reduced the GCT and permitted limb-sparing reconstruction. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 19-year-old right-handed woman with atraumatic swelling of the left wrist presented to an orthopedic surgeon at an outside facility. Physical examination revealed tender fullness on the dorsum of the wrist, slightly reduced range of motion and grip strength, and a neurovascularly intact wrist. The diagnosis was periarticular cyst, and the patient underwent physical therapy. Two years later, the swelling returned, tenderness was increasing, and symptoms did not resolve with cast immobilization. A radiograph showed a lytic lesion in the capitate bone (Figure 1).[[{"fid":"202332","view_mode":"medstat_image_flush_left","attributes":{"class":"media-element file-medstat-image-flush-left","data-delta":"1"},"fields":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 1.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"1":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 1.","field_file_image_credit[und][0][value]":""}}}]]

GCT was diagnosed with percutaneous needle biopsy. A preoperative chest radiograph was reported normal. For initial treatment, the capitate and trapezoid bones were resected en bloc through a dorsal approach. Reconstruction consisted of limited arthrodesis using bone cement without additional fixation.

At 6-month follow-up, the patient was pregnant, and there was a recurrence of the wrist lesion. During the first 2 months of pregnancy, swelling and pain rapidly progressed, and a palpable mass formed. Radiographs showed a lytic lesion extending into the hamate bone (Figure 2), and magnetic resonance imaging (MRI) showed articular extension of the lesion with involvement of the base of the fourth metacarpal. [[{"fid":"202334","view_mode":"medstat_image_flush_right","attributes":{"class":"media-element file-medstat-image-flush-right","data-delta":"2"},"fields":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Figure 2.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"2":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Figure 2.","field_file_image_credit[und][0][value]":""}}}]]Targeted anti-RANKL therapy was not recommended (and was not available at the patient’s home hospital). The patient deferred surgical treatment because of the pregnancy, which proved otherwise uneventful and ended with a full-term delivery.

After the pregnancy, radiographs of the wrist showed complete destruction of the hamate and trapezium bones, with erosion of the bases of the second through fourth metacarpals (Figure 3A). [[{"fid":"202335","view_mode":"medstat_image_flush_left","attributes":{"class":"media-element file-medstat-image-flush-left","data-delta":"3"},"fields":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 3.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"3":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 3.","field_file_image_credit[und][0][value]":""}}}]]The patient presented at our institution 4 years after initial diagnosis. Computed tomography (CT) of the chest showed numerous bilateral pulmonary nodular opacities. Wrist imaging showed soft-tissue extension (Figure 3B). The diagnosis of recurrent metastatic GCT was confirmed with needle biopsies of the wrist mass and the right lung nodule.

Systemic chemotherapy was initiated with 120 mg of denosumab, given subcutaneously on days 1, 8, and 15 and then monthly during the 10 months leading up to surgery. Serum calcium was monitored during treatment and remained within the normal range the entire time, except for once at the start of therapy, when it dropped to 6.8 mg/dL. After 8 months, the soft-tissue mass, originally 8 cm × 8 cm × 6 cm, shrunk and stabilized at 5 cm × 4 cm × 4 cm (Figure 3B), and a bony shell reformed around it. Nodules in both lung fields showed response to denosumab.

Histologic examination revealed scattered osteoclast-like, multinucleated giant cells, consistent with a recurrent lesion (Figure 4). [[{"fid":"202336","view_mode":"medstat_image_flush_right","attributes":{"class":"media-element file-medstat-image-flush-right","data-delta":"4"},"fields":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Figure 4.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"4":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Figure 4.","field_file_image_credit[und][0][value]":""}}}]]After 10 months of treatment with denosumab, the patient underwent resection (dorsal approach) of the residual cement, the soft-tissue mass, the affected carpal bones, half of the third metacarpal, and the second and fourth metacarpal bases. The proximal carpal row was preserved after no intra-articular involvement was verified. The closet margin was marginal; the tumor mass abutted without encompassing the flexor tendons and median nerve. The tumor was meticulously elevated from the neurovascular and tendinous structures, which were not sacrificed. Hydrogen peroxide was used for local adjuvant treatment. Bicortical autogenous ICBG was placed between the remaining scaphoid, lunate, and metacarpal bones. The second, third, and fourth metacarpal bases were stabilized on the overlapping outer table of ICBG with 2.0-mm plates and miniscrews (Figure 5A). Kirschner wires were used to stabilize the proximal bone graft and the scapholunate fossa. Cancellous bone graft was packed between the structural bone graft and neighboring unaffected carpal bones (Figure 5A). Immobilization with a short-arm thumb spica cast was maintained for 6 weeks after surgery and was followed by a 12-week rehabilitation program. The patient returned to normal activities when plain radiographs showed solid bony union (Figure 5B). Fourteen months after initial surgery, tenolysis was performed to free the extensor tendons (index, middle, and ring fingers on dorsum of left hand) from adhesions to the bone graft. At 37-month follow-up (Figure 5C), there was no clinical or radiographic evidence of progression in the wrist.[[{"fid":"202337","view_mode":"medstat_image_flush_left","attributes":{"class":"media-element file-medstat-image-flush-left","data-delta":"5"},"fields":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 5.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"5":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 5.","field_file_image_credit[und][0][value]":""}}}]]

The patient had bilateral pulmonary metastases (Figures 6A, 6B). Treatment with denosumab produced an initial response (smaller pulmonary lesions) and subsequent stability. After 12 months of treatment with denosumab, the patient underwent left thoracotomy and wedge resection of pulmonary metastases on the left. Pathologic evaluation revealed pulmonary parenchyma with calcification and ossification and limited viable tumor. Given the dramatic effects on the left pulmonary metastases, denosumab was continued, and surgical intervention on the right was not attempted. Pulmonary metastases were stable afterward (Figure 6C).[[{"fid":"202338","view_mode":"medstat_image_flush_right","attributes":{"class":"media-element file-medstat-image-flush-right","data-delta":"6"},"fields":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Figure 6.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"6":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Figure 6.","field_file_image_credit[und][0][value]":""}}}]]

At 54-month follow-up, systemic treatment with denosumab was continued. The patient had no pain in the wrist or hand and was able to use the left hand normally. There was some fissuring of the third and fourth digits over each other. However, the patient had good grip strength and was using eating utensils, picking up water bottles, and engaging in other activities without difficulty.

Discussion

GCT isolated to the carpus is rare. However, compared with GCT in the more common locations in long bones, it is also more aggressive, and its local recurrence rates are higher, probably 60% or more if treated with curettage alone.¹⁵ Therefore, excision augmented with adjuvant treatment is recommended.^2,7 Use of bone cement in the hand is relatively uncommon.^4,5,7-10

The diagnosis of GCT in the carpus is difficult and often delayed. The initial complaint is usually mild wrist pain after relatively mild trauma.⁵ The first reported case of GCT in the lunate bone was mistakenly thought to be Kienbock disease.⁵ Similarly, our patient was initially given a nononcologic diagnosis, which prompted conservative management.

Whether the biological behavior of GCT in the carpus differs from that of GCT in other sites is unclear. The high recurrence rates might be attributable in part to suboptimal curettage.^5,6 En bloc resections of involved bone inevitably result in carpal instability or loss of wrist motion if arthrodesis is performed.^4-7,11 In the present case, resection was followed by limited arthrodesis to mitigate motion losses.

Multifocal GCT in the carpal bones often affects younger patients and has a high rate of recurrence.^7,16 In the present case, the patient’s pregnancy delayed treatment and allowed tumor extension into soft tissues and metacarpal bones. Given her young age, en bloc tumor resection was performed, with the proximal carpal row spared to preserve wrist motion. ICBG was carefully shaped to match the defect that remained after tumor resection.⁷ Supporting wrist height to prevent carpal collapse provided a stable base for remaining distal segments of the second through fourth metacarpals. After short-arm thumb spica casting and early rehabilitation, the patient recovered wrist motion and use of the involved fingers distal to the carpometacarpal joints.

In pregnant women, GCTs have been found primarily in the long bones and spine but are rare.^17-21 A review of the literature (1950-present) revealed that the present article is the first report of GCT in the hand or wrist bones of a pregnant woman.^18,20,21 There is no consensus as to whether surgical excision should be performed during pregnancy.^18,20,21 In 1 unusual case, at 18 weeks’ gestation GCT in the distal femur was resected with curettage and bone grafting, and there were no complications.²¹ Therefore, pregnancy termination is not indicated for GCT.

The relationship between tumorigenesis and pregnancy is unclear.^18,20,21 Empirically, pregnancy is thought to promote tumor growth.^18,20 Estrogen and progesterone levels are elevated during pregnancy, potentially influencing tumor cells that are hormonally sensitive.^18,20 An early report in which reverse transcription–polymerase chain reaction showed estrogen receptor expression in GCT osteoclast-like cells was followed by several studies that failed to find estrogen receptors at the protein level.¹⁹ In contrast, progesterone receptors were found in 50% of GCTs in a study.²² However, the etiopathogenic significance of this is unclear. In pregnant women, vascular endothelial growth factor, placental growth factor, and other growth factors induce osteoclast formation.²³ ß-Human chorionic gonadotropin expression (ß-hCG) has been found in 58% of cases, with some showing ß-hCG elevation in the serum.²⁴ Other studies have focused on an immunologic explanation for occurrence of GCT during pregnancy.¹⁸ Oncofetal antigens, which are similar to fetal antigens, have been found in fibrosarcoma and in an osteosarcoma cell line but not in GCT.^18-20 Thus, though occurrence during pregnancy may be coincidental given the frequency of GCT in women of childbearing age, it is plausible that tumor growth may be enhanced by pregnancy. More studies are needed to understand the relationship between giant cell proliferation and pregnancy-related growth factors and hormones.

With GCT, the rate of pulmonary metastases ranges from 0% to 4%; these metastases are usually diagnosed at time of local recurrence, or 2 years to 3 years after initial GCT diagnosis.^2,3,12,14,25 Lung metastases secondary to GCT in the hand or foot bones are rare; our literature review identified only 4 cases.^12,14 Risk factors for lung metastasis include local recurrence, aggressive appearance (Enneking grade 3) on radiograph, Ki-67 antigen expression, and distal radius location.¹⁴ The mechanism of metastasis is unknown.^12,14

Lung metastases are usually excised, but they may spontaneously evolve toward necrosis and ossification.¹² In cases in which surgery is unfeasible, chemotherapy (eg, with doxorubicin) has been used to control progression.^12,14 Radiation can cause sarcomatous transformation and is contraindicated. Interferon^26-28 and other antiangiogenic strategies have been successfully used in systemic therapy for GCT of bone. More recently, bisphosphonates^29-32 and denosumab³³ have been investigated.^29,32-36 The limited toxicity of denosumab makes the drug a very attractive treatment option for recurrent or unresectable GCT of bone.³³ Reported rates of mortality from lung metastases have ranged from 0% to 40%.¹⁴ There is evidence that control of lung metastases during the first 3 years after diagnosis is important for favorable outcomes.^2,3

Malignant stromal cells of GCT of bone have been known to secrete RANKL, which recruits osteoclasts and osteoclast precursor cells, which in turn generate aggressive osteolytic activity.^33,37 Denosumab, a monoclonal antibody that inhibits RANKL, is effective in stopping osteoclastic activity. In a phase 2 trial of denosumab in the treatment of GCT of bone, 96% of treated patients with unresectable disease showed no progression at 13 months.³⁸ In addition, 74% of treated patients who had resectable disease but were likely to have morbid surgery did not require surgery, and 62% of treated patients who underwent surgery were able to have a less morbid procedure. Forty-one percent to 58% of treated patients had a reduction in tumor size.

Denosumab is very well tolerated. The phase 2 trial found serious adverse events in 9% of patients, and in 5% of cases the drug was discontinued because of toxicity.³⁸ Serious adverse events include osteonecrosis of jaw, hypocalcemia, and hypophosphatemia.³⁷ Electrolyte changes with denosumab are easy to monitor and manage. Although the favorable toxicity profile of denosumab allows for long-term therapy, the data on therapy duration in patients with unresectable disease are unclear. Patients who discontinue therapy should be closely monitored, as disease can progress in this setting.³⁷

In contrast to GCT of larger bones, GCT of the wrist is rare and typically more aggressive, and has higher local recurrence rates. In many cases, diagnosis is delayed by insufficient imaging, which optimally should include either CT or MRI (Table). [[{"fid":"202341","view_mode":"medstat_image_flush_right","attributes":{"class":"media-element file-medstat-image-flush-right","data-delta":"7"},"fields":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Table.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"7":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Table.","field_file_image_credit[und][0][value]":""}}}]]For pregnant women with GCT, options include surgical resection with curettage and local adjuvant treatment. After pregnancy, denosumab can be used systemically, and can be effective with metastatic or unresectable disease. Surgical treatment in the wrist can be challenging when partial or complete resections of carpal bones are required. Occupational therapy is recommended for optimization of hand function after surgery.

Take-Home Points

• GCT of bones of the wrist is rare. This article is the only report of a wrist GCT during pregnancy that we could identify.
• Routine treatment usually consists of surgical excision with local adjuvant, and in the wrist, often results in reduced wrist motion.
• GCT of the wrist is more aggressive than the more common locations in long bones, with higher local recurrence rates if treated with surgery alone.
• Diagnosis is often delayed for GCT of the wrist, due to insufficient imaging, which should include CT or MRI.
• For pregnant women with GCT, local adjuvant treatments can be used in addition to surgery. Following pregnancy, denosumab can be used systemically, and can be effective with metastatic or unresectable disease.

Giant cell tumor (GCT) of bone accounts for about 5% of primary bone tumors.^1-3 Only 3% to 5% of GCTs occur in the hand.^4,5 Wrist involvement, which is rare, most often involves the hamate bone.^5-7 Capitate bone involvement is exceedingly rare.^8-11 Although histologically benign, GCT can recur locally after treatment with curettage alone, and lung metastases are found in 2% to 5% of cases.^2,12-14 Therefore, en bloc tumor excision is preferred in the setting of cortical erosion or soft-tissue involvement.^1,4,8 Wrist joint motion is inevitably reduced, and bone graft donor-site morbidity is significant.^6-8

In the unusual case reported here, GCT presented in the capitate bone and, after the patient became pregnant, recurred in the hamate and trapezoid bones with soft-tissue extension and lung metastases. The capitate was excised en bloc and reconstructed with an interposition of polymethylmethacrylate bone cement. Pulmonary metastases developed, and the GCT expanded to involve multiple carpal bones and the bases of the second through fourth metacarpals. A 10-month course of systemic chemotherapy with the RANK ligand (RANKL) inhibitor denosumab was started after the pregnancy. After this treatment, the patient underwent both tumor resection and reconstruction with autogenous bicortical iliac crest bone graft (ICBG) carefully designed to preserve range of motion and maintain the fingers in anatomical position. Treatment with denosumab was continued after surgery. Although this case offers no endpoint for postoperative chemotherapy with denosumab, preoperative treatment dramatically reduced the GCT and permitted limb-sparing reconstruction. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 19-year-old right-handed woman with atraumatic swelling of the left wrist presented to an orthopedic surgeon at an outside facility. Physical examination revealed tender fullness on the dorsum of the wrist, slightly reduced range of motion and grip strength, and a neurovascularly intact wrist. The diagnosis was periarticular cyst, and the patient underwent physical therapy. Two years later, the swelling returned, tenderness was increasing, and symptoms did not resolve with cast immobilization. A radiograph showed a lytic lesion in the capitate bone (Figure 1).[[{"fid":"202332","view_mode":"medstat_image_flush_left","attributes":{"class":"media-element file-medstat-image-flush-left","data-delta":"1"},"fields":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 1.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"1":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 1.","field_file_image_credit[und][0][value]":""}}}]]

GCT was diagnosed with percutaneous needle biopsy. A preoperative chest radiograph was reported normal. For initial treatment, the capitate and trapezoid bones were resected en bloc through a dorsal approach. Reconstruction consisted of limited arthrodesis using bone cement without additional fixation.

At 6-month follow-up, the patient was pregnant, and there was a recurrence of the wrist lesion. During the first 2 months of pregnancy, swelling and pain rapidly progressed, and a palpable mass formed. Radiographs showed a lytic lesion extending into the hamate bone (Figure 2), and magnetic resonance imaging (MRI) showed articular extension of the lesion with involvement of the base of the fourth metacarpal. [[{"fid":"202334","view_mode":"medstat_image_flush_right","attributes":{"class":"media-element file-medstat-image-flush-right","data-delta":"2"},"fields":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Figure 2.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"2":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Figure 2.","field_file_image_credit[und][0][value]":""}}}]]Targeted anti-RANKL therapy was not recommended (and was not available at the patient’s home hospital). The patient deferred surgical treatment because of the pregnancy, which proved otherwise uneventful and ended with a full-term delivery.

After the pregnancy, radiographs of the wrist showed complete destruction of the hamate and trapezium bones, with erosion of the bases of the second through fourth metacarpals (Figure 3A). [[{"fid":"202335","view_mode":"medstat_image_flush_left","attributes":{"class":"media-element file-medstat-image-flush-left","data-delta":"3"},"fields":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 3.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"3":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 3.","field_file_image_credit[und][0][value]":""}}}]]The patient presented at our institution 4 years after initial diagnosis. Computed tomography (CT) of the chest showed numerous bilateral pulmonary nodular opacities. Wrist imaging showed soft-tissue extension (Figure 3B). The diagnosis of recurrent metastatic GCT was confirmed with needle biopsies of the wrist mass and the right lung nodule.

Systemic chemotherapy was initiated with 120 mg of denosumab, given subcutaneously on days 1, 8, and 15 and then monthly during the 10 months leading up to surgery. Serum calcium was monitored during treatment and remained within the normal range the entire time, except for once at the start of therapy, when it dropped to 6.8 mg/dL. After 8 months, the soft-tissue mass, originally 8 cm × 8 cm × 6 cm, shrunk and stabilized at 5 cm × 4 cm × 4 cm (Figure 3B), and a bony shell reformed around it. Nodules in both lung fields showed response to denosumab.

Histologic examination revealed scattered osteoclast-like, multinucleated giant cells, consistent with a recurrent lesion (Figure 4). [[{"fid":"202336","view_mode":"medstat_image_flush_right","attributes":{"class":"media-element file-medstat-image-flush-right","data-delta":"4"},"fields":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Figure 4.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"4":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Figure 4.","field_file_image_credit[und][0][value]":""}}}]]After 10 months of treatment with denosumab, the patient underwent resection (dorsal approach) of the residual cement, the soft-tissue mass, the affected carpal bones, half of the third metacarpal, and the second and fourth metacarpal bases. The proximal carpal row was preserved after no intra-articular involvement was verified. The closet margin was marginal; the tumor mass abutted without encompassing the flexor tendons and median nerve. The tumor was meticulously elevated from the neurovascular and tendinous structures, which were not sacrificed. Hydrogen peroxide was used for local adjuvant treatment. Bicortical autogenous ICBG was placed between the remaining scaphoid, lunate, and metacarpal bones. The second, third, and fourth metacarpal bases were stabilized on the overlapping outer table of ICBG with 2.0-mm plates and miniscrews (Figure 5A). Kirschner wires were used to stabilize the proximal bone graft and the scapholunate fossa. Cancellous bone graft was packed between the structural bone graft and neighboring unaffected carpal bones (Figure 5A). Immobilization with a short-arm thumb spica cast was maintained for 6 weeks after surgery and was followed by a 12-week rehabilitation program. The patient returned to normal activities when plain radiographs showed solid bony union (Figure 5B). Fourteen months after initial surgery, tenolysis was performed to free the extensor tendons (index, middle, and ring fingers on dorsum of left hand) from adhesions to the bone graft. At 37-month follow-up (Figure 5C), there was no clinical or radiographic evidence of progression in the wrist.[[{"fid":"202337","view_mode":"medstat_image_flush_left","attributes":{"class":"media-element file-medstat-image-flush-left","data-delta":"5"},"fields":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 5.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"5":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 5.","field_file_image_credit[und][0][value]":""}}}]]

The patient had bilateral pulmonary metastases (Figures 6A, 6B). Treatment with denosumab produced an initial response (smaller pulmonary lesions) and subsequent stability. After 12 months of treatment with denosumab, the patient underwent left thoracotomy and wedge resection of pulmonary metastases on the left. Pathologic evaluation revealed pulmonary parenchyma with calcification and ossification and limited viable tumor. Given the dramatic effects on the left pulmonary metastases, denosumab was continued, and surgical intervention on the right was not attempted. Pulmonary metastases were stable afterward (Figure 6C).[[{"fid":"202338","view_mode":"medstat_image_flush_right","attributes":{"class":"media-element file-medstat-image-flush-right","data-delta":"6"},"fields":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Figure 6.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"6":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Figure 6.","field_file_image_credit[und][0][value]":""}}}]]

At 54-month follow-up, systemic treatment with denosumab was continued. The patient had no pain in the wrist or hand and was able to use the left hand normally. There was some fissuring of the third and fourth digits over each other. However, the patient had good grip strength and was using eating utensils, picking up water bottles, and engaging in other activities without difficulty.

Discussion

GCT isolated to the carpus is rare. However, compared with GCT in the more common locations in long bones, it is also more aggressive, and its local recurrence rates are higher, probably 60% or more if treated with curettage alone.¹⁵ Therefore, excision augmented with adjuvant treatment is recommended.^2,7 Use of bone cement in the hand is relatively uncommon.^4,5,7-10

The diagnosis of GCT in the carpus is difficult and often delayed. The initial complaint is usually mild wrist pain after relatively mild trauma.⁵ The first reported case of GCT in the lunate bone was mistakenly thought to be Kienbock disease.⁵ Similarly, our patient was initially given a nononcologic diagnosis, which prompted conservative management.

Whether the biological behavior of GCT in the carpus differs from that of GCT in other sites is unclear. The high recurrence rates might be attributable in part to suboptimal curettage.^5,6 En bloc resections of involved bone inevitably result in carpal instability or loss of wrist motion if arthrodesis is performed.^4-7,11 In the present case, resection was followed by limited arthrodesis to mitigate motion losses.

Multifocal GCT in the carpal bones often affects younger patients and has a high rate of recurrence.^7,16 In the present case, the patient’s pregnancy delayed treatment and allowed tumor extension into soft tissues and metacarpal bones. Given her young age, en bloc tumor resection was performed, with the proximal carpal row spared to preserve wrist motion. ICBG was carefully shaped to match the defect that remained after tumor resection.⁷ Supporting wrist height to prevent carpal collapse provided a stable base for remaining distal segments of the second through fourth metacarpals. After short-arm thumb spica casting and early rehabilitation, the patient recovered wrist motion and use of the involved fingers distal to the carpometacarpal joints.

In pregnant women, GCTs have been found primarily in the long bones and spine but are rare.^17-21 A review of the literature (1950-present) revealed that the present article is the first report of GCT in the hand or wrist bones of a pregnant woman.^18,20,21 There is no consensus as to whether surgical excision should be performed during pregnancy.^18,20,21 In 1 unusual case, at 18 weeks’ gestation GCT in the distal femur was resected with curettage and bone grafting, and there were no complications.²¹ Therefore, pregnancy termination is not indicated for GCT.

The relationship between tumorigenesis and pregnancy is unclear.^18,20,21 Empirically, pregnancy is thought to promote tumor growth.^18,20 Estrogen and progesterone levels are elevated during pregnancy, potentially influencing tumor cells that are hormonally sensitive.^18,20 An early report in which reverse transcription–polymerase chain reaction showed estrogen receptor expression in GCT osteoclast-like cells was followed by several studies that failed to find estrogen receptors at the protein level.¹⁹ In contrast, progesterone receptors were found in 50% of GCTs in a study.²² However, the etiopathogenic significance of this is unclear. In pregnant women, vascular endothelial growth factor, placental growth factor, and other growth factors induce osteoclast formation.²³ ß-Human chorionic gonadotropin expression (ß-hCG) has been found in 58% of cases, with some showing ß-hCG elevation in the serum.²⁴ Other studies have focused on an immunologic explanation for occurrence of GCT during pregnancy.¹⁸ Oncofetal antigens, which are similar to fetal antigens, have been found in fibrosarcoma and in an osteosarcoma cell line but not in GCT.^18-20 Thus, though occurrence during pregnancy may be coincidental given the frequency of GCT in women of childbearing age, it is plausible that tumor growth may be enhanced by pregnancy. More studies are needed to understand the relationship between giant cell proliferation and pregnancy-related growth factors and hormones.

With GCT, the rate of pulmonary metastases ranges from 0% to 4%; these metastases are usually diagnosed at time of local recurrence, or 2 years to 3 years after initial GCT diagnosis.^2,3,12,14,25 Lung metastases secondary to GCT in the hand or foot bones are rare; our literature review identified only 4 cases.^12,14 Risk factors for lung metastasis include local recurrence, aggressive appearance (Enneking grade 3) on radiograph, Ki-67 antigen expression, and distal radius location.¹⁴ The mechanism of metastasis is unknown.^12,14

Lung metastases are usually excised, but they may spontaneously evolve toward necrosis and ossification.¹² In cases in which surgery is unfeasible, chemotherapy (eg, with doxorubicin) has been used to control progression.^12,14 Radiation can cause sarcomatous transformation and is contraindicated. Interferon^26-28 and other antiangiogenic strategies have been successfully used in systemic therapy for GCT of bone. More recently, bisphosphonates^29-32 and denosumab³³ have been investigated.^29,32-36 The limited toxicity of denosumab makes the drug a very attractive treatment option for recurrent or unresectable GCT of bone.³³ Reported rates of mortality from lung metastases have ranged from 0% to 40%.¹⁴ There is evidence that control of lung metastases during the first 3 years after diagnosis is important for favorable outcomes.^2,3

Malignant stromal cells of GCT of bone have been known to secrete RANKL, which recruits osteoclasts and osteoclast precursor cells, which in turn generate aggressive osteolytic activity.^33,37 Denosumab, a monoclonal antibody that inhibits RANKL, is effective in stopping osteoclastic activity. In a phase 2 trial of denosumab in the treatment of GCT of bone, 96% of treated patients with unresectable disease showed no progression at 13 months.³⁸ In addition, 74% of treated patients who had resectable disease but were likely to have morbid surgery did not require surgery, and 62% of treated patients who underwent surgery were able to have a less morbid procedure. Forty-one percent to 58% of treated patients had a reduction in tumor size.

Denosumab is very well tolerated. The phase 2 trial found serious adverse events in 9% of patients, and in 5% of cases the drug was discontinued because of toxicity.³⁸ Serious adverse events include osteonecrosis of jaw, hypocalcemia, and hypophosphatemia.³⁷ Electrolyte changes with denosumab are easy to monitor and manage. Although the favorable toxicity profile of denosumab allows for long-term therapy, the data on therapy duration in patients with unresectable disease are unclear. Patients who discontinue therapy should be closely monitored, as disease can progress in this setting.³⁷

In contrast to GCT of larger bones, GCT of the wrist is rare and typically more aggressive, and has higher local recurrence rates. In many cases, diagnosis is delayed by insufficient imaging, which optimally should include either CT or MRI (Table). [[{"fid":"202341","view_mode":"medstat_image_flush_right","attributes":{"class":"media-element file-medstat-image-flush-right","data-delta":"7"},"fields":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Table.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"7":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Table.","field_file_image_credit[und][0][value]":""}}}]]For pregnant women with GCT, options include surgical resection with curettage and local adjuvant treatment. After pregnancy, denosumab can be used systemically, and can be effective with metastatic or unresectable disease. Surgical treatment in the wrist can be challenging when partial or complete resections of carpal bones are required. Occupational therapy is recommended for optimization of hand function after surgery.

Take-Home Points

• GCT of bones of the wrist is rare. This article is the only report of a wrist GCT during pregnancy that we could identify.
• Routine treatment usually consists of surgical excision with local adjuvant, and in the wrist, often results in reduced wrist motion.
• GCT of the wrist is more aggressive than the more common locations in long bones, with higher local recurrence rates if treated with surgery alone.
• Diagnosis is often delayed for GCT of the wrist, due to insufficient imaging, which should include CT or MRI.
• For pregnant women with GCT, local adjuvant treatments can be used in addition to surgery. Following pregnancy, denosumab can be used systemically, and can be effective with metastatic or unresectable disease.

Giant cell tumor (GCT) of bone accounts for about 5% of primary bone tumors.^1-3 Only 3% to 5% of GCTs occur in the hand.^4,5 Wrist involvement, which is rare, most often involves the hamate bone.^5-7 Capitate bone involvement is exceedingly rare.^8-11 Although histologically benign, GCT can recur locally after treatment with curettage alone, and lung metastases are found in 2% to 5% of cases.^2,12-14 Therefore, en bloc tumor excision is preferred in the setting of cortical erosion or soft-tissue involvement.^1,4,8 Wrist joint motion is inevitably reduced, and bone graft donor-site morbidity is significant.^6-8

In the unusual case reported here, GCT presented in the capitate bone and, after the patient became pregnant, recurred in the hamate and trapezoid bones with soft-tissue extension and lung metastases. The capitate was excised en bloc and reconstructed with an interposition of polymethylmethacrylate bone cement. Pulmonary metastases developed, and the GCT expanded to involve multiple carpal bones and the bases of the second through fourth metacarpals. A 10-month course of systemic chemotherapy with the RANK ligand (RANKL) inhibitor denosumab was started after the pregnancy. After this treatment, the patient underwent both tumor resection and reconstruction with autogenous bicortical iliac crest bone graft (ICBG) carefully designed to preserve range of motion and maintain the fingers in anatomical position. Treatment with denosumab was continued after surgery. Although this case offers no endpoint for postoperative chemotherapy with denosumab, preoperative treatment dramatically reduced the GCT and permitted limb-sparing reconstruction. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 19-year-old right-handed woman with atraumatic swelling of the left wrist presented to an orthopedic surgeon at an outside facility. Physical examination revealed tender fullness on the dorsum of the wrist, slightly reduced range of motion and grip strength, and a neurovascularly intact wrist. The diagnosis was periarticular cyst, and the patient underwent physical therapy. Two years later, the swelling returned, tenderness was increasing, and symptoms did not resolve with cast immobilization. A radiograph showed a lytic lesion in the capitate bone (Figure 1).[[{"fid":"202332","view_mode":"medstat_image_flush_left","attributes":{"class":"media-element file-medstat-image-flush-left","data-delta":"1"},"fields":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 1.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"1":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 1.","field_file_image_credit[und][0][value]":""}}}]]

GCT was diagnosed with percutaneous needle biopsy. A preoperative chest radiograph was reported normal. For initial treatment, the capitate and trapezoid bones were resected en bloc through a dorsal approach. Reconstruction consisted of limited arthrodesis using bone cement without additional fixation.

At 6-month follow-up, the patient was pregnant, and there was a recurrence of the wrist lesion. During the first 2 months of pregnancy, swelling and pain rapidly progressed, and a palpable mass formed. Radiographs showed a lytic lesion extending into the hamate bone (Figure 2), and magnetic resonance imaging (MRI) showed articular extension of the lesion with involvement of the base of the fourth metacarpal. [[{"fid":"202334","view_mode":"medstat_image_flush_right","attributes":{"class":"media-element file-medstat-image-flush-right","data-delta":"2"},"fields":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Figure 2.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"2":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Figure 2.","field_file_image_credit[und][0][value]":""}}}]]Targeted anti-RANKL therapy was not recommended (and was not available at the patient’s home hospital). The patient deferred surgical treatment because of the pregnancy, which proved otherwise uneventful and ended with a full-term delivery.

After the pregnancy, radiographs of the wrist showed complete destruction of the hamate and trapezium bones, with erosion of the bases of the second through fourth metacarpals (Figure 3A). [[{"fid":"202335","view_mode":"medstat_image_flush_left","attributes":{"class":"media-element file-medstat-image-flush-left","data-delta":"3"},"fields":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 3.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"3":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 3.","field_file_image_credit[und][0][value]":""}}}]]The patient presented at our institution 4 years after initial diagnosis. Computed tomography (CT) of the chest showed numerous bilateral pulmonary nodular opacities. Wrist imaging showed soft-tissue extension (Figure 3B). The diagnosis of recurrent metastatic GCT was confirmed with needle biopsies of the wrist mass and the right lung nodule.

Systemic chemotherapy was initiated with 120 mg of denosumab, given subcutaneously on days 1, 8, and 15 and then monthly during the 10 months leading up to surgery. Serum calcium was monitored during treatment and remained within the normal range the entire time, except for once at the start of therapy, when it dropped to 6.8 mg/dL. After 8 months, the soft-tissue mass, originally 8 cm × 8 cm × 6 cm, shrunk and stabilized at 5 cm × 4 cm × 4 cm (Figure 3B), and a bony shell reformed around it. Nodules in both lung fields showed response to denosumab.

Histologic examination revealed scattered osteoclast-like, multinucleated giant cells, consistent with a recurrent lesion (Figure 4). [[{"fid":"202336","view_mode":"medstat_image_flush_right","attributes":{"class":"media-element file-medstat-image-flush-right","data-delta":"4"},"fields":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Figure 4.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"4":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Figure 4.","field_file_image_credit[und][0][value]":""}}}]]After 10 months of treatment with denosumab, the patient underwent resection (dorsal approach) of the residual cement, the soft-tissue mass, the affected carpal bones, half of the third metacarpal, and the second and fourth metacarpal bases. The proximal carpal row was preserved after no intra-articular involvement was verified. The closet margin was marginal; the tumor mass abutted without encompassing the flexor tendons and median nerve. The tumor was meticulously elevated from the neurovascular and tendinous structures, which were not sacrificed. Hydrogen peroxide was used for local adjuvant treatment. Bicortical autogenous ICBG was placed between the remaining scaphoid, lunate, and metacarpal bones. The second, third, and fourth metacarpal bases were stabilized on the overlapping outer table of ICBG with 2.0-mm plates and miniscrews (Figure 5A). Kirschner wires were used to stabilize the proximal bone graft and the scapholunate fossa. Cancellous bone graft was packed between the structural bone graft and neighboring unaffected carpal bones (Figure 5A). Immobilization with a short-arm thumb spica cast was maintained for 6 weeks after surgery and was followed by a 12-week rehabilitation program. The patient returned to normal activities when plain radiographs showed solid bony union (Figure 5B). Fourteen months after initial surgery, tenolysis was performed to free the extensor tendons (index, middle, and ring fingers on dorsum of left hand) from adhesions to the bone graft. At 37-month follow-up (Figure 5C), there was no clinical or radiographic evidence of progression in the wrist.[[{"fid":"202337","view_mode":"medstat_image_flush_left","attributes":{"class":"media-element file-medstat-image-flush-left","data-delta":"5"},"fields":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 5.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"5":{"format":"medstat_image_flush_left","field_file_image_caption[und][0][value]":"Figure 5.","field_file_image_credit[und][0][value]":""}}}]]

The patient had bilateral pulmonary metastases (Figures 6A, 6B). Treatment with denosumab produced an initial response (smaller pulmonary lesions) and subsequent stability. After 12 months of treatment with denosumab, the patient underwent left thoracotomy and wedge resection of pulmonary metastases on the left. Pathologic evaluation revealed pulmonary parenchyma with calcification and ossification and limited viable tumor. Given the dramatic effects on the left pulmonary metastases, denosumab was continued, and surgical intervention on the right was not attempted. Pulmonary metastases were stable afterward (Figure 6C).[[{"fid":"202338","view_mode":"medstat_image_flush_right","attributes":{"class":"media-element file-medstat-image-flush-right","data-delta":"6"},"fields":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Figure 6.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"6":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Figure 6.","field_file_image_credit[und][0][value]":""}}}]]

At 54-month follow-up, systemic treatment with denosumab was continued. The patient had no pain in the wrist or hand and was able to use the left hand normally. There was some fissuring of the third and fourth digits over each other. However, the patient had good grip strength and was using eating utensils, picking up water bottles, and engaging in other activities without difficulty.

Discussion

GCT isolated to the carpus is rare. However, compared with GCT in the more common locations in long bones, it is also more aggressive, and its local recurrence rates are higher, probably 60% or more if treated with curettage alone.¹⁵ Therefore, excision augmented with adjuvant treatment is recommended.^2,7 Use of bone cement in the hand is relatively uncommon.^4,5,7-10

The diagnosis of GCT in the carpus is difficult and often delayed. The initial complaint is usually mild wrist pain after relatively mild trauma.⁵ The first reported case of GCT in the lunate bone was mistakenly thought to be Kienbock disease.⁵ Similarly, our patient was initially given a nononcologic diagnosis, which prompted conservative management.

Whether the biological behavior of GCT in the carpus differs from that of GCT in other sites is unclear. The high recurrence rates might be attributable in part to suboptimal curettage.^5,6 En bloc resections of involved bone inevitably result in carpal instability or loss of wrist motion if arthrodesis is performed.^4-7,11 In the present case, resection was followed by limited arthrodesis to mitigate motion losses.

Multifocal GCT in the carpal bones often affects younger patients and has a high rate of recurrence.^7,16 In the present case, the patient’s pregnancy delayed treatment and allowed tumor extension into soft tissues and metacarpal bones. Given her young age, en bloc tumor resection was performed, with the proximal carpal row spared to preserve wrist motion. ICBG was carefully shaped to match the defect that remained after tumor resection.⁷ Supporting wrist height to prevent carpal collapse provided a stable base for remaining distal segments of the second through fourth metacarpals. After short-arm thumb spica casting and early rehabilitation, the patient recovered wrist motion and use of the involved fingers distal to the carpometacarpal joints.

In pregnant women, GCTs have been found primarily in the long bones and spine but are rare.^17-21 A review of the literature (1950-present) revealed that the present article is the first report of GCT in the hand or wrist bones of a pregnant woman.^18,20,21 There is no consensus as to whether surgical excision should be performed during pregnancy.^18,20,21 In 1 unusual case, at 18 weeks’ gestation GCT in the distal femur was resected with curettage and bone grafting, and there were no complications.²¹ Therefore, pregnancy termination is not indicated for GCT.

The relationship between tumorigenesis and pregnancy is unclear.^18,20,21 Empirically, pregnancy is thought to promote tumor growth.^18,20 Estrogen and progesterone levels are elevated during pregnancy, potentially influencing tumor cells that are hormonally sensitive.^18,20 An early report in which reverse transcription–polymerase chain reaction showed estrogen receptor expression in GCT osteoclast-like cells was followed by several studies that failed to find estrogen receptors at the protein level.¹⁹ In contrast, progesterone receptors were found in 50% of GCTs in a study.²² However, the etiopathogenic significance of this is unclear. In pregnant women, vascular endothelial growth factor, placental growth factor, and other growth factors induce osteoclast formation.²³ ß-Human chorionic gonadotropin expression (ß-hCG) has been found in 58% of cases, with some showing ß-hCG elevation in the serum.²⁴ Other studies have focused on an immunologic explanation for occurrence of GCT during pregnancy.¹⁸ Oncofetal antigens, which are similar to fetal antigens, have been found in fibrosarcoma and in an osteosarcoma cell line but not in GCT.^18-20 Thus, though occurrence during pregnancy may be coincidental given the frequency of GCT in women of childbearing age, it is plausible that tumor growth may be enhanced by pregnancy. More studies are needed to understand the relationship between giant cell proliferation and pregnancy-related growth factors and hormones.

With GCT, the rate of pulmonary metastases ranges from 0% to 4%; these metastases are usually diagnosed at time of local recurrence, or 2 years to 3 years after initial GCT diagnosis.^2,3,12,14,25 Lung metastases secondary to GCT in the hand or foot bones are rare; our literature review identified only 4 cases.^12,14 Risk factors for lung metastasis include local recurrence, aggressive appearance (Enneking grade 3) on radiograph, Ki-67 antigen expression, and distal radius location.¹⁴ The mechanism of metastasis is unknown.^12,14

Lung metastases are usually excised, but they may spontaneously evolve toward necrosis and ossification.¹² In cases in which surgery is unfeasible, chemotherapy (eg, with doxorubicin) has been used to control progression.^12,14 Radiation can cause sarcomatous transformation and is contraindicated. Interferon^26-28 and other antiangiogenic strategies have been successfully used in systemic therapy for GCT of bone. More recently, bisphosphonates^29-32 and denosumab³³ have been investigated.^29,32-36 The limited toxicity of denosumab makes the drug a very attractive treatment option for recurrent or unresectable GCT of bone.³³ Reported rates of mortality from lung metastases have ranged from 0% to 40%.¹⁴ There is evidence that control of lung metastases during the first 3 years after diagnosis is important for favorable outcomes.^2,3

Malignant stromal cells of GCT of bone have been known to secrete RANKL, which recruits osteoclasts and osteoclast precursor cells, which in turn generate aggressive osteolytic activity.^33,37 Denosumab, a monoclonal antibody that inhibits RANKL, is effective in stopping osteoclastic activity. In a phase 2 trial of denosumab in the treatment of GCT of bone, 96% of treated patients with unresectable disease showed no progression at 13 months.³⁸ In addition, 74% of treated patients who had resectable disease but were likely to have morbid surgery did not require surgery, and 62% of treated patients who underwent surgery were able to have a less morbid procedure. Forty-one percent to 58% of treated patients had a reduction in tumor size.

Denosumab is very well tolerated. The phase 2 trial found serious adverse events in 9% of patients, and in 5% of cases the drug was discontinued because of toxicity.³⁸ Serious adverse events include osteonecrosis of jaw, hypocalcemia, and hypophosphatemia.³⁷ Electrolyte changes with denosumab are easy to monitor and manage. Although the favorable toxicity profile of denosumab allows for long-term therapy, the data on therapy duration in patients with unresectable disease are unclear. Patients who discontinue therapy should be closely monitored, as disease can progress in this setting.³⁷

In contrast to GCT of larger bones, GCT of the wrist is rare and typically more aggressive, and has higher local recurrence rates. In many cases, diagnosis is delayed by insufficient imaging, which optimally should include either CT or MRI (Table). [[{"fid":"202341","view_mode":"medstat_image_flush_right","attributes":{"class":"media-element file-medstat-image-flush-right","data-delta":"7"},"fields":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Table.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"7":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Table.","field_file_image_credit[und][0][value]":""}}}]]For pregnant women with GCT, options include surgical resection with curettage and local adjuvant treatment. After pregnancy, denosumab can be used systemically, and can be effective with metastatic or unresectable disease. Surgical treatment in the wrist can be challenging when partial or complete resections of carpal bones are required. Occupational therapy is recommended for optimization of hand function after surgery.

LONDON—Nine modifiable risk factors may account for about a third of dementia cases, according to an estimate by the Lancet International Commission on Dementia Prevention, Intervention, and Care. The estimate is part of a commission report that was presented at the 2017 Alzheimer’s Association International Conference and published in Lancet.

The report reviews the evidence for pharmacologic, psychologic, environmental, and social interventions for patients with dementia. It includes algorithms for the management of psychosis, agitation, and depression. And it emphasizes the importance of assessing risks to patients (eg, abuse and nutritional deficiencies), caring for family caregivers, and future planning.

“There has been a great deal of focus on developing medicines to prevent dementia,” said Lon S. Schneider, MD, Professor of Psychiatry and Behavioral Sciences at the Keck School of Medicine of University of Southern California in Los Angeles and one of the report’s authors. “But we cannot lose sight of the … advances we have already made in treating dementia, including preventive approaches.”

Nine Risk Factors

The authors reviewed the literature on dementia risk factors and estimated the potential percentage reduction in new cases of dementia if a risk factor were eliminated (ie, the population attributable fraction). The results suggest that approximately 35% of cases of dementia are attributable to a combination of low education level in childhood, hearing loss, hypertension, obesity, smoking, depression, physical inactivity, social isolation, and diabetes. In comparison, eliminating risk from the ApoE ε4 allele would be expected to reduce the incidence of dementia by 7%.

The model assumes a causal association between a risk factor and dementia. Although randomized controlled trials to establish causality are not possible for many dementia risk factors, causal relations are plausible, the authors said. Potential mechanisms include effects on cognitive reserve, brain damage, and brain inflammation. Other potentially modifiable risk factors that were not included in the analysis due to insufficient data include diet, visual impairment, sleep disorders, and particulate air pollution.

“While public health interventions will not delay, prevent, or cure all potentially modifiable dementia, the management of metabolic, mental health, hearing, and cerebrovascular risk factors might push back the onset of many cases for some years,” the report says.

Treatment Approaches

Patients with Alzheimer’s disease or dementia with Lewy bodies should be offered cholinesterase inhibitors at all stages of disease, or memantine for severe dementia, the commission recommends. Because effects on cognition and function are small, clinicians often cannot determine treatment response in individual patients. Side effects of cholinesterase inhibitors (eg, nausea, vomiting, diarrhea, vivid dreams, and cramps) often influence treatment decisions.

Evidence indicates that nonpharmacologic interventions are superior to antipsychotic medications for the treatment of dementia-related agitation and aggression. Antipsychotic drugs increase the risk of death, cardiovascular adverse events, infection, and excessive sedation and should only be used when symptoms cause distress or increase risk, the report says. Physicians should discuss with the patient, his or her family, and care staff whether the possible benefits of treatment with an antipsychotic drug are likely to outweigh the risks, and they should document the discussion.

“The most effective psychosocial treatments are usually multimodal, individualized care, and train carers in skills, including optimizing communication, coping, and environmental adaptations,” according to the commission report.

—Jake Remaly

Suggested Reading

Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care. Lancet. 2017 Jul 19 [Epub ahead of print].

LONDON—Nine modifiable risk factors may account for about a third of dementia cases, according to an estimate by the Lancet International Commission on Dementia Prevention, Intervention, and Care. The estimate is part of a commission report that was presented at the 2017 Alzheimer’s Association International Conference and published in Lancet.

The report reviews the evidence for pharmacologic, psychologic, environmental, and social interventions for patients with dementia. It includes algorithms for the management of psychosis, agitation, and depression. And it emphasizes the importance of assessing risks to patients (eg, abuse and nutritional deficiencies), caring for family caregivers, and future planning.

“There has been a great deal of focus on developing medicines to prevent dementia,” said Lon S. Schneider, MD, Professor of Psychiatry and Behavioral Sciences at the Keck School of Medicine of University of Southern California in Los Angeles and one of the report’s authors. “But we cannot lose sight of the … advances we have already made in treating dementia, including preventive approaches.”

Nine Risk Factors

The authors reviewed the literature on dementia risk factors and estimated the potential percentage reduction in new cases of dementia if a risk factor were eliminated (ie, the population attributable fraction). The results suggest that approximately 35% of cases of dementia are attributable to a combination of low education level in childhood, hearing loss, hypertension, obesity, smoking, depression, physical inactivity, social isolation, and diabetes. In comparison, eliminating risk from the ApoE ε4 allele would be expected to reduce the incidence of dementia by 7%.

The model assumes a causal association between a risk factor and dementia. Although randomized controlled trials to establish causality are not possible for many dementia risk factors, causal relations are plausible, the authors said. Potential mechanisms include effects on cognitive reserve, brain damage, and brain inflammation. Other potentially modifiable risk factors that were not included in the analysis due to insufficient data include diet, visual impairment, sleep disorders, and particulate air pollution.

“While public health interventions will not delay, prevent, or cure all potentially modifiable dementia, the management of metabolic, mental health, hearing, and cerebrovascular risk factors might push back the onset of many cases for some years,” the report says.

Treatment Approaches

Patients with Alzheimer’s disease or dementia with Lewy bodies should be offered cholinesterase inhibitors at all stages of disease, or memantine for severe dementia, the commission recommends. Because effects on cognition and function are small, clinicians often cannot determine treatment response in individual patients. Side effects of cholinesterase inhibitors (eg, nausea, vomiting, diarrhea, vivid dreams, and cramps) often influence treatment decisions.

Evidence indicates that nonpharmacologic interventions are superior to antipsychotic medications for the treatment of dementia-related agitation and aggression. Antipsychotic drugs increase the risk of death, cardiovascular adverse events, infection, and excessive sedation and should only be used when symptoms cause distress or increase risk, the report says. Physicians should discuss with the patient, his or her family, and care staff whether the possible benefits of treatment with an antipsychotic drug are likely to outweigh the risks, and they should document the discussion.

“The most effective psychosocial treatments are usually multimodal, individualized care, and train carers in skills, including optimizing communication, coping, and environmental adaptations,” according to the commission report.

—Jake Remaly

Suggested Reading

Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care. Lancet. 2017 Jul 19 [Epub ahead of print].

LONDON—Nine modifiable risk factors may account for about a third of dementia cases, according to an estimate by the Lancet International Commission on Dementia Prevention, Intervention, and Care. The estimate is part of a commission report that was presented at the 2017 Alzheimer’s Association International Conference and published in Lancet.

The report reviews the evidence for pharmacologic, psychologic, environmental, and social interventions for patients with dementia. It includes algorithms for the management of psychosis, agitation, and depression. And it emphasizes the importance of assessing risks to patients (eg, abuse and nutritional deficiencies), caring for family caregivers, and future planning.

“There has been a great deal of focus on developing medicines to prevent dementia,” said Lon S. Schneider, MD, Professor of Psychiatry and Behavioral Sciences at the Keck School of Medicine of University of Southern California in Los Angeles and one of the report’s authors. “But we cannot lose sight of the … advances we have already made in treating dementia, including preventive approaches.”

Nine Risk Factors

The authors reviewed the literature on dementia risk factors and estimated the potential percentage reduction in new cases of dementia if a risk factor were eliminated (ie, the population attributable fraction). The results suggest that approximately 35% of cases of dementia are attributable to a combination of low education level in childhood, hearing loss, hypertension, obesity, smoking, depression, physical inactivity, social isolation, and diabetes. In comparison, eliminating risk from the ApoE ε4 allele would be expected to reduce the incidence of dementia by 7%.

The model assumes a causal association between a risk factor and dementia. Although randomized controlled trials to establish causality are not possible for many dementia risk factors, causal relations are plausible, the authors said. Potential mechanisms include effects on cognitive reserve, brain damage, and brain inflammation. Other potentially modifiable risk factors that were not included in the analysis due to insufficient data include diet, visual impairment, sleep disorders, and particulate air pollution.

“While public health interventions will not delay, prevent, or cure all potentially modifiable dementia, the management of metabolic, mental health, hearing, and cerebrovascular risk factors might push back the onset of many cases for some years,” the report says.

Treatment Approaches

Patients with Alzheimer’s disease or dementia with Lewy bodies should be offered cholinesterase inhibitors at all stages of disease, or memantine for severe dementia, the commission recommends. Because effects on cognition and function are small, clinicians often cannot determine treatment response in individual patients. Side effects of cholinesterase inhibitors (eg, nausea, vomiting, diarrhea, vivid dreams, and cramps) often influence treatment decisions.

Evidence indicates that nonpharmacologic interventions are superior to antipsychotic medications for the treatment of dementia-related agitation and aggression. Antipsychotic drugs increase the risk of death, cardiovascular adverse events, infection, and excessive sedation and should only be used when symptoms cause distress or increase risk, the report says. Physicians should discuss with the patient, his or her family, and care staff whether the possible benefits of treatment with an antipsychotic drug are likely to outweigh the risks, and they should document the discussion.

“The most effective psychosocial treatments are usually multimodal, individualized care, and train carers in skills, including optimizing communication, coping, and environmental adaptations,” according to the commission report.

—Jake Remaly

Suggested Reading

Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care. Lancet. 2017 Jul 19 [Epub ahead of print].

BARCELONA – For Clyde Yancy, MD, presentation of the bombshell CANTOS trial results at the annual congress of the European Congress of Cardiology made for “a really good day.”

Those results showed that inhibiting the interleukin-1 beta innate immunity pathway with canakinumab reduced recurrent cardiovascular events and lung cancer. But further, they introduced a new way of identifying and treating patients for secondary prevention.

“Here is an alternative way to get to cardiovascular events; here is bringing inflammation right to the front page of what we do as cardiologists to prevent events; here is a brand-new agent that is a monoclonal antibody against interleukin that may be modifying this risk, and … a remarkable advantage that really needs to be replicated,” said Dr. Yancy, chief of medicine-cardiology at Northwestern University in Chicago, in a video interview.

“This is a really good day” because we’ve got new things to think about, new ways to approach our patients, and [we may soon be] entering the realm where we’ll want personalized therapy based on the unique phenotype a patient represents, and think about the pathways to disease through these brand new schemes” that are helping us understand the burden of disease, he declared.

[email protected]

BARCELONA – For Clyde Yancy, MD, presentation of the bombshell CANTOS trial results at the annual congress of the European Congress of Cardiology made for “a really good day.”

Those results showed that inhibiting the interleukin-1 beta innate immunity pathway with canakinumab reduced recurrent cardiovascular events and lung cancer. But further, they introduced a new way of identifying and treating patients for secondary prevention.

“Here is an alternative way to get to cardiovascular events; here is bringing inflammation right to the front page of what we do as cardiologists to prevent events; here is a brand-new agent that is a monoclonal antibody against interleukin that may be modifying this risk, and … a remarkable advantage that really needs to be replicated,” said Dr. Yancy, chief of medicine-cardiology at Northwestern University in Chicago, in a video interview.

“This is a really good day” because we’ve got new things to think about, new ways to approach our patients, and [we may soon be] entering the realm where we’ll want personalized therapy based on the unique phenotype a patient represents, and think about the pathways to disease through these brand new schemes” that are helping us understand the burden of disease, he declared.

[email protected]

BARCELONA – For Clyde Yancy, MD, presentation of the bombshell CANTOS trial results at the annual congress of the European Congress of Cardiology made for “a really good day.”

Those results showed that inhibiting the interleukin-1 beta innate immunity pathway with canakinumab reduced recurrent cardiovascular events and lung cancer. But further, they introduced a new way of identifying and treating patients for secondary prevention.

“Here is an alternative way to get to cardiovascular events; here is bringing inflammation right to the front page of what we do as cardiologists to prevent events; here is a brand-new agent that is a monoclonal antibody against interleukin that may be modifying this risk, and … a remarkable advantage that really needs to be replicated,” said Dr. Yancy, chief of medicine-cardiology at Northwestern University in Chicago, in a video interview.

“This is a really good day” because we’ve got new things to think about, new ways to approach our patients, and [we may soon be] entering the realm where we’ll want personalized therapy based on the unique phenotype a patient represents, and think about the pathways to disease through these brand new schemes” that are helping us understand the burden of disease, he declared.

[email protected]

Immediate initiation of combined antiretroviral therapy (ART) shows benefits in reducing all-cause mortality in non-AIDS HIV-positive patients aged 50 years or older, according to Sara Lodi, PhD, and her associates.

In a study of 9,596 eligible patients, 2,672 (28%) were U.S. veterans. Results found the 5-year risk of all-cause mortality under immediate ART initiation was 5.3% in the general HIV population and 14.4% in the veterans. The 5-year risk of all-cause mortality was 0.40% lower for the general HIV population and 1.61% lower for veterans compared with immediate initiation versus initiation at CD4 below 350 cells/mm³.

Cynthia Goldsmith, CDC

[email protected]

Immediate initiation of combined antiretroviral therapy (ART) shows benefits in reducing all-cause mortality in non-AIDS HIV-positive patients aged 50 years or older, according to Sara Lodi, PhD, and her associates.

In a study of 9,596 eligible patients, 2,672 (28%) were U.S. veterans. Results found the 5-year risk of all-cause mortality under immediate ART initiation was 5.3% in the general HIV population and 14.4% in the veterans. The 5-year risk of all-cause mortality was 0.40% lower for the general HIV population and 1.61% lower for veterans compared with immediate initiation versus initiation at CD4 below 350 cells/mm³.

Cynthia Goldsmith, CDC

[email protected]

Immediate initiation of combined antiretroviral therapy (ART) shows benefits in reducing all-cause mortality in non-AIDS HIV-positive patients aged 50 years or older, according to Sara Lodi, PhD, and her associates.

In a study of 9,596 eligible patients, 2,672 (28%) were U.S. veterans. Results found the 5-year risk of all-cause mortality under immediate ART initiation was 5.3% in the general HIV population and 14.4% in the veterans. The 5-year risk of all-cause mortality was 0.40% lower for the general HIV population and 1.61% lower for veterans compared with immediate initiation versus initiation at CD4 below 350 cells/mm³.

Cynthia Goldsmith, CDC

[email protected]

The current opioid epidemic in the United States has been universally recognized as one of the most important public health issues to date. This crisis has cost nearly $80 billion in lost productivity, treatment (including emergency, medical, psychiatric, and addiction-specific care), and criminal justice involvement.¹ Opioid overdoses have increased by 200% since 2000, with more than 33,000 individuals dying from opioid overdoses in 2015 alone.^2,3

Devonyu/Thinkstock

Additional associations

A recent study of nearly 5 million veterans enrolled in the Veterans Health Administration demonstrated that, even when adjusted for age and comorbid psychiatric diagnoses, opioid use disorder was associated with an increased risk for suicide; particularly striking was that this risk was doubled in women.¹³

A survey of 40,000 subjects from the 2014 National Survey on Drug Use and Health demonstrated that prescription opioid misuse was associated with an increased risk of suicidal ideation, and weekly misuse was associated with increased suicide planning and attempts.

The data regarding the prevalence of suicidal ideation in patients who have overdosed are limited, although recent evidence from the National Vital Statistics System on adolescent (aged 15-19 years) drug overdose is concerning, with 772 drug overdoses occurring in this age demographic in 2015 alone. Opioids were involved in the vast majority of fatal drug overdoses among this group, and the prevalence of death from opioid overdoses increased during 1999-2007 (0.8/100,000 to 2.7/100,000), stabilized during 2007-2011, declined during 2012-2014 (down to 2.0/100,000) then increased in 2015 (up to 2.4/100,000). While 80.4% of all drug overdoses in this group (including opioids) were considered unintentional, 13.5% were most likely completed suicides.¹⁴

These results suggest that, at the very least, some proportion of opioid overdoses are suicide attempts, and the actual prevalence may be much larger. All of this is difficult to discern as these data come from an epidemiological survey with data input as International Classification of Diseases, 10th revision, codes. Thus, the real-life and real-time quality of the psychiatric and postmortem evaluation that led to the determination of a suicide attempt is unknown. More explicitly, because a thorough evaluation and collateral history may have been lacking, this study may have underestimated the prevalence of overdoses that were actual suicide attempts.

Lessons for physicians

Given the epidemiological evidence linking suicidal thoughts and behavior with opioid use disorders, the frequency of overdoses, demographic factors, and recidivism with naloxone rescue, we should be very concerned that many overdoses are unrecognized suicide attempts. Many physicians can recount giving naloxone to a patient – reversing his or her overdose and simultaneously saving his or her life – only to be confronted with anger and combativeness on the part of the patient. When this response occurs, many physicians may attribute the behavioral dysregulation to the patient’s lack of experience with or tolerance to the drug (especially among naive users) or may disregard the emotional response altogether. The danger in physicians’ reacting like this to such behavior is that substantial ambiguity regarding the patient’s motives still remains: Did the patient intentionally use intravenously thinking he or she would die? Was the patient ambivalent about death? Did the patient wish he or she would die – or not wake up? Or was the patient just was playing a version of “Russian roulette” with needles and lethal quantities of opioids?

When considering logical next steps after naloxone reversal to ensure appropriate diagnosis of and treatment for the patient, a psychiatric consultation and thorough evaluation may be indispensable. This is particularly important given that those who attempt suicide or have active suicidal ideation often are evasive about their behavior and current state of mind.¹⁵ Thus, these individuals may be unwilling to disclose active suicidal ideation, intent, and/or plans when interviewed. A psychiatrist, however, has the skill set to evaluate risk and protective factors, assess for other psychiatric comorbidities carefully, and make recommendations for safe disposition and comprehensive treatment. Just as a comprehensive cardiovascular evaluation, formulation of a differential diagnosis, and treatment of chronic cardiovascular disease is the standard of care after a cardiac emergency intervention, we suggest quite similar practice standards for an opioid overdose intervention.

Dr. Srivastava is a fourth-year psychiatry resident at Washington University in St. Louis. Dr. Gold is the 17th Distinguished Alumni Professor at the University of Florida, Gainesville, and professor of psychiatry (adjunct) at Washington University. He also serves as chairman of the scientific advisory boards for RiverMend Health.

References

1. Med Care. 2016 Oct;54:901-6.

2. MMWR Morb Mortal Wkly Rep. 2016 Dec 30;65(5051):1445-52.

3. MMWR Morb Mortal Wkly Rep. 2016 Jan 1;64(50-51):1378-82.

4. N Engl J Med. 2016 Dec 8;375(23):2213-15.

5. Drug Alcohol Depend. 2017 Sep 1;178:176-87.

6. BMJ. 2013 Jan 30;346:f174.

7. Nora’s Blog. 2017 Apr 20. https://www.drugabuse.gov/about-nida/noras-blog/2017/04/opioid-use-disorders-suicide-hidden-tragedy-guest-blog

8. NCHS Data Brief. 2016 Apr;(241):1-8.

9. Proc Natl Acad Sci U S A. 2015 Dec 8;112(49):15078-83.

10. Addict Behav. 2009 Jun-Jul;34(6-7):498-504.

11. J Affect Disord. 2013 May;147(1-3):17-28.

12. Drug Alcohol Depend. 2004 Dec 7;76 Suppl:S11-9.

13. Addiction. 2017 Jul;112(7):1193-1201.

14. NCHS Data Brief. 2017 Aug;282:1-7.

15. Am J Psychiatry. 2003 Nov;160(11 Suppl):1-60.

The current opioid epidemic in the United States has been universally recognized as one of the most important public health issues to date. This crisis has cost nearly $80 billion in lost productivity, treatment (including emergency, medical, psychiatric, and addiction-specific care), and criminal justice involvement.¹ Opioid overdoses have increased by 200% since 2000, with more than 33,000 individuals dying from opioid overdoses in 2015 alone.^2,3

Devonyu/Thinkstock

Additional associations

A recent study of nearly 5 million veterans enrolled in the Veterans Health Administration demonstrated that, even when adjusted for age and comorbid psychiatric diagnoses, opioid use disorder was associated with an increased risk for suicide; particularly striking was that this risk was doubled in women.¹³

A survey of 40,000 subjects from the 2014 National Survey on Drug Use and Health demonstrated that prescription opioid misuse was associated with an increased risk of suicidal ideation, and weekly misuse was associated with increased suicide planning and attempts.

The data regarding the prevalence of suicidal ideation in patients who have overdosed are limited, although recent evidence from the National Vital Statistics System on adolescent (aged 15-19 years) drug overdose is concerning, with 772 drug overdoses occurring in this age demographic in 2015 alone. Opioids were involved in the vast majority of fatal drug overdoses among this group, and the prevalence of death from opioid overdoses increased during 1999-2007 (0.8/100,000 to 2.7/100,000), stabilized during 2007-2011, declined during 2012-2014 (down to 2.0/100,000) then increased in 2015 (up to 2.4/100,000). While 80.4% of all drug overdoses in this group (including opioids) were considered unintentional, 13.5% were most likely completed suicides.¹⁴

These results suggest that, at the very least, some proportion of opioid overdoses are suicide attempts, and the actual prevalence may be much larger. All of this is difficult to discern as these data come from an epidemiological survey with data input as International Classification of Diseases, 10th revision, codes. Thus, the real-life and real-time quality of the psychiatric and postmortem evaluation that led to the determination of a suicide attempt is unknown. More explicitly, because a thorough evaluation and collateral history may have been lacking, this study may have underestimated the prevalence of overdoses that were actual suicide attempts.

Lessons for physicians

Given the epidemiological evidence linking suicidal thoughts and behavior with opioid use disorders, the frequency of overdoses, demographic factors, and recidivism with naloxone rescue, we should be very concerned that many overdoses are unrecognized suicide attempts. Many physicians can recount giving naloxone to a patient – reversing his or her overdose and simultaneously saving his or her life – only to be confronted with anger and combativeness on the part of the patient. When this response occurs, many physicians may attribute the behavioral dysregulation to the patient’s lack of experience with or tolerance to the drug (especially among naive users) or may disregard the emotional response altogether. The danger in physicians’ reacting like this to such behavior is that substantial ambiguity regarding the patient’s motives still remains: Did the patient intentionally use intravenously thinking he or she would die? Was the patient ambivalent about death? Did the patient wish he or she would die – or not wake up? Or was the patient just was playing a version of “Russian roulette” with needles and lethal quantities of opioids?

When considering logical next steps after naloxone reversal to ensure appropriate diagnosis of and treatment for the patient, a psychiatric consultation and thorough evaluation may be indispensable. This is particularly important given that those who attempt suicide or have active suicidal ideation often are evasive about their behavior and current state of mind.¹⁵ Thus, these individuals may be unwilling to disclose active suicidal ideation, intent, and/or plans when interviewed. A psychiatrist, however, has the skill set to evaluate risk and protective factors, assess for other psychiatric comorbidities carefully, and make recommendations for safe disposition and comprehensive treatment. Just as a comprehensive cardiovascular evaluation, formulation of a differential diagnosis, and treatment of chronic cardiovascular disease is the standard of care after a cardiac emergency intervention, we suggest quite similar practice standards for an opioid overdose intervention.

Dr. Srivastava is a fourth-year psychiatry resident at Washington University in St. Louis. Dr. Gold is the 17th Distinguished Alumni Professor at the University of Florida, Gainesville, and professor of psychiatry (adjunct) at Washington University. He also serves as chairman of the scientific advisory boards for RiverMend Health.

References

1. Med Care. 2016 Oct;54:901-6.

2. MMWR Morb Mortal Wkly Rep. 2016 Dec 30;65(5051):1445-52.

3. MMWR Morb Mortal Wkly Rep. 2016 Jan 1;64(50-51):1378-82.

4. N Engl J Med. 2016 Dec 8;375(23):2213-15.

5. Drug Alcohol Depend. 2017 Sep 1;178:176-87.

6. BMJ. 2013 Jan 30;346:f174.

7. Nora’s Blog. 2017 Apr 20. https://www.drugabuse.gov/about-nida/noras-blog/2017/04/opioid-use-disorders-suicide-hidden-tragedy-guest-blog

8. NCHS Data Brief. 2016 Apr;(241):1-8.

9. Proc Natl Acad Sci U S A. 2015 Dec 8;112(49):15078-83.

10. Addict Behav. 2009 Jun-Jul;34(6-7):498-504.

11. J Affect Disord. 2013 May;147(1-3):17-28.

12. Drug Alcohol Depend. 2004 Dec 7;76 Suppl:S11-9.

13. Addiction. 2017 Jul;112(7):1193-1201.

14. NCHS Data Brief. 2017 Aug;282:1-7.

15. Am J Psychiatry. 2003 Nov;160(11 Suppl):1-60.

The current opioid epidemic in the United States has been universally recognized as one of the most important public health issues to date. This crisis has cost nearly $80 billion in lost productivity, treatment (including emergency, medical, psychiatric, and addiction-specific care), and criminal justice involvement.¹ Opioid overdoses have increased by 200% since 2000, with more than 33,000 individuals dying from opioid overdoses in 2015 alone.^2,3

Devonyu/Thinkstock

Additional associations

A recent study of nearly 5 million veterans enrolled in the Veterans Health Administration demonstrated that, even when adjusted for age and comorbid psychiatric diagnoses, opioid use disorder was associated with an increased risk for suicide; particularly striking was that this risk was doubled in women.¹³

A survey of 40,000 subjects from the 2014 National Survey on Drug Use and Health demonstrated that prescription opioid misuse was associated with an increased risk of suicidal ideation, and weekly misuse was associated with increased suicide planning and attempts.

The data regarding the prevalence of suicidal ideation in patients who have overdosed are limited, although recent evidence from the National Vital Statistics System on adolescent (aged 15-19 years) drug overdose is concerning, with 772 drug overdoses occurring in this age demographic in 2015 alone. Opioids were involved in the vast majority of fatal drug overdoses among this group, and the prevalence of death from opioid overdoses increased during 1999-2007 (0.8/100,000 to 2.7/100,000), stabilized during 2007-2011, declined during 2012-2014 (down to 2.0/100,000) then increased in 2015 (up to 2.4/100,000). While 80.4% of all drug overdoses in this group (including opioids) were considered unintentional, 13.5% were most likely completed suicides.¹⁴

These results suggest that, at the very least, some proportion of opioid overdoses are suicide attempts, and the actual prevalence may be much larger. All of this is difficult to discern as these data come from an epidemiological survey with data input as International Classification of Diseases, 10th revision, codes. Thus, the real-life and real-time quality of the psychiatric and postmortem evaluation that led to the determination of a suicide attempt is unknown. More explicitly, because a thorough evaluation and collateral history may have been lacking, this study may have underestimated the prevalence of overdoses that were actual suicide attempts.

Lessons for physicians

Given the epidemiological evidence linking suicidal thoughts and behavior with opioid use disorders, the frequency of overdoses, demographic factors, and recidivism with naloxone rescue, we should be very concerned that many overdoses are unrecognized suicide attempts. Many physicians can recount giving naloxone to a patient – reversing his or her overdose and simultaneously saving his or her life – only to be confronted with anger and combativeness on the part of the patient. When this response occurs, many physicians may attribute the behavioral dysregulation to the patient’s lack of experience with or tolerance to the drug (especially among naive users) or may disregard the emotional response altogether. The danger in physicians’ reacting like this to such behavior is that substantial ambiguity regarding the patient’s motives still remains: Did the patient intentionally use intravenously thinking he or she would die? Was the patient ambivalent about death? Did the patient wish he or she would die – or not wake up? Or was the patient just was playing a version of “Russian roulette” with needles and lethal quantities of opioids?

When considering logical next steps after naloxone reversal to ensure appropriate diagnosis of and treatment for the patient, a psychiatric consultation and thorough evaluation may be indispensable. This is particularly important given that those who attempt suicide or have active suicidal ideation often are evasive about their behavior and current state of mind.¹⁵ Thus, these individuals may be unwilling to disclose active suicidal ideation, intent, and/or plans when interviewed. A psychiatrist, however, has the skill set to evaluate risk and protective factors, assess for other psychiatric comorbidities carefully, and make recommendations for safe disposition and comprehensive treatment. Just as a comprehensive cardiovascular evaluation, formulation of a differential diagnosis, and treatment of chronic cardiovascular disease is the standard of care after a cardiac emergency intervention, we suggest quite similar practice standards for an opioid overdose intervention.

Dr. Srivastava is a fourth-year psychiatry resident at Washington University in St. Louis. Dr. Gold is the 17th Distinguished Alumni Professor at the University of Florida, Gainesville, and professor of psychiatry (adjunct) at Washington University. He also serves as chairman of the scientific advisory boards for RiverMend Health.

References

1. Med Care. 2016 Oct;54:901-6.

2. MMWR Morb Mortal Wkly Rep. 2016 Dec 30;65(5051):1445-52.

3. MMWR Morb Mortal Wkly Rep. 2016 Jan 1;64(50-51):1378-82.

4. N Engl J Med. 2016 Dec 8;375(23):2213-15.

5. Drug Alcohol Depend. 2017 Sep 1;178:176-87.

6. BMJ. 2013 Jan 30;346:f174.

7. Nora’s Blog. 2017 Apr 20. https://www.drugabuse.gov/about-nida/noras-blog/2017/04/opioid-use-disorders-suicide-hidden-tragedy-guest-blog

8. NCHS Data Brief. 2016 Apr;(241):1-8.

9. Proc Natl Acad Sci U S A. 2015 Dec 8;112(49):15078-83.

10. Addict Behav. 2009 Jun-Jul;34(6-7):498-504.

11. J Affect Disord. 2013 May;147(1-3):17-28.

12. Drug Alcohol Depend. 2004 Dec 7;76 Suppl:S11-9.

13. Addiction. 2017 Jul;112(7):1193-1201.

14. NCHS Data Brief. 2017 Aug;282:1-7.

15. Am J Psychiatry. 2003 Nov;160(11 Suppl):1-60.

VANCOUVER—The investigational agent bis-choline tetrathiomolybdate (WTX101) may help treat Wilson’s disease, according to a study presented at the 21st International Congress of Parkinson’s Disease and Movement Disorders. The drug lowered circulating copper, and this effect was associated with reduced disability, improved neurologic status without initial paradoxical worsening, and stable liver function.

“With dose adjustments, WTX101 demonstrated a favorable safety profile, and with a simple regimen (once daily in most patients), WTX101 has the potential to address several unmet needs in Wilson’s disease,” said Danny Bega, MD, Assistant Professor of Neurology (Movement Disorders) at Northwestern University’s Feinberg School of Medicine in Chicago, and colleagues.

Wilson’s disease is a rare genetic disorder of impaired copper transport, in which copper accumulates pathologically in the CNS, liver, and other tissues. Current treatments for this disease, such as zinc and chelators (eg, D-penicillamine and trientine), require multiple doses and may be tolerated poorly. To address these challenges, Wilson Therapeutics developed WTX101, an oral first-in-class copper-modulating agent given once daily as monotherapy for Wilson’s disease.

Unlike other treatments for Wilson’s disease, WTX101 appears to have direct intracellular activity in hepatocytes, where it binds excess copper and promotes biliary copper excretion. In addition, WTX101 rapidly binds nonceruloplasmin-bound copper (NCC), thus creating a stable complex with albumin.

Eligible Participants

To evaluate the clinical efficacy and safety of WTX101, as well as the copper control that it enables, in patients with Wilson’s disease, Dr. Bega and colleagues conducted an open-label, single-arm, phase II study at 11 sites in the United States and Europe. Eligible participants were age 18 or older and had been diagnosed with Wilson’s disease based on a Leipzig score of ≥ 4. They also had had no prior treatment for Wilson’s disease or ≤ 24 months of chelation or zinc therapy. Finally, participants’ NCC levels were within or above the normal reference range (≥ 0.8 µM).

Patients received WTX101 for 24 weeks. Researchers used a response-guided dosing regimen with individualized doses of between 15 and 120 mg/day based on NCC levels and safety criteria. In most patients, dosing occurred once daily.

The primary end point was change from baseline to 24 weeks in NCC levels corrected for bound copper contained in tetrathiomolybdate-copper-albumin complexes. Secondary end points included clinical, neurologic, and hepatic assessments.

Of 28 participants involved in the study, 15 were women. The mean age was 34.1. Nine patients were treatment naïve, an additional nine patients had prior treatment for fewer than 28 days, and 10 patients had prior treatment for 28 days to two years. The mean Unified Wilson’s Disease Rating Scale (UWDRS) Part 3 score was 22.8. Three patients had no neurologic abnormalities.

In all, 22 patients completed the 24-week study. Three patients discontinued WTX101 due to liver-related adverse events. Investigators discontinued three patients because of neurologic or psychiatric manifestations. At the end of the study, daily dosages were 15 mg for six patients, 30 mg for 13 patients, and 60 mg for nine patients.

Benefits of Treatment and Adverse Events

WTX101 was associated with rapid improvements in NCC. Mean NCC levels were within the upper limit of normal by week 12. At 24 weeks, 71% of patients met the primary end point of achieving or maintaining normalized levels of NCC or a ≥ 25% reduction in NCC from baseline. The mean NCC at baseline was reduced by 72% at week 24.

At week 24, investigators observed significant improvements in trained-rater-assessed neurologic signs, as measured by UWDRS Part 3. The UWDRS Part 3 score improved by ≥ 4 points in 13 patients, stabilized in six patients, and deteriorated by 5 points in two patients.

No participants had early paradoxical neurologic worsening. Significant improvement in patient-reported disability was observed at week 24. In addition, the UWDRS Part 2 score improved by ≥ 1 point in 12 patients and was unchanged in nine patients. No patient reported deterioration.

The Model for End-Stage Liver Disease (MELD) score remained stable in patients throughout the study, and the mean MELD score was 7.7 ±1.9 at baseline and 7.2 ±1.8 at week 24.

Overall, WTX101 was generally well tolerated. Most adverse events were mild or moderate. Psychiatric and gait disturbance were most likely unrelated to the study treatment. Eleven patients who received 30 mg/day or more had elevated liver function tests. These elevations were mostly mild or moderate and normalized within two weeks after dose adjustments.

“Additional clinical evaluation of WTX101 in a larger controlled trial is warranted to further establish its safety and efficacy for the treatment of Wilson’s disease,” said Dr. Bega and colleagues.

This study was sponsored by Wilson Therapeutics, which is headquartered in Stockholm.

—Erica Tricarico

VANCOUVER—The investigational agent bis-choline tetrathiomolybdate (WTX101) may help treat Wilson’s disease, according to a study presented at the 21st International Congress of Parkinson’s Disease and Movement Disorders. The drug lowered circulating copper, and this effect was associated with reduced disability, improved neurologic status without initial paradoxical worsening, and stable liver function.

“With dose adjustments, WTX101 demonstrated a favorable safety profile, and with a simple regimen (once daily in most patients), WTX101 has the potential to address several unmet needs in Wilson’s disease,” said Danny Bega, MD, Assistant Professor of Neurology (Movement Disorders) at Northwestern University’s Feinberg School of Medicine in Chicago, and colleagues.

Wilson’s disease is a rare genetic disorder of impaired copper transport, in which copper accumulates pathologically in the CNS, liver, and other tissues. Current treatments for this disease, such as zinc and chelators (eg, D-penicillamine and trientine), require multiple doses and may be tolerated poorly. To address these challenges, Wilson Therapeutics developed WTX101, an oral first-in-class copper-modulating agent given once daily as monotherapy for Wilson’s disease.

Unlike other treatments for Wilson’s disease, WTX101 appears to have direct intracellular activity in hepatocytes, where it binds excess copper and promotes biliary copper excretion. In addition, WTX101 rapidly binds nonceruloplasmin-bound copper (NCC), thus creating a stable complex with albumin.

Eligible Participants

To evaluate the clinical efficacy and safety of WTX101, as well as the copper control that it enables, in patients with Wilson’s disease, Dr. Bega and colleagues conducted an open-label, single-arm, phase II study at 11 sites in the United States and Europe. Eligible participants were age 18 or older and had been diagnosed with Wilson’s disease based on a Leipzig score of ≥ 4. They also had had no prior treatment for Wilson’s disease or ≤ 24 months of chelation or zinc therapy. Finally, participants’ NCC levels were within or above the normal reference range (≥ 0.8 µM).

Patients received WTX101 for 24 weeks. Researchers used a response-guided dosing regimen with individualized doses of between 15 and 120 mg/day based on NCC levels and safety criteria. In most patients, dosing occurred once daily.

The primary end point was change from baseline to 24 weeks in NCC levels corrected for bound copper contained in tetrathiomolybdate-copper-albumin complexes. Secondary end points included clinical, neurologic, and hepatic assessments.

Of 28 participants involved in the study, 15 were women. The mean age was 34.1. Nine patients were treatment naïve, an additional nine patients had prior treatment for fewer than 28 days, and 10 patients had prior treatment for 28 days to two years. The mean Unified Wilson’s Disease Rating Scale (UWDRS) Part 3 score was 22.8. Three patients had no neurologic abnormalities.

In all, 22 patients completed the 24-week study. Three patients discontinued WTX101 due to liver-related adverse events. Investigators discontinued three patients because of neurologic or psychiatric manifestations. At the end of the study, daily dosages were 15 mg for six patients, 30 mg for 13 patients, and 60 mg for nine patients.

Benefits of Treatment and Adverse Events

WTX101 was associated with rapid improvements in NCC. Mean NCC levels were within the upper limit of normal by week 12. At 24 weeks, 71% of patients met the primary end point of achieving or maintaining normalized levels of NCC or a ≥ 25% reduction in NCC from baseline. The mean NCC at baseline was reduced by 72% at week 24.

At week 24, investigators observed significant improvements in trained-rater-assessed neurologic signs, as measured by UWDRS Part 3. The UWDRS Part 3 score improved by ≥ 4 points in 13 patients, stabilized in six patients, and deteriorated by 5 points in two patients.

No participants had early paradoxical neurologic worsening. Significant improvement in patient-reported disability was observed at week 24. In addition, the UWDRS Part 2 score improved by ≥ 1 point in 12 patients and was unchanged in nine patients. No patient reported deterioration.

The Model for End-Stage Liver Disease (MELD) score remained stable in patients throughout the study, and the mean MELD score was 7.7 ±1.9 at baseline and 7.2 ±1.8 at week 24.

Overall, WTX101 was generally well tolerated. Most adverse events were mild or moderate. Psychiatric and gait disturbance were most likely unrelated to the study treatment. Eleven patients who received 30 mg/day or more had elevated liver function tests. These elevations were mostly mild or moderate and normalized within two weeks after dose adjustments.

“Additional clinical evaluation of WTX101 in a larger controlled trial is warranted to further establish its safety and efficacy for the treatment of Wilson’s disease,” said Dr. Bega and colleagues.

This study was sponsored by Wilson Therapeutics, which is headquartered in Stockholm.

—Erica Tricarico

VANCOUVER—The investigational agent bis-choline tetrathiomolybdate (WTX101) may help treat Wilson’s disease, according to a study presented at the 21st International Congress of Parkinson’s Disease and Movement Disorders. The drug lowered circulating copper, and this effect was associated with reduced disability, improved neurologic status without initial paradoxical worsening, and stable liver function.

“With dose adjustments, WTX101 demonstrated a favorable safety profile, and with a simple regimen (once daily in most patients), WTX101 has the potential to address several unmet needs in Wilson’s disease,” said Danny Bega, MD, Assistant Professor of Neurology (Movement Disorders) at Northwestern University’s Feinberg School of Medicine in Chicago, and colleagues.

Wilson’s disease is a rare genetic disorder of impaired copper transport, in which copper accumulates pathologically in the CNS, liver, and other tissues. Current treatments for this disease, such as zinc and chelators (eg, D-penicillamine and trientine), require multiple doses and may be tolerated poorly. To address these challenges, Wilson Therapeutics developed WTX101, an oral first-in-class copper-modulating agent given once daily as monotherapy for Wilson’s disease.

Unlike other treatments for Wilson’s disease, WTX101 appears to have direct intracellular activity in hepatocytes, where it binds excess copper and promotes biliary copper excretion. In addition, WTX101 rapidly binds nonceruloplasmin-bound copper (NCC), thus creating a stable complex with albumin.

Eligible Participants

To evaluate the clinical efficacy and safety of WTX101, as well as the copper control that it enables, in patients with Wilson’s disease, Dr. Bega and colleagues conducted an open-label, single-arm, phase II study at 11 sites in the United States and Europe. Eligible participants were age 18 or older and had been diagnosed with Wilson’s disease based on a Leipzig score of ≥ 4. They also had had no prior treatment for Wilson’s disease or ≤ 24 months of chelation or zinc therapy. Finally, participants’ NCC levels were within or above the normal reference range (≥ 0.8 µM).

Patients received WTX101 for 24 weeks. Researchers used a response-guided dosing regimen with individualized doses of between 15 and 120 mg/day based on NCC levels and safety criteria. In most patients, dosing occurred once daily.

The primary end point was change from baseline to 24 weeks in NCC levels corrected for bound copper contained in tetrathiomolybdate-copper-albumin complexes. Secondary end points included clinical, neurologic, and hepatic assessments.

Of 28 participants involved in the study, 15 were women. The mean age was 34.1. Nine patients were treatment naïve, an additional nine patients had prior treatment for fewer than 28 days, and 10 patients had prior treatment for 28 days to two years. The mean Unified Wilson’s Disease Rating Scale (UWDRS) Part 3 score was 22.8. Three patients had no neurologic abnormalities.

In all, 22 patients completed the 24-week study. Three patients discontinued WTX101 due to liver-related adverse events. Investigators discontinued three patients because of neurologic or psychiatric manifestations. At the end of the study, daily dosages were 15 mg for six patients, 30 mg for 13 patients, and 60 mg for nine patients.

Benefits of Treatment and Adverse Events

WTX101 was associated with rapid improvements in NCC. Mean NCC levels were within the upper limit of normal by week 12. At 24 weeks, 71% of patients met the primary end point of achieving or maintaining normalized levels of NCC or a ≥ 25% reduction in NCC from baseline. The mean NCC at baseline was reduced by 72% at week 24.

At week 24, investigators observed significant improvements in trained-rater-assessed neurologic signs, as measured by UWDRS Part 3. The UWDRS Part 3 score improved by ≥ 4 points in 13 patients, stabilized in six patients, and deteriorated by 5 points in two patients.

No participants had early paradoxical neurologic worsening. Significant improvement in patient-reported disability was observed at week 24. In addition, the UWDRS Part 2 score improved by ≥ 1 point in 12 patients and was unchanged in nine patients. No patient reported deterioration.

The Model for End-Stage Liver Disease (MELD) score remained stable in patients throughout the study, and the mean MELD score was 7.7 ±1.9 at baseline and 7.2 ±1.8 at week 24.

Overall, WTX101 was generally well tolerated. Most adverse events were mild or moderate. Psychiatric and gait disturbance were most likely unrelated to the study treatment. Eleven patients who received 30 mg/day or more had elevated liver function tests. These elevations were mostly mild or moderate and normalized within two weeks after dose adjustments.

“Additional clinical evaluation of WTX101 in a larger controlled trial is warranted to further establish its safety and efficacy for the treatment of Wilson’s disease,” said Dr. Bega and colleagues.

This study was sponsored by Wilson Therapeutics, which is headquartered in Stockholm.

—Erica Tricarico

BARCELONA – After years of neutral study results in pivotal trials, a drug that raises patients’ high-density lipoprotein cholesterol finally showed a statistically significant and clinically meaningful benefit in a major trial with more than 30,000 patients run for 4 years.

The only catch? It didn’t seem to work by raising HDL.

Instead, it was the off-target effect of also lowering low density lipoprotein (LDL) cholesterol that seems to have driven a modest but clinically significant benefit from anacetrapib, a member of the class of drugs that inhibit the cholesterol ester transfer protein that includes the trial flame-out agents torcetrapib, dalcetrapib, and evacetrapib.

Daily treatment with 100 mg of anacetrapib on top of intensive therapy with atorvastatin led to a 9% relative risk reduction in major coronary events that didn’t become apparent compared with placebo until patients took the drug for more than 2 years, and was “well tolerated,” with a notably benign safety profile, Martin Landray, MD, said at the annual congress of the European Society of Cardiology.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

BARCELONA – After years of neutral study results in pivotal trials, a drug that raises patients’ high-density lipoprotein cholesterol finally showed a statistically significant and clinically meaningful benefit in a major trial with more than 30,000 patients run for 4 years.

The only catch? It didn’t seem to work by raising HDL.

Instead, it was the off-target effect of also lowering low density lipoprotein (LDL) cholesterol that seems to have driven a modest but clinically significant benefit from anacetrapib, a member of the class of drugs that inhibit the cholesterol ester transfer protein that includes the trial flame-out agents torcetrapib, dalcetrapib, and evacetrapib.

Daily treatment with 100 mg of anacetrapib on top of intensive therapy with atorvastatin led to a 9% relative risk reduction in major coronary events that didn’t become apparent compared with placebo until patients took the drug for more than 2 years, and was “well tolerated,” with a notably benign safety profile, Martin Landray, MD, said at the annual congress of the European Society of Cardiology.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

BARCELONA – After years of neutral study results in pivotal trials, a drug that raises patients’ high-density lipoprotein cholesterol finally showed a statistically significant and clinically meaningful benefit in a major trial with more than 30,000 patients run for 4 years.

The only catch? It didn’t seem to work by raising HDL.

Instead, it was the off-target effect of also lowering low density lipoprotein (LDL) cholesterol that seems to have driven a modest but clinically significant benefit from anacetrapib, a member of the class of drugs that inhibit the cholesterol ester transfer protein that includes the trial flame-out agents torcetrapib, dalcetrapib, and evacetrapib.

Daily treatment with 100 mg of anacetrapib on top of intensive therapy with atorvastatin led to a 9% relative risk reduction in major coronary events that didn’t become apparent compared with placebo until patients took the drug for more than 2 years, and was “well tolerated,” with a notably benign safety profile, Martin Landray, MD, said at the annual congress of the European Society of Cardiology.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

Neurologists and patients may be able to predict migraine attacks using a model based on the level of stress from daily hassles, according to research published in the July issue of Headache. The model was well calibrated, but its forecasts were based on participants’ base rates of headache, said the authors. With additional adjustments, the model could enable patients to treat migraine attacks pre-emptively.

Although headache disorders are common, it remains unclear what triggers a migraine attack. Patients have identified many possible triggers, including perceived stress. In people with episodic migraine and chronic migraine, perceived stress is associated with the onset of headache. Researchers previously had not provided evidence that any of the potential triggers could predict a migraine attack, however.

Electronic Diaries Captured Headache Frequency

Timothy T. Houle, PhD, Associate Professor of Anesthesia at Massachusetts General Hospital in Boston, and colleagues conducted the prospective Headache Prediction Study to examine precipitating factors of migraine headache. They recruited participants with episodic migraine who had more than two headache attacks per month and had between four and 14 headache days per month. Secondary headache disorder and change in the nature of headache symptoms in the previous six weeks were among the exclusion criteria.

Participants completed morning and evening diary entries daily using electronic systems. In the entries, the participants recorded headaches, headache characteristics, and abortive medications used since the last entry. Participants used the Daily Stress Inventory to assess stress in their evening diary entries. Using these assessments, the investigators examined the frequency of stressors, the sum of the stress impact ratings, and the average stress impact ratings. The primary analysis was the prediction of a future headache attack based on current levels of stress and headache.

Potential for New Treatment Strategies

Dr. Houle and colleagues enrolled 100 participants between September 2009 and May 2014. Five participants dropped out. Approximately 91% of participants were female, and 87% were Caucasian. Mean age was 40. The 95 participants contributed 4,626 days of diary data. In all, 431 diary entries were missing or unavailable for analysis. Participants had a headache attack on approximately 39% of days. Days that preceded a headache were associated with greater stress than days that did not precede a headache.

After estimating a series of models, the researchers found that a generalized linear mixed-effects model using either the frequency of stressful events or the perceived intensity of stressful events fit the data well. The forecasting model had “promising predictive utility” in the training sample and in a validation sample, said the authors. The model had good calibration between forecast probabilities and observed headache frequencies, but had low levels of resolution, meaning that “the forecast probabilities are close to the individual’s long-run average,” said Dr. Houle.

“This appears to be the first evidence that individual headache attacks can be forecast within an individual sufferer, and this finding creates substantial opportunities for additional treatment strategies if the forecasting model can be refined,” said Dr. Houle. “A forecasting model could be used to enhance pharmacologic treatment opportunities, reduce anxiety about the unpredictability of attacks, increase locus-of-control beliefs, and lead to increased self-efficacy assessments about the self-management of migraine attacks.” Neurologists should consider the investigators’ stress model a first step toward headache prediction, and not a final model for widespread clinical use, he added.

Complexities Need Consideration

These data are “fascinating,” but neurologists should consider several complexities as they develop methods for the short-term prevention of predictable migraine, said Richard B. Lipton, MD, Edwin S. Lowe Chair in Neurology at Albert Einstein College of Medicine in New York and Director of the Montefiore Headache Center, and colleagues in an accompanying editorial. First, they must distinguish group-level and within-person analyses of attack predictors. Trigger factors vary from person to person, and within-person analysis may be crucial to prediction and prevention, said Dr. Lipton. Second, in addition to stress, other trigger factors such as premonitory features, self-prediction, and biomarkers also may aid in forecasting attacks. Finally, researchers can measure and model predictors of impending attacks in various ways (eg, lead–lag effects and cumulative effects).

“Houle et al have set the stage for short-term prediction of headaches in persons with migraine as a potential foundation for short-term preventive therapies,” said Dr. Lipton. “To realize the potential of these approaches, we must refine the art of headache forecasting and then test targeted interventions in carefully selected patients.”

—Erik Greb

Suggested Reading

Houle TT, Turner DP, Golding AN, et al. Forecasting individual headache attacks using perceived stress: Development of a multivariable prediction model for persons with episodic migraine. Headache. 2017;57(7):1041-1050.

Lipton RB, Pavlovic JM, Buse DC. Why migraine forecasting matters. Headache. 2017;57(7):1023-1025.

Neurologists and patients may be able to predict migraine attacks using a model based on the level of stress from daily hassles, according to research published in the July issue of Headache. The model was well calibrated, but its forecasts were based on participants’ base rates of headache, said the authors. With additional adjustments, the model could enable patients to treat migraine attacks pre-emptively.

Although headache disorders are common, it remains unclear what triggers a migraine attack. Patients have identified many possible triggers, including perceived stress. In people with episodic migraine and chronic migraine, perceived stress is associated with the onset of headache. Researchers previously had not provided evidence that any of the potential triggers could predict a migraine attack, however.

Electronic Diaries Captured Headache Frequency

Timothy T. Houle, PhD, Associate Professor of Anesthesia at Massachusetts General Hospital in Boston, and colleagues conducted the prospective Headache Prediction Study to examine precipitating factors of migraine headache. They recruited participants with episodic migraine who had more than two headache attacks per month and had between four and 14 headache days per month. Secondary headache disorder and change in the nature of headache symptoms in the previous six weeks were among the exclusion criteria.

Participants completed morning and evening diary entries daily using electronic systems. In the entries, the participants recorded headaches, headache characteristics, and abortive medications used since the last entry. Participants used the Daily Stress Inventory to assess stress in their evening diary entries. Using these assessments, the investigators examined the frequency of stressors, the sum of the stress impact ratings, and the average stress impact ratings. The primary analysis was the prediction of a future headache attack based on current levels of stress and headache.

Potential for New Treatment Strategies

Dr. Houle and colleagues enrolled 100 participants between September 2009 and May 2014. Five participants dropped out. Approximately 91% of participants were female, and 87% were Caucasian. Mean age was 40. The 95 participants contributed 4,626 days of diary data. In all, 431 diary entries were missing or unavailable for analysis. Participants had a headache attack on approximately 39% of days. Days that preceded a headache were associated with greater stress than days that did not precede a headache.

After estimating a series of models, the researchers found that a generalized linear mixed-effects model using either the frequency of stressful events or the perceived intensity of stressful events fit the data well. The forecasting model had “promising predictive utility” in the training sample and in a validation sample, said the authors. The model had good calibration between forecast probabilities and observed headache frequencies, but had low levels of resolution, meaning that “the forecast probabilities are close to the individual’s long-run average,” said Dr. Houle.

“This appears to be the first evidence that individual headache attacks can be forecast within an individual sufferer, and this finding creates substantial opportunities for additional treatment strategies if the forecasting model can be refined,” said Dr. Houle. “A forecasting model could be used to enhance pharmacologic treatment opportunities, reduce anxiety about the unpredictability of attacks, increase locus-of-control beliefs, and lead to increased self-efficacy assessments about the self-management of migraine attacks.” Neurologists should consider the investigators’ stress model a first step toward headache prediction, and not a final model for widespread clinical use, he added.

Complexities Need Consideration

These data are “fascinating,” but neurologists should consider several complexities as they develop methods for the short-term prevention of predictable migraine, said Richard B. Lipton, MD, Edwin S. Lowe Chair in Neurology at Albert Einstein College of Medicine in New York and Director of the Montefiore Headache Center, and colleagues in an accompanying editorial. First, they must distinguish group-level and within-person analyses of attack predictors. Trigger factors vary from person to person, and within-person analysis may be crucial to prediction and prevention, said Dr. Lipton. Second, in addition to stress, other trigger factors such as premonitory features, self-prediction, and biomarkers also may aid in forecasting attacks. Finally, researchers can measure and model predictors of impending attacks in various ways (eg, lead–lag effects and cumulative effects).

“Houle et al have set the stage for short-term prediction of headaches in persons with migraine as a potential foundation for short-term preventive therapies,” said Dr. Lipton. “To realize the potential of these approaches, we must refine the art of headache forecasting and then test targeted interventions in carefully selected patients.”

—Erik Greb

Suggested Reading

Houle TT, Turner DP, Golding AN, et al. Forecasting individual headache attacks using perceived stress: Development of a multivariable prediction model for persons with episodic migraine. Headache. 2017;57(7):1041-1050.

Lipton RB, Pavlovic JM, Buse DC. Why migraine forecasting matters. Headache. 2017;57(7):1023-1025.

Neurologists and patients may be able to predict migraine attacks using a model based on the level of stress from daily hassles, according to research published in the July issue of Headache. The model was well calibrated, but its forecasts were based on participants’ base rates of headache, said the authors. With additional adjustments, the model could enable patients to treat migraine attacks pre-emptively.

Although headache disorders are common, it remains unclear what triggers a migraine attack. Patients have identified many possible triggers, including perceived stress. In people with episodic migraine and chronic migraine, perceived stress is associated with the onset of headache. Researchers previously had not provided evidence that any of the potential triggers could predict a migraine attack, however.

Electronic Diaries Captured Headache Frequency

Timothy T. Houle, PhD, Associate Professor of Anesthesia at Massachusetts General Hospital in Boston, and colleagues conducted the prospective Headache Prediction Study to examine precipitating factors of migraine headache. They recruited participants with episodic migraine who had more than two headache attacks per month and had between four and 14 headache days per month. Secondary headache disorder and change in the nature of headache symptoms in the previous six weeks were among the exclusion criteria.

Participants completed morning and evening diary entries daily using electronic systems. In the entries, the participants recorded headaches, headache characteristics, and abortive medications used since the last entry. Participants used the Daily Stress Inventory to assess stress in their evening diary entries. Using these assessments, the investigators examined the frequency of stressors, the sum of the stress impact ratings, and the average stress impact ratings. The primary analysis was the prediction of a future headache attack based on current levels of stress and headache.

Potential for New Treatment Strategies

Dr. Houle and colleagues enrolled 100 participants between September 2009 and May 2014. Five participants dropped out. Approximately 91% of participants were female, and 87% were Caucasian. Mean age was 40. The 95 participants contributed 4,626 days of diary data. In all, 431 diary entries were missing or unavailable for analysis. Participants had a headache attack on approximately 39% of days. Days that preceded a headache were associated with greater stress than days that did not precede a headache.

After estimating a series of models, the researchers found that a generalized linear mixed-effects model using either the frequency of stressful events or the perceived intensity of stressful events fit the data well. The forecasting model had “promising predictive utility” in the training sample and in a validation sample, said the authors. The model had good calibration between forecast probabilities and observed headache frequencies, but had low levels of resolution, meaning that “the forecast probabilities are close to the individual’s long-run average,” said Dr. Houle.

“This appears to be the first evidence that individual headache attacks can be forecast within an individual sufferer, and this finding creates substantial opportunities for additional treatment strategies if the forecasting model can be refined,” said Dr. Houle. “A forecasting model could be used to enhance pharmacologic treatment opportunities, reduce anxiety about the unpredictability of attacks, increase locus-of-control beliefs, and lead to increased self-efficacy assessments about the self-management of migraine attacks.” Neurologists should consider the investigators’ stress model a first step toward headache prediction, and not a final model for widespread clinical use, he added.

Complexities Need Consideration

These data are “fascinating,” but neurologists should consider several complexities as they develop methods for the short-term prevention of predictable migraine, said Richard B. Lipton, MD, Edwin S. Lowe Chair in Neurology at Albert Einstein College of Medicine in New York and Director of the Montefiore Headache Center, and colleagues in an accompanying editorial. First, they must distinguish group-level and within-person analyses of attack predictors. Trigger factors vary from person to person, and within-person analysis may be crucial to prediction and prevention, said Dr. Lipton. Second, in addition to stress, other trigger factors such as premonitory features, self-prediction, and biomarkers also may aid in forecasting attacks. Finally, researchers can measure and model predictors of impending attacks in various ways (eg, lead–lag effects and cumulative effects).

“Houle et al have set the stage for short-term prediction of headaches in persons with migraine as a potential foundation for short-term preventive therapies,” said Dr. Lipton. “To realize the potential of these approaches, we must refine the art of headache forecasting and then test targeted interventions in carefully selected patients.”

—Erik Greb

Suggested Reading

Houle TT, Turner DP, Golding AN, et al. Forecasting individual headache attacks using perceived stress: Development of a multivariable prediction model for persons with episodic migraine. Headache. 2017;57(7):1041-1050.

Lipton RB, Pavlovic JM, Buse DC. Why migraine forecasting matters. Headache. 2017;57(7):1023-1025.