Case Reports

An isolated thyroid cartilage fracture is very rare.^1-5 More interestingly, an isolated thyroid cartilage fracture from a wrestling injury, especially in a non-sports competition context, such as horseplay, has not been previously reported in the literature. Sports-related injuries to the larynx and related structures are uncommon.^6,7

Case

A 38-year-old man presented with a complaint of throat pain after wrestling at home, in horseplay, with his 15-year-old son. He reported that when his son placed a choke hold on him, he felt a "crack" in the area of his neck, and soon afterwards felt throat pain with swallowing, along with discomfort with breathing. He also felt a sensation of "fluid building up in his throat." There were no changes noted with his voice and the patient was speaking in full sentences. There was no wheezing or stridor. He denied shortness of breath or any other complaints. He denied pain over the posterior elements of his cervical spine. At the time of the incident, there was no loss of consciousness. Palpation of the neck and chest did not elicit any crepitance to suggest subcutaneous emphysema. The trachea was midline. There was no pain overlying the carotids bilaterally, and the patient had no bruits. The neck examination did not show any surface abnormalities to suggest trauma, such as ecchymosis or swelling. He did have slight tenderness to palpation over the thyroid cartilage.

The patient was sent for a computed tomography (CT) scan of the soft-tissue neck with intravenous (IV) contrast, and a CT scan of the cervical spine. The results showed no cervical spine fracture. However, there was a minimally displaced fracture of the left thyroid cartilage, with soft-tissue swelling that was noted, along with minimal narrowing of the subglottic trachea. There were no abnormal enhancements or fluid collections. No evidence of vocal cord abnormality or asymmetry was seen, and there was no evidence of airway compromise (Figure).

Discussion

Our patient sustained an isolated thyroid cartilage fracture. A thyroid cartilage fracture is a type of laryngeal fracture. Using an anatomic system in which such injuries are classified by location (supraglottic, glottis, or infraglottic), a thyroid cartilage fracture is classified as a supraglottic laryngeal injury.^1,2 In our case, the fracture was due to a blunt force mechanism. Most blunt force laryngeal fractures are associated with multiple trauma.⁸ An isolated thyroid cartilage fracture is very rare.^1-5 More interestingly, an isolated thyroid cartilage fracture from a wrestling injury, especially in a non-sports competition context, such as horseplay, has not been previously reported in the literature.

Sports-related injuries to the larynx and related structures are uncommon.^6,7 When reported, significant force is usually involved. For example, Tasca et al⁶ reported a thyroid cartilage fracture from direct blunt trauma (rugby, opponent stamped on patient’s throat) in which the patient presented with pain with swallowing and a lowering of the pitch of his voice. Rejali et al⁹ reported the case of a midair collision in a soccer match, resulting in an obvious mandibular fracture, but with an arytenoid cartilage fracture that was not initially identified. A football struck a 17-year-old boy with a resulting fracture of the superior cornu of the larynx and a puncture of the laryngeal mucosal wall in a case reported by Saab and Birkinshaw.¹⁰ The patient presented with neck pain and dysphagia, as well as subcutaneous air.¹⁰ A 21-year-old collegiate basketball player was struck in the neck by a teammate’s head while jumping for a rebound. He sustained a fracture of the thyroid cartilage and a fracture of the anterior cricoid ring.³Patients with such injuries "may appear deceptively normal when seeking medical attention."⁸ Kragha² refers to such injuries as "rare but potentially deadly."

Symptoms can include neck pain, voice changes, pain with swallowing, and shortness of breath. Signs can include tenderness, ecchymosis, and even subcutaneous emphysema. There may be loss of prominence of the thyroid cartilage.³ Tracheal deviation and stridor can occur.^10,11 Computed tomography scan and laryngoscopy can be helpful in the diagnostic process; 3-dimensional (3-D) reconstructions may be needed.

Various classification systems have been proposed with related treatment strategies. Percevik et al¹¹ summarized a five-part clinical classification. Group 1 (hematoma, no fracture) and Group 2 (non-displaced fracture) may be treated conservatively. Group 3 (stable, displaced fracture), Group 4 (unstable, displaced fracture), and Group 5 (laryngotracheal disinsertion) are more likely to be treated with surgery.¹¹ Surgical techniques vary and have been refined over time.¹²

In this case, the patient sustained a thyroid cartilage fracture without the energy and force involved in a motor vehicle collision and without significant sports-related force. It is possible that this injury may have involved neck hyperflexion, rather than direct compressive force. Lin et al,¹ described a case of neck hyperflexion in an unrestrained driver, with a resulting isolated thyroid cartilage fracture without direct impact to the neck. Walsh and Trotter⁵ presented a case of a motorcyclist with a blow to the back of the head, with resulting neck hyperflexion, which resulted in a fracture of the thyroid cartilage. Beato-Martínez et al,¹³ reported a case of thyroid cartilage fracture following a sneezing episode. The patient presented with odynophagia, dysphonia and neck pain.¹³ In our review of the literature, we found that only one other similar case has been reported. In that case, a patient experienced a feeling of a neck click, followed by neck pain and hoarseness. He sustained a fracture of the thyroid cartilage.¹⁴

In reviewing the hyperflexion mechanism, Lin et al¹ noted that isolated thyroid cartilage fractures are rare and that "most of these are caused by direct injury to the neck, except for two patients reported in the literature who sustained isolated thyroid cartilage fractures after sneezing." Lin et al¹ proposed an interesting hypothesis—that "the mechanism causing thyroid cartilage fracture during impaction may be the same with sneezing." Sneezing can be associated with sudden and forceful flexion of the neck.

It is certainly possible that this hyperflexion mechanism was involved in our case, given there was no history of significant blunt force to the neck, as in the sports-related injuries discussed. Wrestling holds can produce hyperflexion. The patient described a feeling of a "crack", which is similar to the clicking sound described in one of the sneezing-related cases. An isolated thyroid cartilage fracture is rare in the absence of major trauma. However, as noted by Rejali et al,⁹ this can create a potential management pitfall. "In the context of non-contact sports, the attendant doctor may not realize the significance of apparently minor head and neck trauma."⁹

There are no series data to provide us with an exact incidence of airway compromise. However, seemingly minor insults to the anterior neck can cause posterior compression of the larynx and can result in airway compromise.^9-11

The CT scan is described as an important imaging modality to rule out cervical spine fracture. Although there was no significant blunt force, the cervical spine was exposed to hyperflexion forces. Another important potential consequence is long-term injury to the vocal cords, with subsequent speech difficulties.¹¹ Computed tomography can visualize the thyroid fracture, but many authors point out that visualization of the vocal cords, with nasopharyngeal laryngoscopy or other modality, is an important adjunct to the CT scan.^9-11

Otolaryngologist consultation should be strongly considered. This patient was transferred to a tertiary care center with expertise in thyroid fractures, and planned nasopharyngeal laryngoscopy to be performed at the receiving institution.

Conclusion

Our patient sustained an isolated thyroid cartilage fracture. Most blunt force laryngeal fractures are associated with multiple trauma. An isolated thyroid cartilage fracture is very rare. An isolated thyroid cartilage fracture from a wrestling injury, especially in a non-sports competition context, such as horseplay, has not been previously reported in the literature. Symptoms can include neck pain, voice changes, pain with swallowing, and shortness of breath. Signs can include tenderness, ecchymosis, or even subcutaneous emphysema. There may be loss of the prominence of the thyroid cartilage, tracheal deviation, and stridor. Computed tomography scan imaging with 3-D reconstructions and laryngoscopy can be helpful in the diagnostic process. In our case, the patient sustained a thyroid cartilage fracture without the energy and force involved in a motor vehicle collision and without significant sports-related force. It is possible this injury may have involved neck hyperflexion, rather than direct compressive forces, similar to that described by Lin et al.¹ Certainly, there was no history of significant blunt force to the neck on the level of the sports-related injuries discussed.

An isolated thyroid cartilage fracture is very rare.^1-5 More interestingly, an isolated thyroid cartilage fracture from a wrestling injury, especially in a non-sports competition context, such as horseplay, has not been previously reported in the literature. Sports-related injuries to the larynx and related structures are uncommon.^6,7

Case

A 38-year-old man presented with a complaint of throat pain after wrestling at home, in horseplay, with his 15-year-old son. He reported that when his son placed a choke hold on him, he felt a "crack" in the area of his neck, and soon afterwards felt throat pain with swallowing, along with discomfort with breathing. He also felt a sensation of "fluid building up in his throat." There were no changes noted with his voice and the patient was speaking in full sentences. There was no wheezing or stridor. He denied shortness of breath or any other complaints. He denied pain over the posterior elements of his cervical spine. At the time of the incident, there was no loss of consciousness. Palpation of the neck and chest did not elicit any crepitance to suggest subcutaneous emphysema. The trachea was midline. There was no pain overlying the carotids bilaterally, and the patient had no bruits. The neck examination did not show any surface abnormalities to suggest trauma, such as ecchymosis or swelling. He did have slight tenderness to palpation over the thyroid cartilage.

The patient was sent for a computed tomography (CT) scan of the soft-tissue neck with intravenous (IV) contrast, and a CT scan of the cervical spine. The results showed no cervical spine fracture. However, there was a minimally displaced fracture of the left thyroid cartilage, with soft-tissue swelling that was noted, along with minimal narrowing of the subglottic trachea. There were no abnormal enhancements or fluid collections. No evidence of vocal cord abnormality or asymmetry was seen, and there was no evidence of airway compromise (Figure).

Discussion

Our patient sustained an isolated thyroid cartilage fracture. A thyroid cartilage fracture is a type of laryngeal fracture. Using an anatomic system in which such injuries are classified by location (supraglottic, glottis, or infraglottic), a thyroid cartilage fracture is classified as a supraglottic laryngeal injury.^1,2 In our case, the fracture was due to a blunt force mechanism. Most blunt force laryngeal fractures are associated with multiple trauma.⁸ An isolated thyroid cartilage fracture is very rare.^1-5 More interestingly, an isolated thyroid cartilage fracture from a wrestling injury, especially in a non-sports competition context, such as horseplay, has not been previously reported in the literature.

Sports-related injuries to the larynx and related structures are uncommon.^6,7 When reported, significant force is usually involved. For example, Tasca et al⁶ reported a thyroid cartilage fracture from direct blunt trauma (rugby, opponent stamped on patient’s throat) in which the patient presented with pain with swallowing and a lowering of the pitch of his voice. Rejali et al⁹ reported the case of a midair collision in a soccer match, resulting in an obvious mandibular fracture, but with an arytenoid cartilage fracture that was not initially identified. A football struck a 17-year-old boy with a resulting fracture of the superior cornu of the larynx and a puncture of the laryngeal mucosal wall in a case reported by Saab and Birkinshaw.¹⁰ The patient presented with neck pain and dysphagia, as well as subcutaneous air.¹⁰ A 21-year-old collegiate basketball player was struck in the neck by a teammate’s head while jumping for a rebound. He sustained a fracture of the thyroid cartilage and a fracture of the anterior cricoid ring.³Patients with such injuries "may appear deceptively normal when seeking medical attention."⁸ Kragha² refers to such injuries as "rare but potentially deadly."

Symptoms can include neck pain, voice changes, pain with swallowing, and shortness of breath. Signs can include tenderness, ecchymosis, and even subcutaneous emphysema. There may be loss of prominence of the thyroid cartilage.³ Tracheal deviation and stridor can occur.^10,11 Computed tomography scan and laryngoscopy can be helpful in the diagnostic process; 3-dimensional (3-D) reconstructions may be needed.

Various classification systems have been proposed with related treatment strategies. Percevik et al¹¹ summarized a five-part clinical classification. Group 1 (hematoma, no fracture) and Group 2 (non-displaced fracture) may be treated conservatively. Group 3 (stable, displaced fracture), Group 4 (unstable, displaced fracture), and Group 5 (laryngotracheal disinsertion) are more likely to be treated with surgery.¹¹ Surgical techniques vary and have been refined over time.¹²

In this case, the patient sustained a thyroid cartilage fracture without the energy and force involved in a motor vehicle collision and without significant sports-related force. It is possible that this injury may have involved neck hyperflexion, rather than direct compressive force. Lin et al,¹ described a case of neck hyperflexion in an unrestrained driver, with a resulting isolated thyroid cartilage fracture without direct impact to the neck. Walsh and Trotter⁵ presented a case of a motorcyclist with a blow to the back of the head, with resulting neck hyperflexion, which resulted in a fracture of the thyroid cartilage. Beato-Martínez et al,¹³ reported a case of thyroid cartilage fracture following a sneezing episode. The patient presented with odynophagia, dysphonia and neck pain.¹³ In our review of the literature, we found that only one other similar case has been reported. In that case, a patient experienced a feeling of a neck click, followed by neck pain and hoarseness. He sustained a fracture of the thyroid cartilage.¹⁴

In reviewing the hyperflexion mechanism, Lin et al¹ noted that isolated thyroid cartilage fractures are rare and that "most of these are caused by direct injury to the neck, except for two patients reported in the literature who sustained isolated thyroid cartilage fractures after sneezing." Lin et al¹ proposed an interesting hypothesis—that "the mechanism causing thyroid cartilage fracture during impaction may be the same with sneezing." Sneezing can be associated with sudden and forceful flexion of the neck.

It is certainly possible that this hyperflexion mechanism was involved in our case, given there was no history of significant blunt force to the neck, as in the sports-related injuries discussed. Wrestling holds can produce hyperflexion. The patient described a feeling of a "crack", which is similar to the clicking sound described in one of the sneezing-related cases. An isolated thyroid cartilage fracture is rare in the absence of major trauma. However, as noted by Rejali et al,⁹ this can create a potential management pitfall. "In the context of non-contact sports, the attendant doctor may not realize the significance of apparently minor head and neck trauma."⁹

There are no series data to provide us with an exact incidence of airway compromise. However, seemingly minor insults to the anterior neck can cause posterior compression of the larynx and can result in airway compromise.^9-11

The CT scan is described as an important imaging modality to rule out cervical spine fracture. Although there was no significant blunt force, the cervical spine was exposed to hyperflexion forces. Another important potential consequence is long-term injury to the vocal cords, with subsequent speech difficulties.¹¹ Computed tomography can visualize the thyroid fracture, but many authors point out that visualization of the vocal cords, with nasopharyngeal laryngoscopy or other modality, is an important adjunct to the CT scan.^9-11

Otolaryngologist consultation should be strongly considered. This patient was transferred to a tertiary care center with expertise in thyroid fractures, and planned nasopharyngeal laryngoscopy to be performed at the receiving institution.

Conclusion

Our patient sustained an isolated thyroid cartilage fracture. Most blunt force laryngeal fractures are associated with multiple trauma. An isolated thyroid cartilage fracture is very rare. An isolated thyroid cartilage fracture from a wrestling injury, especially in a non-sports competition context, such as horseplay, has not been previously reported in the literature. Symptoms can include neck pain, voice changes, pain with swallowing, and shortness of breath. Signs can include tenderness, ecchymosis, or even subcutaneous emphysema. There may be loss of the prominence of the thyroid cartilage, tracheal deviation, and stridor. Computed tomography scan imaging with 3-D reconstructions and laryngoscopy can be helpful in the diagnostic process. In our case, the patient sustained a thyroid cartilage fracture without the energy and force involved in a motor vehicle collision and without significant sports-related force. It is possible this injury may have involved neck hyperflexion, rather than direct compressive forces, similar to that described by Lin et al.¹ Certainly, there was no history of significant blunt force to the neck on the level of the sports-related injuries discussed.

An isolated thyroid cartilage fracture is very rare.^1-5 More interestingly, an isolated thyroid cartilage fracture from a wrestling injury, especially in a non-sports competition context, such as horseplay, has not been previously reported in the literature. Sports-related injuries to the larynx and related structures are uncommon.^6,7

Case

A 38-year-old man presented with a complaint of throat pain after wrestling at home, in horseplay, with his 15-year-old son. He reported that when his son placed a choke hold on him, he felt a "crack" in the area of his neck, and soon afterwards felt throat pain with swallowing, along with discomfort with breathing. He also felt a sensation of "fluid building up in his throat." There were no changes noted with his voice and the patient was speaking in full sentences. There was no wheezing or stridor. He denied shortness of breath or any other complaints. He denied pain over the posterior elements of his cervical spine. At the time of the incident, there was no loss of consciousness. Palpation of the neck and chest did not elicit any crepitance to suggest subcutaneous emphysema. The trachea was midline. There was no pain overlying the carotids bilaterally, and the patient had no bruits. The neck examination did not show any surface abnormalities to suggest trauma, such as ecchymosis or swelling. He did have slight tenderness to palpation over the thyroid cartilage.

The patient was sent for a computed tomography (CT) scan of the soft-tissue neck with intravenous (IV) contrast, and a CT scan of the cervical spine. The results showed no cervical spine fracture. However, there was a minimally displaced fracture of the left thyroid cartilage, with soft-tissue swelling that was noted, along with minimal narrowing of the subglottic trachea. There were no abnormal enhancements or fluid collections. No evidence of vocal cord abnormality or asymmetry was seen, and there was no evidence of airway compromise (Figure).

Discussion

Our patient sustained an isolated thyroid cartilage fracture. A thyroid cartilage fracture is a type of laryngeal fracture. Using an anatomic system in which such injuries are classified by location (supraglottic, glottis, or infraglottic), a thyroid cartilage fracture is classified as a supraglottic laryngeal injury.^1,2 In our case, the fracture was due to a blunt force mechanism. Most blunt force laryngeal fractures are associated with multiple trauma.⁸ An isolated thyroid cartilage fracture is very rare.^1-5 More interestingly, an isolated thyroid cartilage fracture from a wrestling injury, especially in a non-sports competition context, such as horseplay, has not been previously reported in the literature.

Sports-related injuries to the larynx and related structures are uncommon.^6,7 When reported, significant force is usually involved. For example, Tasca et al⁶ reported a thyroid cartilage fracture from direct blunt trauma (rugby, opponent stamped on patient’s throat) in which the patient presented with pain with swallowing and a lowering of the pitch of his voice. Rejali et al⁹ reported the case of a midair collision in a soccer match, resulting in an obvious mandibular fracture, but with an arytenoid cartilage fracture that was not initially identified. A football struck a 17-year-old boy with a resulting fracture of the superior cornu of the larynx and a puncture of the laryngeal mucosal wall in a case reported by Saab and Birkinshaw.¹⁰ The patient presented with neck pain and dysphagia, as well as subcutaneous air.¹⁰ A 21-year-old collegiate basketball player was struck in the neck by a teammate’s head while jumping for a rebound. He sustained a fracture of the thyroid cartilage and a fracture of the anterior cricoid ring.³Patients with such injuries "may appear deceptively normal when seeking medical attention."⁸ Kragha² refers to such injuries as "rare but potentially deadly."

Symptoms can include neck pain, voice changes, pain with swallowing, and shortness of breath. Signs can include tenderness, ecchymosis, and even subcutaneous emphysema. There may be loss of prominence of the thyroid cartilage.³ Tracheal deviation and stridor can occur.^10,11 Computed tomography scan and laryngoscopy can be helpful in the diagnostic process; 3-dimensional (3-D) reconstructions may be needed.

Various classification systems have been proposed with related treatment strategies. Percevik et al¹¹ summarized a five-part clinical classification. Group 1 (hematoma, no fracture) and Group 2 (non-displaced fracture) may be treated conservatively. Group 3 (stable, displaced fracture), Group 4 (unstable, displaced fracture), and Group 5 (laryngotracheal disinsertion) are more likely to be treated with surgery.¹¹ Surgical techniques vary and have been refined over time.¹²

In this case, the patient sustained a thyroid cartilage fracture without the energy and force involved in a motor vehicle collision and without significant sports-related force. It is possible that this injury may have involved neck hyperflexion, rather than direct compressive force. Lin et al,¹ described a case of neck hyperflexion in an unrestrained driver, with a resulting isolated thyroid cartilage fracture without direct impact to the neck. Walsh and Trotter⁵ presented a case of a motorcyclist with a blow to the back of the head, with resulting neck hyperflexion, which resulted in a fracture of the thyroid cartilage. Beato-Martínez et al,¹³ reported a case of thyroid cartilage fracture following a sneezing episode. The patient presented with odynophagia, dysphonia and neck pain.¹³ In our review of the literature, we found that only one other similar case has been reported. In that case, a patient experienced a feeling of a neck click, followed by neck pain and hoarseness. He sustained a fracture of the thyroid cartilage.¹⁴

In reviewing the hyperflexion mechanism, Lin et al¹ noted that isolated thyroid cartilage fractures are rare and that "most of these are caused by direct injury to the neck, except for two patients reported in the literature who sustained isolated thyroid cartilage fractures after sneezing." Lin et al¹ proposed an interesting hypothesis—that "the mechanism causing thyroid cartilage fracture during impaction may be the same with sneezing." Sneezing can be associated with sudden and forceful flexion of the neck.

It is certainly possible that this hyperflexion mechanism was involved in our case, given there was no history of significant blunt force to the neck, as in the sports-related injuries discussed. Wrestling holds can produce hyperflexion. The patient described a feeling of a "crack", which is similar to the clicking sound described in one of the sneezing-related cases. An isolated thyroid cartilage fracture is rare in the absence of major trauma. However, as noted by Rejali et al,⁹ this can create a potential management pitfall. "In the context of non-contact sports, the attendant doctor may not realize the significance of apparently minor head and neck trauma."⁹

There are no series data to provide us with an exact incidence of airway compromise. However, seemingly minor insults to the anterior neck can cause posterior compression of the larynx and can result in airway compromise.^9-11

The CT scan is described as an important imaging modality to rule out cervical spine fracture. Although there was no significant blunt force, the cervical spine was exposed to hyperflexion forces. Another important potential consequence is long-term injury to the vocal cords, with subsequent speech difficulties.¹¹ Computed tomography can visualize the thyroid fracture, but many authors point out that visualization of the vocal cords, with nasopharyngeal laryngoscopy or other modality, is an important adjunct to the CT scan.^9-11

Otolaryngologist consultation should be strongly considered. This patient was transferred to a tertiary care center with expertise in thyroid fractures, and planned nasopharyngeal laryngoscopy to be performed at the receiving institution.

Conclusion

Our patient sustained an isolated thyroid cartilage fracture. Most blunt force laryngeal fractures are associated with multiple trauma. An isolated thyroid cartilage fracture is very rare. An isolated thyroid cartilage fracture from a wrestling injury, especially in a non-sports competition context, such as horseplay, has not been previously reported in the literature. Symptoms can include neck pain, voice changes, pain with swallowing, and shortness of breath. Signs can include tenderness, ecchymosis, or even subcutaneous emphysema. There may be loss of the prominence of the thyroid cartilage, tracheal deviation, and stridor. Computed tomography scan imaging with 3-D reconstructions and laryngoscopy can be helpful in the diagnostic process. In our case, the patient sustained a thyroid cartilage fracture without the energy and force involved in a motor vehicle collision and without significant sports-related force. It is possible this injury may have involved neck hyperflexion, rather than direct compressive forces, similar to that described by Lin et al.¹ Certainly, there was no history of significant blunt force to the neck on the level of the sports-related injuries discussed.

Case

A 90-year-old woman with chronic obstructive pulmonary disease; hypertension; chronic kidney disease; diastolic dysfunction; severe tricuspid regurgitation; and atrial fibrillation (AF), for which she was taking rivaroxaban, presented to the ED for evaluation of injuries she sustained during a fall. The patient’s family stated that she fell while walking with the assistance of a walker and landed on her face. There was no reported loss of consciousness. Upon arrival at the ED, the patient’s vital signs were: blood pressure, 188/105 mm Hg; heart rate, 91 beats/min; respiratory rate, 20 breaths/min; and temperature, 97.88°F (36.6°C). Oxygen (O₂) saturation was 90% on room air, but increased to 98% after the patient received 10 L/min of O₂ through a non-rebreather mask.

On physical examination, the patient was awake, alert, and oriented to person, place, and time, with a Glasgow Coma Scale score of 15. She was able to move all four extremities and had 4/5 motor strength in the upper extremities bilaterally, and 3/5 motor strength in the bilateral lower limbs, which her family reported was the same as her baseline. On pulmonary examination, the lungs were clear to auscultation bilaterally and had no stridor. On auscultation she had a regular rate, with no murmurs or rubs.

The patient had nasal bone tenderness with epistaxis that resolved spontaneously and did not require packing; she had no other facial tenderness. The oropharynx was clear. There was mild posterior midline tenderness over C5 and C6, but no skin ecchymosis or neck swelling. Along with the non-rebreather mask, the patient was placed in a neck collar while she awaited transport to radiology for computed tomography (CT) studies.

The CT scan of the cervical spine demonstrated a minimally displaced fracture of the right anterior arch, both sides of the posterior arch of C1, and a comminuted minimally displaced fracture involving the posterior arch and spinous process of C5, with mild retrolisthesis of C5 over C6.

Based on the CT findings, the patient was taken to the operating room (OR) where she underwent awake fiberoptic laryngoscopy. During transfer to the OR, the patient’s O₂ dropped to 87%; however, after successful intubation without complication, O₂ saturation improved to 95%. After intubation, the patient was admitted to the intensive care unit for observation, and rivaroxaban therapy was discontinued.

A CT scan of the neck postintubation showed a mild interval decrease in the retropharyngeal hematoma, but an increase in the anterior disc space at C5-C6 with mild retrolisthesis, which raised suspicion for an anterior longitudinal ligamentous injury. A repeat CT scan on hospital day 4 revealed a new bleed within the old retropharyngeal hematoma, with no increase in thickness or size of the initial hematoma. The head and neck surgical team kept the patient intubated while awaiting resolution of the hematoma, with no plan of surgery.

On hospital day 6, the patient was transferred to another facility for continued long-term care. She was transitioned to a tracheostomy 4 days later. Follow-up approximately 2 weeks after presentation confirmed complete resolution of the hematoma, and no surgical intervention was required.

Discussion

Overview

Retropharyngeal hematomas are infrequent, but potentially life-threatening complications of cervical fractures, foreign body trauma, infection, violent coughing, and anticoagulation therapy.¹ Although retropharyngeal hematomas associated with warfarin have been well described, to our knowledge, there are no reported cases associated with a direct oral anticoagulant (DOAC).²

Though multiple studies have supported the effectiveness and safety of DOACs for prevention of stroke and systemic embolism in patients with AF, the risk of hemorrhage still exists.³ Postmarketing surveillance studies of DOACs report an overall risk of bleeding comparable to warfarin. Gastrointestinal bleeding was found to be slightly higher in patients taking a DOAC compared to those on warfarin, but the risk of intracranial bleeding from DOACs was notably lower.³ With limited effective reversal agents, DOACs present a tremendous challenge in managing acute life-threatening hemorrhage.⁴

Signs and Symptoms

Patients with retropharyngeal hematomas can present with dyspnea, sore throat, dysphagia, or odynophagia. Neck tenderness and swelling can suggest a retropharyngeal hematoma.⁵ The diagnosis of a retropharyngeal hemorrhage is of clinical importance because of the possible threat of airway obstruction—which may not be initially detectable clinically, and depends on how quickly the blood fills the retropharyngeal space.^1,6

Diagnosis

Computed tomography with intravenous contrast is the imaging study of choice for diagnosing retropharyngeal hematomas in the emergent care setting, and can detect the presence of any associated vertebral facture.^5,7,8 Lateral neck X-ray imaging can detect prevertebral swelling, but is not as sensitive as CT and may underestimate the extent of spinal injury; moreover, lesions or early bleeding may be missed.⁹ In the absence of vertebral fracture on CT imaging, magnetic resonance imaging should be considered to evaluate for possible associated ligamentous injury.⁹

Treatment and Management

Airway Management. Given the risk of progression to complete airway obstruction, the first step in managing retropharyngeal hematomas is to secure the patient’s airway. Even though the published literature recommends either endotracheal intubation or tracheostomy, the latter should only be considered as a last resort for patients on DOACs because of the increased risk of bleeding.

The fiberoptic approach to endotracheal intubation minimizes the risk of further trauma and rupture of the hematoma.^1,10 Once the patient’s airway is secure, the hematoma can be managed conservatively with spinal immobilization and observation for resolution, which may take 2 to 3 weeks.^6,11

Surgical Intervention. Some clinicians believe early surgical intervention leads to early recovery and a shorter hospitalization.¹² Surgical intervention using a transoral or anterior cervical approach is recommended for large hematomas that fail to regress.⁶ Surgical intervention may be considered for patients taking warfarin after successful anticoagulation reversal is achieved using fresh frozen plasma (FFP) and vitamin K. However, due to the increased bleeding potential and limited reversal options, there is an increased risk of surgical complications in patients on DOACs.⁵

Direct Oral Anticoagulation Reversal

The anticoagulation effect of DOACs resolves after five half-lives from the last administered dose, which in the case of rivaroxaban, is between 1 to 2 days.¹³ Therefore, when emergent surgical intervention is required for a retropharyngeal hematoma, understanding the options and limitations of reversal agents is necessary.

Idarucizumab. Currently the only DOAC anticoagulation reversal agent approved by the US Food and Drug Administration, idarucizumab is only effective for reversing the anticoagulation effects of dabigatran.^4,14

Prothrombin Complex Concentrate. Also referred to as factor IX complex, prothrombin complex concentrate (PCC) has been shown to correct prolonged prothrombin time in experimental models of bleeding. Although there is no clinical evidence for its use in DOAC-associated bleeding, PCC should be considered in life-threatening cases, including large or expanding prevertebral hematoma, or other cases in which the potential benefit outweighs the potential risk of thrombosis associated with PCC.⁴

Fresh Frozen Plasma. In the absence of PCC, FFP may be considered, though there are no data supporting its use as a reversal agent for rivaroxaban.¹⁵

Conclusion

Although a rare entity, retropharyngeal hematoma should be suspected in patients with cervical fractures or trauma, especially in the setting of anticoagulation. Early airway management should be considered in a patient with a retropharyngeal hematoma, as symptoms of airway obstruction may be insidious. In patients on DOACs, the potential benefit of earlier resolution with surgical intervention must be strongly weighed against the increased risk of bleeding.

Case

A 90-year-old woman with chronic obstructive pulmonary disease; hypertension; chronic kidney disease; diastolic dysfunction; severe tricuspid regurgitation; and atrial fibrillation (AF), for which she was taking rivaroxaban, presented to the ED for evaluation of injuries she sustained during a fall. The patient’s family stated that she fell while walking with the assistance of a walker and landed on her face. There was no reported loss of consciousness. Upon arrival at the ED, the patient’s vital signs were: blood pressure, 188/105 mm Hg; heart rate, 91 beats/min; respiratory rate, 20 breaths/min; and temperature, 97.88°F (36.6°C). Oxygen (O₂) saturation was 90% on room air, but increased to 98% after the patient received 10 L/min of O₂ through a non-rebreather mask.

On physical examination, the patient was awake, alert, and oriented to person, place, and time, with a Glasgow Coma Scale score of 15. She was able to move all four extremities and had 4/5 motor strength in the upper extremities bilaterally, and 3/5 motor strength in the bilateral lower limbs, which her family reported was the same as her baseline. On pulmonary examination, the lungs were clear to auscultation bilaterally and had no stridor. On auscultation she had a regular rate, with no murmurs or rubs.

The patient had nasal bone tenderness with epistaxis that resolved spontaneously and did not require packing; she had no other facial tenderness. The oropharynx was clear. There was mild posterior midline tenderness over C5 and C6, but no skin ecchymosis or neck swelling. Along with the non-rebreather mask, the patient was placed in a neck collar while she awaited transport to radiology for computed tomography (CT) studies.

The CT scan of the cervical spine demonstrated a minimally displaced fracture of the right anterior arch, both sides of the posterior arch of C1, and a comminuted minimally displaced fracture involving the posterior arch and spinous process of C5, with mild retrolisthesis of C5 over C6.

Based on the CT findings, the patient was taken to the operating room (OR) where she underwent awake fiberoptic laryngoscopy. During transfer to the OR, the patient’s O₂ dropped to 87%; however, after successful intubation without complication, O₂ saturation improved to 95%. After intubation, the patient was admitted to the intensive care unit for observation, and rivaroxaban therapy was discontinued.

A CT scan of the neck postintubation showed a mild interval decrease in the retropharyngeal hematoma, but an increase in the anterior disc space at C5-C6 with mild retrolisthesis, which raised suspicion for an anterior longitudinal ligamentous injury. A repeat CT scan on hospital day 4 revealed a new bleed within the old retropharyngeal hematoma, with no increase in thickness or size of the initial hematoma. The head and neck surgical team kept the patient intubated while awaiting resolution of the hematoma, with no plan of surgery.

On hospital day 6, the patient was transferred to another facility for continued long-term care. She was transitioned to a tracheostomy 4 days later. Follow-up approximately 2 weeks after presentation confirmed complete resolution of the hematoma, and no surgical intervention was required.

Discussion

Overview

Retropharyngeal hematomas are infrequent, but potentially life-threatening complications of cervical fractures, foreign body trauma, infection, violent coughing, and anticoagulation therapy.¹ Although retropharyngeal hematomas associated with warfarin have been well described, to our knowledge, there are no reported cases associated with a direct oral anticoagulant (DOAC).²

Though multiple studies have supported the effectiveness and safety of DOACs for prevention of stroke and systemic embolism in patients with AF, the risk of hemorrhage still exists.³ Postmarketing surveillance studies of DOACs report an overall risk of bleeding comparable to warfarin. Gastrointestinal bleeding was found to be slightly higher in patients taking a DOAC compared to those on warfarin, but the risk of intracranial bleeding from DOACs was notably lower.³ With limited effective reversal agents, DOACs present a tremendous challenge in managing acute life-threatening hemorrhage.⁴

Signs and Symptoms

Patients with retropharyngeal hematomas can present with dyspnea, sore throat, dysphagia, or odynophagia. Neck tenderness and swelling can suggest a retropharyngeal hematoma.⁵ The diagnosis of a retropharyngeal hemorrhage is of clinical importance because of the possible threat of airway obstruction—which may not be initially detectable clinically, and depends on how quickly the blood fills the retropharyngeal space.^1,6

Diagnosis

Computed tomography with intravenous contrast is the imaging study of choice for diagnosing retropharyngeal hematomas in the emergent care setting, and can detect the presence of any associated vertebral facture.^5,7,8 Lateral neck X-ray imaging can detect prevertebral swelling, but is not as sensitive as CT and may underestimate the extent of spinal injury; moreover, lesions or early bleeding may be missed.⁹ In the absence of vertebral fracture on CT imaging, magnetic resonance imaging should be considered to evaluate for possible associated ligamentous injury.⁹

Treatment and Management

Airway Management. Given the risk of progression to complete airway obstruction, the first step in managing retropharyngeal hematomas is to secure the patient’s airway. Even though the published literature recommends either endotracheal intubation or tracheostomy, the latter should only be considered as a last resort for patients on DOACs because of the increased risk of bleeding.

The fiberoptic approach to endotracheal intubation minimizes the risk of further trauma and rupture of the hematoma.^1,10 Once the patient’s airway is secure, the hematoma can be managed conservatively with spinal immobilization and observation for resolution, which may take 2 to 3 weeks.^6,11

Surgical Intervention. Some clinicians believe early surgical intervention leads to early recovery and a shorter hospitalization.¹² Surgical intervention using a transoral or anterior cervical approach is recommended for large hematomas that fail to regress.⁶ Surgical intervention may be considered for patients taking warfarin after successful anticoagulation reversal is achieved using fresh frozen plasma (FFP) and vitamin K. However, due to the increased bleeding potential and limited reversal options, there is an increased risk of surgical complications in patients on DOACs.⁵

Direct Oral Anticoagulation Reversal

The anticoagulation effect of DOACs resolves after five half-lives from the last administered dose, which in the case of rivaroxaban, is between 1 to 2 days.¹³ Therefore, when emergent surgical intervention is required for a retropharyngeal hematoma, understanding the options and limitations of reversal agents is necessary.

Idarucizumab. Currently the only DOAC anticoagulation reversal agent approved by the US Food and Drug Administration, idarucizumab is only effective for reversing the anticoagulation effects of dabigatran.^4,14

Prothrombin Complex Concentrate. Also referred to as factor IX complex, prothrombin complex concentrate (PCC) has been shown to correct prolonged prothrombin time in experimental models of bleeding. Although there is no clinical evidence for its use in DOAC-associated bleeding, PCC should be considered in life-threatening cases, including large or expanding prevertebral hematoma, or other cases in which the potential benefit outweighs the potential risk of thrombosis associated with PCC.⁴

Fresh Frozen Plasma. In the absence of PCC, FFP may be considered, though there are no data supporting its use as a reversal agent for rivaroxaban.¹⁵

Conclusion

Although a rare entity, retropharyngeal hematoma should be suspected in patients with cervical fractures or trauma, especially in the setting of anticoagulation. Early airway management should be considered in a patient with a retropharyngeal hematoma, as symptoms of airway obstruction may be insidious. In patients on DOACs, the potential benefit of earlier resolution with surgical intervention must be strongly weighed against the increased risk of bleeding.

Case

A 90-year-old woman with chronic obstructive pulmonary disease; hypertension; chronic kidney disease; diastolic dysfunction; severe tricuspid regurgitation; and atrial fibrillation (AF), for which she was taking rivaroxaban, presented to the ED for evaluation of injuries she sustained during a fall. The patient’s family stated that she fell while walking with the assistance of a walker and landed on her face. There was no reported loss of consciousness. Upon arrival at the ED, the patient’s vital signs were: blood pressure, 188/105 mm Hg; heart rate, 91 beats/min; respiratory rate, 20 breaths/min; and temperature, 97.88°F (36.6°C). Oxygen (O₂) saturation was 90% on room air, but increased to 98% after the patient received 10 L/min of O₂ through a non-rebreather mask.

On physical examination, the patient was awake, alert, and oriented to person, place, and time, with a Glasgow Coma Scale score of 15. She was able to move all four extremities and had 4/5 motor strength in the upper extremities bilaterally, and 3/5 motor strength in the bilateral lower limbs, which her family reported was the same as her baseline. On pulmonary examination, the lungs were clear to auscultation bilaterally and had no stridor. On auscultation she had a regular rate, with no murmurs or rubs.

The patient had nasal bone tenderness with epistaxis that resolved spontaneously and did not require packing; she had no other facial tenderness. The oropharynx was clear. There was mild posterior midline tenderness over C5 and C6, but no skin ecchymosis or neck swelling. Along with the non-rebreather mask, the patient was placed in a neck collar while she awaited transport to radiology for computed tomography (CT) studies.

The CT scan of the cervical spine demonstrated a minimally displaced fracture of the right anterior arch, both sides of the posterior arch of C1, and a comminuted minimally displaced fracture involving the posterior arch and spinous process of C5, with mild retrolisthesis of C5 over C6.

Based on the CT findings, the patient was taken to the operating room (OR) where she underwent awake fiberoptic laryngoscopy. During transfer to the OR, the patient’s O₂ dropped to 87%; however, after successful intubation without complication, O₂ saturation improved to 95%. After intubation, the patient was admitted to the intensive care unit for observation, and rivaroxaban therapy was discontinued.

A CT scan of the neck postintubation showed a mild interval decrease in the retropharyngeal hematoma, but an increase in the anterior disc space at C5-C6 with mild retrolisthesis, which raised suspicion for an anterior longitudinal ligamentous injury. A repeat CT scan on hospital day 4 revealed a new bleed within the old retropharyngeal hematoma, with no increase in thickness or size of the initial hematoma. The head and neck surgical team kept the patient intubated while awaiting resolution of the hematoma, with no plan of surgery.

On hospital day 6, the patient was transferred to another facility for continued long-term care. She was transitioned to a tracheostomy 4 days later. Follow-up approximately 2 weeks after presentation confirmed complete resolution of the hematoma, and no surgical intervention was required.

Discussion

Overview

Retropharyngeal hematomas are infrequent, but potentially life-threatening complications of cervical fractures, foreign body trauma, infection, violent coughing, and anticoagulation therapy.¹ Although retropharyngeal hematomas associated with warfarin have been well described, to our knowledge, there are no reported cases associated with a direct oral anticoagulant (DOAC).²

Though multiple studies have supported the effectiveness and safety of DOACs for prevention of stroke and systemic embolism in patients with AF, the risk of hemorrhage still exists.³ Postmarketing surveillance studies of DOACs report an overall risk of bleeding comparable to warfarin. Gastrointestinal bleeding was found to be slightly higher in patients taking a DOAC compared to those on warfarin, but the risk of intracranial bleeding from DOACs was notably lower.³ With limited effective reversal agents, DOACs present a tremendous challenge in managing acute life-threatening hemorrhage.⁴

Signs and Symptoms

Patients with retropharyngeal hematomas can present with dyspnea, sore throat, dysphagia, or odynophagia. Neck tenderness and swelling can suggest a retropharyngeal hematoma.⁵ The diagnosis of a retropharyngeal hemorrhage is of clinical importance because of the possible threat of airway obstruction—which may not be initially detectable clinically, and depends on how quickly the blood fills the retropharyngeal space.^1,6

Diagnosis

Computed tomography with intravenous contrast is the imaging study of choice for diagnosing retropharyngeal hematomas in the emergent care setting, and can detect the presence of any associated vertebral facture.^5,7,8 Lateral neck X-ray imaging can detect prevertebral swelling, but is not as sensitive as CT and may underestimate the extent of spinal injury; moreover, lesions or early bleeding may be missed.⁹ In the absence of vertebral fracture on CT imaging, magnetic resonance imaging should be considered to evaluate for possible associated ligamentous injury.⁹

Treatment and Management

Airway Management. Given the risk of progression to complete airway obstruction, the first step in managing retropharyngeal hematomas is to secure the patient’s airway. Even though the published literature recommends either endotracheal intubation or tracheostomy, the latter should only be considered as a last resort for patients on DOACs because of the increased risk of bleeding.

The fiberoptic approach to endotracheal intubation minimizes the risk of further trauma and rupture of the hematoma.^1,10 Once the patient’s airway is secure, the hematoma can be managed conservatively with spinal immobilization and observation for resolution, which may take 2 to 3 weeks.^6,11

Surgical Intervention. Some clinicians believe early surgical intervention leads to early recovery and a shorter hospitalization.¹² Surgical intervention using a transoral or anterior cervical approach is recommended for large hematomas that fail to regress.⁶ Surgical intervention may be considered for patients taking warfarin after successful anticoagulation reversal is achieved using fresh frozen plasma (FFP) and vitamin K. However, due to the increased bleeding potential and limited reversal options, there is an increased risk of surgical complications in patients on DOACs.⁵

Direct Oral Anticoagulation Reversal

The anticoagulation effect of DOACs resolves after five half-lives from the last administered dose, which in the case of rivaroxaban, is between 1 to 2 days.¹³ Therefore, when emergent surgical intervention is required for a retropharyngeal hematoma, understanding the options and limitations of reversal agents is necessary.

Idarucizumab. Currently the only DOAC anticoagulation reversal agent approved by the US Food and Drug Administration, idarucizumab is only effective for reversing the anticoagulation effects of dabigatran.^4,14

Prothrombin Complex Concentrate. Also referred to as factor IX complex, prothrombin complex concentrate (PCC) has been shown to correct prolonged prothrombin time in experimental models of bleeding. Although there is no clinical evidence for its use in DOAC-associated bleeding, PCC should be considered in life-threatening cases, including large or expanding prevertebral hematoma, or other cases in which the potential benefit outweighs the potential risk of thrombosis associated with PCC.⁴

Fresh Frozen Plasma. In the absence of PCC, FFP may be considered, though there are no data supporting its use as a reversal agent for rivaroxaban.¹⁵

Conclusion

Although a rare entity, retropharyngeal hematoma should be suspected in patients with cervical fractures or trauma, especially in the setting of anticoagulation. Early airway management should be considered in a patient with a retropharyngeal hematoma, as symptoms of airway obstruction may be insidious. In patients on DOACs, the potential benefit of earlier resolution with surgical intervention must be strongly weighed against the increased risk of bleeding.

Case

A 55-year-old previously healthy woman with an insignificant medical history presented to the ED for evaluation of right-sided numbness, tingling, and inability to sense temperature. The patient stated the numbness and tingling first began in her right leg and thigh 2 months earlier, and had progressively worsened to her entire right-side. She said she first experienced the thermoanesthesia while taking a shower the morning of presentation. While showering, the patient noted that she could not feel any hot or cold sensation on the right side of her body, including her right leg and arm. She also reported decreased sensation to her extremities on the right side.

She denied any new weakness, headache, chest pain, shortness of breath, fever, chills, nausea, vomiting, back pain, neck pain, or any other symptoms. In addition, she denied any difficulty swallowing, speaking, blurry vision, or double vision. Regarding her social history, the patient denied a history of sexually transmitted diseases, including syphilis; or any tobacco, alcohol, or illicit drug use. The patient confirmed that she had never experienced any of the presenting symptoms prior to 2 months ago. There was no history of trauma or falls. A review of systems was otherwise negative.

Vital signs at presentation were: blood pressure, 129/88 mm Hg; heart rate, 99 beats/min; respiratory rate, 18 breaths/min; and temperature, 98.5°F. Oxygen saturation was 98% on room air. Physical examination revealed a middle-aged woman who was awake, alert, and oriented. Her head was normocephalic and atraumatic, and her pupils were 5 mm, equal, round, and reactive to light bilaterally. Her cranial nerves II through XII were intact. She had normal 5/5 strength in both her upper and lower extremities bilaterally, and had 2+ and equal bilateral patella and Achilles deep tendon reflexes. The patient had no truncal ataxia, and she had a normal gait on ambulation. She was unable to sense temperature (assessed by touching a cold metal tray with her right hand). There was no neck or back midline tenderness to palpation of her spine.

Initial laboratory studies included a complete blood count (CBC); basic metabolic panel (BMP), including blood urea nitrogen; and urine drug screen (UDS). The CBC and BMP were within normal limits, except for an elevated creatine kinase of 249 U/L. The UDS was positive for cocaine. A head computed tomography (CT) scan without contrast was unremarkable.

The patient was admitted to the hospital for further evaluation. Additional laboratory workup during the inpatient stay included nonreactive treponemal immunoglobulin G/immunoglobulin M; nonreactive HIV antigen antibody assay; normal thyroid stimulating hormone; normal free thyroxine, folate, and vitamin B₁₂ levels; normal erythrocyte sedimentation rate, and C-reactive protein levels. The patient’s hemoglobin A_1C was also within normal range.

Other imaging studies, which included MR angiography (MRA) of the head and neck, and MRI of the thoracic and lumbar spine, were unremarkable, with the exception of some chronic spondylitic changes.

Due to the significant C3-C4 stenosis, orthopedic surgery services were consulted for a spinal surgery workup. The orthopedic examination identified a few beats of clonus, intact proprioception, and no dysmetria. The patient had decreased sensation to fine touch in the distribution of C7 at the level of the triceps, midphalangeal joints to distal fingertips on the right, fourth, and fifth fingers on the left and right lateral lower extremity. A Hoffmann sign was positive bilaterally. A CT scan of the cervical spine showed severe canal stenosis at the C3-C4 level secondary to a large C3-C4 left paracentral disc protrusion with AP dimensions of the canal measured at 4 to 5 mm. There was no evidence of acute cervical spine fracture or subluxation.

The patient was offered operative and nonoperative management options, including anterior cervical discectomy and fusion vs conservative management with corticosteroid therapy. She agreed to conservative management and received intravenous (IV) dexamethasone with subjective improvement in her symptoms. The patient was discharged home on hospital day 3, with instructions to follow-up with a spine surgeon in 2 weeks. She was also counseled on abstaining from further cocaine or other illicit drug use.

The patient eventually returned for an elective anterior cervical discectomy and fusion 2 months later, after several outpatient visits and progression of symptoms. She was discharged home on postoperative day 1 with pain well-controlled and was able to ambulate without assistance. On follow-up, she reported 15% improvement in her symptoms.

Discussion

Cervical spondylotic myelopathy (CSM) is the most common myelopathy in patients aged 55 years and older. Immediate neuroimaging studies followed by spinal surgery consultation are recommended for patients presenting with acute symptoms suggestive of cord compression.^1,2

Diagnosis and Differential Diagnosis

Diagnosis of CSM can be made with a thorough patient history, neurological examination, and MRI/MRA. However, because cases of cervical disc herniation (CDH) are often atraumatic, the patient history may not always be contributory to the diagnosis and severity of the offending cause.

During our patient’s hospital course, there was initially a concern for Brown-Séquard syndrome (BSS) due to the lateralizing symptoms and radiographic findings. This is a rare condition that can occur in the setting of spinal trauma, unilateral disc herniation, tumors, epidural hematomas, and spinal cord ischemia.^3,4 In one retrospective case review by Sayer et al,⁴ the incidence of CDH causing BSS was only 0.21% (5 per 2,350 patients), and 67% of the cases involved C5-C6 or C6-C7.

Although disc herniation usually presents with symptoms on the ipsilateral side in patients with BSS, there are rare case reports of patients with contralateral symptoms in the form of complete or incomplete BSS manifesting as ipsilateral motor deficit and/or loss of contralateral pain and temperature due to an incomplete spinal cord compression.^5-7 We were able to rule-out BSS in our patient due to the absence of motor symptoms.

Treatment

Corticosteroid Therapy. High-dose IV corticosteroids should be given to all patients with CSM prior to surgery to reduce cord edema caused by spinal cord injury. In one randomized control trial by Bracken et al,⁸ patients given methylprednisolone within 8 hours of spinal cord injury had improvement in motor function, sensation to pinprick, and touch at 6 months when compared to placebo. When the aforementioned steps are taken in the emergent care setting, they may significantly improve patient outcomes.

Surgical Intervention. All cases of CSM in the review literature were treated surgically with laminectomy or hemilaminectomy, anterior discectomy with or without fusion, or corpectomy followed by interbody fusion, with the goal of achieving cord decompression. A large majority of patients underwent anterior discectomy with interbody fusion, and all of the cases recommend early surgical intervention in severe CSM to prevent rapidly worsening symptoms, including permanent hemiparesis.

Early surgical intervention is positively correlated with better outcomes, most often resulting in significant improvement of symptoms to full recovery.^3,4,6,7,9-12 In one case report, surgical intervention did not result in a significant improvement, and the patient had been suffering from progressive symptoms for 7 years prior to diagnosis and treatment.¹¹

Conservative Management. Conservative management of CSM includes immobilization, activity modification, pain management, and/or corticosteroids therapy.¹³ However, for patients undergoing surgical decompression, 50% to 80% reported symptom improvement.^14,15 This evidence strongly supports management of CSM with early diagnosis and surgical intervention. Despite delays in diagnosis and treatment, surgical intervention can still offer significant relief of weakness and sensory deficits associated with severe CSM.¹¹

Conclusion

Cervical spondylotic myelopathy is the most common myelopathy in patients aged 55 years and older. Common symptoms involve upper extremity sensation, gait disturbances, and deterioration of hand use¹⁶; however, there is a large differential for patients presenting to the ED with these symptoms, including mass effect, infection, vascular conditions, metabolic disorders, inflammatory conditions, and trauma.

Our patient with CSM presented with signs of an incomplete cord syndrome with lateralizing features caused by asymmetric disc herniation. This case is unique in that though our patient had some symptom resolution with corticosteroids therapy alone, she ultimately returned for definitive surgical decompression after symptom progression.

Case

A 55-year-old previously healthy woman with an insignificant medical history presented to the ED for evaluation of right-sided numbness, tingling, and inability to sense temperature. The patient stated the numbness and tingling first began in her right leg and thigh 2 months earlier, and had progressively worsened to her entire right-side. She said she first experienced the thermoanesthesia while taking a shower the morning of presentation. While showering, the patient noted that she could not feel any hot or cold sensation on the right side of her body, including her right leg and arm. She also reported decreased sensation to her extremities on the right side.

She denied any new weakness, headache, chest pain, shortness of breath, fever, chills, nausea, vomiting, back pain, neck pain, or any other symptoms. In addition, she denied any difficulty swallowing, speaking, blurry vision, or double vision. Regarding her social history, the patient denied a history of sexually transmitted diseases, including syphilis; or any tobacco, alcohol, or illicit drug use. The patient confirmed that she had never experienced any of the presenting symptoms prior to 2 months ago. There was no history of trauma or falls. A review of systems was otherwise negative.

Vital signs at presentation were: blood pressure, 129/88 mm Hg; heart rate, 99 beats/min; respiratory rate, 18 breaths/min; and temperature, 98.5°F. Oxygen saturation was 98% on room air. Physical examination revealed a middle-aged woman who was awake, alert, and oriented. Her head was normocephalic and atraumatic, and her pupils were 5 mm, equal, round, and reactive to light bilaterally. Her cranial nerves II through XII were intact. She had normal 5/5 strength in both her upper and lower extremities bilaterally, and had 2+ and equal bilateral patella and Achilles deep tendon reflexes. The patient had no truncal ataxia, and she had a normal gait on ambulation. She was unable to sense temperature (assessed by touching a cold metal tray with her right hand). There was no neck or back midline tenderness to palpation of her spine.

Initial laboratory studies included a complete blood count (CBC); basic metabolic panel (BMP), including blood urea nitrogen; and urine drug screen (UDS). The CBC and BMP were within normal limits, except for an elevated creatine kinase of 249 U/L. The UDS was positive for cocaine. A head computed tomography (CT) scan without contrast was unremarkable.

The patient was admitted to the hospital for further evaluation. Additional laboratory workup during the inpatient stay included nonreactive treponemal immunoglobulin G/immunoglobulin M; nonreactive HIV antigen antibody assay; normal thyroid stimulating hormone; normal free thyroxine, folate, and vitamin B₁₂ levels; normal erythrocyte sedimentation rate, and C-reactive protein levels. The patient’s hemoglobin A_1C was also within normal range.

Other imaging studies, which included MR angiography (MRA) of the head and neck, and MRI of the thoracic and lumbar spine, were unremarkable, with the exception of some chronic spondylitic changes.

Due to the significant C3-C4 stenosis, orthopedic surgery services were consulted for a spinal surgery workup. The orthopedic examination identified a few beats of clonus, intact proprioception, and no dysmetria. The patient had decreased sensation to fine touch in the distribution of C7 at the level of the triceps, midphalangeal joints to distal fingertips on the right, fourth, and fifth fingers on the left and right lateral lower extremity. A Hoffmann sign was positive bilaterally. A CT scan of the cervical spine showed severe canal stenosis at the C3-C4 level secondary to a large C3-C4 left paracentral disc protrusion with AP dimensions of the canal measured at 4 to 5 mm. There was no evidence of acute cervical spine fracture or subluxation.

The patient was offered operative and nonoperative management options, including anterior cervical discectomy and fusion vs conservative management with corticosteroid therapy. She agreed to conservative management and received intravenous (IV) dexamethasone with subjective improvement in her symptoms. The patient was discharged home on hospital day 3, with instructions to follow-up with a spine surgeon in 2 weeks. She was also counseled on abstaining from further cocaine or other illicit drug use.

The patient eventually returned for an elective anterior cervical discectomy and fusion 2 months later, after several outpatient visits and progression of symptoms. She was discharged home on postoperative day 1 with pain well-controlled and was able to ambulate without assistance. On follow-up, she reported 15% improvement in her symptoms.

Discussion

Cervical spondylotic myelopathy (CSM) is the most common myelopathy in patients aged 55 years and older. Immediate neuroimaging studies followed by spinal surgery consultation are recommended for patients presenting with acute symptoms suggestive of cord compression.^1,2

Diagnosis and Differential Diagnosis

Diagnosis of CSM can be made with a thorough patient history, neurological examination, and MRI/MRA. However, because cases of cervical disc herniation (CDH) are often atraumatic, the patient history may not always be contributory to the diagnosis and severity of the offending cause.

During our patient’s hospital course, there was initially a concern for Brown-Séquard syndrome (BSS) due to the lateralizing symptoms and radiographic findings. This is a rare condition that can occur in the setting of spinal trauma, unilateral disc herniation, tumors, epidural hematomas, and spinal cord ischemia.^3,4 In one retrospective case review by Sayer et al,⁴ the incidence of CDH causing BSS was only 0.21% (5 per 2,350 patients), and 67% of the cases involved C5-C6 or C6-C7.

Although disc herniation usually presents with symptoms on the ipsilateral side in patients with BSS, there are rare case reports of patients with contralateral symptoms in the form of complete or incomplete BSS manifesting as ipsilateral motor deficit and/or loss of contralateral pain and temperature due to an incomplete spinal cord compression.^5-7 We were able to rule-out BSS in our patient due to the absence of motor symptoms.

Treatment

Corticosteroid Therapy. High-dose IV corticosteroids should be given to all patients with CSM prior to surgery to reduce cord edema caused by spinal cord injury. In one randomized control trial by Bracken et al,⁸ patients given methylprednisolone within 8 hours of spinal cord injury had improvement in motor function, sensation to pinprick, and touch at 6 months when compared to placebo. When the aforementioned steps are taken in the emergent care setting, they may significantly improve patient outcomes.

Surgical Intervention. All cases of CSM in the review literature were treated surgically with laminectomy or hemilaminectomy, anterior discectomy with or without fusion, or corpectomy followed by interbody fusion, with the goal of achieving cord decompression. A large majority of patients underwent anterior discectomy with interbody fusion, and all of the cases recommend early surgical intervention in severe CSM to prevent rapidly worsening symptoms, including permanent hemiparesis.

Early surgical intervention is positively correlated with better outcomes, most often resulting in significant improvement of symptoms to full recovery.^3,4,6,7,9-12 In one case report, surgical intervention did not result in a significant improvement, and the patient had been suffering from progressive symptoms for 7 years prior to diagnosis and treatment.¹¹

Conservative Management. Conservative management of CSM includes immobilization, activity modification, pain management, and/or corticosteroids therapy.¹³ However, for patients undergoing surgical decompression, 50% to 80% reported symptom improvement.^14,15 This evidence strongly supports management of CSM with early diagnosis and surgical intervention. Despite delays in diagnosis and treatment, surgical intervention can still offer significant relief of weakness and sensory deficits associated with severe CSM.¹¹

Conclusion

Cervical spondylotic myelopathy is the most common myelopathy in patients aged 55 years and older. Common symptoms involve upper extremity sensation, gait disturbances, and deterioration of hand use¹⁶; however, there is a large differential for patients presenting to the ED with these symptoms, including mass effect, infection, vascular conditions, metabolic disorders, inflammatory conditions, and trauma.

Our patient with CSM presented with signs of an incomplete cord syndrome with lateralizing features caused by asymmetric disc herniation. This case is unique in that though our patient had some symptom resolution with corticosteroids therapy alone, she ultimately returned for definitive surgical decompression after symptom progression.

Case

A 55-year-old previously healthy woman with an insignificant medical history presented to the ED for evaluation of right-sided numbness, tingling, and inability to sense temperature. The patient stated the numbness and tingling first began in her right leg and thigh 2 months earlier, and had progressively worsened to her entire right-side. She said she first experienced the thermoanesthesia while taking a shower the morning of presentation. While showering, the patient noted that she could not feel any hot or cold sensation on the right side of her body, including her right leg and arm. She also reported decreased sensation to her extremities on the right side.

She denied any new weakness, headache, chest pain, shortness of breath, fever, chills, nausea, vomiting, back pain, neck pain, or any other symptoms. In addition, she denied any difficulty swallowing, speaking, blurry vision, or double vision. Regarding her social history, the patient denied a history of sexually transmitted diseases, including syphilis; or any tobacco, alcohol, or illicit drug use. The patient confirmed that she had never experienced any of the presenting symptoms prior to 2 months ago. There was no history of trauma or falls. A review of systems was otherwise negative.

Vital signs at presentation were: blood pressure, 129/88 mm Hg; heart rate, 99 beats/min; respiratory rate, 18 breaths/min; and temperature, 98.5°F. Oxygen saturation was 98% on room air. Physical examination revealed a middle-aged woman who was awake, alert, and oriented. Her head was normocephalic and atraumatic, and her pupils were 5 mm, equal, round, and reactive to light bilaterally. Her cranial nerves II through XII were intact. She had normal 5/5 strength in both her upper and lower extremities bilaterally, and had 2+ and equal bilateral patella and Achilles deep tendon reflexes. The patient had no truncal ataxia, and she had a normal gait on ambulation. She was unable to sense temperature (assessed by touching a cold metal tray with her right hand). There was no neck or back midline tenderness to palpation of her spine.

Initial laboratory studies included a complete blood count (CBC); basic metabolic panel (BMP), including blood urea nitrogen; and urine drug screen (UDS). The CBC and BMP were within normal limits, except for an elevated creatine kinase of 249 U/L. The UDS was positive for cocaine. A head computed tomography (CT) scan without contrast was unremarkable.

The patient was admitted to the hospital for further evaluation. Additional laboratory workup during the inpatient stay included nonreactive treponemal immunoglobulin G/immunoglobulin M; nonreactive HIV antigen antibody assay; normal thyroid stimulating hormone; normal free thyroxine, folate, and vitamin B₁₂ levels; normal erythrocyte sedimentation rate, and C-reactive protein levels. The patient’s hemoglobin A_1C was also within normal range.

Other imaging studies, which included MR angiography (MRA) of the head and neck, and MRI of the thoracic and lumbar spine, were unremarkable, with the exception of some chronic spondylitic changes.

Due to the significant C3-C4 stenosis, orthopedic surgery services were consulted for a spinal surgery workup. The orthopedic examination identified a few beats of clonus, intact proprioception, and no dysmetria. The patient had decreased sensation to fine touch in the distribution of C7 at the level of the triceps, midphalangeal joints to distal fingertips on the right, fourth, and fifth fingers on the left and right lateral lower extremity. A Hoffmann sign was positive bilaterally. A CT scan of the cervical spine showed severe canal stenosis at the C3-C4 level secondary to a large C3-C4 left paracentral disc protrusion with AP dimensions of the canal measured at 4 to 5 mm. There was no evidence of acute cervical spine fracture or subluxation.

The patient was offered operative and nonoperative management options, including anterior cervical discectomy and fusion vs conservative management with corticosteroid therapy. She agreed to conservative management and received intravenous (IV) dexamethasone with subjective improvement in her symptoms. The patient was discharged home on hospital day 3, with instructions to follow-up with a spine surgeon in 2 weeks. She was also counseled on abstaining from further cocaine or other illicit drug use.

The patient eventually returned for an elective anterior cervical discectomy and fusion 2 months later, after several outpatient visits and progression of symptoms. She was discharged home on postoperative day 1 with pain well-controlled and was able to ambulate without assistance. On follow-up, she reported 15% improvement in her symptoms.

Discussion

Cervical spondylotic myelopathy (CSM) is the most common myelopathy in patients aged 55 years and older. Immediate neuroimaging studies followed by spinal surgery consultation are recommended for patients presenting with acute symptoms suggestive of cord compression.^1,2

Diagnosis and Differential Diagnosis

Diagnosis of CSM can be made with a thorough patient history, neurological examination, and MRI/MRA. However, because cases of cervical disc herniation (CDH) are often atraumatic, the patient history may not always be contributory to the diagnosis and severity of the offending cause.

During our patient’s hospital course, there was initially a concern for Brown-Séquard syndrome (BSS) due to the lateralizing symptoms and radiographic findings. This is a rare condition that can occur in the setting of spinal trauma, unilateral disc herniation, tumors, epidural hematomas, and spinal cord ischemia.^3,4 In one retrospective case review by Sayer et al,⁴ the incidence of CDH causing BSS was only 0.21% (5 per 2,350 patients), and 67% of the cases involved C5-C6 or C6-C7.

Although disc herniation usually presents with symptoms on the ipsilateral side in patients with BSS, there are rare case reports of patients with contralateral symptoms in the form of complete or incomplete BSS manifesting as ipsilateral motor deficit and/or loss of contralateral pain and temperature due to an incomplete spinal cord compression.^5-7 We were able to rule-out BSS in our patient due to the absence of motor symptoms.

Treatment

Corticosteroid Therapy. High-dose IV corticosteroids should be given to all patients with CSM prior to surgery to reduce cord edema caused by spinal cord injury. In one randomized control trial by Bracken et al,⁸ patients given methylprednisolone within 8 hours of spinal cord injury had improvement in motor function, sensation to pinprick, and touch at 6 months when compared to placebo. When the aforementioned steps are taken in the emergent care setting, they may significantly improve patient outcomes.

Surgical Intervention. All cases of CSM in the review literature were treated surgically with laminectomy or hemilaminectomy, anterior discectomy with or without fusion, or corpectomy followed by interbody fusion, with the goal of achieving cord decompression. A large majority of patients underwent anterior discectomy with interbody fusion, and all of the cases recommend early surgical intervention in severe CSM to prevent rapidly worsening symptoms, including permanent hemiparesis.

Early surgical intervention is positively correlated with better outcomes, most often resulting in significant improvement of symptoms to full recovery.^3,4,6,7,9-12 In one case report, surgical intervention did not result in a significant improvement, and the patient had been suffering from progressive symptoms for 7 years prior to diagnosis and treatment.¹¹

Conservative Management. Conservative management of CSM includes immobilization, activity modification, pain management, and/or corticosteroids therapy.¹³ However, for patients undergoing surgical decompression, 50% to 80% reported symptom improvement.^14,15 This evidence strongly supports management of CSM with early diagnosis and surgical intervention. Despite delays in diagnosis and treatment, surgical intervention can still offer significant relief of weakness and sensory deficits associated with severe CSM.¹¹

Conclusion

Cervical spondylotic myelopathy is the most common myelopathy in patients aged 55 years and older. Common symptoms involve upper extremity sensation, gait disturbances, and deterioration of hand use¹⁶; however, there is a large differential for patients presenting to the ED with these symptoms, including mass effect, infection, vascular conditions, metabolic disorders, inflammatory conditions, and trauma.

Our patient with CSM presented with signs of an incomplete cord syndrome with lateralizing features caused by asymmetric disc herniation. This case is unique in that though our patient had some symptom resolution with corticosteroids therapy alone, she ultimately returned for definitive surgical decompression after symptom progression.

Case

An otherwise healthy 20-month-old boy presented to the ED for evaluation after his father witnessed the child ingest a model race car fuel additive. According to the patient’s father, the boy was playing with several closed bottles that were stored in the garage, when he witnessed the boy open up and take a sip of a pink-colored fuel additive, which the father believed to contain 100% methanol. The patient’s father further noted that immediately after drinking the fluid, the patient spat and drooled, and had one episode of nonbloody emesis prior to arrival at the ED.

Initial vital signs at presentation were: blood pressure, 84/54 mm Hg; heart rate, 97 beats/min; respiratory rate, 24 breaths/min; and temperature 98°F. Oxygen saturation was 99% on room air. Physical examination was notable for mild erythema in the posterior oropharynx. Otherwise, the patient was acting appropriately for his age and in no acute distress. Laboratory studies were within normal limits, except for the following: serum anion gap, 18 mEq/L (reference range for children < 3 years old, 10-14 mEq/L); serum bicarbonate, 19 mmol/L (reference range for children 12-24 months, 17-25 mmol/L); and serum creatinine, 2.8 mg/dL (reference range for children 12 to 24 months, 0.2-0.5 mg/dL). A repeat creatinine test taken after bolus of fluid administration was 2.4 mg/dL. A renal ultrasound, performed to investigate the cause of the renal failure, was unremarkable.

What toxic exposures are of concern based on the clinical history?

The history of exposure to a liquid stored in a garage raises the likelihood of exposure to an automobile-related item such as diethylene glycol, ethylene glycol (EG), and methanol.

Diethylene Glycol. Diethylene glycol is an ingredient in brake and power steering fluids, and has toxic properties qualitatively similar to EG.

Ethylene Glycol. A clear, colorless, odorless fluid with a sweet taste, EG is an ingredient in radiator antifreeze, refrigerant fluid, coolants, and pesticides. Like methylene, EG reaches peak plasma concentration within 1 to 4 hours, but toxic clinical findings do not occur for 3 to 6 hours.¹

Methanol. Methanol is a clear, colorless, alcohol found in antifreeze, windshield washer fluid, and race car fuel.² Although methanol reaches peak plasma concentration in about 30 to 60 minutes, signs of systemic toxicity (ie, metabolic acidosis) typically take 6 to 12 hours to manifest.¹

In both EG and methanol, there is a delay in toxic clinical findings because the parent compounds are not toxic in their initial form; rather, major toxicity is derived from their metabolites: formic acid and oxalic acid, respectively.

Other Toxins. Many other potentially toxic liquids are associated with a homeowner’s occupation or avocational interests. These include painting supplies (eg, industrial paints containing lead), gardening materials (eg, pesticides containing organophosphates), fuels (eg, gasoline, polychlorinated biphenyls in coolant, and lubricants), and cleaning supplies (eg, caustics, detergents, and air freshener).

Case Continuation

Since the patient’s elevated anion gap raised concerns for methanol or EG exposure, he was given fomepizole and transferred to a tertiary care children’s hospital for further management and possible hemodialysis. Upon arrival at the receiving hospital, the patient’s vital signs and physical examination remained unchanged. Repeat laboratory studies were notable for a creatinine level of 0.3 mg/dL. The patient’s father was instructed to retrieve the implicated bottle from home. An inspection of the bottle’s ingredients was notable for nitromethane, castor oil, and methanol.

What is nitromethane and what are its uses?

Nitromethane, the simplest nitro compound, is a colorless, viscous, lipid-soluble fluid.³ The polarity of nitromethane permits its use as a stabilizer in a number of chemical solvents, such as dry cleaning fluid, degreasers, and "super glue."^4,5 Nitromethane is also commonly added to model-engine and drag-race fuels, which also contain methanol and castor oil.³ In this capacity, nitromethane functions as an oxygen carrier, allowing more efficient fuel use in combustion cylinders (compared to gasoline), thereby increasing the horsepower of the vehicle.⁶ It is therefore commonly added to fuel for drag racers, radio-controlled cars, and model aircrafts.⁴ In the small concentrations typically inadvertently ingested, the clinical effects of nitromethane itself are inconsequential.

What is the differential for creatinine elevation?

Creatinine itself is a normal breakdown product of muscle metabolism produced by spontaneous conversion from creatine and is found at a fairly constant serum level in proportion to muscle mass.⁷ Thus, as people age and muscle mass decreases, their baseline creatinine levels decrease proportionally.

Elimination. The majority of creatinine (85%-90%) is filtered and excreted by the kidneys, with the remaining 10% to 15% secreted by the tubules, allowing creatinine to be a surrogate measure of the glomerular filtration rate.⁷ Exogenous sources of creatine or creatinine include meat and creatine supplements, the latter of which are used as an "energy source" to enhance athletic performance.

Etiology. The etiology for an elevated serum creatinine concentration includes renal failure, both acute and chronic; volume depletion; hemorrhage (low blood volume); and medications, including diuretics, angiotensin converting enzyme inhibitors, angiotensin-receptor blockers, nonsteroidal anti-inflammatory drugs, and certain antibiotics. These etiologies can also be categorized as processes that increase creatinine production, decrease elimination (H₂ antagonist and trimethoprim both inhibit the cation secretory pump in the tubules), or interfere with the creatinine assay (ketones, keto acids, lipemia, hemolysis, cephalosporins).⁷

Because creatinine is filtered so efficiently by the kidney, neither exogenous nor endogenous creatinine sources are expected to increase serum creatinine in the absence of renal dysfunction. However, transient elevation may occur in body builders who use extreme doses of creatine. Patients with rhabdomyolysis often develop elevated creatinine concentrations, but nearly always in the setting of myoglobinuric renal failure.

Jaffe Reaction and Enzymatic Methods. Serum creatinine can be measured using either the Jaffe reaction or the enzymatic method. In the Jaffe reaction, creatinine reacts with alkaline sodium picrate to form a red-orange chromophore, which absorbs light in the range of 470 to 550 nanometers on spectroscopy.^6,8,9 The active methylene group on nitromethane also reacts with alkaline sodium picrate to form a chromophore which absorbs light in the same wavelength range.¹⁰ Thus, serum creatinine measurements via the Jaffe reaction are falsely elevated due to the cross-reactivity between nitromethane and alkaline sodium picrate. In some reported cases, there is a 20-fold increase in the measured serum creatinine in the presence of nitromethane; renal function, however, remains normal.⁵

This false reading seen in the Jaffe reaction can be avoided by utilizing the enzymatic method of creatinine measurement, a three-step process that ultimately produces hydrogen peroxide, which is measured and accurately correlates with serum creatinine—even in the presence of nitromethane.⁸ This distinction explains the dramatically different creatinine concentrations measured at the two institutions in this case.

Case Conclusion

The patient was monitored overnight at the children’s hospital. Repeat laboratory studies in the morning showed a normal creatinine level of 0.3 mg/dL and a negative methanol level. The patient was discharged home in the care of his father, who was instructed to follow-up with his son’s pediatrician. The father also received counseling on safe storage practices for dangerous chemicals.

Case

An otherwise healthy 20-month-old boy presented to the ED for evaluation after his father witnessed the child ingest a model race car fuel additive. According to the patient’s father, the boy was playing with several closed bottles that were stored in the garage, when he witnessed the boy open up and take a sip of a pink-colored fuel additive, which the father believed to contain 100% methanol. The patient’s father further noted that immediately after drinking the fluid, the patient spat and drooled, and had one episode of nonbloody emesis prior to arrival at the ED.

Initial vital signs at presentation were: blood pressure, 84/54 mm Hg; heart rate, 97 beats/min; respiratory rate, 24 breaths/min; and temperature 98°F. Oxygen saturation was 99% on room air. Physical examination was notable for mild erythema in the posterior oropharynx. Otherwise, the patient was acting appropriately for his age and in no acute distress. Laboratory studies were within normal limits, except for the following: serum anion gap, 18 mEq/L (reference range for children < 3 years old, 10-14 mEq/L); serum bicarbonate, 19 mmol/L (reference range for children 12-24 months, 17-25 mmol/L); and serum creatinine, 2.8 mg/dL (reference range for children 12 to 24 months, 0.2-0.5 mg/dL). A repeat creatinine test taken after bolus of fluid administration was 2.4 mg/dL. A renal ultrasound, performed to investigate the cause of the renal failure, was unremarkable.

What toxic exposures are of concern based on the clinical history?

The history of exposure to a liquid stored in a garage raises the likelihood of exposure to an automobile-related item such as diethylene glycol, ethylene glycol (EG), and methanol.

Diethylene Glycol. Diethylene glycol is an ingredient in brake and power steering fluids, and has toxic properties qualitatively similar to EG.

Ethylene Glycol. A clear, colorless, odorless fluid with a sweet taste, EG is an ingredient in radiator antifreeze, refrigerant fluid, coolants, and pesticides. Like methylene, EG reaches peak plasma concentration within 1 to 4 hours, but toxic clinical findings do not occur for 3 to 6 hours.¹

Methanol. Methanol is a clear, colorless, alcohol found in antifreeze, windshield washer fluid, and race car fuel.² Although methanol reaches peak plasma concentration in about 30 to 60 minutes, signs of systemic toxicity (ie, metabolic acidosis) typically take 6 to 12 hours to manifest.¹

In both EG and methanol, there is a delay in toxic clinical findings because the parent compounds are not toxic in their initial form; rather, major toxicity is derived from their metabolites: formic acid and oxalic acid, respectively.

Other Toxins. Many other potentially toxic liquids are associated with a homeowner’s occupation or avocational interests. These include painting supplies (eg, industrial paints containing lead), gardening materials (eg, pesticides containing organophosphates), fuels (eg, gasoline, polychlorinated biphenyls in coolant, and lubricants), and cleaning supplies (eg, caustics, detergents, and air freshener).

Case Continuation

Since the patient’s elevated anion gap raised concerns for methanol or EG exposure, he was given fomepizole and transferred to a tertiary care children’s hospital for further management and possible hemodialysis. Upon arrival at the receiving hospital, the patient’s vital signs and physical examination remained unchanged. Repeat laboratory studies were notable for a creatinine level of 0.3 mg/dL. The patient’s father was instructed to retrieve the implicated bottle from home. An inspection of the bottle’s ingredients was notable for nitromethane, castor oil, and methanol.

What is nitromethane and what are its uses?

Nitromethane, the simplest nitro compound, is a colorless, viscous, lipid-soluble fluid.³ The polarity of nitromethane permits its use as a stabilizer in a number of chemical solvents, such as dry cleaning fluid, degreasers, and "super glue."^4,5 Nitromethane is also commonly added to model-engine and drag-race fuels, which also contain methanol and castor oil.³ In this capacity, nitromethane functions as an oxygen carrier, allowing more efficient fuel use in combustion cylinders (compared to gasoline), thereby increasing the horsepower of the vehicle.⁶ It is therefore commonly added to fuel for drag racers, radio-controlled cars, and model aircrafts.⁴ In the small concentrations typically inadvertently ingested, the clinical effects of nitromethane itself are inconsequential.

What is the differential for creatinine elevation?

Creatinine itself is a normal breakdown product of muscle metabolism produced by spontaneous conversion from creatine and is found at a fairly constant serum level in proportion to muscle mass.⁷ Thus, as people age and muscle mass decreases, their baseline creatinine levels decrease proportionally.

Elimination. The majority of creatinine (85%-90%) is filtered and excreted by the kidneys, with the remaining 10% to 15% secreted by the tubules, allowing creatinine to be a surrogate measure of the glomerular filtration rate.⁷ Exogenous sources of creatine or creatinine include meat and creatine supplements, the latter of which are used as an "energy source" to enhance athletic performance.

Etiology. The etiology for an elevated serum creatinine concentration includes renal failure, both acute and chronic; volume depletion; hemorrhage (low blood volume); and medications, including diuretics, angiotensin converting enzyme inhibitors, angiotensin-receptor blockers, nonsteroidal anti-inflammatory drugs, and certain antibiotics. These etiologies can also be categorized as processes that increase creatinine production, decrease elimination (H₂ antagonist and trimethoprim both inhibit the cation secretory pump in the tubules), or interfere with the creatinine assay (ketones, keto acids, lipemia, hemolysis, cephalosporins).⁷

Because creatinine is filtered so efficiently by the kidney, neither exogenous nor endogenous creatinine sources are expected to increase serum creatinine in the absence of renal dysfunction. However, transient elevation may occur in body builders who use extreme doses of creatine. Patients with rhabdomyolysis often develop elevated creatinine concentrations, but nearly always in the setting of myoglobinuric renal failure.

Jaffe Reaction and Enzymatic Methods. Serum creatinine can be measured using either the Jaffe reaction or the enzymatic method. In the Jaffe reaction, creatinine reacts with alkaline sodium picrate to form a red-orange chromophore, which absorbs light in the range of 470 to 550 nanometers on spectroscopy.^6,8,9 The active methylene group on nitromethane also reacts with alkaline sodium picrate to form a chromophore which absorbs light in the same wavelength range.¹⁰ Thus, serum creatinine measurements via the Jaffe reaction are falsely elevated due to the cross-reactivity between nitromethane and alkaline sodium picrate. In some reported cases, there is a 20-fold increase in the measured serum creatinine in the presence of nitromethane; renal function, however, remains normal.⁵

This false reading seen in the Jaffe reaction can be avoided by utilizing the enzymatic method of creatinine measurement, a three-step process that ultimately produces hydrogen peroxide, which is measured and accurately correlates with serum creatinine—even in the presence of nitromethane.⁸ This distinction explains the dramatically different creatinine concentrations measured at the two institutions in this case.

Case Conclusion

The patient was monitored overnight at the children’s hospital. Repeat laboratory studies in the morning showed a normal creatinine level of 0.3 mg/dL and a negative methanol level. The patient was discharged home in the care of his father, who was instructed to follow-up with his son’s pediatrician. The father also received counseling on safe storage practices for dangerous chemicals.

Case

An otherwise healthy 20-month-old boy presented to the ED for evaluation after his father witnessed the child ingest a model race car fuel additive. According to the patient’s father, the boy was playing with several closed bottles that were stored in the garage, when he witnessed the boy open up and take a sip of a pink-colored fuel additive, which the father believed to contain 100% methanol. The patient’s father further noted that immediately after drinking the fluid, the patient spat and drooled, and had one episode of nonbloody emesis prior to arrival at the ED.

Initial vital signs at presentation were: blood pressure, 84/54 mm Hg; heart rate, 97 beats/min; respiratory rate, 24 breaths/min; and temperature 98°F. Oxygen saturation was 99% on room air. Physical examination was notable for mild erythema in the posterior oropharynx. Otherwise, the patient was acting appropriately for his age and in no acute distress. Laboratory studies were within normal limits, except for the following: serum anion gap, 18 mEq/L (reference range for children < 3 years old, 10-14 mEq/L); serum bicarbonate, 19 mmol/L (reference range for children 12-24 months, 17-25 mmol/L); and serum creatinine, 2.8 mg/dL (reference range for children 12 to 24 months, 0.2-0.5 mg/dL). A repeat creatinine test taken after bolus of fluid administration was 2.4 mg/dL. A renal ultrasound, performed to investigate the cause of the renal failure, was unremarkable.

What toxic exposures are of concern based on the clinical history?

The history of exposure to a liquid stored in a garage raises the likelihood of exposure to an automobile-related item such as diethylene glycol, ethylene glycol (EG), and methanol.

Diethylene Glycol. Diethylene glycol is an ingredient in brake and power steering fluids, and has toxic properties qualitatively similar to EG.

Ethylene Glycol. A clear, colorless, odorless fluid with a sweet taste, EG is an ingredient in radiator antifreeze, refrigerant fluid, coolants, and pesticides. Like methylene, EG reaches peak plasma concentration within 1 to 4 hours, but toxic clinical findings do not occur for 3 to 6 hours.¹

Methanol. Methanol is a clear, colorless, alcohol found in antifreeze, windshield washer fluid, and race car fuel.² Although methanol reaches peak plasma concentration in about 30 to 60 minutes, signs of systemic toxicity (ie, metabolic acidosis) typically take 6 to 12 hours to manifest.¹

In both EG and methanol, there is a delay in toxic clinical findings because the parent compounds are not toxic in their initial form; rather, major toxicity is derived from their metabolites: formic acid and oxalic acid, respectively.

Other Toxins. Many other potentially toxic liquids are associated with a homeowner’s occupation or avocational interests. These include painting supplies (eg, industrial paints containing lead), gardening materials (eg, pesticides containing organophosphates), fuels (eg, gasoline, polychlorinated biphenyls in coolant, and lubricants), and cleaning supplies (eg, caustics, detergents, and air freshener).

Case Continuation

Since the patient’s elevated anion gap raised concerns for methanol or EG exposure, he was given fomepizole and transferred to a tertiary care children’s hospital for further management and possible hemodialysis. Upon arrival at the receiving hospital, the patient’s vital signs and physical examination remained unchanged. Repeat laboratory studies were notable for a creatinine level of 0.3 mg/dL. The patient’s father was instructed to retrieve the implicated bottle from home. An inspection of the bottle’s ingredients was notable for nitromethane, castor oil, and methanol.

What is nitromethane and what are its uses?

Nitromethane, the simplest nitro compound, is a colorless, viscous, lipid-soluble fluid.³ The polarity of nitromethane permits its use as a stabilizer in a number of chemical solvents, such as dry cleaning fluid, degreasers, and "super glue."^4,5 Nitromethane is also commonly added to model-engine and drag-race fuels, which also contain methanol and castor oil.³ In this capacity, nitromethane functions as an oxygen carrier, allowing more efficient fuel use in combustion cylinders (compared to gasoline), thereby increasing the horsepower of the vehicle.⁶ It is therefore commonly added to fuel for drag racers, radio-controlled cars, and model aircrafts.⁴ In the small concentrations typically inadvertently ingested, the clinical effects of nitromethane itself are inconsequential.

What is the differential for creatinine elevation?

Creatinine itself is a normal breakdown product of muscle metabolism produced by spontaneous conversion from creatine and is found at a fairly constant serum level in proportion to muscle mass.⁷ Thus, as people age and muscle mass decreases, their baseline creatinine levels decrease proportionally.

Elimination. The majority of creatinine (85%-90%) is filtered and excreted by the kidneys, with the remaining 10% to 15% secreted by the tubules, allowing creatinine to be a surrogate measure of the glomerular filtration rate.⁷ Exogenous sources of creatine or creatinine include meat and creatine supplements, the latter of which are used as an "energy source" to enhance athletic performance.

Etiology. The etiology for an elevated serum creatinine concentration includes renal failure, both acute and chronic; volume depletion; hemorrhage (low blood volume); and medications, including diuretics, angiotensin converting enzyme inhibitors, angiotensin-receptor blockers, nonsteroidal anti-inflammatory drugs, and certain antibiotics. These etiologies can also be categorized as processes that increase creatinine production, decrease elimination (H₂ antagonist and trimethoprim both inhibit the cation secretory pump in the tubules), or interfere with the creatinine assay (ketones, keto acids, lipemia, hemolysis, cephalosporins).⁷

Because creatinine is filtered so efficiently by the kidney, neither exogenous nor endogenous creatinine sources are expected to increase serum creatinine in the absence of renal dysfunction. However, transient elevation may occur in body builders who use extreme doses of creatine. Patients with rhabdomyolysis often develop elevated creatinine concentrations, but nearly always in the setting of myoglobinuric renal failure.

Jaffe Reaction and Enzymatic Methods. Serum creatinine can be measured using either the Jaffe reaction or the enzymatic method. In the Jaffe reaction, creatinine reacts with alkaline sodium picrate to form a red-orange chromophore, which absorbs light in the range of 470 to 550 nanometers on spectroscopy.^6,8,9 The active methylene group on nitromethane also reacts with alkaline sodium picrate to form a chromophore which absorbs light in the same wavelength range.¹⁰ Thus, serum creatinine measurements via the Jaffe reaction are falsely elevated due to the cross-reactivity between nitromethane and alkaline sodium picrate. In some reported cases, there is a 20-fold increase in the measured serum creatinine in the presence of nitromethane; renal function, however, remains normal.⁵

This false reading seen in the Jaffe reaction can be avoided by utilizing the enzymatic method of creatinine measurement, a three-step process that ultimately produces hydrogen peroxide, which is measured and accurately correlates with serum creatinine—even in the presence of nitromethane.⁸ This distinction explains the dramatically different creatinine concentrations measured at the two institutions in this case.

Case Conclusion

The patient was monitored overnight at the children’s hospital. Repeat laboratory studies in the morning showed a normal creatinine level of 0.3 mg/dL and a negative methanol level. The patient was discharged home in the care of his father, who was instructed to follow-up with his son’s pediatrician. The father also received counseling on safe storage practices for dangerous chemicals.

Soft tissue sarcomas (STS) are a heterogeneous group of tumors of mesenchymal origin that represent a rare form of adult malignancy. According to the World Health Organization classification system, there are more than 100 histologic subtypes of sarcoma based on tissue of origin. Staging criteria most commonly use the American Joint Committee on Cancer’s TNM Classification of Malignant Tumours. About 50% of soft tissue sarcomas originate in the lower extremity.¹ Advancements in the use of multimodal therapy have reduced the need for amputation and allowed for equally effective treatment strategies that use limb-sparing surgical resections.

Although most sarcoma metastases spread in a hematogenous fashion, nodal spread is underestimated. Certain histologic subtypes carry a higher predilection for nodal involvement: these include rhabdomyosarcoma, synovial sarcoma, epithelioid sarcoma, vascular sarcoma, and clear-cell sarcoma.^2-4 Fong and colleagues have reported that 2.6% of sarcomas have lymphatic spread.³ In the current report, we describe a rare observation of locoregional pelvic nodal metastases from a large undifferentiated pleomorphic sarcoma of the right thigh.

Case presentation and summary

A 63-year-old white woman had a 1-year history of a right thigh mass and an unintentional weight loss of 40 lb. After a year of chiropractic care, she was referred to a physician because of palpable inguinal adenopathy and a 20-cm mass in the medial compartment of the right thigh, with heterogeneous appearance on a magnetic-resonance imaging scan (Figure 1). The patient was referred to the sarcoma transdisciplinary team for evaluation. She was diagnosed by core needle biopsy with a high-grade malignant epithelioid and spindle-cell neoplasm, favoring pleomorphic sarcoma. The metastatic work-up confirmed locoregional right inguinal and retroperitoneal lymph node disease, with 2 lung nodules that were too small to characterize. She also had a paraneoplastic leukocytosis with a white blood cell count of 45,500 cells/ml (normal 10,500 cells/ml).

Discussion

Surgery remains the primary treatment modality for localized soft tissue sarcoma. Obtaining a margin-free resection, while maintaining optimal function, is the objective with extremity sarcoma. In addition to surgical resection, doxorubicin-based adjuvant chemotherapy remains the standard of care with modest improvement in overall survival and disease-free survival, especially in sarcomas of the extremities.^5,6 Gemcitabine also has activity in soft tissue sarcomas⁷ and might synergize with docetaxel. High response rates of 53% with fixed dose infusion rates of these agents in uterine leiomyosarcoma led the Sarcoma Alliance for Research through Collaboration investigators to consider this regimen for other STS.⁸ An overall response rate of 16% was noted across all sarcoma subtypes, and undifferentiated pleomorphic sarcoma had a response rate of 32%.

In our experience, a modified schedule of gemcitabine and docetaxel is better tolerated than the standard every 3 weeks regimen or doxorubicin-based chemotherapies. As previously described, gemcitabine and docetaxel were administered to this patient every 2 weeks.⁹ This regimen, in our experience, is less toxic and preserves the dose intensity of the regimen. A complete pathologic necrosis of the primary tumor and regional nodal basin was observed, as well as pulmonary nodule regression, enabling an R0-wide excision and regional lymphadenectomy. The colonic recurrence was surprising, but easily managed with surgical resection.

Pathologic complete response after neoadjuvant chemotherapy is a rare event, observed in about 10% of patients. However, when observed, complete pathologic necrosis (>95%) provided a distant recurrence-free survival of 100% at 3 years.^10-12

Our patient, despite achieving a complete pathologic response and excellent initial local control, ultimately experienced an isolated metastatic recurrence in the colon within 1 year of therapy. Data supports performing metastatectomy for stage IV extremity sarcoma for isolated pulmonary or hepatic burden in selected patients with improved survival rates.^13,14 As far as we know, there is no published literature describing isolated colon metastases in the absence of liver burden from lower extremity soft tissue sarcomas, or the outcome of surgical resection and adjuvant therapy in these cases.

In conclusion, high-grade pleomorphic sarcoma often follows an aggressive clinical course with ultimately local and distant recurrence. Use of multimodal therapy may have a role in improving local control. Complete pathologic necrosis is a rare event that is predictive of improved outcome. Our case represents an unusual pattern of recurrence among patients with a complete pathologic response to neoadjuvant therapy with isolated colon metastases. Timely, comprehensive management together with vigilant surveillance remain key priorities in the long-term management of high-risk sarcoma.

Soft tissue sarcomas (STS) are a heterogeneous group of tumors of mesenchymal origin that represent a rare form of adult malignancy. According to the World Health Organization classification system, there are more than 100 histologic subtypes of sarcoma based on tissue of origin. Staging criteria most commonly use the American Joint Committee on Cancer’s TNM Classification of Malignant Tumours. About 50% of soft tissue sarcomas originate in the lower extremity.¹ Advancements in the use of multimodal therapy have reduced the need for amputation and allowed for equally effective treatment strategies that use limb-sparing surgical resections.

Although most sarcoma metastases spread in a hematogenous fashion, nodal spread is underestimated. Certain histologic subtypes carry a higher predilection for nodal involvement: these include rhabdomyosarcoma, synovial sarcoma, epithelioid sarcoma, vascular sarcoma, and clear-cell sarcoma.^2-4 Fong and colleagues have reported that 2.6% of sarcomas have lymphatic spread.³ In the current report, we describe a rare observation of locoregional pelvic nodal metastases from a large undifferentiated pleomorphic sarcoma of the right thigh.

Case presentation and summary

A 63-year-old white woman had a 1-year history of a right thigh mass and an unintentional weight loss of 40 lb. After a year of chiropractic care, she was referred to a physician because of palpable inguinal adenopathy and a 20-cm mass in the medial compartment of the right thigh, with heterogeneous appearance on a magnetic-resonance imaging scan (Figure 1). The patient was referred to the sarcoma transdisciplinary team for evaluation. She was diagnosed by core needle biopsy with a high-grade malignant epithelioid and spindle-cell neoplasm, favoring pleomorphic sarcoma. The metastatic work-up confirmed locoregional right inguinal and retroperitoneal lymph node disease, with 2 lung nodules that were too small to characterize. She also had a paraneoplastic leukocytosis with a white blood cell count of 45,500 cells/ml (normal 10,500 cells/ml).

Discussion

Surgery remains the primary treatment modality for localized soft tissue sarcoma. Obtaining a margin-free resection, while maintaining optimal function, is the objective with extremity sarcoma. In addition to surgical resection, doxorubicin-based adjuvant chemotherapy remains the standard of care with modest improvement in overall survival and disease-free survival, especially in sarcomas of the extremities.^5,6 Gemcitabine also has activity in soft tissue sarcomas⁷ and might synergize with docetaxel. High response rates of 53% with fixed dose infusion rates of these agents in uterine leiomyosarcoma led the Sarcoma Alliance for Research through Collaboration investigators to consider this regimen for other STS.⁸ An overall response rate of 16% was noted across all sarcoma subtypes, and undifferentiated pleomorphic sarcoma had a response rate of 32%.

In our experience, a modified schedule of gemcitabine and docetaxel is better tolerated than the standard every 3 weeks regimen or doxorubicin-based chemotherapies. As previously described, gemcitabine and docetaxel were administered to this patient every 2 weeks.⁹ This regimen, in our experience, is less toxic and preserves the dose intensity of the regimen. A complete pathologic necrosis of the primary tumor and regional nodal basin was observed, as well as pulmonary nodule regression, enabling an R0-wide excision and regional lymphadenectomy. The colonic recurrence was surprising, but easily managed with surgical resection.

Pathologic complete response after neoadjuvant chemotherapy is a rare event, observed in about 10% of patients. However, when observed, complete pathologic necrosis (>95%) provided a distant recurrence-free survival of 100% at 3 years.^10-12

Our patient, despite achieving a complete pathologic response and excellent initial local control, ultimately experienced an isolated metastatic recurrence in the colon within 1 year of therapy. Data supports performing metastatectomy for stage IV extremity sarcoma for isolated pulmonary or hepatic burden in selected patients with improved survival rates.^13,14 As far as we know, there is no published literature describing isolated colon metastases in the absence of liver burden from lower extremity soft tissue sarcomas, or the outcome of surgical resection and adjuvant therapy in these cases.

In conclusion, high-grade pleomorphic sarcoma often follows an aggressive clinical course with ultimately local and distant recurrence. Use of multimodal therapy may have a role in improving local control. Complete pathologic necrosis is a rare event that is predictive of improved outcome. Our case represents an unusual pattern of recurrence among patients with a complete pathologic response to neoadjuvant therapy with isolated colon metastases. Timely, comprehensive management together with vigilant surveillance remain key priorities in the long-term management of high-risk sarcoma.

Soft tissue sarcomas (STS) are a heterogeneous group of tumors of mesenchymal origin that represent a rare form of adult malignancy. According to the World Health Organization classification system, there are more than 100 histologic subtypes of sarcoma based on tissue of origin. Staging criteria most commonly use the American Joint Committee on Cancer’s TNM Classification of Malignant Tumours. About 50% of soft tissue sarcomas originate in the lower extremity.¹ Advancements in the use of multimodal therapy have reduced the need for amputation and allowed for equally effective treatment strategies that use limb-sparing surgical resections.

Although most sarcoma metastases spread in a hematogenous fashion, nodal spread is underestimated. Certain histologic subtypes carry a higher predilection for nodal involvement: these include rhabdomyosarcoma, synovial sarcoma, epithelioid sarcoma, vascular sarcoma, and clear-cell sarcoma.^2-4 Fong and colleagues have reported that 2.6% of sarcomas have lymphatic spread.³ In the current report, we describe a rare observation of locoregional pelvic nodal metastases from a large undifferentiated pleomorphic sarcoma of the right thigh.

Case presentation and summary

A 63-year-old white woman had a 1-year history of a right thigh mass and an unintentional weight loss of 40 lb. After a year of chiropractic care, she was referred to a physician because of palpable inguinal adenopathy and a 20-cm mass in the medial compartment of the right thigh, with heterogeneous appearance on a magnetic-resonance imaging scan (Figure 1). The patient was referred to the sarcoma transdisciplinary team for evaluation. She was diagnosed by core needle biopsy with a high-grade malignant epithelioid and spindle-cell neoplasm, favoring pleomorphic sarcoma. The metastatic work-up confirmed locoregional right inguinal and retroperitoneal lymph node disease, with 2 lung nodules that were too small to characterize. She also had a paraneoplastic leukocytosis with a white blood cell count of 45,500 cells/ml (normal 10,500 cells/ml).

Discussion

Surgery remains the primary treatment modality for localized soft tissue sarcoma. Obtaining a margin-free resection, while maintaining optimal function, is the objective with extremity sarcoma. In addition to surgical resection, doxorubicin-based adjuvant chemotherapy remains the standard of care with modest improvement in overall survival and disease-free survival, especially in sarcomas of the extremities.^5,6 Gemcitabine also has activity in soft tissue sarcomas⁷ and might synergize with docetaxel. High response rates of 53% with fixed dose infusion rates of these agents in uterine leiomyosarcoma led the Sarcoma Alliance for Research through Collaboration investigators to consider this regimen for other STS.⁸ An overall response rate of 16% was noted across all sarcoma subtypes, and undifferentiated pleomorphic sarcoma had a response rate of 32%.

In our experience, a modified schedule of gemcitabine and docetaxel is better tolerated than the standard every 3 weeks regimen or doxorubicin-based chemotherapies. As previously described, gemcitabine and docetaxel were administered to this patient every 2 weeks.⁹ This regimen, in our experience, is less toxic and preserves the dose intensity of the regimen. A complete pathologic necrosis of the primary tumor and regional nodal basin was observed, as well as pulmonary nodule regression, enabling an R0-wide excision and regional lymphadenectomy. The colonic recurrence was surprising, but easily managed with surgical resection.

Pathologic complete response after neoadjuvant chemotherapy is a rare event, observed in about 10% of patients. However, when observed, complete pathologic necrosis (>95%) provided a distant recurrence-free survival of 100% at 3 years.^10-12

Our patient, despite achieving a complete pathologic response and excellent initial local control, ultimately experienced an isolated metastatic recurrence in the colon within 1 year of therapy. Data supports performing metastatectomy for stage IV extremity sarcoma for isolated pulmonary or hepatic burden in selected patients with improved survival rates.^13,14 As far as we know, there is no published literature describing isolated colon metastases in the absence of liver burden from lower extremity soft tissue sarcomas, or the outcome of surgical resection and adjuvant therapy in these cases.

In conclusion, high-grade pleomorphic sarcoma often follows an aggressive clinical course with ultimately local and distant recurrence. Use of multimodal therapy may have a role in improving local control. Complete pathologic necrosis is a rare event that is predictive of improved outcome. Our case represents an unusual pattern of recurrence among patients with a complete pathologic response to neoadjuvant therapy with isolated colon metastases. Timely, comprehensive management together with vigilant surveillance remain key priorities in the long-term management of high-risk sarcoma.

The incidence of malignant melanoma has been rising in the United States, especially among non-Hispanic white men and women. Death rates have increased for those aged 65 years or older, and incidence rates have increased for all age groups.¹ It is a serious public health issue.

Given the unique biology of melanoma, metastatic disease can present in a variety of ways. In most cases, the lymph nodes and lungs are involved.² The incidence of brain metastases is 10%-40%, however the percentage may be even higher based on reported incidence of autopsy reports.³ The most common forms of metastatic melanoma to the spine are vertebral and intramedullary.⁴ Specifically, leptomeningeal involvement can be found in 20% of patients in clinical studies and 44%-70% in autopsy series of patients with central nervous system (CNS) metastatic disease.⁵ Despite its incidence, leptomeningeal disease (LMD) from melanoma is rarely discussed in the literature and the diagnosis may be difficult. Even rarer is the documented presentation of intramedullary spinal cord metastases, or “drop metastases.”⁶ In our review of the literature, we found no published case reports to date of drop metastases from melanoma causing cauda equina syndrome.

The prognosis of patients with metastatic melanoma with brain metastases is very poor, with a median overall survival of about 4 months reported in several studies.^7-9 Prognosis is even worse for patients with leptomeningeal involvement, and median survival without therapy is about 4-6 weeks.¹⁰ A combination of intrathecal and systemic chemotherapy can be used to treat LMD.¹¹

Case presentation and summary

This is the case of a 56-year-old man with history of metastatic melanoma that had been initially diagnosed about 4 years before the current case presentation. Original sites of disease were a supraclavicular lymph node and solitary liver metastasis, both of which were resected. The patient then developed biopsy-proven lung involvement that required left and right wedge resections. Mutation testing for BRAF V600E and BRAF V600K was sent and not detected. Therefore the patient did not receive any BRAF-targeted therapies. Subsequently, recurrent metastatic disease to the brain with 2 dominant lesions in the cerebellum and the occiput as well as numerous small lesions at the gray-white matter junction was identified (Figure 1 and Figure 2).

The patient received whole-brain radiation (30 Gy in 10 fractions of 3 Gy each). There was no evidence of disease in his spine at that time. About 2 weeks after completing whole-brain radiation, the patient presented to the hospital with left lower extremity weakness, urinary retention, bowel incontinence, saddle anesthesia, and malaise. The symptoms had begun after he had finished whole-brain radiation and weakness progressed to the point at which he need a cane to be able to walk. A physical examination was significant for hyporreflexia, decreased strength and sensitivity on left lower extremity, saddle anesthesia, and lumbar spinal tenderness to palpation. The results of magnetic-resonance imaging (MRI) of the spine revealed multiple soft-tissue nodules extending from the conus medullaris throughout the cauda equina, consistent with intramedullary metastases, as well as concomitant leptomeningeal involvement (Figure 3).

Conclusions

Although metastatic melanoma to the brain is not uncommon, leptomeningeal and intramedullary drop metastases are an infrequent presentation. Even more rare are intramedullary drop metastasis that are significant enough to cause cauda equina syndrome, as with our patient. The incidence of LMD has increased over the years and may continue to increase, likely because of the improved overall survival and a prolonged control of extracranial disease with newly approved systemic therapeutic drugs, such as molecularly targeted therapy and immunotherapy.¹² Intramedullary metastases are extremely rare, but reported incidence has seemed to be increasing due to detection with MRI. Currently there are fewer than 100 case reports of intramedullary spinal cord metastasis.⁶ In one retrospective study, 40 patients with intramedullary metastatic disease secondary to systemic cancer were identified during 1980-1993.⁶ About half of those cases were from lung cancer, the second most common was breast cancer.

CNS involvement by melanoma can have debilitating complications and confers a poor prognosis. In another retrospective study, several patient characteristics were found to be associated with significantly shorter survival in patients with known brain metastases, including presence of neurologic symptoms and leptomeningeal involvement.³

Malignant cells can reach the CSF by several routes: direct extension, hematogenous, venous access, venous drainage from bone marrow and cranial and peripheral nerves. Once the tumor has reached the CSF, it can seed any portion of the nervous system that has contact with the CSF and become entangled among the cauda equine.¹³

Given the rarity of leptomeningeal and intramedullary involvement of melanoma, there are no standard treatment guidelines. Treatment for LMD usually consists of intrathecal and systemic chemotherapy. Commonly used intrathecal agents are methotrexate, liposomal cytarabine, and thiopeta.¹¹ The goals of treatment are to improve or stabilize neurologic status of the patient and ideally prolong survival. The choice of agent for intrathecal chemotherapy is guided by the primary tumor, however, there is no strong evidence to choose one agent over the other.^12,14 Methotrexate or cytarabine are generally recommended in the National Comprehensive Cancer Network (NCCN) guidelines. Targeted therapy toward the primary tumor is occasionally used for treatment of LMD, for example rituximab can be given intrathecally for lymphoma,¹⁵ and trastuzumab has been given intrathecally for breast cancer.¹⁶ No intrathecal targeted agents are currently available for melanoma. Administration of intrathecal chemotherapy is given via lumbar puncture or Ommaya reservoir. Induction intrathecal chemotherapy is recommended by NCCN to be given for 4-6 weeks. The schedule of administration varies based on the agent used. Most systemic chemotherapy has poor CSF penetration, which is the basis behind using chemotherapy intrathecally in these patients.¹⁴ However, novel therapies for melanoma, such as ipilimumab, have shown activity in the CNS, and it is not known if intrathecal chemotherapy will continue to play role in the management of LMD.¹⁷

Systemic therapy for metastatic melanoma has changed with the development of novel agents, which have shown better efficacy than traditional chemotherapy. The recommendation for first-line systemic therapy of metastatic unresectable melanoma is based on several factors: BRAF mutation status, tempo of disease, and presence or absence of cancer-related symptoms. Immunotherapy for metastatic melanoma that is unresectable includes anti-programmed cell death protein-1 (PD-1) monotherapy (nivolumab or pembrolizumab) or combination therapy with nivolumab plus ipilimumab. Targeted therapy is preferred in cases with an identified BRAF mutation. Combination therapy with dabrafenib plus trametinib or with vemurafenib plus cobimetinib is recommended. Single-agent therapy may also be used with dabrafenib or vemurafenib.¹⁸

Ipilimumab is a monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to potentiate an anti-tumor T-cell response that was approved in 2011 by the US Food and Drug Administration for the treatment of melanoma. A randomized, phase 3 clinical trial showed an increase in overall survival in patients with unresectable metastatic disease who had received previous treatment.¹⁹ Before that, no therapy had been shown to improve overall survival in patients with metastatic melanoma. Patients with CNS metastases were included in this study.¹⁹

The activity of ipilimumab specifically in patients with brain metastasis was further studied in a phase 2 trial that enrolled 72 patients, 1 cohort with symptomatic brain metastases and the other cohort with asymptomatic brain metastases.²⁰ After 12 weeks of therapy, response was assessed by modified World Health Organization criteria for disease control (complete response plus partial response plus stable disease). In all, 18% of patients with asymptomatic brain metastasis achieved disease control, compared with 10% of patients with symptomatic brain metastases. When the brain alone was assessed, 24% of asymptomatic patients and 10% of symptomatic patients achieved disease control. No unexpected toxic effects occurred during the study. Anti-PD1 therapy such as nivolumab, which has shown durable responses in metastatic melanoma, has no published results specifically in patients with active brain metastases.

Of the BRAF-targeted therapy, dabrafenib and vemurafenib have also been studied in patients with brain metastases. For darafenib, 172 patients with BRAF-mutated metastatic melanoma were included in a phase 2 clinical trial that showed an intracranial response of 39% in previously untreated patients and 31% in patients whose brain metastases had progressed after previous local treatment.²¹ Vemurafenib has also shown intracranial response in a phase 2 clinical trial.²²

The role of the aforementioned therapies in patients with metastatic melanoma with CNS disease should not be overlooked because these patients are typically excluded from clinical trials. As already noted, agents such as ipilimumab and the dabrafenib–vemurafenib combination have been studied in patients with brain metastases and have shown disease control, but more studies are needed to truly assess whether there is an improvement in overall survival and whether that will change treatment guidelines. Although patients with parenchymal brain metastases were included in these studies, it is not clear how patients with LMD and intramedullary spinal cord metastases, such as our patient, would be affected. It is also not clear whether intrathecal chemotherapy will continue to play a role in management of metastatic melanoma with LMD, especially if these newer agents have CNS activity in addition to controlling extracranial disease. Although rarely documented, leptomeningeal and intramedullary metastatic disease will likely become increasingly recognized as patients with cancer live longer and diagnostic studies improve. These initial studies showing intracranial disease control show compelling evidence to continue enrolling patients with active CNS disease in clinical trials.

The incidence of malignant melanoma has been rising in the United States, especially among non-Hispanic white men and women. Death rates have increased for those aged 65 years or older, and incidence rates have increased for all age groups.¹ It is a serious public health issue.

Given the unique biology of melanoma, metastatic disease can present in a variety of ways. In most cases, the lymph nodes and lungs are involved.² The incidence of brain metastases is 10%-40%, however the percentage may be even higher based on reported incidence of autopsy reports.³ The most common forms of metastatic melanoma to the spine are vertebral and intramedullary.⁴ Specifically, leptomeningeal involvement can be found in 20% of patients in clinical studies and 44%-70% in autopsy series of patients with central nervous system (CNS) metastatic disease.⁵ Despite its incidence, leptomeningeal disease (LMD) from melanoma is rarely discussed in the literature and the diagnosis may be difficult. Even rarer is the documented presentation of intramedullary spinal cord metastases, or “drop metastases.”⁶ In our review of the literature, we found no published case reports to date of drop metastases from melanoma causing cauda equina syndrome.

The prognosis of patients with metastatic melanoma with brain metastases is very poor, with a median overall survival of about 4 months reported in several studies.^7-9 Prognosis is even worse for patients with leptomeningeal involvement, and median survival without therapy is about 4-6 weeks.¹⁰ A combination of intrathecal and systemic chemotherapy can be used to treat LMD.¹¹

Case presentation and summary

This is the case of a 56-year-old man with history of metastatic melanoma that had been initially diagnosed about 4 years before the current case presentation. Original sites of disease were a supraclavicular lymph node and solitary liver metastasis, both of which were resected. The patient then developed biopsy-proven lung involvement that required left and right wedge resections. Mutation testing for BRAF V600E and BRAF V600K was sent and not detected. Therefore the patient did not receive any BRAF-targeted therapies. Subsequently, recurrent metastatic disease to the brain with 2 dominant lesions in the cerebellum and the occiput as well as numerous small lesions at the gray-white matter junction was identified (Figure 1 and Figure 2).

The patient received whole-brain radiation (30 Gy in 10 fractions of 3 Gy each). There was no evidence of disease in his spine at that time. About 2 weeks after completing whole-brain radiation, the patient presented to the hospital with left lower extremity weakness, urinary retention, bowel incontinence, saddle anesthesia, and malaise. The symptoms had begun after he had finished whole-brain radiation and weakness progressed to the point at which he need a cane to be able to walk. A physical examination was significant for hyporreflexia, decreased strength and sensitivity on left lower extremity, saddle anesthesia, and lumbar spinal tenderness to palpation. The results of magnetic-resonance imaging (MRI) of the spine revealed multiple soft-tissue nodules extending from the conus medullaris throughout the cauda equina, consistent with intramedullary metastases, as well as concomitant leptomeningeal involvement (Figure 3).

Conclusions

Although metastatic melanoma to the brain is not uncommon, leptomeningeal and intramedullary drop metastases are an infrequent presentation. Even more rare are intramedullary drop metastasis that are significant enough to cause cauda equina syndrome, as with our patient. The incidence of LMD has increased over the years and may continue to increase, likely because of the improved overall survival and a prolonged control of extracranial disease with newly approved systemic therapeutic drugs, such as molecularly targeted therapy and immunotherapy.¹² Intramedullary metastases are extremely rare, but reported incidence has seemed to be increasing due to detection with MRI. Currently there are fewer than 100 case reports of intramedullary spinal cord metastasis.⁶ In one retrospective study, 40 patients with intramedullary metastatic disease secondary to systemic cancer were identified during 1980-1993.⁶ About half of those cases were from lung cancer, the second most common was breast cancer.

CNS involvement by melanoma can have debilitating complications and confers a poor prognosis. In another retrospective study, several patient characteristics were found to be associated with significantly shorter survival in patients with known brain metastases, including presence of neurologic symptoms and leptomeningeal involvement.³

Malignant cells can reach the CSF by several routes: direct extension, hematogenous, venous access, venous drainage from bone marrow and cranial and peripheral nerves. Once the tumor has reached the CSF, it can seed any portion of the nervous system that has contact with the CSF and become entangled among the cauda equine.¹³

Given the rarity of leptomeningeal and intramedullary involvement of melanoma, there are no standard treatment guidelines. Treatment for LMD usually consists of intrathecal and systemic chemotherapy. Commonly used intrathecal agents are methotrexate, liposomal cytarabine, and thiopeta.¹¹ The goals of treatment are to improve or stabilize neurologic status of the patient and ideally prolong survival. The choice of agent for intrathecal chemotherapy is guided by the primary tumor, however, there is no strong evidence to choose one agent over the other.^12,14 Methotrexate or cytarabine are generally recommended in the National Comprehensive Cancer Network (NCCN) guidelines. Targeted therapy toward the primary tumor is occasionally used for treatment of LMD, for example rituximab can be given intrathecally for lymphoma,¹⁵ and trastuzumab has been given intrathecally for breast cancer.¹⁶ No intrathecal targeted agents are currently available for melanoma. Administration of intrathecal chemotherapy is given via lumbar puncture or Ommaya reservoir. Induction intrathecal chemotherapy is recommended by NCCN to be given for 4-6 weeks. The schedule of administration varies based on the agent used. Most systemic chemotherapy has poor CSF penetration, which is the basis behind using chemotherapy intrathecally in these patients.¹⁴ However, novel therapies for melanoma, such as ipilimumab, have shown activity in the CNS, and it is not known if intrathecal chemotherapy will continue to play role in the management of LMD.¹⁷

Systemic therapy for metastatic melanoma has changed with the development of novel agents, which have shown better efficacy than traditional chemotherapy. The recommendation for first-line systemic therapy of metastatic unresectable melanoma is based on several factors: BRAF mutation status, tempo of disease, and presence or absence of cancer-related symptoms. Immunotherapy for metastatic melanoma that is unresectable includes anti-programmed cell death protein-1 (PD-1) monotherapy (nivolumab or pembrolizumab) or combination therapy with nivolumab plus ipilimumab. Targeted therapy is preferred in cases with an identified BRAF mutation. Combination therapy with dabrafenib plus trametinib or with vemurafenib plus cobimetinib is recommended. Single-agent therapy may also be used with dabrafenib or vemurafenib.¹⁸

Ipilimumab is a monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to potentiate an anti-tumor T-cell response that was approved in 2011 by the US Food and Drug Administration for the treatment of melanoma. A randomized, phase 3 clinical trial showed an increase in overall survival in patients with unresectable metastatic disease who had received previous treatment.¹⁹ Before that, no therapy had been shown to improve overall survival in patients with metastatic melanoma. Patients with CNS metastases were included in this study.¹⁹

The activity of ipilimumab specifically in patients with brain metastasis was further studied in a phase 2 trial that enrolled 72 patients, 1 cohort with symptomatic brain metastases and the other cohort with asymptomatic brain metastases.²⁰ After 12 weeks of therapy, response was assessed by modified World Health Organization criteria for disease control (complete response plus partial response plus stable disease). In all, 18% of patients with asymptomatic brain metastasis achieved disease control, compared with 10% of patients with symptomatic brain metastases. When the brain alone was assessed, 24% of asymptomatic patients and 10% of symptomatic patients achieved disease control. No unexpected toxic effects occurred during the study. Anti-PD1 therapy such as nivolumab, which has shown durable responses in metastatic melanoma, has no published results specifically in patients with active brain metastases.

Of the BRAF-targeted therapy, dabrafenib and vemurafenib have also been studied in patients with brain metastases. For darafenib, 172 patients with BRAF-mutated metastatic melanoma were included in a phase 2 clinical trial that showed an intracranial response of 39% in previously untreated patients and 31% in patients whose brain metastases had progressed after previous local treatment.²¹ Vemurafenib has also shown intracranial response in a phase 2 clinical trial.²²

The role of the aforementioned therapies in patients with metastatic melanoma with CNS disease should not be overlooked because these patients are typically excluded from clinical trials. As already noted, agents such as ipilimumab and the dabrafenib–vemurafenib combination have been studied in patients with brain metastases and have shown disease control, but more studies are needed to truly assess whether there is an improvement in overall survival and whether that will change treatment guidelines. Although patients with parenchymal brain metastases were included in these studies, it is not clear how patients with LMD and intramedullary spinal cord metastases, such as our patient, would be affected. It is also not clear whether intrathecal chemotherapy will continue to play a role in management of metastatic melanoma with LMD, especially if these newer agents have CNS activity in addition to controlling extracranial disease. Although rarely documented, leptomeningeal and intramedullary metastatic disease will likely become increasingly recognized as patients with cancer live longer and diagnostic studies improve. These initial studies showing intracranial disease control show compelling evidence to continue enrolling patients with active CNS disease in clinical trials.

The incidence of malignant melanoma has been rising in the United States, especially among non-Hispanic white men and women. Death rates have increased for those aged 65 years or older, and incidence rates have increased for all age groups.¹ It is a serious public health issue.

Given the unique biology of melanoma, metastatic disease can present in a variety of ways. In most cases, the lymph nodes and lungs are involved.² The incidence of brain metastases is 10%-40%, however the percentage may be even higher based on reported incidence of autopsy reports.³ The most common forms of metastatic melanoma to the spine are vertebral and intramedullary.⁴ Specifically, leptomeningeal involvement can be found in 20% of patients in clinical studies and 44%-70% in autopsy series of patients with central nervous system (CNS) metastatic disease.⁵ Despite its incidence, leptomeningeal disease (LMD) from melanoma is rarely discussed in the literature and the diagnosis may be difficult. Even rarer is the documented presentation of intramedullary spinal cord metastases, or “drop metastases.”⁶ In our review of the literature, we found no published case reports to date of drop metastases from melanoma causing cauda equina syndrome.

The prognosis of patients with metastatic melanoma with brain metastases is very poor, with a median overall survival of about 4 months reported in several studies.^7-9 Prognosis is even worse for patients with leptomeningeal involvement, and median survival without therapy is about 4-6 weeks.¹⁰ A combination of intrathecal and systemic chemotherapy can be used to treat LMD.¹¹

Case presentation and summary

This is the case of a 56-year-old man with history of metastatic melanoma that had been initially diagnosed about 4 years before the current case presentation. Original sites of disease were a supraclavicular lymph node and solitary liver metastasis, both of which were resected. The patient then developed biopsy-proven lung involvement that required left and right wedge resections. Mutation testing for BRAF V600E and BRAF V600K was sent and not detected. Therefore the patient did not receive any BRAF-targeted therapies. Subsequently, recurrent metastatic disease to the brain with 2 dominant lesions in the cerebellum and the occiput as well as numerous small lesions at the gray-white matter junction was identified (Figure 1 and Figure 2).

The patient received whole-brain radiation (30 Gy in 10 fractions of 3 Gy each). There was no evidence of disease in his spine at that time. About 2 weeks after completing whole-brain radiation, the patient presented to the hospital with left lower extremity weakness, urinary retention, bowel incontinence, saddle anesthesia, and malaise. The symptoms had begun after he had finished whole-brain radiation and weakness progressed to the point at which he need a cane to be able to walk. A physical examination was significant for hyporreflexia, decreased strength and sensitivity on left lower extremity, saddle anesthesia, and lumbar spinal tenderness to palpation. The results of magnetic-resonance imaging (MRI) of the spine revealed multiple soft-tissue nodules extending from the conus medullaris throughout the cauda equina, consistent with intramedullary metastases, as well as concomitant leptomeningeal involvement (Figure 3).

Conclusions

Although metastatic melanoma to the brain is not uncommon, leptomeningeal and intramedullary drop metastases are an infrequent presentation. Even more rare are intramedullary drop metastasis that are significant enough to cause cauda equina syndrome, as with our patient. The incidence of LMD has increased over the years and may continue to increase, likely because of the improved overall survival and a prolonged control of extracranial disease with newly approved systemic therapeutic drugs, such as molecularly targeted therapy and immunotherapy.¹² Intramedullary metastases are extremely rare, but reported incidence has seemed to be increasing due to detection with MRI. Currently there are fewer than 100 case reports of intramedullary spinal cord metastasis.⁶ In one retrospective study, 40 patients with intramedullary metastatic disease secondary to systemic cancer were identified during 1980-1993.⁶ About half of those cases were from lung cancer, the second most common was breast cancer.

CNS involvement by melanoma can have debilitating complications and confers a poor prognosis. In another retrospective study, several patient characteristics were found to be associated with significantly shorter survival in patients with known brain metastases, including presence of neurologic symptoms and leptomeningeal involvement.³

Malignant cells can reach the CSF by several routes: direct extension, hematogenous, venous access, venous drainage from bone marrow and cranial and peripheral nerves. Once the tumor has reached the CSF, it can seed any portion of the nervous system that has contact with the CSF and become entangled among the cauda equine.¹³

Given the rarity of leptomeningeal and intramedullary involvement of melanoma, there are no standard treatment guidelines. Treatment for LMD usually consists of intrathecal and systemic chemotherapy. Commonly used intrathecal agents are methotrexate, liposomal cytarabine, and thiopeta.¹¹ The goals of treatment are to improve or stabilize neurologic status of the patient and ideally prolong survival. The choice of agent for intrathecal chemotherapy is guided by the primary tumor, however, there is no strong evidence to choose one agent over the other.^12,14 Methotrexate or cytarabine are generally recommended in the National Comprehensive Cancer Network (NCCN) guidelines. Targeted therapy toward the primary tumor is occasionally used for treatment of LMD, for example rituximab can be given intrathecally for lymphoma,¹⁵ and trastuzumab has been given intrathecally for breast cancer.¹⁶ No intrathecal targeted agents are currently available for melanoma. Administration of intrathecal chemotherapy is given via lumbar puncture or Ommaya reservoir. Induction intrathecal chemotherapy is recommended by NCCN to be given for 4-6 weeks. The schedule of administration varies based on the agent used. Most systemic chemotherapy has poor CSF penetration, which is the basis behind using chemotherapy intrathecally in these patients.¹⁴ However, novel therapies for melanoma, such as ipilimumab, have shown activity in the CNS, and it is not known if intrathecal chemotherapy will continue to play role in the management of LMD.¹⁷

Systemic therapy for metastatic melanoma has changed with the development of novel agents, which have shown better efficacy than traditional chemotherapy. The recommendation for first-line systemic therapy of metastatic unresectable melanoma is based on several factors: BRAF mutation status, tempo of disease, and presence or absence of cancer-related symptoms. Immunotherapy for metastatic melanoma that is unresectable includes anti-programmed cell death protein-1 (PD-1) monotherapy (nivolumab or pembrolizumab) or combination therapy with nivolumab plus ipilimumab. Targeted therapy is preferred in cases with an identified BRAF mutation. Combination therapy with dabrafenib plus trametinib or with vemurafenib plus cobimetinib is recommended. Single-agent therapy may also be used with dabrafenib or vemurafenib.¹⁸

Ipilimumab is a monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to potentiate an anti-tumor T-cell response that was approved in 2011 by the US Food and Drug Administration for the treatment of melanoma. A randomized, phase 3 clinical trial showed an increase in overall survival in patients with unresectable metastatic disease who had received previous treatment.¹⁹ Before that, no therapy had been shown to improve overall survival in patients with metastatic melanoma. Patients with CNS metastases were included in this study.¹⁹

The activity of ipilimumab specifically in patients with brain metastasis was further studied in a phase 2 trial that enrolled 72 patients, 1 cohort with symptomatic brain metastases and the other cohort with asymptomatic brain metastases.²⁰ After 12 weeks of therapy, response was assessed by modified World Health Organization criteria for disease control (complete response plus partial response plus stable disease). In all, 18% of patients with asymptomatic brain metastasis achieved disease control, compared with 10% of patients with symptomatic brain metastases. When the brain alone was assessed, 24% of asymptomatic patients and 10% of symptomatic patients achieved disease control. No unexpected toxic effects occurred during the study. Anti-PD1 therapy such as nivolumab, which has shown durable responses in metastatic melanoma, has no published results specifically in patients with active brain metastases.

Of the BRAF-targeted therapy, dabrafenib and vemurafenib have also been studied in patients with brain metastases. For darafenib, 172 patients with BRAF-mutated metastatic melanoma were included in a phase 2 clinical trial that showed an intracranial response of 39% in previously untreated patients and 31% in patients whose brain metastases had progressed after previous local treatment.²¹ Vemurafenib has also shown intracranial response in a phase 2 clinical trial.²²

The role of the aforementioned therapies in patients with metastatic melanoma with CNS disease should not be overlooked because these patients are typically excluded from clinical trials. As already noted, agents such as ipilimumab and the dabrafenib–vemurafenib combination have been studied in patients with brain metastases and have shown disease control, but more studies are needed to truly assess whether there is an improvement in overall survival and whether that will change treatment guidelines. Although patients with parenchymal brain metastases were included in these studies, it is not clear how patients with LMD and intramedullary spinal cord metastases, such as our patient, would be affected. It is also not clear whether intrathecal chemotherapy will continue to play a role in management of metastatic melanoma with LMD, especially if these newer agents have CNS activity in addition to controlling extracranial disease. Although rarely documented, leptomeningeal and intramedullary metastatic disease will likely become increasingly recognized as patients with cancer live longer and diagnostic studies improve. These initial studies showing intracranial disease control show compelling evidence to continue enrolling patients with active CNS disease in clinical trials.

Serum sickness was first described by von Pirquet and Schick¹ as a constellation of signs and symptoms displayed in patients receiving equine serum as an antitoxin for the treatment of scarlet fever and diphtheria. Serum sickness is an immune complex–mediated hypersensitivity reaction that can be clinically diagnosed in patients who present with fever, rash, and polyarthralgia or polyarthritis following exposure to heterologous serum proteins.^2,3 Symptom onset typically occurs within 1 to 2 weeks of first exposure to the serum, and resolution frequently occurs with discontinuation of the offending agent. Other symptoms may include malaise, gastrointestinal tract concerns, headache, blurred vision, or lymphadenopathy.⁴ Proteinuria, hematuria, and a transient decrease in creatinine clearance also have been reported in serum sickness.⁴

Serum sickness is caused by a type III immune complex–mediated hypersensitivity reaction to heterologous rabbit or equine serum proteins. Nonhuman proteins present in antithymocyte globulin (ATG) stimulate the production of IgG, IgM, IgA, and IgE antibodies.^2-4 If the resultant immune complexes overwhelm the mononuclear phagocyte system, these complexes are deposited in blood vessels and tissues, which leads to complement activation and the production of complement fragments such as C3a and C5a.⁵ C3a is an anaphylatoxin that causes mast cell degranulation and the consequent formation of urticarial lesions. C5a is a neutrophil chemoattractant that promotes inflammation at the site of complement deposition.

Serum sickness–like reactions may occur days to weeks following administration of certain drugs, such as cefaclor or penicillin. Although the symptoms and timing of serum sickness–like reactions are similar to serum sickness, they are not caused by an immune complex–mediated mechanism and are believed to be secondary to an idiosyncratic delayed drug reaction.⁶

Thymoglobulin, a type of ATG, is a polyclonal antibody generated in rabbits that targets numerous human epitopes, including cell surface markers on T cells (CD2, CD3, CD4, CD8), B cells (CD21, CD19, CD40), and adhesion molecules (CD6, CD25, CD44, CD45, and the integrin LFA-1 [lymphocyte function-associated antigen-1]).^7,8 Thymoglobulin has proven efficacy in the setting of cardiac transplantation.^9-11 Although calcineurin inhibitors form the foundation in the armamentarium of immunosuppressive agents in cardiac transplantation, their nephrotoxicity has limited their unrestrained use in patients.⁹ By delaying the need for calcineurin inhibitors, thymoglobulin preserves greater renal function without increasing the risk for acute rejection.^9,10 Akin to its use in the patient presented in this case report, thymoglobulin also is used in the treatment of acute cellular rejection in heart transplant recipients with signs of heart failure.¹¹

Case Report

A 35-year-old man with a history of familial cardiomyopathy who underwent orthotopic heart transplantation presented with grade 3R acute cellular rejection. The patient’s immunosuppressive regimen consisted of thymoglobulin 150 mg once daily, tacrolimus 2.5 mg twice daily, hydrocortisone 100 mg once daily, and mycophenolate mofetil 1000 mg twice daily. On day 7 of thymoglobulin treatment, the dermatology department was consulted to evaluate a pruritic eruption. The patient reported that he noticed redness of the palms and soles, as well as redness accentuated in the axilla, groin, and other skin creases 2 days prior. The patient also reported symmetric bilateral hand pain that had started 1 day following rash onset. He denied fever and remained afebrile throughout his hospitalization.

On physical examination, the patient displayed a blanching, erythematous, edematous, evanescent macular rash with some areas of wheal formation symmetrically distributed in the bilateral axillae, inframammary folds, and groin (Figure, A and B). The palms and soles were tender with diffuse blanching erythema. The eruption was accentuated at the lateral and medial borders of both feet (Figure, C). There was concern that the patient may have a form of serum sickness with a blunted incomplete response due to his concomitant use of immunosuppressive agents. Shortly after evaluation, the patient left the hospital against medical advice before the recommended evaluation and systemic workup could be implemented.

The patient returned for an outpatient appointment approximately 1 week later. Medical records indicated that the patient’s skin eruption had resolved. Tests for antithymoglobulin antibodies at this visit were negative. The antithymoglobulin antibody enzyme-linked immunosorbent assay has a diagnostic sensitivity of 86%¹² and large interlaboratory variability.¹³ Given the presence of other features of serum sickness, a false-negative result was considered by dermatology. Nonetheless, one must consider other differential diagnoses, including a simple cutaneous adverse drug eruption or viral exanthem that might have in fact been causative.

Comment

We present an atypical case of possible serum sickness in a heart transplant recipient following thymoglobulin treatment of acute cellular rejection of the cardiac allograft. Serum sickness is a clinical diagnosis supported by laboratory data. Some authors have suggested major and minor diagnostic criteria to aid with the diagnosis.⁷ Major diagnostic criteria include onset more than 7 days after the initial thymoglobulin administration, persistent high fevers (temperature, >38.4°C), persistent arthritis/arthralgia, and positive heterologous antibodies on enzyme-linked immunosorbent assay. Minor diagnostic criteria include rash, acute renal failure, trismus, and low serum complement (C3 and C4).

The variable cutaneous presentations of serum sickness are important to recognize in the process of making the correct diagnosis. Rash is frequently reported in serum sickness, with some studies displaying rates of up to 93%.^4,14 The skin findings are most frequently described as urticarial or serpiginous macular lesions.³ Other variations of the eruption exist, and morbilliform eruptions or a combination of morbilliform and urticarial eruptions have been reported.³ It is important to judge cutaneous eruptions of serum sickness within the context of the potential cytopenia in a patient being treated with ATG. As such, purpuric eruptions have been attributed to serum sickness in thrombocytopenic patients receiving ATG for bone marrow failure.¹⁴

Usually, cutaneous eruptions of serum sickness initially are identified in the groin, axilla, and periumbilical region, and then they proceed to include the trunk and extremities. Erythema of the palms and soles frequently is described as well as a linear accentuation of the rash along the lateral and medial borders of the feet and hands at the margin of the plantar or palmar skin, respectively.¹⁴ The mucous membranes frequently are spared in serum sickness.

Despite the lack of evidence-based guidelines, case series and literature reviews have suggested a treatment regimen for serum sickness,^7,15-18 calling for immediate withdrawal of the offending agent. Antihistamines may be added to control pruritus and rash. Patients with high fever, a progressive rash, or severe arthralgia have benefited from short courses of oral^16,18 or intravenous^7,17 glucocorticoids. The extent of the eruption in our patient was concerning, particularly because he was already receiving systemic corticosteroids in conjunction with other immunosuppressives, which may have explained his lack of fever.

Because our patient satisfied some diagnostic criteria for serum sickness and failed to satisfy others, our team was faced with the challenge of balancing the risks of possible serum sickness with the risks of the potential for progressive cardiac rejection from the withdrawal of thymoglobulin.⁷ There is some evidence in the literature for the use of therapeutic plasma exchange (TPE) for the treatment of serum sickness if the offending agent could not be discontinued. Tanriover et al¹⁹ presented a case series of 5 renal transplant recipients treated with thymoglobulin who developed serum sickness. The diagnosis of serum sickness was made clinically and augmented by the presence of antiheterologous antibodies. All 5 patients had persistent symptoms of serum sickness despite 2 days of glucocorticoid treatment. Interestingly, 3 patients had complete resolution of all symptoms after a single TPE treatment, and 2 patients achieved resolution of fever and arthritis after 2 consecutive days of TPE treatments.¹⁹ Because plasmapheresis is used to treat cardiac allograft rejection in patients showing signs of heart failure,¹¹ the employment of TPE in these patients may have dual beneficial effects of concurrently treating serum sickness and allograft rejection.

Given the patient’s noncompliance and leaving the hospital against medical advice, a full workup was not able to be pursued in this case, though fortunately the eruption and his other symptoms had resolved by the time he was seen for outpatient follow-up 1 week later. Noncompliance with immunosuppressive therapy is a considerable risk factor for morbidity and mortality following heart transplantation. These patients have more transplant coronary artery disease and substantially shorter clinical event-free time.²⁰ Our patient demonstrates the need for proactive compliance-enhancing interventions in heart transplant patients who experience allograft rejection.

Serum sickness was first described by von Pirquet and Schick¹ as a constellation of signs and symptoms displayed in patients receiving equine serum as an antitoxin for the treatment of scarlet fever and diphtheria. Serum sickness is an immune complex–mediated hypersensitivity reaction that can be clinically diagnosed in patients who present with fever, rash, and polyarthralgia or polyarthritis following exposure to heterologous serum proteins.^2,3 Symptom onset typically occurs within 1 to 2 weeks of first exposure to the serum, and resolution frequently occurs with discontinuation of the offending agent. Other symptoms may include malaise, gastrointestinal tract concerns, headache, blurred vision, or lymphadenopathy.⁴ Proteinuria, hematuria, and a transient decrease in creatinine clearance also have been reported in serum sickness.⁴

Serum sickness is caused by a type III immune complex–mediated hypersensitivity reaction to heterologous rabbit or equine serum proteins. Nonhuman proteins present in antithymocyte globulin (ATG) stimulate the production of IgG, IgM, IgA, and IgE antibodies.^2-4 If the resultant immune complexes overwhelm the mononuclear phagocyte system, these complexes are deposited in blood vessels and tissues, which leads to complement activation and the production of complement fragments such as C3a and C5a.⁵ C3a is an anaphylatoxin that causes mast cell degranulation and the consequent formation of urticarial lesions. C5a is a neutrophil chemoattractant that promotes inflammation at the site of complement deposition.

Serum sickness–like reactions may occur days to weeks following administration of certain drugs, such as cefaclor or penicillin. Although the symptoms and timing of serum sickness–like reactions are similar to serum sickness, they are not caused by an immune complex–mediated mechanism and are believed to be secondary to an idiosyncratic delayed drug reaction.⁶

Thymoglobulin, a type of ATG, is a polyclonal antibody generated in rabbits that targets numerous human epitopes, including cell surface markers on T cells (CD2, CD3, CD4, CD8), B cells (CD21, CD19, CD40), and adhesion molecules (CD6, CD25, CD44, CD45, and the integrin LFA-1 [lymphocyte function-associated antigen-1]).^7,8 Thymoglobulin has proven efficacy in the setting of cardiac transplantation.^9-11 Although calcineurin inhibitors form the foundation in the armamentarium of immunosuppressive agents in cardiac transplantation, their nephrotoxicity has limited their unrestrained use in patients.⁹ By delaying the need for calcineurin inhibitors, thymoglobulin preserves greater renal function without increasing the risk for acute rejection.^9,10 Akin to its use in the patient presented in this case report, thymoglobulin also is used in the treatment of acute cellular rejection in heart transplant recipients with signs of heart failure.¹¹

Case Report

A 35-year-old man with a history of familial cardiomyopathy who underwent orthotopic heart transplantation presented with grade 3R acute cellular rejection. The patient’s immunosuppressive regimen consisted of thymoglobulin 150 mg once daily, tacrolimus 2.5 mg twice daily, hydrocortisone 100 mg once daily, and mycophenolate mofetil 1000 mg twice daily. On day 7 of thymoglobulin treatment, the dermatology department was consulted to evaluate a pruritic eruption. The patient reported that he noticed redness of the palms and soles, as well as redness accentuated in the axilla, groin, and other skin creases 2 days prior. The patient also reported symmetric bilateral hand pain that had started 1 day following rash onset. He denied fever and remained afebrile throughout his hospitalization.

On physical examination, the patient displayed a blanching, erythematous, edematous, evanescent macular rash with some areas of wheal formation symmetrically distributed in the bilateral axillae, inframammary folds, and groin (Figure, A and B). The palms and soles were tender with diffuse blanching erythema. The eruption was accentuated at the lateral and medial borders of both feet (Figure, C). There was concern that the patient may have a form of serum sickness with a blunted incomplete response due to his concomitant use of immunosuppressive agents. Shortly after evaluation, the patient left the hospital against medical advice before the recommended evaluation and systemic workup could be implemented.

The patient returned for an outpatient appointment approximately 1 week later. Medical records indicated that the patient’s skin eruption had resolved. Tests for antithymoglobulin antibodies at this visit were negative. The antithymoglobulin antibody enzyme-linked immunosorbent assay has a diagnostic sensitivity of 86%¹² and large interlaboratory variability.¹³ Given the presence of other features of serum sickness, a false-negative result was considered by dermatology. Nonetheless, one must consider other differential diagnoses, including a simple cutaneous adverse drug eruption or viral exanthem that might have in fact been causative.

Comment

We present an atypical case of possible serum sickness in a heart transplant recipient following thymoglobulin treatment of acute cellular rejection of the cardiac allograft. Serum sickness is a clinical diagnosis supported by laboratory data. Some authors have suggested major and minor diagnostic criteria to aid with the diagnosis.⁷ Major diagnostic criteria include onset more than 7 days after the initial thymoglobulin administration, persistent high fevers (temperature, >38.4°C), persistent arthritis/arthralgia, and positive heterologous antibodies on enzyme-linked immunosorbent assay. Minor diagnostic criteria include rash, acute renal failure, trismus, and low serum complement (C3 and C4).

The variable cutaneous presentations of serum sickness are important to recognize in the process of making the correct diagnosis. Rash is frequently reported in serum sickness, with some studies displaying rates of up to 93%.^4,14 The skin findings are most frequently described as urticarial or serpiginous macular lesions.³ Other variations of the eruption exist, and morbilliform eruptions or a combination of morbilliform and urticarial eruptions have been reported.³ It is important to judge cutaneous eruptions of serum sickness within the context of the potential cytopenia in a patient being treated with ATG. As such, purpuric eruptions have been attributed to serum sickness in thrombocytopenic patients receiving ATG for bone marrow failure.¹⁴

Usually, cutaneous eruptions of serum sickness initially are identified in the groin, axilla, and periumbilical region, and then they proceed to include the trunk and extremities. Erythema of the palms and soles frequently is described as well as a linear accentuation of the rash along the lateral and medial borders of the feet and hands at the margin of the plantar or palmar skin, respectively.¹⁴ The mucous membranes frequently are spared in serum sickness.

Despite the lack of evidence-based guidelines, case series and literature reviews have suggested a treatment regimen for serum sickness,^7,15-18 calling for immediate withdrawal of the offending agent. Antihistamines may be added to control pruritus and rash. Patients with high fever, a progressive rash, or severe arthralgia have benefited from short courses of oral^16,18 or intravenous^7,17 glucocorticoids. The extent of the eruption in our patient was concerning, particularly because he was already receiving systemic corticosteroids in conjunction with other immunosuppressives, which may have explained his lack of fever.

Because our patient satisfied some diagnostic criteria for serum sickness and failed to satisfy others, our team was faced with the challenge of balancing the risks of possible serum sickness with the risks of the potential for progressive cardiac rejection from the withdrawal of thymoglobulin.⁷ There is some evidence in the literature for the use of therapeutic plasma exchange (TPE) for the treatment of serum sickness if the offending agent could not be discontinued. Tanriover et al¹⁹ presented a case series of 5 renal transplant recipients treated with thymoglobulin who developed serum sickness. The diagnosis of serum sickness was made clinically and augmented by the presence of antiheterologous antibodies. All 5 patients had persistent symptoms of serum sickness despite 2 days of glucocorticoid treatment. Interestingly, 3 patients had complete resolution of all symptoms after a single TPE treatment, and 2 patients achieved resolution of fever and arthritis after 2 consecutive days of TPE treatments.¹⁹ Because plasmapheresis is used to treat cardiac allograft rejection in patients showing signs of heart failure,¹¹ the employment of TPE in these patients may have dual beneficial effects of concurrently treating serum sickness and allograft rejection.

Given the patient’s noncompliance and leaving the hospital against medical advice, a full workup was not able to be pursued in this case, though fortunately the eruption and his other symptoms had resolved by the time he was seen for outpatient follow-up 1 week later. Noncompliance with immunosuppressive therapy is a considerable risk factor for morbidity and mortality following heart transplantation. These patients have more transplant coronary artery disease and substantially shorter clinical event-free time.²⁰ Our patient demonstrates the need for proactive compliance-enhancing interventions in heart transplant patients who experience allograft rejection.

Serum sickness was first described by von Pirquet and Schick¹ as a constellation of signs and symptoms displayed in patients receiving equine serum as an antitoxin for the treatment of scarlet fever and diphtheria. Serum sickness is an immune complex–mediated hypersensitivity reaction that can be clinically diagnosed in patients who present with fever, rash, and polyarthralgia or polyarthritis following exposure to heterologous serum proteins.^2,3 Symptom onset typically occurs within 1 to 2 weeks of first exposure to the serum, and resolution frequently occurs with discontinuation of the offending agent. Other symptoms may include malaise, gastrointestinal tract concerns, headache, blurred vision, or lymphadenopathy.⁴ Proteinuria, hematuria, and a transient decrease in creatinine clearance also have been reported in serum sickness.⁴

Serum sickness is caused by a type III immune complex–mediated hypersensitivity reaction to heterologous rabbit or equine serum proteins. Nonhuman proteins present in antithymocyte globulin (ATG) stimulate the production of IgG, IgM, IgA, and IgE antibodies.^2-4 If the resultant immune complexes overwhelm the mononuclear phagocyte system, these complexes are deposited in blood vessels and tissues, which leads to complement activation and the production of complement fragments such as C3a and C5a.⁵ C3a is an anaphylatoxin that causes mast cell degranulation and the consequent formation of urticarial lesions. C5a is a neutrophil chemoattractant that promotes inflammation at the site of complement deposition.

Serum sickness–like reactions may occur days to weeks following administration of certain drugs, such as cefaclor or penicillin. Although the symptoms and timing of serum sickness–like reactions are similar to serum sickness, they are not caused by an immune complex–mediated mechanism and are believed to be secondary to an idiosyncratic delayed drug reaction.⁶

Thymoglobulin, a type of ATG, is a polyclonal antibody generated in rabbits that targets numerous human epitopes, including cell surface markers on T cells (CD2, CD3, CD4, CD8), B cells (CD21, CD19, CD40), and adhesion molecules (CD6, CD25, CD44, CD45, and the integrin LFA-1 [lymphocyte function-associated antigen-1]).^7,8 Thymoglobulin has proven efficacy in the setting of cardiac transplantation.^9-11 Although calcineurin inhibitors form the foundation in the armamentarium of immunosuppressive agents in cardiac transplantation, their nephrotoxicity has limited their unrestrained use in patients.⁹ By delaying the need for calcineurin inhibitors, thymoglobulin preserves greater renal function without increasing the risk for acute rejection.^9,10 Akin to its use in the patient presented in this case report, thymoglobulin also is used in the treatment of acute cellular rejection in heart transplant recipients with signs of heart failure.¹¹

Case Report

A 35-year-old man with a history of familial cardiomyopathy who underwent orthotopic heart transplantation presented with grade 3R acute cellular rejection. The patient’s immunosuppressive regimen consisted of thymoglobulin 150 mg once daily, tacrolimus 2.5 mg twice daily, hydrocortisone 100 mg once daily, and mycophenolate mofetil 1000 mg twice daily. On day 7 of thymoglobulin treatment, the dermatology department was consulted to evaluate a pruritic eruption. The patient reported that he noticed redness of the palms and soles, as well as redness accentuated in the axilla, groin, and other skin creases 2 days prior. The patient also reported symmetric bilateral hand pain that had started 1 day following rash onset. He denied fever and remained afebrile throughout his hospitalization.

On physical examination, the patient displayed a blanching, erythematous, edematous, evanescent macular rash with some areas of wheal formation symmetrically distributed in the bilateral axillae, inframammary folds, and groin (Figure, A and B). The palms and soles were tender with diffuse blanching erythema. The eruption was accentuated at the lateral and medial borders of both feet (Figure, C). There was concern that the patient may have a form of serum sickness with a blunted incomplete response due to his concomitant use of immunosuppressive agents. Shortly after evaluation, the patient left the hospital against medical advice before the recommended evaluation and systemic workup could be implemented.

The patient returned for an outpatient appointment approximately 1 week later. Medical records indicated that the patient’s skin eruption had resolved. Tests for antithymoglobulin antibodies at this visit were negative. The antithymoglobulin antibody enzyme-linked immunosorbent assay has a diagnostic sensitivity of 86%¹² and large interlaboratory variability.¹³ Given the presence of other features of serum sickness, a false-negative result was considered by dermatology. Nonetheless, one must consider other differential diagnoses, including a simple cutaneous adverse drug eruption or viral exanthem that might have in fact been causative.

Comment

We present an atypical case of possible serum sickness in a heart transplant recipient following thymoglobulin treatment of acute cellular rejection of the cardiac allograft. Serum sickness is a clinical diagnosis supported by laboratory data. Some authors have suggested major and minor diagnostic criteria to aid with the diagnosis.⁷ Major diagnostic criteria include onset more than 7 days after the initial thymoglobulin administration, persistent high fevers (temperature, >38.4°C), persistent arthritis/arthralgia, and positive heterologous antibodies on enzyme-linked immunosorbent assay. Minor diagnostic criteria include rash, acute renal failure, trismus, and low serum complement (C3 and C4).

The variable cutaneous presentations of serum sickness are important to recognize in the process of making the correct diagnosis. Rash is frequently reported in serum sickness, with some studies displaying rates of up to 93%.^4,14 The skin findings are most frequently described as urticarial or serpiginous macular lesions.³ Other variations of the eruption exist, and morbilliform eruptions or a combination of morbilliform and urticarial eruptions have been reported.³ It is important to judge cutaneous eruptions of serum sickness within the context of the potential cytopenia in a patient being treated with ATG. As such, purpuric eruptions have been attributed to serum sickness in thrombocytopenic patients receiving ATG for bone marrow failure.¹⁴

Usually, cutaneous eruptions of serum sickness initially are identified in the groin, axilla, and periumbilical region, and then they proceed to include the trunk and extremities. Erythema of the palms and soles frequently is described as well as a linear accentuation of the rash along the lateral and medial borders of the feet and hands at the margin of the plantar or palmar skin, respectively.¹⁴ The mucous membranes frequently are spared in serum sickness.

Despite the lack of evidence-based guidelines, case series and literature reviews have suggested a treatment regimen for serum sickness,^7,15-18 calling for immediate withdrawal of the offending agent. Antihistamines may be added to control pruritus and rash. Patients with high fever, a progressive rash, or severe arthralgia have benefited from short courses of oral^16,18 or intravenous^7,17 glucocorticoids. The extent of the eruption in our patient was concerning, particularly because he was already receiving systemic corticosteroids in conjunction with other immunosuppressives, which may have explained his lack of fever.

Because our patient satisfied some diagnostic criteria for serum sickness and failed to satisfy others, our team was faced with the challenge of balancing the risks of possible serum sickness with the risks of the potential for progressive cardiac rejection from the withdrawal of thymoglobulin.⁷ There is some evidence in the literature for the use of therapeutic plasma exchange (TPE) for the treatment of serum sickness if the offending agent could not be discontinued. Tanriover et al¹⁹ presented a case series of 5 renal transplant recipients treated with thymoglobulin who developed serum sickness. The diagnosis of serum sickness was made clinically and augmented by the presence of antiheterologous antibodies. All 5 patients had persistent symptoms of serum sickness despite 2 days of glucocorticoid treatment. Interestingly, 3 patients had complete resolution of all symptoms after a single TPE treatment, and 2 patients achieved resolution of fever and arthritis after 2 consecutive days of TPE treatments.¹⁹ Because plasmapheresis is used to treat cardiac allograft rejection in patients showing signs of heart failure,¹¹ the employment of TPE in these patients may have dual beneficial effects of concurrently treating serum sickness and allograft rejection.

Given the patient’s noncompliance and leaving the hospital against medical advice, a full workup was not able to be pursued in this case, though fortunately the eruption and his other symptoms had resolved by the time he was seen for outpatient follow-up 1 week later. Noncompliance with immunosuppressive therapy is a considerable risk factor for morbidity and mortality following heart transplantation. These patients have more transplant coronary artery disease and substantially shorter clinical event-free time.²⁰ Our patient demonstrates the need for proactive compliance-enhancing interventions in heart transplant patients who experience allograft rejection.

Atopic dermatitis (AD) is the most common inflammatory skin condition, affecting approximately 15% to 20% of the global population.^1,2 Atopic dermatitis is characterized by a chronic relapsing dermatitis with pruritus, often beginning in infancy or childhood. Atopic dermatitis is caused by a defect in epidermal barrier function, which results in increased transepidermal water loss.¹ The criteria for AD include a pruritic skin condition plus 3 or more of the following: history of involvement of the skin creases, history of asthma or hay fever, history of AD in a first-degree relative (in children), 1-year history of generally dry skin, visible flexural eczema, and an age of onset of less than 2 years. Adults with AD frequently present with hand or facial dermatitis.¹

UV light therapies including narrowband UVB (NB-UVB), UVA1, and psoralen plus UVA (PUVA) have all been used as effective treatments of AD.^3,4 UV light is beneficial for AD patients due to its immunomodulatory effects, thickening of the stratum corneum, and the reduction of Staphylococcus aureus in the skin.² Most patients with AD improve with light therapy; however, it is estimated that 1% to 3% of patients with AD will experience a paradoxical worsening of their AD after exposure to UV light.^2,5 This condition is referred to as photosensitive AD and is characterized by a photodistributed rash in patients who fulfill the criteria of AD. Photosensitive AD has a female predominance and generally affects patients with late-onset disease with development of AD after puberty.^2,5 The pathogenesis for the development of photosensitivity in patients with AD who previously tolerated exposure to sunlight is unknown.⁵ We describe a case of photosensitive AD exacerbated by UVB exposure.

Case Report

A 55-year-old Asian woman presented for evaluation of a rash on the head, neck, and arms. She reported that she had developed a pruritic rash with edema after sun exposure at 16 years of age. Since then, the rash has been intermittent and completely resolved at times with periods of decreased sun exposure; however, the rash recently had been persistent and worsening despite practicing strict sun protection with daily sunscreen application, protective clothing, and sun avoidance. She was not taking systemic medications or supplements at the time but was applying high-potency topical corticosteroids and calcineurin inhibitors with minimal improvement under the care of a dermatologist.

On physical examination the patient had thin, well-demarcated, erythematous papules and plaques with scaling, primarily on sun-exposed skin on the forehead (Figure 1A), cheeks (Figure 1B), eyelids, upper lip, neck (Figures 1B and 1C), upper chest (Figure 1C), and dorsal aspect of the hands, with excoriated pink papules on the forearms, shoulders, and back. A punch biopsy of the right neck showed spongiotic dermatitis with a perivascular lymphohistiocytic infiltrate (Figure 2). Further workup was pursued including complete blood cell count, comprehensive metabolic profile, liver function panel, Sjögren syndrome antigen A/Sjögren syndrome antigen B test, antinuclear antibody test, human immunodeficiency virus 1/2 antigen/antibody test, hepatitis panel, and mycobacterium tuberculosis test, which were all within reference range. Photodermatosis was suspected and she underwent phototesting including UVA, NB-UVB, and visible light. Phototesting confirmed she had a UVB photosensitivity with a markedly decreased minimal erythema dose (MED) to NB-UVB. The MED to NB-UVB was positive at 24 hours to all tested sites, the lowest of which was 0.135 J/cm². Eczematous changes began to develop at day 6 at doses of 0.945 and 1.080 J/cm². The patient also underwent visible light testing, which was negative. The patient was patch tested for multiple standardized agents as well as personal products, all of which were negative. Subsequent photopatch testing revealed a slightly positive reaction to benzophenone 4, a common ingredient in sunscreens.

The patient was then started on mycophenolate mofetil and prednisone. Repeat MED testing to NB-UVB was performed. Her repeat MED to NB-UVB was determined to be 0.405 J/cm², and hardening commenced at 3 times per week at 70% of the MED (0.2835 J/cm²). She began to flare and develop an eczematous reaction, thus the dose was decreased to 50% of the MED (0.2025 J/cm²), which she tolerated.

Comment

Classification and Clinical Presentation
The literature on photosensitive AD is scant, and this disease entity is rare. Alternative names include photoaggravated AD, photosensitive eczema, and light-exacerbated eczema.⁵ Two main studies have been conducted in recent years that were intended to characterize photosensitive AD. ten Berge et al⁵ conducted a retrospective study of 145 patients with AD that were phototested in 2009. They found that 3% of their total AD patient population had photosensitive AD.⁵ In 2016, Ellenbogen et al² performed a similar single-center retrospective analysis of 17 patients with long-standing AD who suddenly developed photosensitivity.

Patients with photosensitive AD typically present with lesions on sun-exposed skin with coexisting eczematous lesions in sites with a predilection for AD.² In the study conducted by ten Berge et al,⁵ 2 main reaction patterns were observed: erythematous papules with pruritus and an eczematous reaction. The authors suggested one subset of patients demonstrated polymorphous light eruption (PMLE), a common photoinduced eruption thought to represent a delayed-type hypersensitivity, coexisting with AD while the other subset had true photosensitive AD.^5,6 Ellenbogen et al² also found 2 reaction patterns, which they labeled papular (PMLE type) and eczematous (photosensitive AD type). The authors contested the theory of coexisting PMLE in AD because PMLE gets better in the summer with UV radiation hardening.² On the contrary, photosensitive AD worsens with uncontrolled exposure to sunlight. Only with controlled exposure to small doses of UV radiation at a time does this condition improve. Ellenbogen et al² believe both reaction patterns are consistent with photosensitive AD and the PMLE type should be termed papular photosensitive AD type.

Histopathology
The histopathologic findings of photosensitive AD are nonspecific but are characterized by spongiotic dermatitis with a perivascular lymphohistiocytic infiltrate.²

Diagnosis With Phototesting
Phototesting of patients with AD should be considered if there is a suspicion for photosensitivity based on persistent disease despite use of photoprotection and local treatment.^5-7 Patients may not notice a correlation of skin exacerbations with UV exposure, especially if they are only sensitive to UVA, as it is still present on cloudy days and can penetrate glass windows.⁸ Phototesting evaluates the degree of sensitivity to UV light and the specific wavelength eliciting the cutaneous response. Phototesting consists of determining the MED to UVA and UVB, the minimal phototoxic dose for PUVA, and visible light exposure. Further evaluation may include photoprovocation testing or photopatch testing, as these patients can have coexisting photocontact allergies.

The MED is defined as the minimal dose of UV light needed to induce perceptible erythema in exposed skin.⁵ It is dependent on the light source and patient’s skin type, and individual units may vary. To determine the MED to UVA or UVB, 2×2-cm skin fields are irradiated with increasing cumulative UVA/UVB. The dose varies by skin type and it is then read at 24 hours. The majority of patients with photosensitive AD are reported to have a normal MED; however, some studies have reported the MED to be decreased.^5,7-9 ten Berge et al⁵ found 7% of their study participants exhibited a lower MED, as seen in our patient.

The minimal phototoxic dose for PUVA is defined as the least exposure dose of UVA 1 hour after ingestion of 0.4 mg/kg of methoxsalen that produces pink erythema with 4 distinct borders at 48, 72, or 96 hours after ingestion.¹⁰ Visible light exposure is tested using a slide projector as the light source to an approximately 10×5-cm area of skin for 45 minutes. Any immediate or delayed reaction is abnormal and considered positive.¹⁰

Photoprovocation testing has been performed in several studies.^2,5 It consists of exposing an 8-cm area of skin to 80 J/cm² UVA and 10 mJ/cm² UVB, which is read at 24, 48, or 72 hours. A papular or eczematous reaction is considered positive.^2,11

The results of phototesting have varied between studies. ten Berge et al⁵ phototested 107 patients with AD and photosensitivity and 17% were found to be solely sensitive to UVA whereas 67% were found to be sensitive to UVA and UVB. In contrast, Ellenbogen et al² only tested 17 patients with AD and photosensitivity and they found that 56% (9/16) were sensitive to UVA alone while only 44% (7/16) were sensitive to UVA and UVB.

Photopatch testing can help to rule out photosensitivity due to a substance in the presence of UV light. In studies of patients with photosensitive AD (N=125), photocontact reactions occurred in 23% and were predominantly associated with sunscreens, skin care products, and fragrances.^5,12 Photopatch testing is done by placing duplicate sets of patches on nonlesional skin using the Finn Chamber technique. A published list of allergens, which were agreed upon by the European Society of Contact Dermatitis and the European Society for Photodermatology in 2000 are seen in Table 1.¹³ The list contains mainly UV filters and drugs. The patients’ own products also should be tested in addition to the published list of allergens, but a maximum of 30 patches should be placed at one time. The patches are removed at either 24 or 48 hours; some researchers have found greater sensitivity with the 48-hour time period, while others have not found a significant difference.¹⁰ One set of skin fields then is covered with an impermeable occlusive dressing as a control while the other is irradiated with 5 J/cm² of a broad-spectrum UVA light source. UVA fluorescent lamps are the light source of choice because of their widespread availability, reproducible broad spectrum, and beam uniformity.¹⁰ In the study conducted by ten Berge et al,⁵ photopatch testing was performed on 125 patients, and 29 patients were found to be positive to one or more substances. Ellenbogen et al² photopatch tested 5 patients with photosensitive AD and a clinical suspicion of photoallergy; however, all 5 were negative. Our patient underwent traditional patch testing due to clinical suspicion of a coexisting contact allergy, which was negative.

Conclusion

Photosensitive AD is a rare entity characterized by a photodistributed rash and involvement of non–sun-exposed skin. Patients will either have a history of AD or fulfill the criteria of AD. They have positive photoprovocation testing and generally have a normal MED. They may have positive photopatch testing with coexisting photoallergies. Histopathology is nonspecific but shows spongiotic dermatitis with perivascular lymphohistiocytic infiltrate. Diagnosis is essential, as this disease can be life altering and affect quality of life. Effective treatment options are available, and the therapeutic ladder is based on severity of disease.^2,5

Atopic dermatitis (AD) is the most common inflammatory skin condition, affecting approximately 15% to 20% of the global population.^1,2 Atopic dermatitis is characterized by a chronic relapsing dermatitis with pruritus, often beginning in infancy or childhood. Atopic dermatitis is caused by a defect in epidermal barrier function, which results in increased transepidermal water loss.¹ The criteria for AD include a pruritic skin condition plus 3 or more of the following: history of involvement of the skin creases, history of asthma or hay fever, history of AD in a first-degree relative (in children), 1-year history of generally dry skin, visible flexural eczema, and an age of onset of less than 2 years. Adults with AD frequently present with hand or facial dermatitis.¹

UV light therapies including narrowband UVB (NB-UVB), UVA1, and psoralen plus UVA (PUVA) have all been used as effective treatments of AD.^3,4 UV light is beneficial for AD patients due to its immunomodulatory effects, thickening of the stratum corneum, and the reduction of Staphylococcus aureus in the skin.² Most patients with AD improve with light therapy; however, it is estimated that 1% to 3% of patients with AD will experience a paradoxical worsening of their AD after exposure to UV light.^2,5 This condition is referred to as photosensitive AD and is characterized by a photodistributed rash in patients who fulfill the criteria of AD. Photosensitive AD has a female predominance and generally affects patients with late-onset disease with development of AD after puberty.^2,5 The pathogenesis for the development of photosensitivity in patients with AD who previously tolerated exposure to sunlight is unknown.⁵ We describe a case of photosensitive AD exacerbated by UVB exposure.

Case Report

A 55-year-old Asian woman presented for evaluation of a rash on the head, neck, and arms. She reported that she had developed a pruritic rash with edema after sun exposure at 16 years of age. Since then, the rash has been intermittent and completely resolved at times with periods of decreased sun exposure; however, the rash recently had been persistent and worsening despite practicing strict sun protection with daily sunscreen application, protective clothing, and sun avoidance. She was not taking systemic medications or supplements at the time but was applying high-potency topical corticosteroids and calcineurin inhibitors with minimal improvement under the care of a dermatologist.

On physical examination the patient had thin, well-demarcated, erythematous papules and plaques with scaling, primarily on sun-exposed skin on the forehead (Figure 1A), cheeks (Figure 1B), eyelids, upper lip, neck (Figures 1B and 1C), upper chest (Figure 1C), and dorsal aspect of the hands, with excoriated pink papules on the forearms, shoulders, and back. A punch biopsy of the right neck showed spongiotic dermatitis with a perivascular lymphohistiocytic infiltrate (Figure 2). Further workup was pursued including complete blood cell count, comprehensive metabolic profile, liver function panel, Sjögren syndrome antigen A/Sjögren syndrome antigen B test, antinuclear antibody test, human immunodeficiency virus 1/2 antigen/antibody test, hepatitis panel, and mycobacterium tuberculosis test, which were all within reference range. Photodermatosis was suspected and she underwent phototesting including UVA, NB-UVB, and visible light. Phototesting confirmed she had a UVB photosensitivity with a markedly decreased minimal erythema dose (MED) to NB-UVB. The MED to NB-UVB was positive at 24 hours to all tested sites, the lowest of which was 0.135 J/cm². Eczematous changes began to develop at day 6 at doses of 0.945 and 1.080 J/cm². The patient also underwent visible light testing, which was negative. The patient was patch tested for multiple standardized agents as well as personal products, all of which were negative. Subsequent photopatch testing revealed a slightly positive reaction to benzophenone 4, a common ingredient in sunscreens.

The patient was then started on mycophenolate mofetil and prednisone. Repeat MED testing to NB-UVB was performed. Her repeat MED to NB-UVB was determined to be 0.405 J/cm², and hardening commenced at 3 times per week at 70% of the MED (0.2835 J/cm²). She began to flare and develop an eczematous reaction, thus the dose was decreased to 50% of the MED (0.2025 J/cm²), which she tolerated.

Comment

Classification and Clinical Presentation
The literature on photosensitive AD is scant, and this disease entity is rare. Alternative names include photoaggravated AD, photosensitive eczema, and light-exacerbated eczema.⁵ Two main studies have been conducted in recent years that were intended to characterize photosensitive AD. ten Berge et al⁵ conducted a retrospective study of 145 patients with AD that were phototested in 2009. They found that 3% of their total AD patient population had photosensitive AD.⁵ In 2016, Ellenbogen et al² performed a similar single-center retrospective analysis of 17 patients with long-standing AD who suddenly developed photosensitivity.

Patients with photosensitive AD typically present with lesions on sun-exposed skin with coexisting eczematous lesions in sites with a predilection for AD.² In the study conducted by ten Berge et al,⁵ 2 main reaction patterns were observed: erythematous papules with pruritus and an eczematous reaction. The authors suggested one subset of patients demonstrated polymorphous light eruption (PMLE), a common photoinduced eruption thought to represent a delayed-type hypersensitivity, coexisting with AD while the other subset had true photosensitive AD.^5,6 Ellenbogen et al² also found 2 reaction patterns, which they labeled papular (PMLE type) and eczematous (photosensitive AD type). The authors contested the theory of coexisting PMLE in AD because PMLE gets better in the summer with UV radiation hardening.² On the contrary, photosensitive AD worsens with uncontrolled exposure to sunlight. Only with controlled exposure to small doses of UV radiation at a time does this condition improve. Ellenbogen et al² believe both reaction patterns are consistent with photosensitive AD and the PMLE type should be termed papular photosensitive AD type.

Histopathology
The histopathologic findings of photosensitive AD are nonspecific but are characterized by spongiotic dermatitis with a perivascular lymphohistiocytic infiltrate.²

Diagnosis With Phototesting
Phototesting of patients with AD should be considered if there is a suspicion for photosensitivity based on persistent disease despite use of photoprotection and local treatment.^5-7 Patients may not notice a correlation of skin exacerbations with UV exposure, especially if they are only sensitive to UVA, as it is still present on cloudy days and can penetrate glass windows.⁸ Phototesting evaluates the degree of sensitivity to UV light and the specific wavelength eliciting the cutaneous response. Phototesting consists of determining the MED to UVA and UVB, the minimal phototoxic dose for PUVA, and visible light exposure. Further evaluation may include photoprovocation testing or photopatch testing, as these patients can have coexisting photocontact allergies.

The MED is defined as the minimal dose of UV light needed to induce perceptible erythema in exposed skin.⁵ It is dependent on the light source and patient’s skin type, and individual units may vary. To determine the MED to UVA or UVB, 2×2-cm skin fields are irradiated with increasing cumulative UVA/UVB. The dose varies by skin type and it is then read at 24 hours. The majority of patients with photosensitive AD are reported to have a normal MED; however, some studies have reported the MED to be decreased.^5,7-9 ten Berge et al⁵ found 7% of their study participants exhibited a lower MED, as seen in our patient.

The minimal phototoxic dose for PUVA is defined as the least exposure dose of UVA 1 hour after ingestion of 0.4 mg/kg of methoxsalen that produces pink erythema with 4 distinct borders at 48, 72, or 96 hours after ingestion.¹⁰ Visible light exposure is tested using a slide projector as the light source to an approximately 10×5-cm area of skin for 45 minutes. Any immediate or delayed reaction is abnormal and considered positive.¹⁰

Photoprovocation testing has been performed in several studies.^2,5 It consists of exposing an 8-cm area of skin to 80 J/cm² UVA and 10 mJ/cm² UVB, which is read at 24, 48, or 72 hours. A papular or eczematous reaction is considered positive.^2,11

The results of phototesting have varied between studies. ten Berge et al⁵ phototested 107 patients with AD and photosensitivity and 17% were found to be solely sensitive to UVA whereas 67% were found to be sensitive to UVA and UVB. In contrast, Ellenbogen et al² only tested 17 patients with AD and photosensitivity and they found that 56% (9/16) were sensitive to UVA alone while only 44% (7/16) were sensitive to UVA and UVB.

Photopatch testing can help to rule out photosensitivity due to a substance in the presence of UV light. In studies of patients with photosensitive AD (N=125), photocontact reactions occurred in 23% and were predominantly associated with sunscreens, skin care products, and fragrances.^5,12 Photopatch testing is done by placing duplicate sets of patches on nonlesional skin using the Finn Chamber technique. A published list of allergens, which were agreed upon by the European Society of Contact Dermatitis and the European Society for Photodermatology in 2000 are seen in Table 1.¹³ The list contains mainly UV filters and drugs. The patients’ own products also should be tested in addition to the published list of allergens, but a maximum of 30 patches should be placed at one time. The patches are removed at either 24 or 48 hours; some researchers have found greater sensitivity with the 48-hour time period, while others have not found a significant difference.¹⁰ One set of skin fields then is covered with an impermeable occlusive dressing as a control while the other is irradiated with 5 J/cm² of a broad-spectrum UVA light source. UVA fluorescent lamps are the light source of choice because of their widespread availability, reproducible broad spectrum, and beam uniformity.¹⁰ In the study conducted by ten Berge et al,⁵ photopatch testing was performed on 125 patients, and 29 patients were found to be positive to one or more substances. Ellenbogen et al² photopatch tested 5 patients with photosensitive AD and a clinical suspicion of photoallergy; however, all 5 were negative. Our patient underwent traditional patch testing due to clinical suspicion of a coexisting contact allergy, which was negative.

Conclusion

Photosensitive AD is a rare entity characterized by a photodistributed rash and involvement of non–sun-exposed skin. Patients will either have a history of AD or fulfill the criteria of AD. They have positive photoprovocation testing and generally have a normal MED. They may have positive photopatch testing with coexisting photoallergies. Histopathology is nonspecific but shows spongiotic dermatitis with perivascular lymphohistiocytic infiltrate. Diagnosis is essential, as this disease can be life altering and affect quality of life. Effective treatment options are available, and the therapeutic ladder is based on severity of disease.^2,5

Atopic dermatitis (AD) is the most common inflammatory skin condition, affecting approximately 15% to 20% of the global population.^1,2 Atopic dermatitis is characterized by a chronic relapsing dermatitis with pruritus, often beginning in infancy or childhood. Atopic dermatitis is caused by a defect in epidermal barrier function, which results in increased transepidermal water loss.¹ The criteria for AD include a pruritic skin condition plus 3 or more of the following: history of involvement of the skin creases, history of asthma or hay fever, history of AD in a first-degree relative (in children), 1-year history of generally dry skin, visible flexural eczema, and an age of onset of less than 2 years. Adults with AD frequently present with hand or facial dermatitis.¹

UV light therapies including narrowband UVB (NB-UVB), UVA1, and psoralen plus UVA (PUVA) have all been used as effective treatments of AD.^3,4 UV light is beneficial for AD patients due to its immunomodulatory effects, thickening of the stratum corneum, and the reduction of Staphylococcus aureus in the skin.² Most patients with AD improve with light therapy; however, it is estimated that 1% to 3% of patients with AD will experience a paradoxical worsening of their AD after exposure to UV light.^2,5 This condition is referred to as photosensitive AD and is characterized by a photodistributed rash in patients who fulfill the criteria of AD. Photosensitive AD has a female predominance and generally affects patients with late-onset disease with development of AD after puberty.^2,5 The pathogenesis for the development of photosensitivity in patients with AD who previously tolerated exposure to sunlight is unknown.⁵ We describe a case of photosensitive AD exacerbated by UVB exposure.

Case Report

A 55-year-old Asian woman presented for evaluation of a rash on the head, neck, and arms. She reported that she had developed a pruritic rash with edema after sun exposure at 16 years of age. Since then, the rash has been intermittent and completely resolved at times with periods of decreased sun exposure; however, the rash recently had been persistent and worsening despite practicing strict sun protection with daily sunscreen application, protective clothing, and sun avoidance. She was not taking systemic medications or supplements at the time but was applying high-potency topical corticosteroids and calcineurin inhibitors with minimal improvement under the care of a dermatologist.

On physical examination the patient had thin, well-demarcated, erythematous papules and plaques with scaling, primarily on sun-exposed skin on the forehead (Figure 1A), cheeks (Figure 1B), eyelids, upper lip, neck (Figures 1B and 1C), upper chest (Figure 1C), and dorsal aspect of the hands, with excoriated pink papules on the forearms, shoulders, and back. A punch biopsy of the right neck showed spongiotic dermatitis with a perivascular lymphohistiocytic infiltrate (Figure 2). Further workup was pursued including complete blood cell count, comprehensive metabolic profile, liver function panel, Sjögren syndrome antigen A/Sjögren syndrome antigen B test, antinuclear antibody test, human immunodeficiency virus 1/2 antigen/antibody test, hepatitis panel, and mycobacterium tuberculosis test, which were all within reference range. Photodermatosis was suspected and she underwent phototesting including UVA, NB-UVB, and visible light. Phototesting confirmed she had a UVB photosensitivity with a markedly decreased minimal erythema dose (MED) to NB-UVB. The MED to NB-UVB was positive at 24 hours to all tested sites, the lowest of which was 0.135 J/cm². Eczematous changes began to develop at day 6 at doses of 0.945 and 1.080 J/cm². The patient also underwent visible light testing, which was negative. The patient was patch tested for multiple standardized agents as well as personal products, all of which were negative. Subsequent photopatch testing revealed a slightly positive reaction to benzophenone 4, a common ingredient in sunscreens.

The patient was then started on mycophenolate mofetil and prednisone. Repeat MED testing to NB-UVB was performed. Her repeat MED to NB-UVB was determined to be 0.405 J/cm², and hardening commenced at 3 times per week at 70% of the MED (0.2835 J/cm²). She began to flare and develop an eczematous reaction, thus the dose was decreased to 50% of the MED (0.2025 J/cm²), which she tolerated.

Comment

Classification and Clinical Presentation
The literature on photosensitive AD is scant, and this disease entity is rare. Alternative names include photoaggravated AD, photosensitive eczema, and light-exacerbated eczema.⁵ Two main studies have been conducted in recent years that were intended to characterize photosensitive AD. ten Berge et al⁵ conducted a retrospective study of 145 patients with AD that were phototested in 2009. They found that 3% of their total AD patient population had photosensitive AD.⁵ In 2016, Ellenbogen et al² performed a similar single-center retrospective analysis of 17 patients with long-standing AD who suddenly developed photosensitivity.

Patients with photosensitive AD typically present with lesions on sun-exposed skin with coexisting eczematous lesions in sites with a predilection for AD.² In the study conducted by ten Berge et al,⁵ 2 main reaction patterns were observed: erythematous papules with pruritus and an eczematous reaction. The authors suggested one subset of patients demonstrated polymorphous light eruption (PMLE), a common photoinduced eruption thought to represent a delayed-type hypersensitivity, coexisting with AD while the other subset had true photosensitive AD.^5,6 Ellenbogen et al² also found 2 reaction patterns, which they labeled papular (PMLE type) and eczematous (photosensitive AD type). The authors contested the theory of coexisting PMLE in AD because PMLE gets better in the summer with UV radiation hardening.² On the contrary, photosensitive AD worsens with uncontrolled exposure to sunlight. Only with controlled exposure to small doses of UV radiation at a time does this condition improve. Ellenbogen et al² believe both reaction patterns are consistent with photosensitive AD and the PMLE type should be termed papular photosensitive AD type.

Histopathology
The histopathologic findings of photosensitive AD are nonspecific but are characterized by spongiotic dermatitis with a perivascular lymphohistiocytic infiltrate.²

Diagnosis With Phototesting
Phototesting of patients with AD should be considered if there is a suspicion for photosensitivity based on persistent disease despite use of photoprotection and local treatment.^5-7 Patients may not notice a correlation of skin exacerbations with UV exposure, especially if they are only sensitive to UVA, as it is still present on cloudy days and can penetrate glass windows.⁸ Phototesting evaluates the degree of sensitivity to UV light and the specific wavelength eliciting the cutaneous response. Phototesting consists of determining the MED to UVA and UVB, the minimal phototoxic dose for PUVA, and visible light exposure. Further evaluation may include photoprovocation testing or photopatch testing, as these patients can have coexisting photocontact allergies.

The MED is defined as the minimal dose of UV light needed to induce perceptible erythema in exposed skin.⁵ It is dependent on the light source and patient’s skin type, and individual units may vary. To determine the MED to UVA or UVB, 2×2-cm skin fields are irradiated with increasing cumulative UVA/UVB. The dose varies by skin type and it is then read at 24 hours. The majority of patients with photosensitive AD are reported to have a normal MED; however, some studies have reported the MED to be decreased.^5,7-9 ten Berge et al⁵ found 7% of their study participants exhibited a lower MED, as seen in our patient.

The minimal phototoxic dose for PUVA is defined as the least exposure dose of UVA 1 hour after ingestion of 0.4 mg/kg of methoxsalen that produces pink erythema with 4 distinct borders at 48, 72, or 96 hours after ingestion.¹⁰ Visible light exposure is tested using a slide projector as the light source to an approximately 10×5-cm area of skin for 45 minutes. Any immediate or delayed reaction is abnormal and considered positive.¹⁰

Photoprovocation testing has been performed in several studies.^2,5 It consists of exposing an 8-cm area of skin to 80 J/cm² UVA and 10 mJ/cm² UVB, which is read at 24, 48, or 72 hours. A papular or eczematous reaction is considered positive.^2,11

The results of phototesting have varied between studies. ten Berge et al⁵ phototested 107 patients with AD and photosensitivity and 17% were found to be solely sensitive to UVA whereas 67% were found to be sensitive to UVA and UVB. In contrast, Ellenbogen et al² only tested 17 patients with AD and photosensitivity and they found that 56% (9/16) were sensitive to UVA alone while only 44% (7/16) were sensitive to UVA and UVB.

Photopatch testing can help to rule out photosensitivity due to a substance in the presence of UV light. In studies of patients with photosensitive AD (N=125), photocontact reactions occurred in 23% and were predominantly associated with sunscreens, skin care products, and fragrances.^5,12 Photopatch testing is done by placing duplicate sets of patches on nonlesional skin using the Finn Chamber technique. A published list of allergens, which were agreed upon by the European Society of Contact Dermatitis and the European Society for Photodermatology in 2000 are seen in Table 1.¹³ The list contains mainly UV filters and drugs. The patients’ own products also should be tested in addition to the published list of allergens, but a maximum of 30 patches should be placed at one time. The patches are removed at either 24 or 48 hours; some researchers have found greater sensitivity with the 48-hour time period, while others have not found a significant difference.¹⁰ One set of skin fields then is covered with an impermeable occlusive dressing as a control while the other is irradiated with 5 J/cm² of a broad-spectrum UVA light source. UVA fluorescent lamps are the light source of choice because of their widespread availability, reproducible broad spectrum, and beam uniformity.¹⁰ In the study conducted by ten Berge et al,⁵ photopatch testing was performed on 125 patients, and 29 patients were found to be positive to one or more substances. Ellenbogen et al² photopatch tested 5 patients with photosensitive AD and a clinical suspicion of photoallergy; however, all 5 were negative. Our patient underwent traditional patch testing due to clinical suspicion of a coexisting contact allergy, which was negative.

Conclusion

Photosensitive AD is a rare entity characterized by a photodistributed rash and involvement of non–sun-exposed skin. Patients will either have a history of AD or fulfill the criteria of AD. They have positive photoprovocation testing and generally have a normal MED. They may have positive photopatch testing with coexisting photoallergies. Histopathology is nonspecific but shows spongiotic dermatitis with perivascular lymphohistiocytic infiltrate. Diagnosis is essential, as this disease can be life altering and affect quality of life. Effective treatment options are available, and the therapeutic ladder is based on severity of disease.^2,5

THE CASE

A 34-year-old Eritrean man presented to the emergency department with complaints of diffuse abdominal pain and distention. He had emigrated to the United States 3 months earlier, following 5 years in a refugee camp in Ethiopia. Two weeks earlier, the patient sought care at his primary care clinic and was diagnosed with post-operative urinary retention and constipation following a recent hemorrhoidectomy. A Foley catheter was inserted and provided a short period of relief.

Following the visit, however, his abdominal pain worsened. He also experienced increasing abdominal distention, a declining appetite, and persistent nausea. The patient said that he was unable to urinate and had not had a bowel movement in 6 days. He also described fevers, drenching night sweats, chills, and a 4-kg weight loss over 2 months.

On physical examination, the patient had a wasted appearance. He was afebrile, alert, and oriented, but anxious and writhing in pain. An abdominal examination revealed some distention, generalized guarding, and tenderness. There was dullness to percussion in all regions without rebound, and no caput medusa was noted. The remainder of the physical examination was unremarkable.

Pertinent laboratory values included negative screens for human immunodeficiency virus (HIV) 1 and 2, and a purified protein derivative test that produced 10 mm of induration at 48 hours. An interferon-gamma release assay was not performed following these results. A computerized tomography (CT) scan of the abdomen and pelvis with intravenous and oral contrast revealed thickening of the peritoneal lining with infiltration of the mesenteric fat and large loculated fluid collections in the abdominal cavity (FIGURE). A CT scan of the patient’s lungs showed some mild atelectasis with left-sided effusion.

After hospital admission, the patient spiked fevers as high as 103.3° F and developed progressively worsening ascites. An ultrasound-guided paracentesis was performed, during which almost 2 liters of yellow, hazy fluid was removed. Fluid and blood cultures were negative.

THE DIAGNOSIS

With a high clinical suspicion for tuberculosis (TB) peritonitis, we requested a surgical consultation and a peritoneal biopsy was performed. The patient was started on ethambutol, isoniazid, pyrazinamide, pyridoxine, and rifampin while the biopsy results were pending.

Pathology subsequently confirmed a diagnosis of TB peritonitis, reporting dense fibroconnective tissue with areas of chronic inflammation and occasional accumulations of histiocytes with multinucleated giant cells showing granulomatous inflammation. An acid-fast (AF) bacilli stain for Mycobacteria showed a single curved bacillus compatible with Mycobacterium tuberculosis.

The patient was discharged following a 3-week hospital stay. At his follow-up visit several weeks later, the patient reported marked improvement and increasing exercise tolerance. He had gained weight, and the abdominal distention and tenderness had resolved.

DISCUSSION

Worldwide, TB is one of the top 10 causes of death. The World Health Organization estimates that there were 1.4 million TB deaths globally in 2015.¹ And while rates of TB are decreasing in the United States, there was a resurgence from 1985 to 1992.² This was attributable to the HIV/acquired immunodeficiency syndrome epidemic, increased immigration from countries endemic for TB, and deterioration of the TB public health infrastructure.³

Transmission. M tuberculosis is a rod-shaped, nonspore-forming AF bacillus that typically infects the lungs, but may infect other areas of the body. Transmission typically occurs via airborne spread of droplets from an infected individual. Possible other methods of disease dissemination include ingestion of infected sputum, hematogenous spread from active pulmonary TB, or ingestion of contaminated milk or food.

M tuberculosis elicits a proinflammatory phase, which facilitates the formation of a granuloma within the host tissues. The host’s immune response to M tuberculosis plays a role in the risk of developing this type of TB.³

TB presentation is classified as pulmonary, extrapulmonary, or both. Clinicians are generally attentive to the classic symptoms of pulmonary TB: cough, weight loss, night sweats, and fever. Presentation of extrapulmonary TB, however, may vary.⁴

Black patients have a significantly higher incidence of extrapulmonary tuberculosis than nonblack counterparts.

According to one study, the most common presenting symptoms for peritoneal TB are weight loss, abdominal pain, and/or fever, all of which our patient experienced.⁵ In addition, our patient was an immigrant from Africa, and black patients have been shown to have a significantly higher incidence of extrapulmonary TB than their nonblack counterparts.⁶ Although our patient was HIV-negative, a recent meta-analysis confirmed the strong association between extrapulmonary TB and HIV, emphasizing the importance of including HIV screens in the standard work-up for TB.⁷

Other symptoms may include microcytosis, anemia, thrombocytosis, and an elevated erythrocyte sedimentation rate. Although a chest x-ray is often negative, advanced imaging, such as CT or magnetic resonance imaging, is often abnormal and may point to the diagnosis.⁵

Treatment of extrapulmonary TB is generally the same as that for pulmonary TB and, interestingly, the incidence of multi-drug resistant extrapulmonary TB is not necessarily higher than it is for pulmonary TB (<1% vs 1.6%).^3,7 In light of this, a standard regimen—like the one our patient received—is generally utilized for 6 to 9 months. Nonetheless, resistance testing should still be performed.^3,4

THE TAKEAWAY

While considered uncommon, more than 20% of TB cases in the United States are extrapulmonary (the most common form is TB lymphadenitis).^7,8 It is imperative to identify appropriate risk factors, including associated comorbidities, patient characteristics, and population/endemic differences in immigrant populations.

In this case, although the symptom combination of persistent abdominal pain, fever, and weight loss may not trigger suspicion of a TB diagnosis in isolation, combining the symptoms with knowledge of the patient’s immigration status should at least raise an eyebrow. Given their nonpulmonary symptoms, many of these patients will not present to pulmonologists, making diagnosis particularly relevant to primary care.

THE CASE

A 34-year-old Eritrean man presented to the emergency department with complaints of diffuse abdominal pain and distention. He had emigrated to the United States 3 months earlier, following 5 years in a refugee camp in Ethiopia. Two weeks earlier, the patient sought care at his primary care clinic and was diagnosed with post-operative urinary retention and constipation following a recent hemorrhoidectomy. A Foley catheter was inserted and provided a short period of relief.

Following the visit, however, his abdominal pain worsened. He also experienced increasing abdominal distention, a declining appetite, and persistent nausea. The patient said that he was unable to urinate and had not had a bowel movement in 6 days. He also described fevers, drenching night sweats, chills, and a 4-kg weight loss over 2 months.

On physical examination, the patient had a wasted appearance. He was afebrile, alert, and oriented, but anxious and writhing in pain. An abdominal examination revealed some distention, generalized guarding, and tenderness. There was dullness to percussion in all regions without rebound, and no caput medusa was noted. The remainder of the physical examination was unremarkable.

Pertinent laboratory values included negative screens for human immunodeficiency virus (HIV) 1 and 2, and a purified protein derivative test that produced 10 mm of induration at 48 hours. An interferon-gamma release assay was not performed following these results. A computerized tomography (CT) scan of the abdomen and pelvis with intravenous and oral contrast revealed thickening of the peritoneal lining with infiltration of the mesenteric fat and large loculated fluid collections in the abdominal cavity (FIGURE). A CT scan of the patient’s lungs showed some mild atelectasis with left-sided effusion.

After hospital admission, the patient spiked fevers as high as 103.3° F and developed progressively worsening ascites. An ultrasound-guided paracentesis was performed, during which almost 2 liters of yellow, hazy fluid was removed. Fluid and blood cultures were negative.

THE DIAGNOSIS

With a high clinical suspicion for tuberculosis (TB) peritonitis, we requested a surgical consultation and a peritoneal biopsy was performed. The patient was started on ethambutol, isoniazid, pyrazinamide, pyridoxine, and rifampin while the biopsy results were pending.

Pathology subsequently confirmed a diagnosis of TB peritonitis, reporting dense fibroconnective tissue with areas of chronic inflammation and occasional accumulations of histiocytes with multinucleated giant cells showing granulomatous inflammation. An acid-fast (AF) bacilli stain for Mycobacteria showed a single curved bacillus compatible with Mycobacterium tuberculosis.

The patient was discharged following a 3-week hospital stay. At his follow-up visit several weeks later, the patient reported marked improvement and increasing exercise tolerance. He had gained weight, and the abdominal distention and tenderness had resolved.

DISCUSSION

Worldwide, TB is one of the top 10 causes of death. The World Health Organization estimates that there were 1.4 million TB deaths globally in 2015.¹ And while rates of TB are decreasing in the United States, there was a resurgence from 1985 to 1992.² This was attributable to the HIV/acquired immunodeficiency syndrome epidemic, increased immigration from countries endemic for TB, and deterioration of the TB public health infrastructure.³

Transmission. M tuberculosis is a rod-shaped, nonspore-forming AF bacillus that typically infects the lungs, but may infect other areas of the body. Transmission typically occurs via airborne spread of droplets from an infected individual. Possible other methods of disease dissemination include ingestion of infected sputum, hematogenous spread from active pulmonary TB, or ingestion of contaminated milk or food.

M tuberculosis elicits a proinflammatory phase, which facilitates the formation of a granuloma within the host tissues. The host’s immune response to M tuberculosis plays a role in the risk of developing this type of TB.³

TB presentation is classified as pulmonary, extrapulmonary, or both. Clinicians are generally attentive to the classic symptoms of pulmonary TB: cough, weight loss, night sweats, and fever. Presentation of extrapulmonary TB, however, may vary.⁴

Black patients have a significantly higher incidence of extrapulmonary tuberculosis than nonblack counterparts.

According to one study, the most common presenting symptoms for peritoneal TB are weight loss, abdominal pain, and/or fever, all of which our patient experienced.⁵ In addition, our patient was an immigrant from Africa, and black patients have been shown to have a significantly higher incidence of extrapulmonary TB than their nonblack counterparts.⁶ Although our patient was HIV-negative, a recent meta-analysis confirmed the strong association between extrapulmonary TB and HIV, emphasizing the importance of including HIV screens in the standard work-up for TB.⁷

Other symptoms may include microcytosis, anemia, thrombocytosis, and an elevated erythrocyte sedimentation rate. Although a chest x-ray is often negative, advanced imaging, such as CT or magnetic resonance imaging, is often abnormal and may point to the diagnosis.⁵

Treatment of extrapulmonary TB is generally the same as that for pulmonary TB and, interestingly, the incidence of multi-drug resistant extrapulmonary TB is not necessarily higher than it is for pulmonary TB (<1% vs 1.6%).^3,7 In light of this, a standard regimen—like the one our patient received—is generally utilized for 6 to 9 months. Nonetheless, resistance testing should still be performed.^3,4

THE TAKEAWAY

While considered uncommon, more than 20% of TB cases in the United States are extrapulmonary (the most common form is TB lymphadenitis).^7,8 It is imperative to identify appropriate risk factors, including associated comorbidities, patient characteristics, and population/endemic differences in immigrant populations.

In this case, although the symptom combination of persistent abdominal pain, fever, and weight loss may not trigger suspicion of a TB diagnosis in isolation, combining the symptoms with knowledge of the patient’s immigration status should at least raise an eyebrow. Given their nonpulmonary symptoms, many of these patients will not present to pulmonologists, making diagnosis particularly relevant to primary care.

THE CASE

A 34-year-old Eritrean man presented to the emergency department with complaints of diffuse abdominal pain and distention. He had emigrated to the United States 3 months earlier, following 5 years in a refugee camp in Ethiopia. Two weeks earlier, the patient sought care at his primary care clinic and was diagnosed with post-operative urinary retention and constipation following a recent hemorrhoidectomy. A Foley catheter was inserted and provided a short period of relief.

Following the visit, however, his abdominal pain worsened. He also experienced increasing abdominal distention, a declining appetite, and persistent nausea. The patient said that he was unable to urinate and had not had a bowel movement in 6 days. He also described fevers, drenching night sweats, chills, and a 4-kg weight loss over 2 months.

On physical examination, the patient had a wasted appearance. He was afebrile, alert, and oriented, but anxious and writhing in pain. An abdominal examination revealed some distention, generalized guarding, and tenderness. There was dullness to percussion in all regions without rebound, and no caput medusa was noted. The remainder of the physical examination was unremarkable.

Pertinent laboratory values included negative screens for human immunodeficiency virus (HIV) 1 and 2, and a purified protein derivative test that produced 10 mm of induration at 48 hours. An interferon-gamma release assay was not performed following these results. A computerized tomography (CT) scan of the abdomen and pelvis with intravenous and oral contrast revealed thickening of the peritoneal lining with infiltration of the mesenteric fat and large loculated fluid collections in the abdominal cavity (FIGURE). A CT scan of the patient’s lungs showed some mild atelectasis with left-sided effusion.

After hospital admission, the patient spiked fevers as high as 103.3° F and developed progressively worsening ascites. An ultrasound-guided paracentesis was performed, during which almost 2 liters of yellow, hazy fluid was removed. Fluid and blood cultures were negative.

THE DIAGNOSIS

With a high clinical suspicion for tuberculosis (TB) peritonitis, we requested a surgical consultation and a peritoneal biopsy was performed. The patient was started on ethambutol, isoniazid, pyrazinamide, pyridoxine, and rifampin while the biopsy results were pending.

Pathology subsequently confirmed a diagnosis of TB peritonitis, reporting dense fibroconnective tissue with areas of chronic inflammation and occasional accumulations of histiocytes with multinucleated giant cells showing granulomatous inflammation. An acid-fast (AF) bacilli stain for Mycobacteria showed a single curved bacillus compatible with Mycobacterium tuberculosis.

The patient was discharged following a 3-week hospital stay. At his follow-up visit several weeks later, the patient reported marked improvement and increasing exercise tolerance. He had gained weight, and the abdominal distention and tenderness had resolved.

DISCUSSION

Worldwide, TB is one of the top 10 causes of death. The World Health Organization estimates that there were 1.4 million TB deaths globally in 2015.¹ And while rates of TB are decreasing in the United States, there was a resurgence from 1985 to 1992.² This was attributable to the HIV/acquired immunodeficiency syndrome epidemic, increased immigration from countries endemic for TB, and deterioration of the TB public health infrastructure.³

Transmission. M tuberculosis is a rod-shaped, nonspore-forming AF bacillus that typically infects the lungs, but may infect other areas of the body. Transmission typically occurs via airborne spread of droplets from an infected individual. Possible other methods of disease dissemination include ingestion of infected sputum, hematogenous spread from active pulmonary TB, or ingestion of contaminated milk or food.

M tuberculosis elicits a proinflammatory phase, which facilitates the formation of a granuloma within the host tissues. The host’s immune response to M tuberculosis plays a role in the risk of developing this type of TB.³

TB presentation is classified as pulmonary, extrapulmonary, or both. Clinicians are generally attentive to the classic symptoms of pulmonary TB: cough, weight loss, night sweats, and fever. Presentation of extrapulmonary TB, however, may vary.⁴

Black patients have a significantly higher incidence of extrapulmonary tuberculosis than nonblack counterparts.

According to one study, the most common presenting symptoms for peritoneal TB are weight loss, abdominal pain, and/or fever, all of which our patient experienced.⁵ In addition, our patient was an immigrant from Africa, and black patients have been shown to have a significantly higher incidence of extrapulmonary TB than their nonblack counterparts.⁶ Although our patient was HIV-negative, a recent meta-analysis confirmed the strong association between extrapulmonary TB and HIV, emphasizing the importance of including HIV screens in the standard work-up for TB.⁷

Other symptoms may include microcytosis, anemia, thrombocytosis, and an elevated erythrocyte sedimentation rate. Although a chest x-ray is often negative, advanced imaging, such as CT or magnetic resonance imaging, is often abnormal and may point to the diagnosis.⁵

Treatment of extrapulmonary TB is generally the same as that for pulmonary TB and, interestingly, the incidence of multi-drug resistant extrapulmonary TB is not necessarily higher than it is for pulmonary TB (<1% vs 1.6%).^3,7 In light of this, a standard regimen—like the one our patient received—is generally utilized for 6 to 9 months. Nonetheless, resistance testing should still be performed.^3,4

THE TAKEAWAY

While considered uncommon, more than 20% of TB cases in the United States are extrapulmonary (the most common form is TB lymphadenitis).^7,8 It is imperative to identify appropriate risk factors, including associated comorbidities, patient characteristics, and population/endemic differences in immigrant populations.

In this case, although the symptom combination of persistent abdominal pain, fever, and weight loss may not trigger suspicion of a TB diagnosis in isolation, combining the symptoms with knowledge of the patient’s immigration status should at least raise an eyebrow. Given their nonpulmonary symptoms, many of these patients will not present to pulmonologists, making diagnosis particularly relevant to primary care.

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.